Rx Side Effects

<body topmargin=0 leftmargin=0 marginheight=0 marginwidth=0> <table cellpadding=0 cellspacing=0 border=0><tr> <td valign="top" colspan=2 height=110 BGCOLOR="#666699" TEXT="#080000" bgproperties="fixed" background="09f00840erlcjm.png"> <div> <B>McCallWellness</B><B>.com</B><FONT SIZE="1" COLOR="#FFFFCC" FACE="Times New Roman" ><B>    </B></FONT></div> <div> <B><U>H</U></B><A HREF="index.htm" TARGET="_top" TITLE="McCallWellness.com"><U><B><U>ome</U></B></U></A><B>   |   </B><A HREF="id19.htm" TARGET="_top" TITLE="Mission "><U>Mission </U></A>   |   <A HREF="id84.htm" TARGET="_top" TITLE="Current News"><U>Current News</U></A>   |   <A HREF="new_patient_information_package.htm" TARGET="_top" TITLE="New Patients"><U>New Patients</U></A>   |   <A HREF="id36.htm" TARGET="_top" TITLE="Exams/Tests"><U>Exams/Tests</U></A>   |   <A HREF="id78.htm" TARGET="_top" TITLE="Supplements"><U>Supplements</U></A>   |   <A HREF="id41.htm" TARGET="_top" TITLE="Seminar Series"><U>Seminar Series</U></A>   |   <B>Rx Side Effects</B>   |   <A HREF="id35.htm" TARGET="_top" TITLE="Mind "><U>Mind </U></A>   |   <A HREF="id31.htm" TARGET="_top" TITLE="Fasting"><U>Fasting</U></A>   |   <A HREF="id72.htm" TARGET="_top" TITLE=" Support Groups"><U> Support Groups</U></A>   |   <A HREF="id23.htm" TARGET="_top" TITLE="Vaccines"><U>Vaccines</U></A>   |   <A HREF="id24.htm" TARGET="_top" TITLE="Children"><U>Children</U></A>   |   <A HREF="id73.htm" TARGET="_top" TITLE="Recipes"><U>Recipes</U></A>   |   <A HREF="id70.htm" TARGET="_top" TITLE="Juicing"><U>Juicing</U></A>   |   <A HREF="id69.htm" TARGET="_top" TITLE="Organic"><U>Organic</U></A>   |   <A HREF="id76.htm" TARGET="_top" TITLE="Sponsors"><U>Sponsors</U></A>   |   <A HREF="id20.htm" TARGET="_top" TITLE="Contact/Links"><U>Contact/Links</U></A></div> <div> </div> </td> </tr><tr> <td valign="top" width=200 BGCOLOR="#CCCCFF" TEXT="#080000" background="09911c00egdysm.png"> <div> <A HREF="id65_m.htm#death_by_medicine_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>Death by Medicine </U></B></U></A><B><U>...The Number one cause of death</U></B></div> <div> <A HREF="id65_m.htm#the_side_effects_of_nsaids" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>The side effects of NSAIDs</U></B></U></A></div> <div> <A HREF="id65_m.htm#caffeine" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>Caffeine</U></B></U></A></div> <div> <A HREF="id65_m.htm#the_aspartame_scandal_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>The Aspartame Scandal </U></B></U></A></div> <div> <A HREF="id65_m.htm#1__anti_inflammatory_medications__" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>1.Anti-inflammatory Medications</U></B></U></A></div> <div> <A HREF="id65_m.htm#2___antibiotic_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>2.Antibiotic Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#4__antidepressant_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>4. Antidepressant Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#4_antidepressant_medications_plus" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>4 Antidepressant Medications II</U></B></U></A></div> <div> <A HREF="id65_m.htm#_5_antidiabetic_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>5.Antidiabetic Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#_6__antihypertensive_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>6.Antihypertensive Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#7__cardiovascular_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>7.Cardiovascular Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#7__cardiovascular_medications_plus" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>7.Cardiovascular Medications II</U></B></U></A></div> <div> <A HREF="id65_m.htm#__7_cardiovascular_medications_iii" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>7.Cardiovascular Medications III</U></B></U></A></div> <div> <A HREF="id65_m.htm#8__diuretics_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>8.Diuretics </U></B></U></A></div> <div> <B><U>8.</U></B><A HREF="id65_m.htm#diuretics_ii_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>Diuretics II </U></B></U></A></div> <div> <A HREF="id65_m.htm#9__cholesterol_lowering_medications__1" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>9.Cholesterol-Lowering Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#9_cholesterol_lowering_medicationsstatin" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>9.Cholesterol-Lowering MedicationsStatin</U></B></U></A></div> <div> <A HREF="id65_m.htm#9__corticosteroids_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>9 Corticosteroids </U></B></U></A></div> <div> <A HREF="id65_m.htm#11__cortocosteriods" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>9. Cortocosteriods</U></B></U></A></div> <div> <A HREF="id65_m.htm#10__gastrointestinal_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>10. Gastrointestinal Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#10_gastrointestinal_medications_ii" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>10.Gastrointestinal Medications II</U></B></U></A></div> <div> <A HREF="id65_m.htm#11__oral_contraceptives_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>11  Oral Contraceptives </U></B></U></A></div> <div> <A HREF="id65_m.htm#12__osteoporosis_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>12  Osteoporosis Medications </U></B></U></A></div> <div> <A HREF="id65_m.htm#13_psychotherapeutic_medications_" TARGET="TRLX_Middle" TITLE="Rx Side Effects"><U><B><U>13.Psychotherapeutic Medications </U></B></U></A></div> <bR> <bR> </td> <td valign="top" height=370 BGCOLOR="#FFFFFF" TEXT="#080000"> <div> <B>Rx Side Effects</B></div> <bR> <div> <B>Group lectures and one on one consult available on this topic </B><A HREF="id20.htm" TARGET="_top" TITLE="Contact/Links"><U><B><U>(contact)</U></B></U></A></div> <bR> <div>  <A NAME="the_side_effects_of_nsaids"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A>The side effects of NSAIDs (nonsteroidal antiinflammatory drug) are not appreciated by the average consumer. A recent review by Wolfe et. al.1 helps put the problem in perspective for one of the problems, i.e. gastrointestinal toxicity. On the basis of conservative figures "...the annual number of hospitalizations in the United States for serious gastrointestinal complications is estimated to be at least 103,000. At an estimated cost of $15,000 to $20,000 per hospitalization, the annual direct costs of such complications exceed $2 billion." The emphasis of cost fails to recognize the more important mortality rate for patients hospitalized for NSAID-induced upper gastrointestinal bleeding which is reported by Wolfe et. al.1 as about 5 to 10 percent. They further report, "It has been estimated conservatively that 16,500 NSAID-related deaths occur among  patients with rheumatoid arthritis or osteoarthritis every year in the United States. This figure is similar to the number of deaths from the acquired immunodeficiency syndrome [AIDS] and considerable greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin's disease." </div> <div> NSAIDs cause problems in the entire gastrointestinal tract,2 ranging from peptic ulcers3,4,5 to small intestine6 and colon problems. In a study to determine the safety of low-dose daily aspirin therapy in the gastrointestinal tract, it was concluded that the safety of even 10 mg of daily aspirin is questionable,7 which is way below the typical baby aspirin dosage of 80 mg. The problems do not stop in the gut; the breakdown of the gut mucous membranes leads to leaky gut syndrome with all of its ramifications, including liver toxicity.</div> <div> One of the most common reasons for taking NSAIDs is to relieve joint pain. Unfortunately the very thing that is expected to gain relief often makes the condition worse by blocking glycosaminoglycans (GAGS) production necessary for repair,8,9,10 in one in vitro study by as much as 60-70%.11 Therapeutic levels of aspirin in vitro have effects of suppressing proteoglycan biosynthesis in normal and degenerating articular cartilage similar to several other NSAIDs12 and permeate osteoarthritic cartilage 35% more than in normal cartilage.13,14 Glucosamine is in the popular press as an aid to improve the symptoms of osteoarthritis or joint pain. It is one of the glycosamionglycans.and the more NSAIDs are taken to control joint pain the more the very thing that repairs the joints is destroyed. It is a vicious circle.</div> <div> 1. Wolfe, Michael M., et al, "Gastrointestinal Toxicity of Nonsteroidal Antiinfammatory Drugs" <I>New Eng Jn of Med</I> Vol 340, No 24 (Jun 17, 1999)</div> <div> 2.     Roth, S.H., “Nonsteroidal anti-inflammatory drugs: Gastropathy, deaths, and medical practice,” <I>Ann Intern Med</I>, Vol 109, No 5 (Sep 1, 1988).</div> <div>      3.Gabriel, S.E., L. Jaakkimainen, & C. Bombardier, “Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis,” <I>Ann Intern Med</I>, Vol 115, No 10 (Nov 15, 1991).</div> <div>      4.Griffin, M.R. et al., “Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons,” <I>Ann Intern</I> <I>Med</I>, Vol 114, No 4 (Feb 15, 1991).</div> <div>      5.Langman, M.J. et al., “Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs,” <I>Lancet</I>, Vol 343 (Apr 30, 1994).</div> <div>      6.Melo Gomes, J.A. et al., “Double-blind comparison of efficacy and gastroduodenal safety of diclofenac/misoprostol, piroxicam, and naproxen in the treatment of osteoarthritis,” <I>Ann Rheum Dis</I>, Vol 52, No 12 (Dec 1993).</div> <div>      7.Cryer, B., & M. Feldman, “Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury,” <I>Gastroenterology</I>, Vol 117, No 1 (Jul 1999).</div> <div> 8.     Dekel, S., J. Falconer, & M.J. Francis, “The effect of anti-inflammatory drugs on glycosaminoglycan sulphation in pig cartilage,” <I>Prostaglandins Med</I>, Vol 4, No 3 (Mar 1980).</div> <div> 9. de Vries, B.J., W.B. van den Berg, & L.B. van de Putte, “Salicylate-induced depletion of endogenous inorganic sulfate. Potential role in the suppression of sulfated glycosaminoglycan synthesis in murine articular cartilage,” <I>Arthritis Rheum</I>, Vol 28, No 8 (Aug 1985).</div> <div> 10. Hugenberg, S.T., K.D. Brandt, & C.A. Cole, “Effect of sodium salicylate, aspirin, and ibuprofen on enzymes required by the chondrocyte for synthesis of chondroitin sulfate,” <I>J Rheumatol</I>, Vol 20, No 12 (Dec 1993).</div> <div> 11. Yoo, J.U., R.S. Papay, & C.J. Malemud, “Suppression of proteoglycan synthesis in chondrocyte cultures derived from canine intervertebral disc,” <I>Spine</I>, Vol 17, No 2 (Feb 1992).</div> <div> 12. Brandt, K.D., & M.J. Palmoski, “Effects of salicylates and other nonsteroidal anti-inflammatory drugs on articular cartilage,” <I>Am J</I> <I>Med</I>, Vol 77, No 1A (Jul 13, 1984).</div> <div> 13. Brandt, K.D., “Effects of nonsteroidal antiinflammatory drugs on chondrocyte metabolism <I>in vitro</I> and <I>in vivo</I>,” <I>Am J Med</I>, Vol 83, No 5A (Nov 20, 1987).</div> <div> 14. Palmoski, M.J., R.A. Colyer, & K.D. Brandt, “Marked suppression by salicylate of the augmented proteoglycan synthesis in osteoarthritis cartilage,” <I>Arthritis Rheum</I>, Vol 23, No 1 (Jan 1980).</div> <bR> <bR> <div> <I><B><U>Pharaceuticals Side effects and Depletions </U></B></I></div> <div>  </div> <div> 1.  <B>Anti-inflammatory Medications </B></div> <div> <B>2. Antibiotic Medications</B></div> <div> <B>3. Anticonvulsant Medications</B></div> <div> <B>4. Antidepressant Medications </B></div> <div> 5. Antidiabetic Medications </div> <div> 6. Antihypertensive Medications </div> <div> <B>7. Cardiovascular Medications </B></div> <div> <B>8. Cholesterol-Lowering Medications </B></div> <div> <B>9. Corticosteroids Diuretics </B></div> <div> <B>10, Gastrointestinal Medications </B></div> <div> <B>11. Oral Contraceptives </B></div> <div> <B>12. Osteoporosis Medications </B></div> <div> <B>13. Psychotherapeutic Medications</B></div> <bR> <bR> <bR> <div> <B><U> <A NAME="1__anti_inflammatory_medications__"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>1. Anti-inflammatory Medications   Nonsteroidal Anti-inflammatory Drugs (NSAIDs)</U></B> </div> <div>  </div> <div> Diclofenac (Cataflam® Oral; Solaraze™ Topical; Voltaren® Ophthalmic; Voltaren® Oral; Voltaren®-XR Oral) </div> <div> Diflunisal (Dolobid®) </div> <div> Etodolac (Lodine®; Lodine® XL) </div> <div> Fenoprofen (Nalfon®) </div> <div> Ibuprofen (Advil® Migraine Liqui-Gels [OTC]; Advil®[OTC]; Children's Advil® Oral Suspension [OTC]; Children's Motrin® Oral Suspension [OTC]; Genpril®[OTC]; Haltran®[OTC]; Junior Strength Motrin®[OTC]; Menadol®[OTC]; Midol® IB [OTC]; Motrin®; Motrin® IB [OTC]; Motrin® Migraine Pain [OTC]; Nuprin®[OTC]) </div> <div> Indomethacin (Indocin®) </div> <div> Ketoprofen (Actron®[OTC]; Orudis®; Orudis® KT [OTC]; Oruvail®) </div> <div> Ketorolac Tromethamine (no brand names listed) </div> <div> Meclofenamate (no brand names listed) </div> <div> Nabumetone (Relafen®) </div> <div> Naproxen (Aleve®[OTC]; Anaprox®; EC-Naprosyn®; Naprelan®; Naprosyn®) </div> <div> Oxaprozin (Daypro™) </div> <div> Piroxicam (Feldene®) </div> <div> Sulindac (Clinoril®) </div> <div> Tolmetin (Tolectin®; Tolectin® DS) </div> <bR> <div> <B>Depletions </B></div> <div> Iron </div> <div> <B>Mechanism </B></div> <div>    NSAIDs can damage the stomach as well as the small and large intestines, causing ulceration, chronic bleeding, and eventually iron deficiency (Bertschinger et al. 1996; Bjarnason and Macpherson 1994; Davies 1995). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Iron deficiency may be associated with oxidative DNA damage (Ames 2000). In children, iron deficiency leads to cognitive dysfunction. Other pathologies associated with depleted levels of iron include anemia and compromised immune function. Symptoms include dizziness, fatigue, shortness of breath, pallor, and tachycardia (Covington 1999).</div> <bR> <div> <B>Replacement Therapy </B></div> <div>    Therapeutic doses for replacement therapy for adults range from 100 to 200 mg/day (2 to 3 mg/kg/day) of elemental iron, usually in 3 divided doses (Covington 1999). Iron levels should be monitored carefully; excess levels could also be associated with oxidative DNA damage as well as increased risk of cancer and heart disease (Ames 2000). The oral lethal dose of elemental iron is estimated to be 200 to 250 mg/kg with symptoms presenting after ingestion of 30 to 60 mg/kg (Covington 1999). Iron supplements can cause GI irritation; administering the supplement with food will prevent GI upset and bleeding (Hines Burnham et al. 2000).</div> <div>   </div> <div> Melatonin </div> <bR> <div> <B>Mechanism </B></div> <div>   Plasma levels of melatonin were significantly reduced after administration of both ibuprofen (400 mg) and indomethacin (75 mg) compared to controls, perhaps through interference with prostaglandin synthesis (Surrall et al. 1987).</div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).</div> <bR> <div> <B>Replacement Therapy </B></div> <div>   Optimal doses for melatonin therapy have not been established (Avery et al. 1998). Commonly available doses range from 0.3 to 5 mg. Physiological blood levels are achieved with doses of 0.3 mg; higher doses (1 mg) result in supraphysiological levels of melatonin in the blood. The efficacy of melatonin supplementation is dependent upon the time of administration, as effects are related to circadian rhythms.</div> <div>  </div> <div> <I><B>Vitamin B9 (Folic Acid) </B></I></div> <bR> <div> <B>Mechanism </B></div> <div>   Non-steroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, have antifolate activity (Baggott et al. 1992). It is not known if chronic ibuprofen treatment will cause a folate deficiency.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.</div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>   The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum folate levels, age, gender, dietary habits, and medication regimen.</div> <div>   </div> <div>  Zinc </div> <div> <B>Mechanism </B></div> <div>   Administration of naproxen (250 mg tid) in ten healthy volunteers for either 7 or 14 days resulted in a 35% increase in urinary zinc excretion but serum zinc levels remained unchanged (Elling et al. 1980). However, another report indicates that serum zinc levels were altered by NSAID therapy and decreased to 10.47 mmol/L in patients treated with NSAIDs (Balogh et al. 1980).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.</div> <div>     </div> <div> <B>References </B></div> <div>   Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.</div> <bR> <div> Baggott JE, Morgan SL, Ha T, et al. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. Biochem J. 1992;282(Pt 1):197-202.</div> <bR> <div> Balogh Z, El-Ghobarey AF, Fell GS, et al. Plasma zinc and its relationship to clinical symptoms and drug treatment in rheumatoid arthritis. Ann Rheum Dis. 1980;39:329-332.</div> <bR> <div> Bertschinger P, Zala GF, Fried M. [Effect of non-steroidal antirheumatic agents on the gastrointestinal tract: clinical aspects and pathophysiology]. Schweiz Med Wochenschr. 1996;126(37):1566-1568.</div> <bR> <div> Bjarnason I, Macpherson AJ. Intestinal toxicity of non-steroidal anti-inflammatory drugs. Pharmacol Ther. 1994;62(1-2):145-157.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999: 467-545.</div> <bR> <div> Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum. 1995;38(12):1311-1321.</div> <bR> <div> Elling H, Kiilerich S, Sabro J, Elling P. Influence of a non-steroid anti-rheumatic drug on serum and urinary zinc in healthy volunteers. Scand J Rheumatol. 1980;9:161-163.</div> <bR> <div> Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.</div> <bR> <div> Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.</div> <bR> <div> Hines Burnham T, et al, eds. Drug Facts and Comparisons. St Louis, MO: Facts and Comparisons; 2000.</div> <bR> <div> Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.</div> <bR> <div> Surrall K, Smith JA, Bird H, Okala B, Othman H, Padwick DJ. Effect of ibuprofen and indomethacin on human plasma melatonin. J Pharm Pharmacol. 1987;39(10):840-843. </div> <div>  </div> <div>    </div> <div> <B> <A NAME="2___antibiotic_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>2.  Antibiotic Medications </B></div> <div>  </div> <div>    Antibiotic Combination: Sulfa Drugs </div> <div> Antibiotic Combination: Sulfa Drugs Co-Trimoxazole Trimethoprim-Sulfamethoxazole Cephalosporin Antibiotics Cefprozil Cefuroxime Loracarbef Macrolide Antibiotics Azithromycin Clarithromycin Erythromycin, Systemic Penicillin Derivatives Amoxicillin Amoxicillin and Clavulanate Potassium Penicillin V Potassium Quinolone Antibiotics Cinoxacin Ciprofloxacin Enoxacin Gatifloxacin Levofloxacin Lomefloxacin Moxifloxacin Nalidixic Acid Norfloxacin Ofloxacin Sparfloxacin Trovafloxacin Tetracycline Derivatives Doxycycline Minocycline Tetracycline</div> <div>  </div> <div>   Co-Trimoxazole (Bactrim™; Bactrim™ DS; Septra®; Septra® DS; Sulfatrim®; Sulfatrim® DS) </div> <bR> <div> Trimethoprim-Sulfamethoxazole (no brand names listed) </div> <div> <B><U>   </U></B></div> <div> <B><U>Depletions </U></B></div> <div> <I><B><U>  </U></B></I></div> <div>   Probiotics; Bifidobacteria bifidum; Lactobacillus Acidophilus; Saccaromyces boulardii </div> <div>  </div> <div> <B>Mechanism </B></div> <div>    Alteration of intestinal microflora is a common side effect of antibiotic treatment (Nord 1993; Beaugerie 1996). These changes can affect the availability of vitamins B and K. </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   Altering the balance of probiotic organisms in the gastrointestinal tract may reduce resistance to infection and disease. Symptoms of deficiency include gas, abdominal distress, diarrhea, and yeast infections (Galland 1997).</div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>   Prophylactic administration of a combination of L. acidophilus and L. bulgaricus prevents ampicillin-induced diarrhea (Gotz et al. 1979). Other bacterial strains that may prevent or treat antibiotic-induced diarrhea include L. casei GG, Saccaromyces boulardii, and Bifidobacterium longum (either alone or combined with L. acidophilus) (Elmer et al. 1996). Administration of preparations containing 1 to 2 billion organisms are typically required (Murray and Pizzorno 1998). Positive results have been observed with S. boulardii at doses of 250 mg bid (Surawicz et al. 1989) or 1 g/day containing 3 x 1010 colony-forming units (the equivalent of 2 x 250 mg capsules bid) (McFarland et al. 1995). </div> <div>  </div> <div>   <FONT SIZE="3" COLOR="#FF6600" FACE="Times New Roman" ><I><B>Vitamin B2 (Riboflavin); Vitamin B12 (Cobalamin); Vitamin H (Biotin) </B></I></FONT></div> <div>  </div> <div> <B>Mechanism </B></div> <div>   Intestinal bacteria synthesize vitamin K and B vitamins such as biotin, B2, B12, and folic acid; they are a potentially rich source of these nutrients (Albert et al. 1980; Hill 1997). Although it is unusual to see measurable deficiencies, chronic antibiotic therapy could deplete these vitamins by altering and destroying the normal intestinal bacteria that synthesize them (Hill 1997).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Vitamin B2: Riboflavin deficiency usually occurs as a result of deficiencies in dietary protein and is associated with other B vitamin deficiencies (Covington 1999). Depleted levels of riboflavin affect carbohydrate and amino acid metabolism by interfering with enzyme systems involved in the production of ATP. Lack of an adequate supply of riboflavin disturbs several physiological and biochemical processes and results in retarded growth in infants and children (Covington 1999; Powers 1999). Symptoms include corneal vascularization, glossitis, cheilosis, seborrheic dermatitis, and impaired wound healing (Covington 1999).</div> <bR> <div> Vitamin B12: Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia. </div> <bR> <div> Vitamin H: Although biotin deficiency is uncommon, nonspecific symptoms such as changes in skin color as well as the development of non-pruritic dermatitis, alopecia, and muscle pain may be indicative of depleted biotin levels (Covington 1999). Additionally, low levels of this nutrient may be associated with hypercholesterolemia, anemia, anorexia, depression, and insomnia</div> <div>  </div> <div> <B>  Replacement Therapy </B></div> <div>   Note: B vitamins are best if given as B-complex.</div> <bR> <div> Vitamin B2: Doses of 5 to 25 mg/day are recommended for the treatment of riboflavin deficiency (Covington 1999). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum riboflavin levels, age, gender, dietary habits, and medication regimen.</div> <bR> <div> Vitamin B12: Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.</div> <bR> <div> Vitamin H: Biotin deficiency is treated with doses between 1 mg and 10 mg to resolve symptoms and prevent recurrence (Mock et al. 1996). Replacement therapy should be based upon the patient's clinical presentation, serum biotin levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div> Vitamin B9 (Folic Acid) </div> <bR> <div> <B>Mechanism </B></div> <div>   Trimethoprim acts as a folate antagonist by inhibiting dihydrofolate reductase; high-dose trimethoprim therapy decreases serum folate concentrations (Lambie and Johnson 1985; Naderer et al. 1997). Co-Trimoxazole does not appear to depress serum folate levels to the same extent as trimethoprim monotherapy (Bateson et al. 1976). However, there have been reports of co-trimoxazole affecting folate metabolism, usually following long-term or high-dose therapy (Taraszewski et al. 1989). Patients with compromised folate status prior to co-trimoxazole therapy may be at greater risk for developing a folate deficiency.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum folate levels, age, gender, dietary habits, and medication regimen. Folate therapy has had a negative outcome on AIDS patients diagnosed with pneumocystis carinii pneumonia (Bygbjerg et al. 1988; Safrin et al. 1994). Therefore, folic acid supplementation may not be warranted in this population of patients. </div> <bR> <div> Note: Folate may be administered concomitantly without interfering with the antibacterial action of trimethoprim (Hines Burnham et al. 2000).</div> <div> <I><B><U> </U></B></I></div> <div> <I><B>Vitamin K</B></I><I> </I></div> <bR> <div> <B>Mechanism </B></div> <div>   Broad spectrum antibiotics reduce hepatic vitamin K2 (menaquinone) stores as well as gut microflora, which can deplete vitamin K by diminishing bacterial synthesis of this nutrient (Conly and Stein 1994; Stieger et al. 1992).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Interference with intestinal synthesis of vitamin K is usually not sufficient to cause a deficiency (Covington 1999). However, a reduction in prothrombin and other vitamin K-dependent factors may indicate a deficiency (Olson 1999). Severe deficiency may be associated with detectable plasma levels of descarboxyprothrombin (Vermeer and Schurgers 2000). Signs and symptoms of deficiency include coagulation disorders manifested by hypoprothrombinemia with internal and external hemorrhage (Covington 1999).</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Generally, 45 to 80 mcg/day are recommended for daily intake to maintain overall health (Covington 1999). Individual requirements should be tailored to the patient's clinical presentation, serum levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div>    </div> <div> <B>References  </B></div> <div>   Albert MJ, Mathan VI, Baker SJ. Vitamin B12 synthesis by human small intestinal bacteria. Nature. 1980;283(5749):781-782.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Bateson MC, Hayes JP, Pendharker P. Cotrimoxazole and folate metabolism. Lancet. 1976;2(7981):339-340.</div> <bR> <div> Beaugerie L. [Diarrhea caused by antibiotic therapy]. Rev Prat. 1996;46(2):171-176.</div> <bR> <div> Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.</div> <bR> <div> Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on cytopenia occurring during co-trimoxazole treatment of Pneumocystis carinii pneumonia. Scand J Infect Dis. 1988;20(6):685-686.</div> <bR> <div> Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.</div> <bR> <div> Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.</div> <bR> <div> Conly J, Stein K. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med. 1994;17(6):531-539.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA. 1996;275(11):870-876.</div> <bR> <div> Galland L. The Four Pillars of Healing. New York, NY: Random House; 1997:186-199.</div> <bR> <div> Gotz, V, Romankiewicz JA, Moss J, et al. Prophylaxis against ampicillin-associated diarrhea with a lactobacillus preparation. Am J Hosp Pharm. 1979;36(6):754-757.</div> <bR> <div> Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev. 1997;6(Suppl 1):S43-45.</div> <bR> <div> Hines Burnham, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000:1346.</div> <bR> <div> Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs. 1985;30(2):145-155.</div> <bR> <div> Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.</div> <bR> <div> McFarland LV, Surawicz CM, Greenberg RN, et al. Prevention of Beta-lactam-associated diarrhea by Saccharomyces boulardi compared with placebo. Am J Gastroenterol. 1995;90(3):439-448.</div> <bR> <div> Mock DM. Biotin. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: ILSI Press; 1996:231.</div> <bR> <div> Murray, M, Pizzorno, J. Encyclopedia of Natural Medicine 2nd ed. Rocklin: Prima Publishing; 1998:435.</div> <bR> <div> Naderer O, Nafziger AN, Bertino JS Jr. Effects of moderate-dose versus high-dose trimethorprim on serum creatinine and creatinine clearance and adverse reactions. Antimicrob Agents Chemother. 1997;41(11):2466-2470.</div> <bR> <div> Nord CE. The effect of antimicrobial agents on the ecology of the human intestinal microflora. Vet Microbiol. 1993;35(3-4):193-197.</div> <bR> <div> Olson RE. Vitamin K. In: Shils, ME, Olson JA, Shike, M, eds. Modern Nutrition in health and disease. 9th ed. Media, PA: Williams & Wilkins; 1999:363-380.</div> <bR> <div> Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.</div> <bR> <div> Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994;170(4):912-917.</div> <bR> <div> Stieger R, Baumgartner K, Neff U. [Dangerous hypothrombinemic hemorrhage in antibiotic therapy]. Helv Chir Acta. 1992;58(6):775-778.</div> <bR> <div> Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospecive study. Gastroenterol. 1989;96(4):981-988.</div> <bR> <div> Taraszewski R, Harvey R, Rosman P. Death from drug-induced hemolytic anemia. Postgrad med. 1989;85(7):79-80, 84.</div> <bR> <div> Vermeer C, Schurgers LJ. A comprehensive review of vitamin K and vitamin K antagonists. Hematol Oncol Clin North Am. 2000;14(2):339-353.</div> <div>  </div> <div> <B> <A NAME="4__antidepressant_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>4. Antidepressant Medications </B></div> <div>   </div> <div>   Selective Serotonin Reuptake Inhibitors (SSRIs) </div> <div>  </div> <div>   Fluoxetine (Prozac®; Prozac® Weekly™; Sarafem™) </div> <div> <B><U>Depletions</U></B> </div> <div>  </div> <div> Melatonin </div> <div> <B>Mechanism </B></div> <div>   In a controlled clinical study, melatonin levels were reduced significantly in study participants treated with fluoxetine (20 mg/day) for six weeks (Childs et al. 1995). The decrease in melatonin levels associated with this drug may be explained by down-regulation of b-adrenoreceptors, reduction in cAMP accumulation, or interference with suprachiasmatic nucleus output.</div> <bR> <div> <B>Significance of Depletion </B></div> <div>   Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).</div> <bR> <div> <B><U>Replacement Therapy </U></B></div> <div>   Optimal doses for melatonin therapy have not been established (Avery et al. 1998). Commonly available doses range from 0.3 to 5 mg. Physiological blood levels are achieved with doses of 0.3 mg; higher doses (1 mg) result in supraphysiological levels of melatonin in the blood. The efficacy of melatonin supplementation is dependent upon the time of administration, as effects are related to circadian rhythms.</div> <div>  </div> <div>   <B>Protein & Amino Acids </B></div> <bR> <div> <B>Mechanism </B></div> <div>   Fluoxetine reduces leucine absorption by 37% in vitro and 30% in vivo; it may affect the nutritional status of patients by reducing absorption of neutral amino acids (Urdaneta et al. 1998). More research is needed to confirm these effects.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Deficiencies of protein are characterized by compromised immune status, generalized decreases in function and strength, apathy, weight loss, increased susceptibility to infection, impaired wound healing, and growth retardation in children (Covington 1999). Severe depletion may be characterized by muscle wasting, deterioration in skin and hair, decreased heart rate, blood pressure, and body temperature.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Nutritional repletion through dietary means is the preferred treatment approach in cases of protein depletion or deficiency (Covington 1999). Adopting a balanced diet consisting of high levels of calories, protein, vitamins, and minerals is one option available for the treatment of patients with depleted levels of protein. Oral or parenteral supplementation offers another therapeutic approach to restore nutritional status, maintain caloric intake, and achieve recommended dietary allowances for protein (generally 600 to 800 mg/kg protein) (Reeds and Beckett 1996).</div> <div>  </div> <div> <B>References </B></div> <div>   Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.</div> <bR> <div> Childs PA, Rodin I, Martin NJ, et al. Effect of fluoxetine on melatonin in patients with seasonal affective disorder and matched controls. Br J Psychiatry. 1995;166:196-198.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Reeds P, Beckett P. Protein and amino acids. In: Ziegler E, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: International Life Sciences Institute; 1996:67-86.</div> <bR> <div> Urdaneta E, Idonte I, Larraldo J. Drug-nutrient interactions: inhibition of amino acid intestinal absorption by fluoxetine. Br J Nutr. 1998;79(5):439-446.</div> <div>  </div> <div>  </div> <div> <B> <A NAME="4_antidepressant_medications_plus"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>4 Antidepressant Medications PLUS</B></div> <div>  </div> <div>  </div> <div> Tricyclic Antidepressants </div> <div> Amitriptyline (Elavil®; Vanatrip®) </div> <div> Amoxapine (Asendin) </div> <div> Clomipramine (Anafranil®) </div> <div> Desipramine (Norpramin®) </div> <div> Doxepin (Sinequan® Oral; Zonalon® Topical Cream) </div> <div> Imipramine (Tofranil-PM®; Tofranil®) </div> <div> Nortriptyline (Aventyl®; Pamelor®) </div> <div> Protriptyline (Vivactil®) </div> <div> Trimipramine (Surmontil®) </div> <bR> <div> <B>Depletions </B></div> <div>  </div> <div>   Coenzyme Q10 </div> <div>  </div> <div> <B> Mechanism </B></div> <div>   In vitro, tricyclic antidepressants (TCAs) inhibited CoQ10-NADH-oxidase and CoQ10-succinate dehydrogenase, two enzymes that are important for cardiac function because they donate electrons to CoQ10 in the mitochondria (Kishi et al. 1980). Inhibiting these enzymes disrupts mitochondrial function and may play a role in the development of cardiotoxic side effects associated with psychotropic drugs. </div> <bR> <div> <B>Significance of Depletion </B></div> <div>   Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999).</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Daily doses as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). The addition of low concentrations of CoQ10 reverses TCA-induced inhibition of CoQ10-NADH-oxidase and CoQ10-succinate dehydrogenase (Kishi et al. 1980). CoQ10 treatment may prevent some of the cardiac side effects associated with tricyclic antidepressant treatment. More research is needed to confirm these effects.</div> <div>  </div> <div>   Vitamin B2 (Riboflavin) </div> <div>  </div> <div> <B>Mechanism </B></div> <div>   Amitriptyline may enhance vitamin B2 excretion (Tinguely et al. 1985) and inhibit its metabolism to flavin-adenine dinucleotide (FAD) in tissues (Pinto et al. 1981; Pinto et al. 1982).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Riboflavin deficiency usually occurs as a result of deficiencies in dietary protein and is associated with other B vitamin deficiencies (Covington 1999). Depleted levels of riboflavin affect carbohydrate and amino acid metabolism by interfering with enzyme systems involved in the production of ATP. Lack of an adequate supply of riboflavin disturbs several physiological and biochemical processes and results in retarded growth in infants and children (Covington 1999; Powers 1999). Signs and symptoms include corneal vascularization, glossitis, cheilosis, seborrheic dermatitis, and impaired wound healing (Covington 1999).</div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>   Doses of 5 to 25 mg/day are recommended for the treatment of riboflavin deficiency (Covington 1999). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum riboflavin levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div>  </div> <div> <B>References </B></div> <div>    Artuch R, Colome C, Vilaseca MA, et al. Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993;19391):88-92.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.</div> <bR> <div> Kishi T, Makino K, Okamoto T, et al. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q. Biomedical and Clinical Aspects of Coenzyme Q. Vol 2. Yamamura Y, et al, eds. Elsevier/North-Holland Biomedical Press: Amsterdam; 1980.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers R, et al. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Pinto J, et al. Inhibition of riboflavin metabolism in rat tissues by chlorpromazine, imipramine, and amitriptyline. J Clin Invest. 1981;67(5):1500-1506.</div> <bR> <div> Pinto J, Huang YP, Pelliccione N, et al. Cardiac sensitivity to the inhibitory effects of chlorpromazine, imipramine and amitriptyline upon formation of flavins. Biochem Pharmacol. 1982;31(21):3495-3499.</div> <bR> <div> Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <bR> <div> Tinguely D, Jonzier M, Schopf J, et al. Determination of compliance with riboflavin in an antidepressive therapy. Arzneimittelforschung. 1985;35(2):536-538.</div> <div>  </div> <div>    </div> <div>  </div> <div> <B> <A NAME="9__corticosteroids_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>9  Corticosteroids </B></div> <div>  </div> <div> Inhalant, Systemic, and Topical Preparations </div> <div>  </div> <div> Beclomethasone (Beclovent®; Beconase®; Beconase® AQ; QVAR™; Vancenase®; Vancenase® AQ; Vanceril®) </div> <div> Budesonide (Pulmicort Respules™; Pulmicort® Turbuhaler®; Rhinocort®; Rhinocort® Aqua™) </div> <div> Dexamethasone (AK-Dex® Ophthalmic; Baldex®; Dalalone D.P.®; Dalalone L.A.®; Dalalone®; Decadron®; Decadron® Phosphate; Decadron®-LA; Decaject-LA®; Decaject®; Decaspray®; Dexacort® Phosphate Turbinaire®; Dexasone®; Dexasone® L.A.; Dexone®; Dexone® LA; Hexadrol®; Hexadrol® Phosphate; Maxidex®; Solurex L.A.®; Solurex®) </div> <div> Fluticasone (Cutivate™; Flonase®; Flovent®; Flovent® Diskus®; Flovent® Rotadisk®) </div> <div> Hydrocortisone (A-hydroCort®; Ala-Cort®; Ala-Scalp®; Anucort-HC® Suppository; Anusol-HC® Suppository; Anusol® HC 1 [OTC]; Anusol® HC 2.5% [OTC]; Cetacort®; Clocort® Maximum Strength; Cort-Dome®; Cortaid® Maximum Strength [OTC]; Cortaid® With Aloe [OTC]; Cortef®; Cortef® Feminine Itch; Cortenema®; Corticaine®; Cortifoam®; Cortizone®-10 [OTC]; Cortizone®-5 [OTC]; Delcort®; Dermacort®; DermiCort®; Dermolate®[OTC]; Dermtex® HC With Aloe; Eldecort®; Gynecort®[OTC]; Hemril-HC® Uniserts®; Hi-Cor® 1.0; Hi-Cor® 2.5; Hycort®; Hydrocort®; Hydrocortone® Acetate; Hydrocortone® Phosphate; HydroTex®[OTC]; Hytone®; LactiCare-HC®; Lanacort®[OTC]; Locoid®; Nutracort®; Orabase® HCA; Pandel®; Penecort®; Procort®[OTC]; Proctocort™; S-T Cort®; Scalpicin®; Solu-Cortef®; Synacort®; Tegrin®-HC [OTC]; Texacort®; Westcort®) </div> <div> Methylprednisolone (A-methaPred® Injection; depMedalone® Injection; Depo-Medrol® Injection; Depoject® Injection; Depopred® Injection; Duralone® Injection; M-Prednisol® Injection; Medralone® Injection; Medrol® Oral; Solu-Medrol® Injection) </div> <div> Mometasone Furoate (Elocon®; Nasonex®) </div> <div> Prednisone (Deltasone®; Liquid Pred®; Meticorten®; Orasone®; Prednicen-M®) </div> <div> Triamcinolone (Amcort®; Aristocort®; Aristocort® A; Aristocort® Forte; Aristocort® Intralesional; Aristospan® Intra-Articular; Aristospan® Intralesional; Atolone®; Azmacort™; Delta-Tritex®; Flutex®; Kenacort®; Kenaject-40®; Kenalog-10®; Kenalog-40®; Kenalog®; Kenalog® H; Kenalog® in Orabase®; Kenonel®; Nasacort®; Nasacort® AQ; Tac™-3; Tac™-40; Tri-Kort®; Tri-Nasal®; Triacet™; Triam Forte®; Triam-A®; Triderm®; Trilog®; Trilone®; Tristoject®) </div> <bR> <div> <B><U>Depletions </U></B></div> <div> <B><U> </U></B></div> <div>  Calcium </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Corticosteroids increase renal calcium excretion and decrease intestinal calcium absorption (Gennari 1993; Lems et al. 1998). By altering normal calcium metabolism and reducing osteoblast activity, corticosteroids increase not only bone loss, but the risk for developing osteoporosis as well (Nielson et al. 1988; Reid and Ibbertson 1986). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998).</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Calcium supplementation in the form of citrate, malate, gluconate, or carbonate salts may range from 1000 mg to 1500 mg or more daily (Adler and Rosen 1999; Covington 1999). Doses as high as 3000 mg/day with 10 to 50 mcg/day of 25-OH-D3 may be appropriate if plasma calcium and phosphate levels are stable and within normal range (Drüeke 1999). In cases where calcium deficits are associated with vitamin D deficiency, up to 6000 mg/day of calcium (acetate or carbonate) may be warranted. These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.</div> <div>  </div> <div> Dehydroepiandrosterone (DHEA) </div> <div>  </div> <div> <B>Mechanism </B></div> <div>   Long-term treatment with corticosteroids suppresses DHEA production in post-menopausal women (Smith et al. 1994).</div> <bR> <div> <B>Significance of Depletion </B></div> <div>   Decreased plasma levels of DHEA have been linked to various pathologies such as certain cancers, cardiovascular disorders, inflammatory diseases, and type II diabetes mellitus (Hinson and Raven 1999). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Daily doses of 50 mg in patients aged 40 to 70 years produced DHEA levels equivalent to those found in young adults within 2 weeks of initiation of replacement therapy (Morales et al. 1994). These levels were maintained for 3 months of the study and patients reported improvements in their general sense of physical and psychological well-being; no side effects were associated with DHEA therapy at this dose. It has been suggested that doses should not exceed 25 mg/day for women or 50 mg/day for men (Huppert et al. 2000). Long-term safety and efficacy of DHEA supplementation has not been established (Murray and Pizzorno 1998). </div> <div>  </div> <div> Magnesium </div> <div>  </div> <div> <B>Mechanism </B></div> <div>   Corticosteroids reduce magnesium levels in serum and bone (Atkinson et al. 1998; Rolla et al. 1990; Simeckova et al. 1985).</div> <div>   </div> <div> <B>Significance of Depletion </B></div> <div>   Magnesium deficiency affects calcium and vitamin D metabolism and is primarily associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.</div> <div> <B><U> </U></B></div> <div> Melatonin </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>  </div> <div>   Corticosteroids may reduce nocturnal melatonin levels (Demisch et al. 1988).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Optimal doses for melatonin therapy have not been established (Avery et al. 1998). Commonly available doses range from 0.3 to 5 mg. Physiological blood levels are achieved with doses of 0.3 mg; higher doses (1 mg) result in supraphysiological levels of melatonin in the blood. The efficacy of melatonin supplementation is dependent upon the time of administration, as effects are related to circadian rhythms. </div> <bR> <div> Note: Corticosteroid effects on the immune system may be modulated by melatonin (Rogers et al. 1997). In vitro, the combination of melatonin and corticosteroids produced significantly greater suppression of lymphocyte proliferation than corticosteroids alone.</div> <div>  </div> <div> Potassium </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Corticosteroids enhance potassium excretion (Adam et al. 1984; Stanton et al. 1985).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Potassium depletion as a consequence of prolonged drug therapy is usually associated with chloride deficiency and manifests as hypokalemic, hypochloremic metabolic acidosis (Covington 1999). Signs and symptoms of deficiency include anorexia, apprehension, drowsiness, listlessness, fatigue, nausea, muscle cramps and weakness, tetany, excessive thirst, altered mental status, and irrational behavior. Severe hypokalemia could also result in clinical manifestations of cardiac arrythmia, including primarily palpitations, cardiac arrest, and death. A loss from total body stores of approximately 100 to 200 mEq of potassium is usually required to cause a decrease in serum potassium levels of 1 mEq/L.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   The usual range of treatment is 20 to 100 mEq/day of potassium (PDR 2000). The appropriate doses for replacement therapy should be determined on an individual basis, considering the patient's age, gender, clinical presentation, serum potassium levels, dietary habits, and medication regimen. The chloride salt is appropriate treatment for cases of alkalosis (Covington 1999). In cases of acidosis, other potassium salts such as bicarbonate, citrate, acetate, or gluconate are preferred.</div> <div>  </div> <div> <I><B>Protein & Amino Acids </B></I></div> <div>  </div> <div> <B>Mechanism</B></div> <div>   Corticosteroids may cause protein wasting (Garrel et al. 1988).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Deficiencies of protein are characterized by compromised immune status, generalized decreases in function and strength, apathy, weight loss, increased susceptibility to infection, impaired wound healing, and growth retardation in children (Covington 1999). Severe depletion may be characterized by muscle wasting, deterioration in skin and hair, decreased heart rate, blood pressure, and body temperature. </div> <div>   </div> <div>   <A NAME="_5_antidiabetic_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A> <B><U>5.Antidiabetic Medications </U></B></div> <div>     Biguanide Agent </div> <div>    Metformin (Glucophage®; Glucophage® XR) </div> <bR> <bR> <div> <B>Depletions </B></div> <div>   </div> <div> <I><B>  Vitamin B9 (Folic Acid); Vitamin B12 (Cobalamin) </B></I></div> <div>  <B><U> </U></B></div> <div> <B><U> Mechanism</U></B> </div> <div>  </div> <div>   Several studies have shown reduced absorption of vitamin B12 in approximately 1/3 of patients treated with biguanides or other medications that are part of this class of compounds (Adams et al. 1983; Berger 1985; Rieder et al. 1980). In another trial, metformin treatment significantly decreased levels of vitamin B12 and folate and increased homocysteine levels as well (Carlsen et al. 1997).</div> <div>  </div> <div>  <B><U>Significance of Depletion </U></B></div> <div>   Vitamin B9: Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.</div> <bR> <div> Vitamin B12: Symptomatic vitamin B12 deficiency is rare because complications of vitamin B12 deficiency may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia. Only five cases of megaloblastic anemia associated with metformin therapy have been reported; no increased incidence of neuropathy has been observed (Hines Burnham et al. 2000).</div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>   Vitamin B9: The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, age, gender, dietary habits, and medication regimen.</div> <bR> <div> Vitamin B12: Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.</div> <div>   </div> <div> <B>References </B></div> <div>   Adams JF, Clark JS, Ireland JT, et al. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia. 1983;24(1):16-18.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.</div> <bR> <div> Carlsen SM, Folling I, Grill V, et al. Metformin increases total and serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Lab Invest. 1997;57(6):521-527.</div> <bR> <div> Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.</div> <bR> <div> Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000.</div> <bR> <div> Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.</div> <bR> <div> Rieder HP, Berger W, Fridrich R. [Vitamin status in diabetic neuropathy]. Z Ernahrungswiss. 1980;19(1):1-13.</div> <div>  </div> <div>   Antidiabetic Medications </div> <div>     Sulfonylureas </div> <div>   Glimepiride (Amaryl®) </div> <div> Glyburide (Diabeta®; Glynase™ PresTab™; Micronase®) </div> <bR> <div> <B><U>Depletions </U></B></div> <div> <B><U> </U></B></div> <div>  Coenzyme Q10 </div> <bR> <div> <B><U> Mechanism</U></B> </div> <div>   Patients with non-insulin-dependent diabetes mellitus (NIDDM) have significantly lower serum coenzyme Q10 levels compared to healthy controls (Miyake et al. 1999). Because glyburide inhibits NADH-oxidase, an enzyme that donates electrons to CoQ10, it could lead to a deficiency in diabetic patients with already low CoQ10 levels (Kishi et al. 1976). </div> <bR> <div> <B>Significance of Depletion </B></div> <div>   Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Munkholm et al. 1999); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). CoQ10 supplementation (100 mg bid) was well tolerated and did not interfere with glycemic control in one study with NIDDM patients (Eriksson et al. 1999).</div> <div>  </div> <div> <B>References </B></div> <div>   Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> Eriksson JG, Forsen TJ, Mortensen SA, Rohde M. The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus. Biofactors. 1999;9(2-4):315-318.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993; 28(19391):88-92.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Kishi T, Kishi H, Watanabe T, Folkers K. Bioenergetics in clinical medicine. XI. Studies on coenzyme Q and diabetes mellitus. J Med. 1976;7(3-4):307-321.</div> <bR> <div> Miyake Y, Shouzu A, Nishikawa M, et al. Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients. Arzneimittelforschung. 1999;49(4):324-329.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers R, et al. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <bR> <bR> <bR> <div> <B> <A NAME="11__cortocosteriods"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>9 Cortocosteriods</B></div> <bR> <div> <B>Replacement Therapy </B></div> <div>    Nutritional repletion through dietary means is the preferred treatment approach in cases of protein depletion or deficiency (Covington 1999). Adopting a balanced diet consisting of high levels of calories, protein, vitamins, and minerals is one option available for the treatment of patients with depleted levels of protein. Oral or parenteral supplementation offers another therapeutic approach to restore nutritional status, maintain caloric intake, and achieve recommended dietary allowances for protein (generally 600 to 800 mg/kg protein) (Reeds and Beckett 1996).</div> <div>    </div> <div>  </div> <div> <I><B>Selenium </B></I></div> <div>  </div> <div> <B>Mechanism </B></div> <div>   Corticosteroids may deplete selenium levels (Peretz et al. 1987). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Selenium deficiency may lead to oxidative DNA damage (Ames 2000). Chronically low levels of this trace element are associated with pathologies such as cardiovascular disease, rheumatic disorders, muscle, and digestive problems (Navarro-Alarcon and Lopez-Martinez 2000). In addition, there may be a connection between depleted selenium levels and cancer, cirrhosis, and diabetes.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   The recommended dietary allowance (RDA) for selenium ranges from 0.70 to 3.50 mg/day (Ames 2000). Doses of 0.02 to 0.05 mg/day have been suggested to prevent selenium deficiency and its associated disorders (Navarro-Alarcon and Lopez-Martinez 2000). Optimal and toxic levels of this nutrient have not been established (Ames 2000). Selenium supplementation may play a role in cancer prevention, including prostate, breast, colon, and cervical carcinoma. </div> <div>  </div> <div> <I><B>Vitamin B6 (Pyridoxine) </B></I></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B>  </div> <div>   Corticosteroids may deplete vitamin B6 levels (Sur et al. 1993). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Usually, vitamin B6 deficiency is accompanied by depletions of other B vitamins (National Research Council 1989). Signs and symptoms of low levels of this vitamin include epileptiform convulsions with abnormal EEG findings, dermatitis, anemia, weakness, mental confusion, irritability, nervousness, insomnia, and abnormal tryptophan metabolism (Covington 1999; National Research Council 1989; Wilson 1998). Depleted levels may increase the risk of colon and prostate cancers, heart disease, brain dysfunction, and birth defects (Ames 2000). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Neuropathology resulting from vitamin B6 deficiency should be treated with doses of 50 to 200 mg/day (Covington 1999). Dietary deficiency usually responds to doses of 10 to 20 mg/day. Doses should be tailored to account for the patient's age, gender, clinical presentation, serum vitamin B6 levels, dietary habits, and medication regimen.</div> <div>  </div> <div> <B>Vitamin B9 (Folic Acid) </B></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Corticosteroids may deplete folic acid levels (Frequin et al. 1993). </div> <div>    </div> <div> <B>Significance of Depletion </B></div> <div>   Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.</div> <div>    </div> <div> <B>Replacement Therapy </B></div> <div>   The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum folate levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>Vitamin B12 (Cobalamin) </B></I></div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>   Corticosteroids may deplete vitamin B12 levels (Frequin et al. 1993). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>Vitamin C (Ascorbic Acid) </B></I></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Corticosteroids may inhibit cellular uptake of ascorbic acid and reduce concentrations in the aqueous humor and testicular tissues (Chowdhury and Kapil 1984; Levine and Pollard 1983; Mehra et al. 1982). </div> <div>    </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   Patients with depleted levels of vitamin C may present with anemia, icterus, edema, lethargy, fatigue, fever, ecchymoses, hypotension, convulsions, gum disorders, tooth loss, emotional changes, and perifollicular hyperkeratotic papules (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). In addition, they may exhibit signs of poor wound healing, increased susceptibility to infection, and markedly defective collagen synthesis. Severe deficiency results in scurvy, which is potentially fatal (Carr and Frei 1999; National Research Council 1989; Wilson 1998). Scurvy involves degenerative changes in capillaries, bone, and connective tissue, resulting in clinical symptoms that include weakness, joint tenderness and swelling, and spontaneous hemorrhages (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). Patients with vitamin C deficiency may also be at increased risk of developing cataracts and heart disease (Ames 2000).</div> <div>   </div> <div> <B>Replacement Therapy </B></div> <div>   Treatment of scurvy requires doses between 300 and 1000 mg/day for adults (Covington 1999). Other recommendations range from the recommended dietary allowance (RDA) of 60 mg to 2000 mg/day for adults (Carr and Frei 1999; Wilson 1998). One study proposes that no adult receive more than 1000 mg/day because higher doses could cause nausea and diarrhea (Ausman 1999). To minimize the possibility of gastric upset, buffered and sustained-release vitamin C preparations are recommended. Specific doses account for the patient's age, gender, overall health status, dietary habits, and medication regimen. Smokers must consume 2 to 3 times more vitamin C than non-smokers (Ames 2000).</div> <div>    </div> <div>  Vitamin D </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Corticosteroid therapy reduces serum 1,25-dihydroxyvitamin-D3 in children (Chesney et al. 1978). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Because vitamin D is fat-soluble, prolonged periods of deficiency are required to produce symptoms (National Research Council 1989). While the long evolution is often asymptomatic (Rao 1999), depleted levels are characterized by inadequate mineralization of the bone, which could lead to rickets (in children) and osteomalacia (in adults) (Covington 1999; National Research Council 1989; Rao 1999). Other signs and symptoms of low levels of vitamin D include increased risk of fractures, osteoporosis, phosphaturia, hyperparathyroidism, chronic muscle weakness, hypovitaminosis D, bone pain, pseudofractures, waddling gait, or severe, chronic hypocalcemia (Holick et al. 1998; National Research Council 1989; Rao 1999; Vieth 1999). Subclinical vitamin D deficiency has been reported in postmenopausal women with osteoporosis (Rao 1999). The prevalence of vitamin D deficiency is more common in women, certain ethnic populations, and increases with age.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Coadministration of vitamin D with calcium offsets the bone loss induced by chronic corticosteroid therapy (Frauman 1996; Hachulla and Cortet 1998; Weryha et al. 1998). Doses of vitamin D3 ranging from 1000 to 2000 IU/day or 25-OH-D3 ranging from 10 to 25 mcg/day have been used to treat vitamin D deficiency, which is characterized by low plasma levels of 25-OH-D3 (Drüeke 1999). Other recommendations involve doses between 200 to 800 IU/day for adults (Rao 1999) and 50,000 IU/month for elderly patients with osteomalacia (Holick et al. 1998). </div> <div> <I><B><U> </U></B></I></div> <div> Zinc </div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>   Corticosteroids alter zinc metabolism and can cause depletion (Flynn et al. 1971; Fodor et al. 1975; Fontaine et al. 1991; Yunice, et al. 1981).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.</div> <div>  </div> <div> <B>References </B></div> <div>   Adam WR, Goland GJ, Wellard RM. Renal potassium adaptation in the rat: role of glucocorticoids and aldosterone. Am J Physiol. 1984;246(3 Pt 2):F300-F308.</div> <bR> <div> Adler RA, Rosen CJ. Glucocorticoids and osteoporosis. Endocrinol Metab Clin North Am. 1999;23:641-654.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition. Int J Cancer Suppl. 1998;11:35-39.</div> <bR> <div> Ausman LM. Criteria and recommendations for vitamin C intake. Nutr Review. 1999;57(7):222-229.</div> <bR> <div> Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.</div> <bR> <div> Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.</div> <bR> <div> Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.</div> <bR> <div> Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.</div> <bR> <div> Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999;69:1086-1087.</div> <bR> <div> Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.</div> <bR> <div> Chesney RW, Maxess RB, Harnstra AJ, et al. Reduction of serum-1,12-dihydroxyitamin- D3 in children receiving glucocorticoids. Lancet. 1978;2(8100):1123-1125.</div> <bR> <div> Chowdhury AR, Kapil N. Interaction of dexamethasone and dehydroepiandrosterone on testicular ascorbic acid and cholesterol in prepubertal rat. Arch Androl. 1984;12(1):65-67.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Demisch L, et al. Influence of dexamethasone on nocturnal melatonin production in healthy adult subjects. J Pineal Res. 1988;5(3):317-322.</div> <bR> <div> Drüeke T. Medical management of secondary hyperparathyroidism in uremia. Am J Med Sci. 1999;317(6):383-389.</div> <bR> <div> Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.</div> <bR> <div> Flynn A, Pories WJ, Strain WH, et al. Rapid serum-zinc depletion associated with corticosteroid therapy. Lancet. 1971;2(7735):1169-1172.</div> <bR> <div> Fodor L, Ahnefeld FW, Fazekas AT. [Studies on the glucocorticoid control of zinc metabolism]. Infusionsther Klin Ernahr. 1975;2(3):210-213.</div> <bR> <div> Fontaine J, Neve J, Peretz A, et al. Effects of acute and chronic prednisolone treatment on serum zinc levels in rats with adjuvant arthritis. Agents Actions. 1991;33(3-4):247-253.</div> <bR> <div> Frauman AG. An overview of the adverse reactions to adrenal corticosteroids. Adverse Drug React Toxicol Rev. 1996;15(4):203-206.</div> <bR> <div> Frequin ST, et al. Decreased vitamin B12 and folate levels in cerebrospinal fluid and serum of multiple sclerosis patients after high-dose intravenous methylprednisolone. J Neurol. 1993;240(5):305-308.</div> <bR> <div> Garrel DR, Delmas PD, Welsh C, et al. Effects of moderate physical training on prednisone-induced protein wasting: a study of whole-body and bone protein metabolism. Metab. 1988;37(3):257-262.</div> <bR> <div> Gennari C. Differential effect of glucocorticoids on calcium absorption and bone mass. Br J Rheumatol. 1993;32(Suppl 2):11-14.</div> <bR> <div> Hachulla E, Cortet B. [Prevention of glucocorticoid induced osteoporosis]. Rev Med Interne. 1998;19(7):492-500.</div> <bR> <div> Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.</div> <bR> <div> Hinson JP, Raven PW. DHEA deficiency syndrome: a new term for old age? J Endocrinol. 1999;163:1-5.</div> <bR> <div> Holick MF, Krane SM, Potts JT. Calcium, phosphorus, and bone metabolism: calcium-regulating hormones. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2221-2222.</div> <bR> <div> Huppert FA, Van Niekerk JK, Herbert J. Dehydroepiandrosterone (DHEA) supplementation for cognition and well-being. Cochrane Database Syst Rev 2000;(2):CD000304.</div> <bR> <div> Lems WF, Jacobs JW, Netelenbos JC, et al. [Pharmacological prevention of osteoporosis in patients on corticosteroid medication]. Ned Tijdschr Geneeskd. 1998;142(34):10904-10908.</div> <bR> <div> Levine MA & Pollard HB. Hydrocortisone inhibition of ascorbic acid transport by chromaffin cells. FEBS Lett. 1983;158(1)L134-L138.</div> <bR> <div> Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.</div> <bR> <div> Mehra KS, Kumar A, Dubey SS, Palodhi GR. The effect of vitamin A and cortisone on ascorbic acid content in the aqueous humor. Ann Ophthalmol. 1982;14(11):1013-1015.</div> <bR> <div> Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. Endocrinol Metab. 1994;78(6):1360-1367.</div> <bR> <div> Murray M, Pizzorno J. Encyclopedia of Natural Medicine. 2nd ed. Rocklin, CA: Prima Publishing; 1998.</div> <bR> <div> National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.</div> <bR> <div> Navarro-Alarcon M, Lopez-Martinez MC. Essentiality of selenium in the human body: relationship with different diseases. Sci Total Environ. 2000;249:347-371.</div> <bR> <div> Nielson HK, Charles P, Mosekilde L. The effect of single oral doses of prednisone on the circadian rhythm of serum osteocalcin in normal subjects. J Clin Endocrinol Metab. 1988;67(5):1025-1030.</div> <bR> <div> Peretz A, Neve J, Vertongen F, et al. Selenium status in relation to clinical variables and corticosteroid treatment in rheumatoid arthritis. J Rheumatol. 1987;14(6):1104-1107.</div> <bR> <div> Physicians' Desk Reference, 54th ed. Montvale, NJ: Medical Economics Company; 2000:459.</div> <bR> <div> Potts JT. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2241.</div> <bR> <div> Rao DS. Perspective on assessment of vitamin D nutrition. J Clin Densitom. 1999:2(4):457-464.</div> <bR> <div> Reeds P, Beckett P. Protein and amino acids. In: Ziegler E, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: International Life Sciences Institute; 1996:67-86.</div> <bR> <div> Reid IR, Ibbertson HK. Calcium supplements in the prevention of steroid-induced osteoporosis. Am J Clin Nutr. 1986;44(2):287-290.</div> <bR> <div> Rogers N, van den Heuvel C, Dawson D. Effect of melatonin and corticosteroid on in vitro cellular immune function in humans. J Pineal Res. 1997;22(2):75-80.</div> <bR> <div> Rolla G, Bucca C, Bugiani M. Hypomagnesemia in chronic obstructive lung disease: effect of therapy. Magnes Trace Elem. 1990;9(3):132-136.</div> <bR> <div> Simeckova A, Neradilova M, Reisenauer R. Effect of prednisolone on the rat bone calcium, phosphorus and magnesium concentration. Physiol Bohemoslov. 1985;34(2):155-160.</div> <bR> <div> Smith BJ, et al. Does beclomethasone dipropionate suppress dehydroepiandrosterone sulfate in postmenopausal women? Aust N Z J Med. 1994;24(4):396-401. </div> <bR> <div> Stanton B, Giebisch G, Klein-Robbenhaar G, et al. Effects of adrenalectomy and chronic adrenal corticosteroid replacement on potassium transport in rat kidney. J Clin Invest. 1985;75(4):1317-1326.</div> <bR> <div> Sur S, Camara M, Buchmeier A, Morgan S, Nelson HS. Double-blind trial of pyridoxine (vitamin B6) in the treatment of steroid-dependant asthma. Ann Allergy. 1993;70(2):147-152.</div> <bR> <div> Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842-856.</div> <bR> <div> Weryha G, Klein M, Guillemin F, Leclere J. [Corticosteroid osteoporosis in the adult]. Presse Med. 1998;27(32):1641-1646.</div> <bR> <div> Wilson JD. Vitamin deficiency and excess. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:483-485.</div> <bR> <div> Yunice, AA, Czerwinski AW, Lindeman RD. Influence of synthetic corticosteroids on plasma zinc and copper levels in humans. Am J Med Sci. 1981;282(2):68-74.</div> <div>  </div> <div>  </div> <div>  </div> <div>  <A NAME="_6__antihypertensive_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A> <B><U>6. Antihypertensive Medications </U></B></div> <div>  </div> <div>  </div> <div>   Alpha2-Adrenergic Agonist </div> <div> Clonidine (Catapres-TTS® Transdermal; Catapres® Oral; Duraclon®) </div> <bR> <div> <B><U>Depletions </U></B></div> <div> <B><U> </U></B></div> <div> Coenzyme Q10 </div> <div> <B><U> </U></B></div> <div> <B><U> Mechanism</U></B> </div> <div>   Clonidine inhibits myocardial CoQ10-NADH-oxidase, an enzyme important for cardiac function (Kishi et al. 1975). Some of the adverse myocardial reactions that occur during clonidine treatment may be related to depletion of this enzyme. </div> <div>  </div> <div>   <B><U>Significance of Depletion </U></B></div> <div>   Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999). </div> <div>   </div> <div> <B>Replacement Therapy </B></div> <div>   Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). There are no known studies showing clinical benefits of CoQ10 replacement in the presence of clonidine specifically.</div> <bR> <div> <B>References </B></div> <div>   Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993; 28(19391):88-92.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.</div> <bR> <div> Kishi H, Kishi T, Folkers K. Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs. Res Commun Chem Pathol Pharmacol. 1975;12(3):533-540.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers R, et al. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <div>  </div> <div> <B> </B><B> <A NAME="7__cardiovascular_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>7. Cardiovascular Medications </B></div> <div>  </div> <div>    Angiotensin-Converting Enzyme (ACE) Inhibitors </div> <div>   Benazepril (Lotensin®) </div> <div> Captopril (Capoten®) </div> <div> Enalapril (Vasotec®; Vasotec® I.V.) </div> <div> Fosinopril (Monopril®) </div> <div> Lisinopril (Prinivil®; Zestril®) </div> <div> Moexipril (Univasc®) </div> <div> Perindopril Erbumine (Aceon®) </div> <div> Quinapril (Accupril®) </div> <div> Ramipril (Altace™) </div> <div> Spirapril (no brand names listed) </div> <div> Trandolapril (Mavik®) </div> <bR> <div> <B><U>Depletions </U></B></div> <div> <B><U> </U></B></div> <div> Zinc </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>    The ACE inhibitors benazepril, captopril, and enalapril significantly reduce serum zinc levels and increase urinary zinc excretion (Golik et al. 1998; Peczkowska. 1996). The effect is more pronounced with captopril; depletion of zinc from red blood cells occurs after three months of use (Golik et al. 1990). Hypertensive patients treated with captopril or enalapril may be at risk for zinc deficiency (Golik et al. 1998). Although it has not yet been reported, zinc loss could theoretically occur with fosinopril, lisinopril, quinapril, and ramipril. </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>    Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.</div> <div>  </div> <div>  </div> <div> <B>References </B></div> <div>    Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.</div> <bR> <div> Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.</div> <bR> <div> Golik A, Modai D, Averbukh Z, et al. Zinc metabolism in patients treated with captopril versus enalapril. Metab. 1990;39(7):665-667.</div> <bR> <div> Golik A, Zaidenstein R, Dishi V, et al. Effects of captopril and enalapril on zinc metabolism in hypertensive patients. J Am Coll Nutr. 1998;17(1):75-78.</div> <bR> <div> Peczkowska M. [Influence of angiotensin I converting enzyme inhibitors on selected parameters of zinc metabolism]. Pol Arch Med Wewn. 1996;96(1):32-38.</div> <div>  </div> <div> <B> </B><B> <A NAME="7__cardiovascular_medications_plus"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>7. Cardiovascular Medications PLUS</B></div> <div>  </div> <div> Beta-Adrenergic Blockers </div> <div> Acebutolol (Sectral®) </div> <div> Atenolol (Tenormin®) </div> <div> Betaxolol (Betoptic®; Betoptic® S; Kerlone®) </div> <div> Bisoprolol (Zebeta®) </div> <div> Carteolol (Cartrol® Oral; Ocupress® Ophthalmic) </div> <div> Celiprolol (no brand names listed) </div> <div> Esmolol (Brevibloc® Injection) </div> <div> Labetalol (no brand names listed) </div> <div> Levobetaxolol (Betaxon®) </div> <div> Levobunolol (AKBeta®; Betagan® Liquifilm®) </div> <div> Metipranolol (OptiPranolol® Ophthalmic) </div> <div> Metoprolol (Lopressor®; Toprol XL®) </div> <div> Nadolol (Corgard®) </div> <div> Penbutolol (Levatol®) </div> <div> Pindolol (Visken®) </div> <div> Propranolol (Inderal®; Inderal® LA) </div> <div> Sotalol (Betapace AF™; Betapace®) </div> <div> Timolol (Betimol®; Blocadren®; Timoptic-XE®; Timoptic®; Timoptic® OcuDose®) </div> <bR> <div>  </div> <div> <B><U>Depletions </U></B></div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Coenzyme Q10</U></B></I><B><U> </U></B></div> <div> <B><U>  </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>    Beta-adrenergic blockers, particularly propranolol, inhibit myocardial CoQ10- succinoxidase and CoQ10-NADH-oxidase; both enzymes are important for cardiac function (Kishi et al. 1975). Some of the adverse myocardial reactions associated with beta-blocker therapy may be related to depletion of these enzymes. Metoprolol and timolol are less inhibitory than propranolol.</div> <div>      </div> <div> <B>Significance of Depletion </B></div> <div>    Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999).</div> <bR> <div> Note: Administration of CoQ10 (90 mg po) with ocular timolol in 16 glaucoma patients mitigated the cardiovascular side effects of the drug by delaying inotropic blockade and minimizing chronotropic blockade without affecting intraocular pressure (Takahashi et al. 1989). </div> <div>  </div> <div> Melatonin </div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>   Propranolol can reduce the synthesis as well as plasma levels of endogenous melatonin significantly; effects may be less pronounced with chronic beta-blocker therapy (Arendt et al. 1985; Rommell and Demisch 1994). These changes did not affect subjective sleep quality. </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).</div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>   Optimal doses for melatonin therapy have not been established (Avery et al. 1998). Commonly available doses range from 0.3 to 5 mg. Physiological blood levels are achieved with doses of 0.3 mg; higher doses (1 mg) result in supraphysiological levels of melatonin in the blood. The efficacy of melatonin supplementation is dependent upon the time of administration, as effects are related to circadian rhythms. </div> <div>  </div> <div>  </div> <div> <B>References </B></div> <div>    Arendt J, Bojkowski C, Franey C, Wright J, Marks V. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrin Metab. 1985;60:1166-1173.</div> <bR> <div> Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.</div> <bR> <div> Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993; 28(19391):88-92.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.</div> <bR> <div> Kishi H, Kishi T, Folkers K. Bienergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs. Res Commun Chem Pathol Pharmacol. 1975;12(3):533-540.</div> <bR> <div> Kishi T, Watanabe T, Folkers K. Bioenergetics in clinical medicine. XV. Inhibition of coenzyme Q10-enzymes by clinically used adrenergic blockers of beta-receptors. Res Commun Chem Pathol Pharmacol. 1977;17(1):157-164.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers R, et al. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Rommell T, Demisch L. Influence of chronic beta-adrenoreceptor blocker treatment on melatonin secretion and sleep quality in patients with essential hypertension. J Neural Transm [Gen Sect]. 1994;95:39-48.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <bR> <div> Takahashi N, Iwasaka T, Sugiura T, et al. Effect of coenzyme Q10 on hemodynamic response to ocular timolol. J Cardiovasc Pharmacol. 1989;14(3):462-468.</div> <div>  </div> <div>    </div> <div> <B><U> <A NAME="__7_cardiovascular_medications_iii"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>7.Cardiovascular Medications III</U></B></div> <div>  </div> <div>    Cardiac Glycosides </div> <div>    Digoxin (Lanoxicaps®; Lanoxin®) </div> <bR> <div> <B>Depletions </B></div> <div>  </div> <div>   Magnesium </div> <div>  </div> <div> <B>Mechanism </B></div> <div>   Digoxin increases the renal excretion of magnesium (Schwinger and Erdmann 1992). Low magnesium concentrations increase cardiac glycoside toxicity. </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Magnesium deficiency affects calcium and vitamin D metabolism and is primarily associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>  Vitamin B1 (Thiamine) </B></I></div> <div>  </div> <div> <B>Mechanism </B></div> <div>  </div> <div>   Digoxin inhibits thiamine uptake by cardiac cells; chronic use may cause a deficiency of this nutrient (Zangen et al. 1998). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Early nonspecific manifestations of depleted thiamine levels include weakness, fatigue, anorexia, constipation, nystagmus, and mental status changes such as memory loss, confusion, and depression (Covington 1999). Beriberi is the classic condition associated with thiamine deficiency. Symptoms include polyneuritis, cardiac disturbances (bradycardia, heart failure, hypertrophy), and possibly edema. Thiamine deficiency rarely occurs alone; it is usually accompanied by deficiencies in other B vitamins. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Although the recommended daily allowance (RDA) for this nutrient ranges from 1.1 to 1.5 mg for adults depending on gender, treatment of beriberi requires oral doses as high as 5 to 10 mg/day for one month to achieve tissue saturation and replenish body stores of thiamine (Covington 1999). Treatment of deficiency secondary to alcoholism may require up to 40 mg/day of thiamine orally; cardiovascular disease may warrant a total daily intake of 90 mg (Marcus and Coulston 1996). Replacement therapy should be tailored to the patient's needs depending on age, gender, clinical presentation, serum vitamin B1 levels, dietary habits, and medication regimen.</div> <div>  </div> <div>   </div> <div> <B>References </B></div> <div>    Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Marcus R, Coulston AM. Water-soluble vitamins. In: Hardman JG, Limbird LE, et al, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill Health Professions Division; 1996:1557-1558.</div> <bR> <div> Schwinger RH, Erdmann E. Heart failure and electrolyte disturbances. Methods Find Exp Clin Pharmacol. 1992;14(4);315-325.</div> <bR> <div> Zangen A, Botzer D, Zangen R, Shainberg A. Furosemide and digoxin inhibit thiamine uptake in cardiac cells. Eur J Pharmacol. 1998;61(1):151-155. </div> <div>  </div> <div>    </div> <div> <B> <A NAME="7___cardiovascular_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>7.  Cardiovascular Medications </B><B> Electrolytes</B></div> <div>   </div> <div> <B>  Electrolytes    </B></div> <div> Potassium Chloride (Cena-K®; Gen-K®; K+ 10®; K+ Care®; K-Dur® 10; K-Dur® 20; K-Lease®; K-Lor™; K-Norm®; K-Tab®; K/Lyte®/Cl; Kaochlor®; Kaochlor® SF; Kaon-Cl-10®; Kaon-Cl®; Kay Ciel®; Klor-Con®; Klor-Con® 10; Klor-Con® 8; Klor-Con®/25; Klorvess®; Klotrix®; Micro-K® 10; Micro-K® 10 Extencaps®; Micro-K® LS; Potasalan®; Rum-K®; Slow-K®; Ten-K®) </div> <div>     </div> <div> <B>Depletions </B></div> <div> <I><B><U>  </U></B></I></div> <div> <FONT SIZE="3" COLOR="#000000" FACE="Times New Roman" ><I><B><U>  </U></B></I></FONT><I><B><U>Vitamin B12 (Cobalamin)</U></B></I> </div> <div>  </div> <div> <B>Mechanism </B></div> <div>   In two separate studies, slow-release potassium chloride caused vitamin B12 malabsorption in heart patients (Palva et al. 1972). The interference with vitamin B12 absorption may be secondary to slight acidification of the contents of the ileum. </div> <bR> <div> <B>Significance of Depletion </B></div> <div>   Potassium supplementation is rarely of sufficient duration to cause vitamin B12 deficiency (Palva et al. 1972). However, low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div>  </div> <div> <B>References </B></div> <div>    Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Palva IP, Salokannel SJ, Timonen T, Palva HLA. Drug-induced malabsorption of vitamin B12. IV. Malabsorption and deficiency of B12 during treatment with slow-release potassium chloride. Acta Med. Scand. 1972;191:355-357. </div> <div>  </div> <div> <B> <A NAME="9__cholesterol_lowering_medications__1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>9. Cholesterol-Lowering Medications </B></div> <div>   </div> <div>   Fibric Acid Derivatives </div> <div> Gemfibrozil (Lopid®) </div> <div>  </div> <div> <B>Depletions </B></div> <div>  </div> <div> <I><B><U>Coenzyme Q10 </U></B></I></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   In one study, gemfibrozil treatment in men with combined hyperlipidemia reduced serum coenzyme Q10 levels (Aberg et al. 1998). The clinical significance of these results is not known; more research is needed to determine whether chronic gemfibrozil therapy depletes CoQ10.</div> <bR> <div> <B>Significance of Depletion </B></div> <div>   Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). There are no known studies showing clinical benefits of CoQ10 replacement in the presence of gemfibrozil specifically.</div> <div>  </div> <div> Vitamin E </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   There are conflicting reports regarding the effect of gemfibrozil on vitamin E status in hyperlipidemic patients. In one study, gemfibrozil treatment in men with combined hyperlipidemia reduced serum gamma- and alpha-tocopherol levels (Aberg et al. 1998). In another study, gemfibrozil had no effect on vitamin E status and increased the LDL vitamin E/lipid peroxide ratio concentrations (Yoshida et al. 1998). The clinical significance of these results is not known; more research is needed to establish whether chronic gemfibrozil therapy depletes vitamin E.</div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   While clinical deficiency of this nutrient is uncommon, vitamin E deficiency negatively affects muscle tissue, erthrocytes, nervous and reproductive systems (Covington 1999). Depleted levels of this nutrient may be associated with cancer, heart disease, and immune dysfunction (Ames 2000). </div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>   Supplementation with doses of vitamin E ranging from 50 IU/day to 560 IU/day have been associated with positive effects, including significantly reduced risk of coronary heart disease as well as colon and prostate cancer (Ames 2000). Additionally, adequate levels of vitamin E lower lipid peroxidation and enhance immunity. However, high doses (1050 IU) of vitamin E may increase lipid peroxidation. Optimal and toxic levels of this nutrient have not yet been established.</div> <div>  </div> <div> <B>References </B></div> <div>   Aberg F, Appelkvist EL, Broijersen A, et al. Gemfibrozil-induced decrease in serum ubiquinone and alpha- and gamma-tocopherol levels in men with combined hyperlipidaemia. Eur J Clin Invest. 1998;28(3):235-242.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Chan A, Reichmann H, Kogel A, Beck A, Gold R. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The actvities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993;19391):88-92.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers K, Wilkinson EG. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <bR> <div> Yoshida H, Ishikawa T, Ayaori M, et al. Beneficial effect of gemfibrozil on the chemical composition and oxidative susceptibility of low density lipoprotein: a randomized, double-blind, placebo-controlled study. Atherscl. 1998;139(1):179-187.</div> <div>  </div> <div>    </div> <div> <B><U> <A NAME="9_cholesterol_lowering_medicationsstatin"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>9.Cholesterol-Lowering Medications Statin</U></B></div> <div>  </div> <div> HMG-CoA Reductase Inhibitors </div> <div> Atorvastatin (Lipitor®) </div> <div> Fluvastatin (Lescol®; Lescol® XL) </div> <div> Lovastatin (Mevacor®) </div> <div> Pravastatin (Pravachol®) </div> <div> Simvastatin (Zocor®) </div> <bR> <div> <B>Depletions </B></div> <div> <I><B><U> </U></B></I></div> <div> Coenzyme Q10 </div> <div> <I><B><U> </U></B></I></div> <div> <B><U>Mechanism</U></B> </div> <div>  Statins lower levels of coenzyme Q10 by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the synthesis of mevalonate, a precursor of CoQ10 (ubiquinone), and cholesterol, a carrier for CoQ10 (Bargossi et al. 1994; Belichard et al. 1993; Bliznakov and Wilkins 1998; De Pinieux et al. 1996; Folkers et al. 1990; Ghirlanda et al. 1993; Laaksonen et al. 1994; Mortensen et al. 1997). Specifically, lovastatin, pravastatin, and simvastatin significantly deplete plasma and platelet levels of CoQ10 (Hanaki et al. 1993; Kaikkonen et al. 1999). Simvastatin may cause a dose-dependent decrease in CoQ10 levels that is greater than the reduction in cholesterol (Watts et al. 1993). Although it has not been reported, atorvastatin and fluvastatin could theoretically have similar effects on CoQ10 levels.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). Concomitant administration of CoQ10 (100 mg) and simvastatin (20 mg) to hypercholesterolemic patients for 6 months prevented reductions in both plasma and platelet CoQ10 levels without affecting the cholesterol-lowering effect of the drug (Bargossi et al. 1994). Similarly, CoQ10 supplementation can reverse the CoQ10-lowering effect of lovastatin (Loop et al. 1994). In one study, supplementation with CoQ10 during lovastatin treatment restored depleted LDL CoQ10 levels, but did not improve LDL antioxidative capacity (Palomaki et al. 1998). </div> <div>  </div> <div> <B>References </B></div> <div>   Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Bargossi AM, Grossi G, Fiorella PL, et al. Exogenous CoQ10 supplementation prevents ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Aspects Med. 1994;15(Suppl):S187-S193.</div> <bR> <div> Belichard P, Pruneau D, Zhiri A. Effect of a long-term treatment with lovastatin or fenofibrate on hepatic and cardiac ubiquinone levels in cardiomyopathic hamster. Biochim Biophys Acta. 1993;1169(1):98-102. </div> <bR> <div> Bliznakov EG, Wilkins DJ. Biochemical and clinical consequences of inhibiting coenzyme Q10 biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (statins): A critical review. Adv Ther. 1998;15(4):218-228.</div> <bR> <div> Chan A, Reichmann H, Kogel A, Beck A, Gold R. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> De Pinieux G, et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol. 1996;42(3):333-337.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993;19391):88-92.</div> <bR> <div> Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA. 1990;87(22):8931-8934.</div> <bR> <div> Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect of HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol. 1993;33(3):226-229.</div> <bR> <div> Hanaki Y, Sugiyama S, Ozawa T, Ohno M. Coenzyme Q10 and coronary artery disease. Clin Invest. 1993;71(8 Suppl):S112-S115.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Kaikkonen J, Nyyssonen K, Tuomainen TP, et al. Determinants of plasma coenzyme Q10 in humans. FEBS Lett. 1999;443(2):163-166.</div> <bR> <div> Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.</div> <bR> <div> Laaksonen R, Ojala JP, Tikkanen MJ, Himberg JJ. Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin Pharmacol. 1994;46(4):313-317.</div> <bR> <div> Loop RA, Anthony M, Willis RA, Folkers K. Effects of ethanol, lovastatin and coenzyme Q10 treatment on antioxidants and TBA reactive material in liver of rats. Mol Aspects Med. 1994;15(Suppl):S195-S206.</div> <bR> <div> Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med. 1997; 18(Suppl);S137-S144.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers K, Wilkinson EG. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Palomaki A, et al. Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex vivo. J Lipid Res. 1998 Jul;39(7):1430-1437.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Watts GF, Castelluccio C, Rice-Evans C, et al. Plasma coenzyme Q (ubiquinone) concentrations in patients with simvastatin. J Clin Pathol. 1993;46(11):1055-1057.</div> <div>  </div> <bR> <div> <B> <A NAME="8__diuretics_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>8. Diuretics </B></div> <div>    Loop Diuretics </div> <div>  </div> <div> Bumetanide (Bumex®) </div> <div> Ethacrynic Acid (Edecrin®) </div> <div> Furosemide (Lasix®) </div> <div> Torsemide (Demadex®) </div> <bR> <div> <I><B><U>   </U></B></I></div> <div> <I><B><U>Depletions </U></B></I></div> <div> <I><B><U> </U></B></I></div> <div> Calcium </div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>   Short-term treatment with furosemide (4 to 7 days) increased urinary calcium excretion and reduced serum ionized calcium levels in normal subjects (Fujita et al. 1985). However, along with marked calciuresis, furosemide (40 mg) elevated serum calcium levels in another study with five healthy male volunteers (Ogawa et al. 1984). Chronic treatment (25 days) with furosemide (40 mg/day) altered calcium levels in rats (Warshaw et al. 1980). The effects on calcium may be less pronounced with bumetanide; urinary calcium loss was initially elevated but was followed by retention at 24 hours in 16 healthy volunteers treated with the drug (0.25 to 1 mg po) (Davies et al. 1974). More studies are needed to clarify the clinical effects of loop diuretics on calcium metabolism and homeostasis.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998).</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Calcium supplementation in the form of citrate, malate, gluconate, or carbonate salts may range from 1000 mg to 1500 mg or more daily (Adler and Rosen 1999; Covington 1999). Doses as high as 3000 mg/day with 10 to 50 mcg/day of 25-OH-D3 may be appropriate if plasma calcium and phosphate levels are stable and within normal range (Drüeke 1999). In cases where calcium deficits are associated with vitamin D deficiency, up to 6000 mg/day of calcium (acetate or carbonate) may be warranted. These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.</div> <div>     </div> <div> Magnesium </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Loop diuretics inhibit passive magnesium absorption and promote urinary loss of this electrolyte that could lead to a deficiency (Abrams 1981; Davies et al. 1974; Leary et al. 1990; Quamme 1997; Ryan 1986). </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   Magnesium deficiency can be a serious side effect of loop diuretic therapy; it is implicated in the development of cardiac arrhythmias and sudden death in certain patient populations, including those with congestive heart failure (Iseri et al. 1975; Schwinger and Erdmann 1992). Severely depleted levels of magnesium affect calcium and vitamin D metabolism and are associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.</div> <div>   </div> <div> <B>Replacement Therapy </B></div> <div>   The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>Phosphorus </B></I></div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>   The rate of phosphorus elimination doubled in healthy volunteers treated with bumetanide (2 mg/day) compared to furosemide or placebo (Carriere and Dandavino 1976). This effect was observed under conditions of normal diet and fluid intake as well as over-hydration. In contrast, furosemide produced no phosphaturic effect under the conditions studied.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Although rare, suboptimal intake of phosphorus can lead to hypophosphatemia, which is associated with general debility characterized by muscle weakness, bone pain, paraesthesia, ataxia, acute respiratory failure, mental confusion, seizures, anorexia, anemia, increased susceptibility to infection, and even death (Cashman and Flynn 1999; Covington 1999). In chronic situations, patients with severely depleted phosphate levels below approximately 0.3 mmol/L may exhibit signs of rickets (children) or osteomalacia (adults) (Cashman and Flynn 1999).</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   The recommended dietary allowance (RDA) for phosphorus ranges from 100 to 1250 mg/day depending on age (Cashman and Flynn 1999; Covington 1999). Doses for replacement therapy should be adjusted to reflect individual circumstances, including the patient's age, gender, clinical presentation, serum phosphate levels, dietary habits, and medication regimen.</div> <div>  </div> <div> <I>Potassium </I></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Loop diuretics increase potassium excretion (Rastogi et al. 1985). This may occur as a result of inhibition of renal reabsorption of cations at the proximal and distal tubules as well as at the Loop of Henle (Hines Burnham et al. 2000). Increased potassium excretion could lead to hypokalemia, which could be of particular concern in patients with hepatic cirrhosis, congestive heart failure, and ventricular arrhythmias.</div> <bR> <div> <B>Significance of Depletion </B></div> <div>   Potassium depletion as a consequence of prolonged drug therapy is usually associated with chloride deficiency and manifests as hypokalemic, hypochloremic metabolic acidosis (Covington 1999). Signs and symptoms of deficiency include anorexia, apprehension, drowsiness, listlessness, fatigue, nausea, muscle cramps and weakness, tetany, excessive thirst, altered mental status, and irrational behavior. Severe hypokalemia could also result in clinical manifestations of cardiac arrythmia, including primarily palpitations, cardiac arrest, and death. A loss from total body stores of approximately 100 to 200 mEq of potassium is usually required to cause a decrease in serum potassium levels of 1 mEq/L. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   The usual range of treatment is 20 to 100 mEq/day of potassium (PDR 2000). The appropriate doses for replacement therapy should be determined on an individual basis, considering the patient's age, gender, clinical presentation, serum potassium levels, dietary habits, and medication regimen. The chloride salt is appropriate treatment for cases of alkalosis (Covington 1999). In cases of acidosis, other potassium salts such as bicarbonate, citrate, acetate, or gluconate are preferred.</div> <div>  </div> <div> <B><U>Vitamin B1 (Thiamine) </U></B></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Low doses of furosemide (1, 3, and 10 mg IV over 6 hours) caused significant urinary losses of thiamine in healthy volunteers (Rieck et al. 1999). Long-term furosemide therapy can cause thiamine deficiency and impair cardiac performance in patients with CHF; poor dietary intake of thiamine increases this risk (Brady et al. 1995; Seligmann et al. 1991). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Early nonspecific manifestations of depleted thiamine levels include weakness, fatigue, anorexia, constipation, nystagmus, and mental status changes such as memory loss, confusion, and depression (Covington 1999). Beriberi is the classic condition associated with thiamine deficiency. Symptoms include polyneuritis, cardiac disturbances (bradycardia, heart failure, hypertrophy), and possibly edema. Thiamine deficiency rarely occurs alone; it is usually accompanied by deficiencies in other B vitamins.</div> <div>     </div> <div> <B>Replacement Therapy </B></div> <div>   Although the recommended dietary allowance (RDA) for this nutrient ranges from 1.1 to 1.5 mg for adults depending on gender, treatment of beriberi requires oral doses as high as 5 to 10 mg/day for one month to achieve tissue saturation and replenish body stores of thiamine (Covington 1999). Treatment of deficiency secondary to alcoholism may require up to 40 mg/day of thiamine orally; cardiovascular disease may warrant a total daily intake of 90 mg (Marcus and Coulston 1996). Replacement therapy should be tailored to the patient's needs depending on age, gender, clinical presentation, serum vitamin B1 levels, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>Vitamin B6 (Pyridoxine); Vitamin C (Ascorbic Acid) </B></I></div> <div> <I><B> </B></I></div> <div> Mechanism </div> <div>   Furosemide (20 mg IV) increased urinary excretion of vitamins B6 and C in patients with chronic renal failure; these patients should be monitored for deficiency of these vitamins if they are on chronic treatment with this drug (Mydlik et al. 1998). </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Vitamin B6: Usually, vitamin B6 deficiency is accompanied by depletions of other B vitamins (National Research Council 1989). Signs and symptoms of low levels of this vitamin include epileptiform convulsions with abnormal EEG findings, dermatitis, anemia, weakness, mental confusion, irritability, nervousness, insomnia, and abnormal tryptophan metabolism (Covington 1999; National Research Council 1989; Wilson 1998). Depleted levels may increase the risk of colon and prostate cancers, heart disease, brain dysfunction, and birth defects (Ames 2000). </div> <bR> <div> <B>Vitamin C</B><FONT SIZE="3" COLOR="#000000" FACE="Times New Roman" >: Patients with depleted levels of vitamin C may present with anemia, icterus, edema, lethargy, fatigue, fever, ecchymoses, hypotension, convulsions, gum disorders, tooth loss, emotional changes, and perifollicular hyperkeratotic papules (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). In addition, they may exhibit signs of poor wound healing, increased susceptibility to infection, and markedly defective collagen synthesis. Severe deficiency results in scurvy, which is potentially fatal (Carr and Frei 1999; National Research Council 1989; Wilson 1998). Scurvy involves degenerative changes in capillaries, bone, and connective tissue, resulting in clinical symptoms that include weakness, joint tenderness and swelling, and spontaneous hemorrhages (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). Patients with vitamin C deficiency may also be at increased risk of developing cataracts and heart disease (Ames 2000).</FONT></div> <div>  </div> <div>   </div> <div> <B>Replacement Therapy </B></div> <div>   Vitamin B6: Neuropathology resulting from vitamin B6 deficiency should be treated with doses of 50 to 200 mg/day (Covington 1999). Dietary deficiency usually responds to doses of 10 to 20 mg/day. Doses should be tailored to account for the patient's age, gender, clinical presentation, serum vitamin B6 levels, dietary habits, and medication regimen.</div> <bR> <div> Vitamin C: Treatment of scurvy requires doses between 300 and 1000 mg/day for adults (Covington 1999). Other recommendations range from the recommended dietary allowance (RDA) of 60 mg to 2000 mg/day for adults (Carr and Frei 1999; Wilson 1998). One study proposes that no adult receive more than 1000 mg/day because higher doses could cause nausea and diarrhea (Ausman 1999). To minimize the possibility of gastric upset, buffered and sustained-release vitamin C preparations are recommended. Specific doses account for the patient's age, gender, overall health status, dietary habits, and medication regimen. Smokers must consume 2 to 3 times more vitamin C than non-smokers (Ames 2000).</div> <div>  </div> <div> <B>References </B></div> <div>    Abrams J. Intramuscular bumetanide and furosemide in congestive heart failure. J Clin Pharmacol. 1981;21:673-679.</div> <bR> <div> Adler RA, Rosen CJ. Glucocorticoids and osteoporosis. Endocrinol Metab Clin North Am. 1999;23:641-654.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Ausman LM. Criteria and recommendations for vitamin C intake. Nutr Review. 1999;57(7):222-229.</div> <bR> <div> Brady JA, Rock CL, Horneffer MR. Thiamin status, diuretic medications, and the management of congestive heart failure. J Am Diet Assoc. 1995;95(5):541-544.</div> <bR> <div> Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999;69:1086-1107.</div> <bR> <div> Carriere S, Dandavino R. Bumetanide, a new loop diuretic. Clin Pharm Ther. 1976;20:424-438.</div> <bR> <div> Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Davies DL, Lant AF, Millard NR, Smith AJ, Ward JW, Wilson GM. Renal action, therapeutic use, and pharmacokinetics of the diuretic bumetanide. Clin Pharmacol Ther. 1974;15:141-155.</div> <bR> <div> Drüeke T. Medical management of secondary hyperparathyroidism in uremia. Am J Med Sci. 1999;317(6):383-389.</div> <bR> <div> Fujita T, Delea CS, Bartter FC. The effects of oral furosemide on the response of urinary excretion of cyclic adenosine monophosphate and phosphate to parathyroid extract in normal subjects. Nephron. 1985;41(4):333-336.</div> <bR> <div> Gabow PA, Hanson TJ, Popovtzer MM, Schrier RW. Furosemide-induced reduction in ionized calcium in hypoparathyroid patients. Ann Intern Med. 1977;86(5):579-581.</div> <bR> <div> Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000:624-626.</div> <bR> <div> Iseri LT, Freed J, Bures AR. Magnesium deficiency and cardiac disorders. Am J Med. 1975;58(6):837-846.</div> <bR> <div> Leary WP, Reyes AJ, Wynne RD, van der Byl K. Renal excretory actions of furosemide, of hydrocholorothiazide and of the vasodilator flosequinan in healthy subjects. J Int Med Res. 1990;18:120-141.</div> <bR> <div> Marcus R, Coulston AM. Water-soluble vitamins. In: Hardman JG, Limbird LE, et al, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill Health Professions Division; 1996:1557-1558.</div> <bR> <div> Mydlik M, Derzslova K, Zemberova E, Rajnic A. [The effect of furosemide on urinary excretion of oxalic acid, vitamin C and vitamin B6 in chronic renal failure]. Vnitr Lek. 1998;44(3):127-131.</div> <bR> <div> National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.</div> <bR> <div> Ogawa K, Hatano T, Yammoto M, Matsui N. Influence of acute diuresis on calcium balance - a comparative study of furosemide and azosemide. Int J Clin Pharmacol, Ther, Toxicol. 1984;22(8):401-405.</div> <bR> <div> Physicians' Desk Reference, PDR. 52nd ed. Montvale, NJ: Medical Economics Company; 1998.</div> <bR> <div> Potts JT. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2241.</div> <bR> <div> Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52(5):1180-1195.</div> <bR> <div> Rastogi S, Bayliss JM, Nascimento L, Arruda JA. Hyperkalemic renal tubular acidosis: effect of furosemide in humans and in rats. Kidney Int. 1985;28(5):801-817.</div> <bR> <div> Rieck J, Halkin H, Almog S, et al. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med. 1999;134(3):238-243.</div> <bR> <div> Ryan MP. Magnesium and potassium-sparing diuretics. Magnesium. 1986;5(5-6):282-292.</div> <bR> <div> Schwinger RH, Erdmann E. Heart failure and electrolyte disturbances. Methods Find Exp Clin Pharmacol. 1992;14(4):315-325.</div> <bR> <div> Seligmann H, Halkin H, Rauchfleisch S, et al. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med. 1991;91(2):151-155.</div> <bR> <div> Warshaw BL, Anand SK, Kerian A, Lieberman E. The effect of chronic furosemide administration on urinary calcium excretion and calcium balance in growing rats. Pediatr Res. 1980;14(10):1118-1121.</div> <bR> <div> Wilson JD. Vitamin deficiency and excess. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:483-485.</div> <div>  </div> <div> <B> <A NAME="diuretics_ii_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>8. </B><B>Diuretics II </B></div> <div> Thiazide Diuretics </div> <div> Hydrochlorothiazide (Aquazide®; Esidrix®; Ezide®; Hydrocot®; HydroDIURIL®; Microzide™; Oretic®) </div> <bR> <div> <I><B><U>Depletions </U></B></I></div> <div> <I><B><U> </U></B></I></div> <div> <I><B> Chloride; Sodium </B></I></div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>     Thiazides increase urinary excretion of sodium and chloride. Patients should be observed for clinical signs of hyponatremia or hypochloremic alkalosis (Hines Burnham et al. 2000).</div> <div>  </div> <div>    </div> <div> <B>Significance of Depletion </B></div> <div>    Because of the wide availability of sodium in dietary sources, deficiency is uncommon (National Research Council 1989). Sodium deficiency is associated with nausea, headache, lethargy, confusion, stupor, seizures, and possibly coma (Singer and Brenner 1998; National Research Council 1989). Severe deficiency may increase the potential for harmful hormone and lipid effects, myocardial infarctions, cardiovascular mortality (Kaplan 2000). Development of symptoms depends in large part on the rate of the loss of sodium (Singer and Brenner 1998). Clinical problems with depletion are more common in elderly and debilitated patients.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    The US dietary guideline for sodium is 2.4 g/day, the equivalent of 6 g/day sodium chloride (Kaplan 2000). Since these are general recommendations for health maintenance, doses for replacement therapy should be adjusted on an individual basis, depending on the patient's age, gender, clinical presentation, serum levels, dietary habits, and medication regimen.</div> <div>      </div> <div> <I><B>Coenzyme Q10 </B></I></div> <div> <I><B><U>  </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>    Thiazide diuretics inhibit CoQ10-NADH-oxidase in heart tissue; this enzyme is important for cardiac function (Kishi et al. 1975). More research is needed to determine if chronic thiazide treatment could lead to a CoQ10 deficiency. However, beta-adrenergic blockers also inhibit CoQ10-NADH-oxidase as well as CoQ10-succinoxidase. The potential for CoQ10 depletion is greater in patients managed on combination therapy consisting of both a beta-blocker and a thiazide diuretic.</div> <div>     </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999). </div> <div>  </div> <div>    </div> <div> <B>Replacement Therapy </B></div> <div>    Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). There are no known studies showing clinical benefits of CoQ10 replacement in the presence of thiazide diuretics specifically.</div> <div>  </div> <div> Magnesium; Potassium </div> <div> <I><B><U>    </U></B></I></div> <div> <I><B><U>Mechanism </U></B></I></div> <div>   Hypomagnesemia and hypokalemia occur in a high percentage of patients receiving thiazide monotherapy (Dyckner and Wester 1987). Hypokalemia reduces magnesium transport in the distal tubule, increasing urinary magnesium excretion (Dai et al. 1997). Other clinical studies have demonstrated that hydrochlorothiazide also decreases concentrations of magnesium and potassium in mononuclear cells (Abraham et al. 1991).</div> <bR> <div> When HCTZ is combined with triamterene, a potassium-sparing diuretic, there is a reduction in potassium and hydrogen loss (PDR 1998). However, triamterene does not compensate entirely for the kaliuretic effect of HCTZ; some patients may remain hypokalemic while taking this combination therapy. Hyperkalemia may actually develop in some individuals, particularly elderly or severely ill patients, and those with diabetes (with or without renal impairment) (Hollenberg and Mickiewicz 1989). Patients receiving HCTZ with triamterene should be monitored carefully for signs of hypo- or hyperkalemia (PDR 1998).</div> <bR> <div> When HCTZ is combined with losartan, an angiotensin II receptor antagonist, the hypokalemic response to HCTZ decreases as the dose of losartan increases (PDR 1998).</div> <bR> <div> Combining HCTZ with lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, may attenuate the thiazide-induced potassium loss because lisinopril reduces the production of aldosterone (PDR 1998). As a result, magnesium-wasting may not occur with the combination of lisinopril and HCTZ. Nevertheless, patients should be observed for fluid or electrolyte imbalances while taking this drug combination.</div> <div>  </div> <div>    </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   Magnesium: Severely depleted levels of magnesium affect calcium and vitamin D metabolism and are associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.</div> <bR> <div> Potassium: Potassium depletion as a consequence of prolonged drug therapy is usually associated with chloride deficiency and manifests as hypokalemic, hypochloremic metabolic acidosis (Covington 1999). Signs and symptoms of deficiency include anorexia, apprehension, drowsiness, listlessness, fatigue, nausea, muscle cramps and weakness, tetany, excessive thirst, altered mental status, and irrational behavior. Severe hypokalemia could also result in clinical manifestations of cardiac arrythmia, including primarily palpitations, cardiac arrest, and death. A loss from total body stores of approximately 100 to 200 mEq of potassium is usually required to cause a decrease in serum potassium levels of 1 mEq/L. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Magnesium: The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.</div> <bR> <div> Potassium: The usual range of treatment is 20 to 100 mEq/day of potassium (PDR 1998). The appropriate doses for replacement therapy should be determined on an individual basis, considering the patient's age, gender, clinical presentation, serum potassium levels, dietary habits, and medication regimen. The chloride salt is appropriate treatment for cases of alkalosis (Covington 1999). In cases of acidosis, other potassium salts such as bicarbonate, citrate, acetate, or gluconate are preferred.</div> <bR> <div> Note: Treatment with potassium hydrochloride (1 g bid) alone or with magnesium hydroxide (500 mg bid) suppressed ventricular ectopic activity in thiazide-treated hypertensive patients at risk for developing ventricular extrasystoles (Lumme and Jounela 1989).</div> <div>  </div> <div> Zinc </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>   Chronic treatment with thiazides increases urinary zinc excretion and could lead to zinc deficiency (Mountokalakis et al. 1984; Reyes et al. 1982; Wester 1980). The use of thiazide diuretics in conditions such as hepatic cirrhosis, diabetes mellitus, gastrointestinal disorders, renal insufficiency, alcoholism, and pregnancy may increase the likelihood of a zinc deficiency (Reyes et al. 1982; Reyes et al. 1983). Because ACE inhibitors also reduce serum zinc levels and increase urinary zinc excretion (Golik et al. 1998; Peczkowska 1996), zinc levels should be carefully monitored in patients receiving a combination of HCTZ and ACE inhibitors.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.</div> <div>  </div> <div> <B>References </B></div> <div>   Abraham AS, Brooks BA, Grafstein Y, et al. Effects of hydrochlorothiazide, diltiazem and enalapril on mononuclear cell sodium and magnesium levels in systemic hypertension. Am J Cardiol. 1991;68:1357-1361.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.</div> <bR> <div> Chan A, Reichmann H, Kogel A, Beck A, Gold R. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Dai LJ, Friedman PA, Quamme GA. Cellular mechanisms of chlorothiazide and cellular potassium depletion on Mg2+ uptake in mouse distal convoluted tubule cells. Kidney Int. 1997;51(4):1008-1017.</div> <bR> <div> Dyckner T, Wester PO. Potassium/magnesium depletion in patients with cardiovascular disease. Am J Med. 1987;82(3A):11-17.</div> <bR> <div> Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993;19391):88-92.</div> <bR> <div> Golik A, Zaidenstein R, Dishi V, et al. Effects of captopril and enalapril on zinc metabolism in hypertensive patients. J Am Coll Nutr. 1998;17(1):75-78.</div> <bR> <div> Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.</div> <bR> <div> Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000:617.</div> <bR> <div> Hollenberg NK, Mickiewicz C. Hyperkalemia in diabetes mellitus: Effect of a triamterene-hydrochlorothiazide combination. Arch Intern Med. 1989; 149(6):1327-1330.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.</div> <bR> <div> Kaplan NM. The dietary guideline for sodium: should we shake it up? N Am J Clin Nutr. 2000;71:1020-1026.</div> <bR> <div> Kishi T, Watanabe T, Folkers K. Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs. Res Commun Chem Pathol Pharmacol. 1975;12(3):533-540.</div> <bR> <div> Lumme JA, Jounela AJ. The effect of potassium and potassium plus magnesium supplementation on ventricular extrasystoles in mild hypertensives treated with hydrochlorothiazide. Int J Cardiol. 1989;25(1):93-97.</div> <bR> <div> Mountokalakis T, Dourakis S, Karatzas N, et al. Zinc deficiency in mild hypertensive patients treated with diuretics. J Hypertens Suppl. 1984;2(3):S571-S572.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers K, Wilkinson EG. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Peczkowska M. [Influence of angiotensin I converting enzyme inhibitors on selected parameters of zinc metabolism]. Pol Arch Med Wewn. 1996;96(1):32-38.</div> <bR> <div> Physicians' Desk Reference, PDR. 52nd ed. Montvale, NJ: Medical Economics Company; 1998.</div> <bR> <div> Reyes AJ, Leary WP, Lockett CJ, et al. Diuretics and zinc. S Afr Med J. 1982;62(11):373-375.</div> <bR> <div> Reyes AJ, Olhaberry JV, Leary WP, et al. Urinary zinc excretion, diuretics, zinc deficiency and some side effects of diuretics. S Afr Med J. 1983;64(24):936-941.</div> <bR> <div> Singer GG, Brenner BM. Fluid and electrolyte disturbances. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:269.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <bR> <div> Wester PO. Urinary zinc excretion during treatment with different diuretics. Acta Med Scand. 1980;208:209-212. </div> <div>  </div> <div> .</div> <div>  </div> <div> <B> <A NAME="10__gastrointestinal_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>10. Gastrointestinal Medications </B></div> <div>   </div> <div> Histamine H2 Antagonists </div> <div>  </div> <div> Cimetidine (Tagamet®; Tagamet® HB [OTC]) </div> <div> Famotidine (Mylanta AR® (Discontinued by Manufacturer); Pepcid RPD™; Pepcid®; Pepcid® AC [OTC]) </div> <div> Nizatidine (Axid®; Axid® AR [OTC]) </div> <div> Ranitidine Bismuth Citrate (Tritec®) </div> <div> Ranitidine Hydrochloride (no brand names listed) </div> <bR> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Depletions </U></B></I></div> <div> <I><B><U> </U></B></I></div> <div> Calcium </div> <div> <I><B><U>  </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>   In several trials, cimetidine reduced calcium absorption which was thought to be secondary to the effects of the drug on vitamin D metabolism rather than inhibition of gastric acid secretion (Bo-Linn et al. 1984; Caron et al. 1987; Ghishan et al. 1981). However, in a double-blind, placebo-controlled crossover study with 8 primary hyperparathyroid patients treated with cimetidine or placebo for 2 months, serum calcium levels declined significantly in only one patient and parathyroid hormone was affected in only one patient (Fisken et al. 1982). Periodic assessment of calcium levels and/or bone density may be appropriate in patients on chronic cimetidine therapy, particularly postmenopausal women.</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>   Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Calcium supplementation in the form of citrate, malate, gluconate, or carbonate salts may range from 1000 mg to 1500 mg or more daily (Adler and Rosen 1999; Covington 1999). Doses as high as 3000 mg/day with 10 to 50 mcg/day of 25-OH-D3 may be appropriate if plasma calcium and phosphate levels are stable and within normal range (Drüeke 1999). In cases where calcium deficits are associated with vitamin D deficiency, up to 6000 mg/day of calcium (acetate or carbonate) may be warranted. These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.</div> <div>  </div> <div> Iron </div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>   High doses of H2 receptor antagonists may significantly reduce non-heme iron absorption by reducing gastric acid secretion (Aymard et al. 1988; Skikne et al. 1981).</div> <div>    </div> <div> <B>Significance of Depletion </B></div> <div>   Iron deficiency may be associated with oxidative DNA damage (Ames 2000). In children, iron deficiency leads to cognitive dysfunction. Other pathologies associated with depleted levels of iron include anemia and compromised immune function. Symptoms include dizziness, fatigue, shortness of breath, pallor, and tachycardia (Covington 1999).</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>   Therapeutic doses for replacement therapy for adults range from 100 to 200 mg/day (2 to 3 mg/kg/day) of elemental iron, usually in 3 divided doses (Covington 1999). Iron levels should be monitored carefully; excess levels could also be associated with oxidative DNA damage as well as increased risk of cancer and heart disease (Ames 2000). The oral lethal dose of elemental iron is estimated to be 200 to 250 mg/kg with symptoms presenting after ingestion of 30 to 60 mg/kg (Covington 1999). Iron supplements can cause GI irritation; administering the supplement with food will prevent GI upset and bleeding (Hines Burnham et al. 2000).</div> <div>  </div> <div> <I><B>Vitamin B9 (Folic Acid)</B></I><FONT SIZE="3" COLOR="#000000" FACE="Times New Roman" ><I><B><U> </U></B></I></FONT></div> <div> <I><B><U>  </U></B></I></div> <div> <I><B><U>Mechanism</U></B></I> </div> <div>    Chronic use of H2 receptor antagonists may cause folic acid deficiency, particularly if the diet is already low in folate; the optimum pH for folic acid absorption is 5.5 to 6.0 (Russell et al. 1988). Cimetidine reduces folate absorption by decreasing gastric acid secretion and increasing the pH of the proximal small intestine. However, folate absorption was not significantly affected by ranitidine, even though this drug also increased the pH of the proximal small intestine. Folic acid depletion has not been reported with famotidine or nizatidine, but may occur with nizatidine because it also increases gastric pH. </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>    Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.</div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>Vitamin B12 (Cobalamin) </B></I></div> <div> <I><B><U> </U></B></I></div> <div> <I><B><U>Mechanism </U></B></I></div> <div>    H2 receptor antagonists can cause vitamin B12 deficiency by reducing gastric acid secretion (Force and Nahata 1992). Gastric acid helps cleave vitamin B12 from food and is necessary for B12 absorption (Festen 1991; Force and Nahata 1992). </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div>  Vitamin D </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>    Short-term treatment with cimetidine may inhibit vitamin D-hydroxylase activity and alter vitamin D metabolism (Bengoa et al. 1984; Odes et al. 1990). This has not been reported with famotidine, nizatidine, or ranitidine. Whether chronic cimetidine therapy can contribute to a calcium or vitamin D deficiency is unknown. </div> <div>  </div> <div> <B><U>Significance of Depletion</U></B> </div> <div>    Because vitamin D is fat-soluble, prolonged periods of deficiency are required to produce symptoms (National Research Council 1989). While the long evolution is often asymptomatic (Rao 1999), depleted levels are characterized by inadequate mineralization of the bone, which could lead to rickets (in children) and osteomalacia (in adults) (Covington 1999; National Research Council 1989; Rao 1999). Other signs and symptoms of low levels of vitamin D include increased risk of fractures, osteoporosis, phosphaturia, hyperparathyroidism, chronic muscle weakness, hypovitaminosis D, bone pain, pseudofractures, waddling gait, or severe, chronic hypocalcemia (Holick et al. 1998; National Research Council 1989; Rao 1999; Vieth 1999). Subclinical vitamin D deficiency has been reported in postmenopausal women with osteoporosis (Rao 1999). The prevalence of vitamin D deficiency is more common in women, certain ethnic populations, and increases with age. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    Doses of vitamin D3 ranging from 1000 to 2000 IU/day or 25-OH-D3 ranging from 10 to 25 mcg/day have been used to treat vitamin D deficiency, which is characterized by low plasma levels of 25-OH-D3 (Drüeke 1999). Other recommendations involve doses between 200 to 800 IU/day for adults (Rao 1999) and 50,000 IU/month for elderly patients with osteomalacia (Holick et al. 1998). </div> <div>     </div> <div> Zinc </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism </U></B></div> <div>    Optimal pH for zinc absorption is 3 or less (Henderson et al. 1995). Famotidine reduces zinc absorption by increasing gastric pH above five. Likewise, ranitidine reduces zinc absorption by inhibiting gastric acid secretion and increasing gastric pH (Sturniolo et al. 1991). Cimetidine and nizatidine may also reduce zinc absorption by decreasing gastric acid secretion; research indicates that zinc levels in the prostate gland are depleted by cimetidine (Pinelli et al. 1987). </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000). </div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>   Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.</div> <div>  </div> <div>    </div> <div> <B>References </B></div> <div>    Adler RA, Rosen CJ. Glucocorticoids and osteoporosis. Endocrinol Metab Clin North Am. 1999;23:641-654.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Aymard JP, Aymard B, Netter P, et al. Haematological adverse effects of histamine H2-receptor antagonists. Med Toxicol Adverse Drug Exp. 1988;3(6):430-448.</div> <bR> <div> Bengoa JM, Bolt MJ, Rosenberg IH. Hepatic vitamin D 25-hydroxylase inhibition by cimetidine and isoniazid. J Lab Clin Med. 1984;104(4):546-552.</div> <bR> <div> Bo-Linn GW, Davis GR, Buddrus DJ, et al. An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium. J Clin Invest. 1984;73(3):640-647.</div> <bR> <div> Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.</div> <bR> <div> Caron P, Gaillard J, Barousse C, et al. [Cimetidine treatment of primary hyperparathyroidism]. Biomed Pharmacother. 1987;41(3):143-146.</div> <bR> <div> Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Drüeke T. Medical management of secondary hyperparathyroidism in uremia. Am J Med Sci. 1999;317(6):383-389.</div> <bR> <div> Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.</div> <bR> <div> Festen HP. Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol. 1991;188:1-7.</div> <bR> <div> Fisken R, Wilkinson R, Heath D. The effects of cimetidine on serum calcium and parathyroid hormone levels in primary hyperparathyroidism. Br J Clin Pharm. 1982;14:701-705.</div> <bR> <div> Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on vitamin B12 absorption. Ann Pharmacother. 1992;26(10):1283-1286.</div> <bR> <div> Ghishan FK, Walker F, Meneely R, Patwardhan R, Speeg KV Jr. Intestinal calcium transport: effect of cimetidine. J Nutr. 1981;111(12):2157-2161.</div> <bR> <div> Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.</div> <bR> <div> Henderson LM, et al. Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young healthy volunteers. JPEN J Parenter Enteral Nutr. 1995 Sep-Oct;19(5):393-397.</div> <bR> <div> Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons; 2000:31.</div> <bR> <div> Holick MF, Krane SM, Potts JT. Calcium, phosphorus, and bone metabolism: calcium-regulating hormones. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2221-2222.</div> <bR> <div> Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.</div> <bR> <div> National Research Council, Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.</div> <bR> <div> Odes HS, Fraser GM, Krugliak P, et al. Effect of cimetidine on hepatic vitamin D metabolism in humans. Digestion. 1990;46(2):61-64.</div> <bR> <div> Pinelli P, Trivulzio S, Colombo R, et al. Antiprostatic effect of cimetidine in rats. Agents Actions. 1987:22(3-4):197-201.</div> <bR> <div> Potts JT. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2241.</div> <bR> <div> Rao DS. Perspective on assessment of vitamin D nutrition. J Clin Densitom. 1999:2(4):457-464.</div> <bR> <div> Russell RM, Golner BB, Kransinski SD, et al. Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med. 1988;112)4):458-463.</div> <bR> <div> Skikne BS, Lynch SR, Cook JD. Role of gastric acid in food iron absorption. Gastroenterol. 1981;81(6):1068-1071.</div> <bR> <div> Sturniolo GC, Montino MC, Rossetto L, et al. Inhibition of gastric acid secretion reduces zinc absorption in man. J Am Coll Nutr. 1991;10(4):372-375.</div> <bR> <div> Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842-56.</div> <div>  </div> <bR> <div>  </div> <div> <B> <A NAME="10_gastrointestinal_medications_ii"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>10.Gastrointestinal Medications II</B></div> <div>   </div> <div> Proton Pump Inhibitors </div> <div>  </div> <div> Lansoprazole (Prevacid®) </div> <div> Omeprazole (Prilosec™) </div> <div>   </div> <div> <B>Depletions </B></div> <div>  </div> <div> <I><B>Vitamin B12 (Cobalamin) </B></I></div> <div>  </div> <div> <B>Mechanism </B></div> <div>    Omeprazole reduces the absorption of protein-bound vitamin B12 (Marcuard et al. 1994; Saltzman et al. 1994). Prolonged treatment with omeprazole can significantly decrease serum cobalamin levels and cause cobalamin deficiency in some patients (Bellou et al. 1996; Termanini et al. 1998). However, in one study, omeprazole reduced absorption of protein-bound, but not unbound, cyanocobalamin; no change in serum cobalamin was observed in patients after 7 years of treatment (Schenk et al. 1996). It is not known whether lansoprazole adversely affects cobalamin status. Given the uncertainty of the depletion of serum vitamin B12 levels, periodic monitoring may be useful.</div> <div>  </div> <div>  <B><U>Significance of Depletion </U></B></div> <div>    Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia. </div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>    Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.</div> <bR> <div> Note: Unlike protein-bound vitamin B12 in foods, supplemental vitamin B12 is not affected by gastric acid dysfunction (Carmel et al. 1988).</div> <div>   </div> <div> <B>References </B></div> <div>    Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Bellou A, Aimone-Gastin I, De Korwin JD, et al. Cobalamin deficiency with megaloblastic anaemia in one patient under long-term omeprazole therapy. J Intern Med. 1996;240(3):161-164.</div> <bR> <div> Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.</div> <bR> <div> Carmel R, Sinow RM, Siegel ME, Samloff IM. Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels. Arch Intern Med. 1988;148(8):1715-1719.</div> <bR> <div> Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.</div> <bR> <div> Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin. Ann Intern Med. 1994;120(3):211-215.</div> <bR> <div> Saltzman JR, Kemp JA, Golner BB, et al. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am Coll Nutr. 1994;13(6):584-591. </div> <bR> <div> Schenk BE, Festen HP, Kuipers EJ, et al. Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin. Aliment Pharmacol Ther. 1996;10(4):541-545.</div> <bR> <div> Termanini B, Gibril F, Sutliff VE, et al. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med. 1998;104(5):422-430. </div> <div>  </div> <div> <B> <A NAME="11__oral_contraceptives_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>11  Oral Contraceptives </B></div> <div>   </div> <div> Monophasic, Biphasic, and Triphasic Preparations </div> <div> Ethinyl Estradiol and Desogestrel (Apri®; Desogen®; Mircette™; Ortho-Cept®) </div> <div> Ethinyl Estradiol and Levonorgestrel (Alesse™; Levlen®; Levlite®; Levora®; Nordette®; PREVEN™; Tri-Levlen®; Triphasil®) </div> <div> Ethinyl Estradiol and Norethindrone (Brevicon®; Estrostep® 21; Estrostep® Fe; Femhrt™; Genora® 0.5/35; Genora® 1/35; Jenest-28™; Loestrin®; Modicon™; Nelova™ 0.5/35E; Nelova™ 10/11; Norethin™ 1/35E; Norinyl® 1+35; Ortho-Novum® 1/35; Ortho-Novum® 10/11; Ortho-Novum® 7/7/7; Ovcon® 35; Ovcon® 50; Tri-Norinyl®) </div> <div> Ethinyl Estradiol and Norgestimate (Ortho Tri-Cyclen®; Ortho-Cyclen®; Ortho-Prefest®) </div> <div>   </div> <div> <B><U>Depletions </U></B></div> <div> <B><U>  </U></B></div> <div> <I><B>Magnesium </B></I></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>    Oral contraceptives (OCs) reduce serum magnesium levels by shifting circulating magnesium from serum to tissues (Olatunbosun et al. 1974; Seelig 1990; Seelig 1993; Stanton and Lowenstein 1987). This may deplete magnesium levels and increase dietary requirements.</div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Magnesium deficiency affects calcium and vitamin D metabolism and is primarily associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.</div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>    The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.</div> <div>    </div> <div> <I><B>Vitamin B2 (Riboflavin)</B></I><FONT SIZE="3" COLOR="#000000" FACE="Times New Roman" ><I><B><U> </U></B></I></FONT></div> <div>   </div> <div> <B>Mechanism </B></div> <div>    Oral contraceptives interfere with riboflavin metabolism and may cause deficiency in women with already compromised riboflavin status (Ahmed et al. 1975; Matsui and Rozovski 1982; Newman et al. 1978; Webb 1980). </div> <div>     </div> <div> <B>Significance of Depletion </B></div> <div>    Riboflavin deficiency usually occurs as a result of deficiencies in dietary protein and is associated with other B vitamin deficiencies (Covington 1999). Depleted levels of riboflavin affect carbohydrate and amino acid metabolism by interfering with enzyme systems involved in the production of ATP. Lack of an adequate supply of riboflavin disturbs several physiological and biochemical processes and results in retarded growth in infants and children (Covington 1999; Powers 1999). Symptoms include corneal vascularization, glossitis, cheilosis, seborrheic dermatitis, and impaired wound healing (Covington 1999). </div> <div>  </div> <div> <I><B><U>Replacement Therapy</U></B></I></div> <div>   Doses of 5 to 25 mg/day are recommended for the treatment of riboflavin deficiency (Covington 1999). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum riboflavin levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>Vitamin B6 (Pyridoxine) </B></I></div> <div>  </div> <div> <B>Mechanism </B></div> <div>   Oral contraceptives deplete vitamin B6 levels, possibly through induction of tryptophan oxidase (Bermond 1982; Prasad et al. 1976; Slap 1981). Side effects such as depression may be due to altered metabolism of vitamin B6, folate, and B12 (Kane 1976). </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>   Usually, vitamin B6 deficiency is accompanied by depletions of other B vitamins (National Research Council 1989). Signs and symptoms of low levels of this vitamin include epileptiform convulsions with abnormal EEG findings, dermatitis, anemia, weakness, mental confusion, irritability, nervousness, insomnia, and abnormal tryptophan metabolism (Covington 1999; National Research Council 1989; Wilson 1998). Depleted levels may increase the risk of colon and prostate cancers, heart disease, brain dysfunction, and birth defects (Ames 2000). </div> <div>  </div> <div> <B><U>Replacement Therapy</U></B> </div> <div>    In one study, vitamin B6 supplements (150 mg/day) reduced the severity of headache and dizziness but had no effect on nausea, vomiting, depression, or irritability (Villegas-Salas et al. 1997). Other researchers have also reported clinical improvement with doses of 40 mg/day of vitamin B6 (Bermond 1982). Neuropathology resulting from vitamin B6 deficiency should be treated with doses of 50 to 200 mg/day (Covington 1999). Dietary deficiency usually responds to doses of 10 to 20 mg/day. Doses should be tailored to account for the patient's age, gender, clinical presentation, serum vitamin B6 levels, dietary habits, and medication regimen.</div> <div>     </div> <div> <I><B>Vitamin B9 (Folic Acid) </B></I></div> <div>   </div> <div> <B>Mechanism </B></div> <div>    Oral contraceptives can lower serum folate levels and reduce folate stores in the body (Li et al. 1995; Prasad et al. 1976; Shojania 1982). However, a recent study with 229 adolescent females on OCs (age 14 to 20 years) reported that oral contraceptive use was not associated with significantly lower serum or RBC folate levels (Green et al. 1998).</div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>    Women who stop taking oral contraceptives to conceive should be assessed to ensure they have adequate folate stores before becoming pregnant (Shojania 1982). Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.</div> <div>     </div> <div> <B>Replacement Therapy </B></div> <div>    The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum folate levels, age, gender, dietary habits, and medication regimen.</div> <div>     </div> <div> <I><B>Vitamin B12 (Cobalamin) </B></I></div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism </U></B></div> <div>   Studies have shown that oral contraceptives have either a minor impact or no impact on serum vitamin B12 levels; it is probably not significant enough to cause a deficiency (Kornberg et al. 1989; Seelig 1990; Shojania 1982). Several studies have found no significant effect of OCs on vitamin B12 status (Hjelt et al. 1985; Prasad et al. 1976).</div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia. </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div> <I><B>Vitamin C (Ascorbic Acid) </B></I></div> <div>  </div> <div> <B><U>Mechanism </U></B></div> <div>    Oral contraceptives reduce plasma, leukocyte, and platelet ascorbic acid levels (Nash et al. 1979; Rivers 1975; Webb 1980). This reduction may be due to increased ascorbic acid turnover in tissues (Weininger and King 1982). </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Patients with depleted levels of vitamin C may present with anemia, icterus, edema, lethargy, fatigue, fever, ecchymoses, hypotension, convulsions, gum disorders, tooth loss, emotional changes, and perifollicular hyperkeratotic papules (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). In addition, they may exhibit signs of poor wound healing, increased susceptibility to infection, and markedly defective collagen synthesis. Severe deficiency results in scurvy, which is potentially fatal (Carr and Frei 1999; National Research Council 1989; Wilson 1998). Scurvy involves degenerative changes in capillaries, bone, and connective tissue, resulting in clinical symptoms that include weakness, joint tenderness and swelling, and spontaneous hemorrhages (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). Patients with vitamin C deficiency may also be at increased risk of developing cataracts and heart disease (Ames 2000).</div> <div>  </div> <div> <B><U>Replacement Therapy </U></B></div> <div>    Treatment of scurvy requires doses between 300 and 1000 mg/day for adults (Covington 1999). Other recommendations range from the recommended dietary allowance (RDA) of 60 mg to 2000 mg/day for adults (Carr and Frei 1999; Wilson 1998). One study proposes that no adult receive more than 1000 mg/day because higher doses could cause nausea and diarrhea (Ausman 1999). To minimize the possibility of gastric upset, buffered and sustained-release vitamin C preparations are recommended. Specific doses account for the patient's age, gender, overall health status, dietary habits, and medication regimen. Smokers must consume 2 to 3 times more vitamin C than non-smokers (Ames 2000).</div> <div>  </div> <div> Zinc </div> <div> <B><U>  </U></B></div> <div> <B><U>Mechanism </U></B></div> <div>    Oral contraceptives reduce serum zinc levels (Dorea et al. 1982; Tyrer 1984). </div> <div>  </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000). </div> <div>     </div> <div> <B>Replacement Therapy </B></div> <div>    Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.</div> <div>  </div> <div> <B>References </B></div> <div>    Ahmed F, Bamji MS, Iyengar L. Effect of oral contraceptive agents on vitamin nutrition status. Am J Clin Nutr. 1975;28(6):606-615.</div> <bR> <div> Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.</div> <bR> <div> Ausman LM. Criteria and recommendations for vitamin C intake. Nutr Review. 1999;57(7):222-229.</div> <bR> <div> Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.</div> <bR> <div> Bermond P. Therapy of side effects of oral contraceptive agents with vitamin B6. Acta Vitaminol Enzymol. 1982;4(1-2):45-54.</div> <bR> <div> Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.</div> <bR> <div> Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.</div> <bR> <div> Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999;69:1086-1087.</div> <bR> <div> Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Dorea JG, Ferraz E, Queiroz EF. [Effects of anovulatory steroids on serum levels of zinc and copper]. Arch Latinoam Nutr. 1982;32(1):101-110.</div> <bR> <div> Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.</div> <bR> <div> Green TJ, Houghton LA, Donovan U, et al. Oral contraceptives did not affect biochemical folate indexes and homocysteine concentrations in adolescent females. J Am Diet Assoc. 1998;98:49-55.</div> <bR> <div> Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.</div> <bR> <div> Hjelt K, Brynskov J, Hippe E, Lundstrom P, Munck O. Oral contraceptives and the cobalamin (vitamin B12) metabolism. Acta Obstet Gynecol Scand. 1985;64(1):59-63.</div> <bR> <div> Kane FJ Jr. Evaluation of emotional reactions to oral contraceptive use. Am J Obstet Gynecol. 1976;126(8):968-972.</div> <bR> <div> Kornberg A, Segal R, Theitler J, et al. Folic acid deficiency, megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives. Isr J Med Sci. 1989;25(3):142-145.</div> <bR> <div> Li X, Ran J, Rao H. [Megaloblastic changes in cervical epithelium associated with oral contraceptives and changes after treatment with folic acid]. Chung Hua Fu Chan Ko Tsa Chih. 1995;30(7):410-413.</div> <bR> <div> Matsui MS, Rozovski SJ. Drug-nutrient interaction. Clin Ther. 1982;4(6):423-440.</div> <bR> <div> Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.</div> <bR> <div> Nash AL, Cornish EJ, Hain R. Metabolic effects of oral contraceptives containing 30 micrograms and 50 micrograms of oestrogen. Med J Aust. 1979;2(6):277-281.</div> <bR> <div> National Research Council, Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.</div> <bR> <div> Newman LJ, Lopez R, Cole HS, et al. Riboflavin deficiency in women taking oral contraceptive agents. Am J Clin Nutr. 1978;31(2):247-249.</div> <bR> <div> Olatunbosun DA, Adeniyi FA, Adadevoh BK. Effect of oral contraceptives on serum magnesium levels. Int J Fertil. 1974;19(4):224-226.</div> <bR> <div> Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.</div> <bR> <div> Prasad AS, Lei KY, Moghissi KS, et al. Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid. Am J Obstet Gynecol. 1976;125(8):1063-1069.</div> <bR> <div> Rivers JM. Oral contraceptives and ascorbic acid. Am J Clin Nutr. 1975;28(5):550-554.</div> <bR> <div> Seelig MS. Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment. Magnes Res. 1990;3(3):197-215.</div> <bR> <div> Seelig MS. Interrelationship of magnesium and estrogen in cardiovascular and bone disorders, eclampsia, migraine and premenstrual syndrome. J Am Coll Nutr. 1993;12(4):442-458.</div> <bR> <div> Shojania AM. Oral contraceptives: effect of folate and vitamin B12 metabolism. Can Med Assoc J. 1982;126(3):244-247.</div> <bR> <div> Slap GB. Oral contraceptives and depression: impact, prevalence and cause. J Adolesc Health Care. 1981;2(1):53-64.</div> <bR> <div> Stanton MF, Lowenstein FW. Serum magnesium in women during pregnancy, while taking contraceptives, and after menopause. J Am Coll Nutr. 1987;6(4):313-319.</div> <bR> <div> Tyrer LB. Nutrition and the pill. J Reprod Med. 1984;29(7 Suppl):547-550.</div> <bR> <div> Villegas-Salas E, Ponce de Leon R, Juarez-Perez, Grubb GS. Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive. Contraception. 1997;55(4):245-248.</div> <bR> <div> Webb JL. Nutritional effects of oral contraceptive use: a review. J Reprod Med. 1980;25(4):150-156.</div> <bR> <div> Weininger J, King JC. Effect of oral contraceptive agents on ascorbic acid metabolism in the rhesus monkey. Am J Clin Nutr. 1982;35(6):1408-1416.</div> <bR> <div> Wilson JD. Vitamin deficiency and excess. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:483-485.</div> <div>  </div> <div> <B>  </B></div> <bR> <div> <B> <A NAME="12__osteoporosis_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>12  Osteoporosis Medications </B></div> <div>  </div> <div> Bisphosphonate Derivatives </div> <div> Alendronate (Fosamax®) </div> <div>  </div> <div> <B><U>Depletions </U></B></div> <div> <B><U> </U></B></div> <div> Calcium; Phosphorus </div> <div> <B><U> </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>    Small decreases in calcium and phosphate may occur with these medications, particularly in patients with Paget's disease (O'Doherty et al. 1992; PDR 1998). Bisphosphonates also cause symptomatic hypocalcemia in prostate cancer patients with diffuse metastatic invasion of the skeleton (Adami 1997). </div> <div>    </div> <div> <B><U>Significance of Depletion </U></B></div> <div>    Calcium: Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998).</div> <bR> <div> Phosphorus: Although rare, suboptimal intake of phosphorus can lead to hypophosphatemia, which is associated with general debility characterized by muscle weakness, bone pain, paraesthesia, ataxia, acute respiratory failure, mental confusion, seizures, anorexia, anemia, increased susceptibility to infection, and even death (Cashman and Flynn 1999; Covington 1999). In chronic situations, patients with severely depleted phosphate levels below approximately 0.3 mmol/L may exhibit signs of rickets (children) or osteomalacia (adults) (Cashman and Flynn 1999).</div> <div>     </div> <div> <B>Replacement Therapy </B></div> <div>   Calcium: Daily calcium supplementation between 500 and 1000 mg has been used in clinical studies with alendronate (Fleisch 1997; Gonnelli et al. 1999; Pols et al. 1999). These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.</div> <bR> <div> Note: Calcium and other minerals should be taken at least two hours before or after alendronate administration to minimize interference with absorption of the drug (PDR 1998).</div> <bR> <div> Phosphorus: The recommended dietary allowance (RDA) for phosphorus ranges from 100 to 1250 mg/day depending on age (Cashman and Flynn 1999; Covington 1999). Doses for replacement therapy should be adjusted to reflect individual circumstances, including the patient's age, gender, clinical presentation, serum phosphate levels, dietary habits, and medication regimen.</div> <div>  </div> <div> <B>References </B></div> <div>   Adami S. Bisphosphonates in prostate carcinoma. Cancer. 1997;80(8 Suppl):1674-1679.</div> <bR> <div> Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Fleisch HA. Bisphosphonates: preclinical aspects and use in osteoporosis. Ann Med. 1997;29(1):55-62.</div> <bR> <div> Gonnelli S, Cepollaro C, Pondrelli C, et al. Bone turnover and the response to alendronate treatment in postmenopausal osteoporosis. Calcif Tissue Int. 1999;65(5):359-364.</div> <bR> <div> O'Doherty DP, Gertz BJ, Tindale W, et al. Effects of five daily 1 h infusions of alendronate on Paget's disease of bone. J Bone Miner Res. 1992;7(1):81-87.</div> <bR> <div> Physicians' Desk Reference, PDR. 52nd ed. Montvale, NJ: Medical Economics Company; 1998.</div> <bR> <div> Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Foxamax International Trial Study Group. Osteoporos Int. 1999;9(5):461-468. </div> <bR> <div> Potts JT. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2241.</div> <div>  </div> <div> <B><U> <A NAME="13_psychotherapeutic_medications_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>13.Psychotherapeutic Medications </U></B></div> <div>  </div> <div>  Phenothiazines </div> <div> Chlorpromazine (Thorazine®) </div> <div> Prochlorperazine (Compazine®; Compro®) </div> <div> Promethazine (Anergan®; Phenergan®) </div> <div> Trifluoperazine (Stelazine®) </div> <div> <B><U>     </U></B></div> <div> <B><U>Depletions </U></B></div> <div> <B><U> </U></B></div> <div> Coenzyme Q10 </div> <div> <B><U>  </U></B></div> <div> <B><U>Mechanism</U></B> </div> <div>    Cardiac toxicity is a potential side effect of phenothiazine treatment (Deglin et al. 1977; McGee and Alexander 1979). In vitro, phenothiazines inhibited CoQ10-NADH-oxidase and CoQ10-succinate dehydrogenase, two enzymes that are important for cardiac function because they donate electrons to CoQ10 in the mitochondria (Kishi et al. 1980). Inhibiting these enzymes disrupts mitochondrial function and may play a role in the development of cardiotoxic side effects associated with phenothiazines. </div> <div>      </div> <div> <B>Significance of Depletion </B></div> <div>    Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999). </div> <div>     </div> <div> <B>Replacement Therapy </B></div> <div>    Daily doses as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). The addition of low concentrations of CoQ10 reverses phenothiazine-induced inhibition of CoQ10-NADH-oxidase and CoQ10-succinate dehydrogenase (Chiba 1984; Kishi et al. 1980). CoQ10 treatment may prevent some of the cardiac side effects associated with phenothiazine treatment. More research is needed to confirm these effects. </div> <div>  </div> <div> <B>Vitamin B2 (Riboflavin) </B></div> <div> <B><U>  </U></B></div> <div> <B><U>Mechanism </U></B></div> <div> <B><U> </U></B>  Chlorpromazine promotes riboflavin excretion in animal and human studies (Pinto and Rivlin 1987). This could deplete riboflavin levels in nutritionally compromised patients. This effect has not been reported with promethazine. </div> <div>  </div> <div> <B>Significance of Depletion </B></div> <div>    Riboflavin deficiency usually occurs as a result of deficiencies in dietary protein and is associated with other B vitamin deficiencies (Covington 1999). Depleted levels of riboflavin affect carbohydrate and amino acid metabolism by interfering with enzyme systems involved in the production of ATP. Lack of an adequate supply of riboflavin disturbs several physiological and biochemical processes and results in retarded growth in infants and children (Covington 1999; Powers 1999). Symptoms include corneal vascularization, glossitis, cheilosis, seborrheic dermatitis, and impaired wound healing (Covington 1999). </div> <div>  </div> <div> <B>Replacement Therapy </B></div> <div>    Doses of 5 to 25 mg/day are recommended for the treatment of riboflavin deficiency (Covington 1999). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum riboflavin levels, age, gender, dietary habits, and medication regimen.</div> <div>  </div> <div> <B><U>Editorial Note</U></B> </div> <div> This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.</div> <div>   </div> <div> <B>References </B></div> <div>    Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.</div> <bR> <div> Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.</div> <bR> <div> Chiba M. A protective action of coenzyme Q10 on chlorpromazine-induced cell damage in the cultured rat myocardial cells. Jpn Heart J. 1984;25(1):127-137.</div> <bR> <div> Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.</div> <bR> <div> Deglin SM, Deglin JM, Chung EK. Drug-induced cardiovascular diseases. Drugs. 1977;14(1):29-40.</div> <bR> <div> Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993;1:88-92.</div> <bR> <div> Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.</div> <bR> <div> Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.</div> <bR> <div> Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.</div> <bR> <div> Kishi T, Makino K, Okamoto T, et al. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q. Biomedical and Clinical Aspects of Coenzyme Q. Yamamura Y, et al, eds. Elsevier/North-Holland Biomedical Press: Amsterdam. 1980;2:139-154.</div> <bR> <div> McGee JL, Alexander MR. Phenothiazine analgesia-fact or fantasy? Am J Hosp Pharm. 1979;36(5):633-640.</div> <bR> <div> Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.</div> <bR> <div> Nakamura R, Littarru GP, Folkers R, et al. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.</div> <bR> <div> Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.</div> <bR> <div> Pinto JT, Rivlin RS. Drugs that promote renal excretion of riboflavin. Drug Nutr Interact. 1987;5(3):143-151.</div> <bR> <div> Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.</div> <bR> <div> Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.</div> <bR> <div> Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.</div> <bR> <bR> <DIV ALIGN="LEFT"></DIV> <div>  <A NAME="caffeine"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A>Caffeine</div> <div> <B>by George E. Meinig, DDS, FACD</B></div> <div> Caffeine has a detrimental effect on one's calcium-phosphorus balance and on one's blood sugar. Some people drink weaker tea than coffee so they may not get quite as much caffeine, but most people drink more tea than coffee so it ends up the same. There is 100 to 150 mg. of caffeine in a 6 oz. cup of coffee, while tea is usually 60 to 75 mg. Coke (12 oz.) runs 40 to 72 mg., while 6 oz. of cocoa runs about 50 mg.</div> <div> Ernie Banks, star baseball player for the Chicago Cubs, was suffering so much from arthritis in his knees that he could barely stand. A nutritionist was consulted on recommendation of his friend, Billy Williams. He soon discovered Ernie was drinking tea in huge quantities. Hot, cold, iced, any way he could get it.</div> <div> This caused a severe calcium-phosphorus imbalance which is common to rheumatoid arthritis. The tannic acid in tea doesn't help much either. Tannin is used to cure leather and biting on a tea bag is a good way to stop a bleeding tooth extraction wound, but I don't think either of these goodies qualify it for a human beverage. Along with the detrimental effects to the calcium balance is a lowering of blood sugar. Also the University of Hawaii Nutrition Department found a serious depletion of vitamin B1 in tea and coffee consumers.</div> <div> My report on Ernie Banks didn't say whether he used sugar in his tea but most people use excessive amounts in order to make the stuff likable. Sugar, of course, compounds the calcium-phosphorus problem.</div> <div> Ernie's knees were well in 60 days with the switch to water instead of tea. Professional teams spare no expense on medical care and all sorts of fancy, expensive physical therapy equipment, but it is rare for them to consult a nutritionist. My observation of the eating habits of many athletes and their coaches makes me wonder why they don't recognize the potential improvement that could be attained in their athletic ability if they paid more attention to better feeding of their muscles and brains. Perhaps they too have fallen for all those television junk food ads by past athletes and think that is the way to become an "All American Boy."</div> <DIV ALIGN="LEFT"></DIV> <div> All information Copyright ©1997,1998, 1999, 2000, 2001 PPNF. All rights reserved.</div> <div> Contact The Price-Pottenger Nutrition Foundation at <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>info@price-pottenger.org</U></FONT> </div> <bR> <bR> <div> <B> <A NAME="the_aspartame_scandal_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>The Aspartame Scandal</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>by </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B><U>Betty Martini</U></B></FONT></div> <div> The Thalidomide of the 90’s is Aspartame, otherwise known as Equal, Nutrasweet or Spoonful.</div> <div> In May, 1992 an article in Flying Safety Magazine explained the dangers of this ubiquitous substance. Some people have triggered aspartame related disorders with doses as small as that carried in a single stick of chewing gum. This could mean a pilot who drinks diet sodas is more susceptible to flicker vertigo or to flicker-induced epileptic activity. It also means that all pilots are potential victims of sudden memory loss, dizziness during instrument flight and gradual loss of vision. Some pilots have experienced grand mal seizures in the cockpits of commercial airline flights and have lost medical certification to fly -- and with it their careers.</div> <div> The FDA has received more than 10,000 consumer complaints on Nutra-Poison. That’s 80% of all complaints about food additives, yet they remain comatose and have done nothing to alert the American consumer who assumes, since it’s so highly advertised, that it must be safe as mother’s milk.</div> <div> If you are using aspartame and have headaches, depression, slurred speech, loss of memory, fibromyalgia type symptoms, loss of sensation in lower legs or shooting pains, loss of equilibrium, vertigo, anxiety attacks, chronic fatigue, vision loss, floaters, retinal detachment, seizures, heart palpitations, etc., you have Aspartame Disease! Many physicians are diagnosing multiple sclerosis when in reality it is methanol toxicity which mimics MS. Get off this dangerous drug right away. MS is not a death sentence, but methanol toxicity is!</div> <div> Fifty-one percent of FDA approved drugs have serious risks and could cause adverse reactions that lead to severe or permanent disability or death. The Center for Disease Control, Johns Hopkins University and the New Jersey School of Medicine estimate that 80,000-120,000 Americans are killed by prescription drugs every year. That this atrocious holocaust persists has everything to do with money and nothing to do with public health. Monsanto reaps $2 billion per year from the Aspartame toxic bonanza. This can buy a lot of bureaucrats! Does FDA mean Fatal Drugs Allowed? The FDA works for industry, not citizens. FDA head Arthur Hayes overruled his own board of inquiry to approve aspartame and then went to work for their public relations firm. Federal attorney Sam Skinner was assigned to prosecute Searle for fraudulent tests in their application, but switched sides and went to work for Searle’s lawyers and the case died when the statute of limitations ran out. Honest FDA toxicologist, the late Dr. Adrian Gross, wrote to Senator Howard Metzenbaum: “The views of the FDA’s Center for Food Safety read like a script written for Abbott & Costello in the sense of their having perceptions inside-out and upside-down. ... FDA may have gone through the motions. ... such a ‘process’ or dance represents a farce and a mockery.”</div> <div> Aspartame is a molecule composed of three components: aspartic acid, phenylalanine and methanol. Methanol is wood alcohol that has killed or blinded thousands of skid row drunks. It converts into formaldehyde and formic acid (ant sting poison) in the gut. Formaldehyde, a deadly neurotoxin, is common embalming fluid, a Class A carcinogen. Phenylalanine is also neurotoxic when unaccompanied by the other amino acids in proteins. Aspartic acid causes brain lesions and neuroendocrine disorders in experimental animals. There are 92 documented symptoms including headaches, numbness, fatigue, blurred vision, heart palpitations, memory loss, dizziness, muscle spasms, weight gain, seizures, rashes, blindness, tachycardia, tinnitus, joint pain, nausea, depression , hearing loss, irritability, slurred speech, anxiety attacks, loss of taste, vertigo and insomnia.</div> <div> Nutrasweet is in about 9,000 foods and on every restaurant table for the same reasons tobacco is everywhere: Greed, Addiction and Profit! The NutraSweet Company and sister Searle, whose chemists discovered aspartame while testing an ulcer drug, are owned by Monsanto. If you are taking other medicine, consider possible reactions you may have. In 1969, Searle approached Dr. Harry Waisman to study the effects of aspartame on primates. Seven infant monkeys were fed the chemical in milk. One died after 300 days; five others had grand mal seizures. Searle deleted these findings when they submitted this study to the FDA! The best way to understand NutraSweet is to think of it as a minute dose of nerve gas that eradicates brain and nerve functions. Some diseases triggered by aspartame include brain tumors and other cancers, Alzheimers, multiple sclerosis, diabetes, epilepsy, mental retardation, fibromyalgia, lymphoma, Graves disease, birth defects, chronic fatigue syndrome, systemic lupus, Epstein Barr, Parkinsons and ... death!</div> <div> Researchers at Massachusetts Institute of Technology surveyed 80 people who suffered brain seizures after eating or drinking products with aspartame. Said the Community Nutrition Institute: “These 80 cases meet the FDA’s own definition of an imminent hazard to the public health, which requires the FDA to expeditiously remove a product from the market.”</div> <div> America is seeing a tremendous increase in seizures. Phenylalanine in aspartame lowers the seizure threshold in the brain and blocks serotonin production. Today our nation is swept by a rage of violence. Researchers attribute this in part to low brain serotonin levels inducing depression, rage and paranoia. So President Clinton, Diet Coke in hand, programs billions of dollars to buy penitentiaries for the paranoid. Fetal tissue cannot tolerate methanol and Dr. James Bowen calls NutraSweet instant birth control. The fetal placenta can concentrate phenylalanine and cause mental retardation. Aspartame tests on animals produced brain and mammary tumors. No wonder breast cancer is growing exponentially! During Operation Desert Storm truckloads of diet drinks cooked in the Arabian sun and at 86 degrees aspartame liberates methanol in the can! Thousands of service men and women returned home with chronic fatigue syndrome and weird toxic symptoms.</div> <div> On July 28, 1993 the National Soft Drink Association drafted a 30-page protest questioning the safety of aspartame in soft drinks. Then they found weight-conscious Americans would sip soda all day if it was sugarless, so they forgot their objections; nor did they tell us that aspartame makes you crave carbohydrates and so you gain weight. The formaldehyde stores in the fat cells, particularly on the hips and thighs. Drink diet soda, get fat now and later develop seizures, diabetes, blindness, Epstein Barr, MS, depression and death.</div> <div> Similarly, the American Diabetic Association, which now receives mega-funds from NutraSweet, ignored a 1987 abstract submitted by Dr. H. J. Roberts (world expert on aspartame and diabetic specialist) summarizing 58 diabetic aspartame reactors. He says: “I now advise all patients with diabetes and hypoglycemia to avoid aspartame products.” In his book Excitotoxins: The Taste that Kills, Russell Blaylock, MD, a neurosurgeon, says aspartame may trigger clinical diabetes! He says that excitotoxins such as NutraSweet literally stimulate neurons to death, causing brain damage of varying degrees. “What really concerns me about aspartame,” he says, “is its association with brain tumors as well as pancreatic, uterine and ovarian tumors. ... and that so many develop an Alzheimers-like syndrome with prolonged exposure.”</div> <div> NutraSweet/Equal/Spoonful are the deadliest toxins in our society because of their ubiquitous presence in thousands of foods, even vitamins, medicines, Kool Aid, Jell-O, diet foods and the packets on every restaurant table. We are dosed with millions of pounds every year. Every product containing aspartame should contain the following warning: Chemical Poison: Keep Out of Reach of Humans! Genocidal!</div> <div>  <A NAME="author_info"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><I>Betty Martini can be contacted at </I><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>bettym19@mindspring.com</U></FONT></div> <div> <I>Betty Martini's Web Page is</I> <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>http://www.dorway.com/betty</U></FONT> </div> <bR> <DIV ALIGN="LEFT"></DIV> <div> All information Copyright ©1997,1998, 1999, 2000, 2001 PPNF. All rights reserved.</div> <div> Contact The Price-Pottenger Nutrition Foundation at <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>info@price-pottenger.org</U></FONT> </div> <bR> <bR> <bR> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="596" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP HEIGHT= 55 WIDTH="592"><div> <B> <A NAME="death_by_medicine_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Death by Medicine </B></div> <div> By Gary Null, PhD; Carolyn Dean MD, ND; Martin Feldman, MD; Debora Rasio, MD; and Dorothy Smith, PhD<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> </tD> </tR> <tR> <tD VALIGN=TOP HEIGHT= 590 WIDTH="592"><div> Something is wrong when regulatory agencies pretend that vitamins are dangerous, yet ignore published statistics showing that government-sanctioned medicine is the real hazard. </div> <div> Until now, Life Extension could cite only isolated statistics to make its case about the dangers of conventional medicine. No one had ever analyzed and combined ALL of the published literature dealing with injuries and deaths caused by government-protected medicine. That has now changed. </div> <div> A group of researchers meticulously reviewed the statistical evidence and their findings are absolutely shocking.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >4</FONT> These researchers have authored a paper titled “Death by Medicine” that presents compelling evidence that today's system frequently causes more harm than good. </div> <div> This fully referenced report shows the number of people having in-hospital, adverse reactions to prescribed drugs to be 2.2 million per year. The number of unnecessary antibiotics prescribed annually for viral infections is 20 million per year. The number of unnecessary medical and surgical procedures performed annually is 7.5 million per year. The number of people exposed to unnecessary hospitalization annually is 8.9 million per year.</div> <div> The most stunning statistic, however, is that the total number of deaths caused by conventional medicine is an astounding 783,936 per year. It is now evident that the American medical system is the leading cause of death and injury in the US. (By contrast, the number of deaths attributable to heart disease in 2001 was 699,697, while the number of deaths attributable to cancer was 553,251.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >5</FONT>) </div> <div> We had intended to publish the entire text of “Death By Medicine” in this month's issue. The article uncovered so many problems with conventional medicine however, that it became too long to fit within these pages. We have instead put it on our website (www.lef.org).</div> <div> We placed this article on our website to memorialize the failure of the American medical system. By exposing these gruesome statistics in painstaking detail, we provide a basis for competent and compassionate medical professionals to recognize the inadequacies of today's system and at least attempt to institute meaningful reforms.</div> </tD> </tR> </TABLE></div> <div> Natural medicine is under siege, as pharmaceutical company lobbyists urge lawmakers to deprive Americans of the benefits of dietary supplements. Drug-company front groups have launched slanderous media campaigns to discredit the value of healthy lifestyles. The FDA continues to interfere with those who offer natural products that compete with prescription drugs. </div> <div> These attacks against natural medicine obscure a lethal problem that until now was buried in thousands of pages of scientific text. In response to these baseless challenges to natural medicine, the Nutrition Institute of America commissioned an independent review of the quality of “government-approved” medicine. The startling findings from this meticulous study indicate that conventional medicine is “the leading cause of death” in the United States . </div> <div> The Nutrition Institute of America is a nonprofit organization that has sponsored independent research for the past 30 years. To support its bold claim that conventional medicine is America 's number-one killer, the Nutritional Institute of America mandated that every “count” in this “indictment” of US medicine be validated by published, peer-reviewed scientific studies. </div> <div> What you are about to read is a stunning compilation of facts that documents that those who seek to abolish consumer access to natural therapies are misleading the public. Over 700,000 Americans die each year at the hands of government-sanctioned medicine, while the FDA and other government agencies pretend to protect the public by harassing those who offer safe alternatives. </div> <div> A definitive review of medical peer-reviewed journals and government health statistics shows that American medicine frequently causes more harm than good. </div> <div> Each year approximately 2.2 million US hospital patients experience adverse drug reactions (ADRs) to prescribed medications.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(1)</FONT> In 1995, Dr. Richard Besser of the federal Centers for Disease Control and Prevention (CDC) estimated the number of unnecessary antibiotics prescribed annually for viral infections to be 20 million; in 2003, Dr. Besser spoke in terms of tens of millions of unnecessary antibiotics prescribed annually.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(2, 2a)</FONT> Approximately 7.5 million unnecessary medical and surgical procedures are performed annually in the US,<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(3)</FONT> while approximately 8.9 million Americans are hospitalized unnecessarily.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(4)</FONT> </div> <div> As shown in the following table, the estimated total number of iatrogenic deaths-that is, deaths induced inadvertently by a physician or surgeon or by medical treatment or diagnostic procedures- in the US annually is 783,936. It is evident that the American medical system is itself the leading cause of death and injury in the US . By comparison, approximately 699,697 Americans died of heart in 2001, while 553,251 died of cancer.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(5)</FONT></div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="590" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 19 ><NOBR><div> Table 1: Estimated Annual Mortality and Economic Cost of Medical Intervention</div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 248 ><NOBR><div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="579" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 WIDTH="197"><div> <B>Condition</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="72"><div> <B>Deaths</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> <B>Cost</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="195"><div> <B>Author</B></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 ><NOBR><div> Adverse Drug Reactions </div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> 106,000</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> $12 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="195"><div> Lazarou<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(1)</FONT>, Suh <FONT SIZE="1" COLOR="#003366" FACE="Arial" >(49)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="197"><div> Medical error </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="72"><div> 98,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> $2 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="195"><div> IOM<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(6)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="197"><div> Bedsores </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="72"><div> 115,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> $55 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> Xakellis<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(7)</FONT>, Barczak <FONT SIZE="1" COLOR="#003366" FACE="Arial" >(8)</FONT></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="197"><div> Infection </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="72"><div> 88,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> $5 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> Weinstein<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(9)</FONT>, MMWR <FONT SIZE="1" COLOR="#003366" FACE="Arial" >(10)</FONT></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="197"><div> Malnutrition </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> 108,800</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> -----------</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="195"><div> Nurses Coalition<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(11)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="197"><div> Outpatients </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> 199,000</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> $77 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> Starfield<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(12)</FONT>, Weingart<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(112)</FONT></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 ><NOBR><div> Unnecessary Procedures </div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="72"><div> 37,136</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> $122 billion</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="195"><div> HCUP<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(3,13)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="197"><div> Surgery-Related </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="72"><div> 32,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="102"><div> $9 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="195"><div> AHRQ<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(85)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 WIDTH="197"><div> <B>Total</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> <B>783,936</B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> <B>$282 billion</B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="195"><div>  </div> </tD> </tR> </TABLE></div> <bR> </NOBR></tD> </tR> </TABLE></div> <div> Using Leape's 1997 medical and drug error rate of 3 million<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(14)</FONT> multiplied by the 14% fatality rate he used in 1994<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16)</FONT> produces an annual death rate of 420,000 for drug errors and medical errors combined. Using this number instead of Lazorou's 106,000 drug errors and the Institute of Medicine 's (IOM) estimated 98,000 annual medical errors would add another 216,000 deaths, for a total of 999,936 deaths annually.</div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="590" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 19 ><NOBR><div> Table 2: Estimated Annual Mortality and Economic Cost of Medical Intervention</div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 226 ><NOBR><div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="579" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 WIDTH="199"><div> <B>Condition</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="73"><div> <B>Deaths</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="97"><div> <B>Cost</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="197"><div> <B>Author</B></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="199"><div> ADR/med error </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> 420,000</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> $200 billion</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="197"><div> Leape<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(14)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="199"><div> Bedsores </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="73"><div> 115,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="97"><div> $55 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> Xakellis<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(7)</FONT>, Barczak <FONT SIZE="1" COLOR="#003366" FACE="Arial" >(8)</FONT></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="199"><div> Infection </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="73"><div> 88,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="97"><div> $5 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> Weinstein<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(9)</FONT>, MMWR <FONT SIZE="1" COLOR="#003366" FACE="Arial" >(10)</FONT></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="199"><div> Malnutrition </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> 108,800</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="97"><div> -----------</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="197"><div> Nurses Coalition<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(11)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="199"><div> Outpatients </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> 199,000</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="97"><div> $77 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> Starfield<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(12)</FONT>, Weingart<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(112)</FONT></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 ><NOBR><div> Unnecessary Procedures </div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="73"><div> 37,136</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> $122 billion</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="197"><div> HCUP<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(3,13)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="199"><div> Surgery-Related </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="73"><div> 32,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="97"><div> $9 billion</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="197"><div> AHRQ<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(85)</FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 WIDTH="199"><div> <B>Total</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> <B>999,936 </B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="97"><div>  </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="197"><div>  </div> </tD> </tR> </TABLE></div> <bR> </NOBR></tD> </tR> </TABLE></div> <div> The enumerating of unnecessary medical events is very important in our analysis. Any invasive, unnecessary medical procedure must be considered as part of the larger iatrogenic picture. Unfortunately, cause and effect go unmonitored. The figures on unnecessary events represent people who are thrust into a dangerous health care system. Each of these 16.4 million lives is being affected in ways that could have fatal consequences. Simply entering a hospital could result in the following:</div> <div> In 16.4 million people, a 2.1% chance (affecting 186,000) of a serious adverse drug reaction<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(1)</FONT> </div> <div> In 16.4 million people, a 5-6% chance (affecting 489,500) of acquiring a nosocomial infection<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(9)</FONT> </div> <div> In16.4 million people, a 4-36% chance (affecting 1.78 million) of having an iatrogenic injury (medical error and adverse drug reactions).<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16)</FONT> </div> <div> In 16.4 million people, a 17% chance (affecting 1.3 million) of a procedure error.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(40)</FONT> </div> <div> These statistics represent a one-year time span. Working with the most conservative figures from our statistics, we project the following 10-year death rates.</div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="590" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 19 ><NOBR><div> Table 3: Estimated 10-Year Death Rates from Medical Intervention</div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 252 ><NOBR><div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="579" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 WIDTH="218"><div> <B>Condition</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> <B>10-Year Deaths </B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> <B>Author</B></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 ><NOBR><div> Adverse Drug Reaction</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 1.06 million </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (1)</div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 21 WIDTH="218"><div> Medical error</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 0.98 million</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (6)<FONT SIZE="3" COLOR="#003366" FACE="Arial" > </FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="218"><div> Bedsores</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 1.15 million</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (7,8)</div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="218"><div> Nosocomial Infection</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 0.88 million</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (9,10)</div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 21 WIDTH="218"><div> Malnutrition</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 1.09 million</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (11)<FONT SIZE="3" COLOR="#003366" FACE="Arial" > </FONT></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="218"><div> Outpatients</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 1.99 million</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (12, 112)</div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 ><NOBR><div> Unnecessary Procedures</div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 371,360</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (3,13)</div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="218"><div> Surgery-related </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> 320,000</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div> (85)</div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 WIDTH="218"><div> <B>Total</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="276"><div> <B>7,841,360</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="75"><div>  </div> </tD> </tR> </TABLE></div> <bR> </NOBR></tD> </tR> </TABLE></div> <div> Our estimated 10-year total of 7.8 million iatrogenic deaths is more than all the casualties from all the wars fought by the US throughout its entire history. </div> <div> Our projected figures for unnecessary medical events occurring over a 10-year period also are dramatic.</div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="590" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 19 WIDTH="586"><div> Table 4: Estimated 10-Year Unnecessary Medical Events</div> </tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 116 ><NOBR><div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="578" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 ><NOBR><div> <B>Unnecessary Events</B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> <B>10-year Number</B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF><NOBR><div> <B>Iatrogenic Events</B></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="214"><div> Hospitalization</div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="169"><div> 89 million<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(4)</FONT></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="185"><div> 17 million </div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 19 WIDTH="214"><div> Procedures </div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="169"><div> 75 million<FONT SIZE="1" COLOR="#003366" FACE="Arial" >(3)</FONT></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="185"><div> 15 million </div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#FFFFFF HEIGHT= 20 WIDTH="214"><div> <B>Total</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="169"><div> <B>164 million</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#FFFFFF WIDTH="185"><div>  </div> </tD> </tR> </TABLE></div> <bR> </NOBR></tD> </tR> </TABLE></div> <div> These figures show that an estimated 164 million people-more than half of the total US population-receive unneeded medical treatment over the course of a decade.</div> <div> <B>INTRODUCTION</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Never before have the complete statistics on the multiple causes of iatrogenesis been combined in one article. Medical science amasses tens of thousands of papers annually, each representing a tiny fragment of the whole picture. To look at only one piece and try to understand the benefits and risks is like standing an inch away from an elephant and trying to describe everything about it. You have to step back to see the big picture, as we have done here. Each specialty, each division of medicine keeps its own records and data on morbidity and mortality. We have now completed the painstaking work of reviewing thousands of studies and putting pieces of the puzzle together.</div> <div> <B>Is American Medicine Working?</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> US health care spending reached $1.6 trillion in 2003, representing 14% of the nation's gross national product.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(15)</FONT> Considering this enormous expenditure, we should have the best medicine in the world. We should be preventing and reversing disease, and doing minimal harm. Careful and objective review, however, shows we are doing the opposite. Because of the extraordinarily narrow, technologically driven context in which contemporary medicine examines the human condition, we are completely missing the larger picture. </div> <div> Medicine is not taking into consideration the following critically important aspects of a healthy human organism: <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(a)</FONT> stress and how it adversely affects the immune system and life processes; <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(b)</FONT> insufficient exercise; <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(c)</FONT> excessive caloric intake; <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(d)</FONT> highly processed and denatured foods grown in denatured and chemically damaged soil; and <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(e)</FONT> exposure to tens of thousands of environmental toxins. Instead of minimizing these disease-causing factors, we cause more illness through medical technology, diagnostic testing, overuse of medical and surgical procedures, and overuse of pharmaceutical drugs. The huge disservice of this therapeutic strategy is the result of little effort or money being spent on preventing disease.</div> <div> <B>Underreporting of Iatrogenic Events</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> As few as 5% and no more than 20% of iatrogenic acts are ever reported.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16,24,25,33,34)</FONT> This implies that if medical errors were completely and accurately reported, we would have an annual iatrogenic death toll much higher than 783,936. In 1994, Leape said his figure of 180,000 medical mistakes resulting in death annually was equivalent to three jumbo-jet crashes every two days.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16)</FONT> Our considerably higher figure is equivalent to six jumbo jets are falling out of the sky each day. </div> <div> What we must deduce from this report is that medicine is in need of complete and total reform-from the curriculum in medical schools to protecting patients from excessive medical intervention. It is obvious that we cannot change anything if we are not honest about what needs to be changed. This report simply shows the degree to which change is required. </div> <div> We are fully aware of what stands in the way of change: powerful pharmaceutical and medical technology companies, along with other powerful groups with enormous vested interests in the business of medicine. They fund medical research, support medical schools and hospitals, and advertise in medical journals. With deep pockets, they entice scientists and academics to support their efforts. Such funding can sway the balance of opinion from professional caution to uncritical acceptance of new therapies and drugs. You have only to look at the people who make up the hospital, medical, and government health advisory boards to see conflicts of interest. The public is mostly unaware of these interlocking interests. </div> <div> For example, a 2003 study found that nearly half of medical school faculty who serve on institutional review boards <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(IRB)</FONT> to advise on clinical trial research also serve as consultants to the pharmaceutical industry.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(17)</FONT> The study authors were concerned that such representation could cause potential conflicts of interest. A news release by Dr. Erik Campbell, the lead author, said, "Our previous research with faculty has shown us that ties to industry can affect scientific behavior, leading to such things as trade secrecy and delays in publishing research. It's possible that similar relationships with companies could affect IRB members' activities and attitudes.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(18)</FONT></div> <div> <B>Medical Ethics and Conflict of Interest in Scientific Medicine </B></div> <div> Jonathan Quick, director of essential drugs and medicines policy for the World Health Organization (WHO), wrote in a recent WHO bulletin: "If clinical trials become a commercial venture in which self-interest overrules public interest and desire overrules science, then the social contract which allows research on human subjects in return for medical advances is broken."<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(19)</FONT> </div> <div> As former editor of the <I>New England Journal of Medicine </I>, Dr. Marcia Angell struggled to bring greater attention to the problem of commercializing scientific research. In her outgoing editorial entitled “ Is Academic Medicine for Sale?” Angell said that growing conflicts of interest are tainting science and called for stronger restrictions on pharmaceutical stock ownership and other financial incentives for researchers:<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(20)</FONT> “When the boundaries between industry and academic medicine become as blurred as they are now, the business goals of industry influence the mission of medical schools in multiple ways.” She did not discount the benefits of research but said a Faustian bargain now existed between medical schools and the pharmaceutical industry. </div> <div> Angell left the <I>New England Journal </I>in June 2000. In June 2002, the <I>New England Journal of Medicine </I>announced that it would accept journalists who accept money from drug companies because it was too difficult to find ones who have no ties. Another former editor of the journal, Dr. Jerome Kassirer, said that was not the case and that plenty of researchers are available who do not work for drug companies.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(21)</FONT> According to an ABC news report, pharmaceutical companies spend over $2 billion a year on over 314,000 events attended by doctors. </div> <div> The ABC news report also noted that a survey of clinical trials revealed that when a drug company funds a study, there is a 90% chance that the drug will be perceived as effective whereas a non-drug-company-funded study will show favorable results only 50% of the time. It appears that money can't buy you love but it can buy any "scientific" result desired. </div> <div> Cynthia Crossen, a staffer for the Wall Street Journal, i n 1996 published <I>Tainted Truth </I>: <I>The Manipulation of Fact in America </I>, a book about the widespread practice of lying with statistics.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(22)</FONT> Commenting on the state of scientific research, she wrote: “The road to hell was paved with the flood of corporate research dollars that eagerly filled gaps left by slashed government research funding.” Her data on financial involvement showed that in l981 the drug industry “gave” $292 million to colleges and universities for research. By l991, this figure had risen to $2.1 billion</div> <div> Dr. Lucian L. Leape opened medicine's Pandora's box in his 1994 paper, “Error in Medicine,” which appeared in the <I>Journal of the American Medical Association </I><FONT SIZE="1" COLOR="#000000" FACE="Arial" >(JAMA)</FONT>.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16)</FONT> He found that Schimmel reported in 1964 that 20% of hospital patients suffered iatrogenic injury, with a 20% fatality rate. In 1981 Steel reported that 36% of hospitalized patients experienced iatrogenesis with a 25% fatality rate, and adverse drug reactions were involved in 50% of the injuries. In 1991, Bedell reported that 64% of acute heart attacks in one hospital were preventable and were mostly due to adverse drug reactions. </div> <div> Leape focused on the “Harvard Medical Practice Study” published in 1991, <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16a)</FONT> which found a 4% iatrogenic injury rate for patients, with a 14% fatality rate, in 1984 in New York State. From the 98,609 patients injured and the 14% fatality rate, he estimated that in the entire U.S. 180,000 people die each year partly as a result of iatrogenic injury. </div> <div> Why Leape chose to use the much lower figure of 4% injury for his analysis remains in question. Using instead the average of the rates found in the three studies he cites <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(36%, 20%, and 4%)</FONT> would have produced a 20% medical error rate. The number of iatrogenic deaths using an average rate of injury and his 14% fatality rate would be 1,189,576. </div> <div> Leape acknowledged that the literature on medical errors is sparse and represents only the tip of the iceberg, noting that when errors are specifically sought out, reported rates are “distressingly high.” He cited several autopsy studies with rates as high as 35-40% of missed diagnoses causing death. He also noted that an intensive care unit reported an average of 1.7 errors per day per patient, and 29% of those errors were potentially serious or fatal. </div> <div> Leape calculated the error rate in the intensive care unit study. First, he found that each patient had an average of 178 “activities” (staff/procedure/medical interactions) a day, of which 1.7 were errors, which means a 1% failure rate. This may not seem like much, but Leape cited industry standards showing that in aviation, a 0.1% failure rate would mean two unsafe plane landings per day at Chicago's O'Hare International Airport; in the US Postal Service, a 0.1% failure rate would mean 16,000 pieces of lost mail every hour; and in the banking industry, a 0.1% failure rate would mean 32,000 bank checks deducted from the wrong bank account. </div> <div> In trying to determine why there are so many medical errors, Leape acknowledged the lack of reporting of medical errors. Medical errors occur in thousands of different locations and are perceived as isolated and unusual events. But the most important reason that the problem of medical errors is unrecognized and growing, according to Leape, is that doctors and nurses are unequipped to deal with human error because of the culture of medical training and practice. Doctors are taught that mistakes are unacceptable. Medical mistakes are therefore viewed as a failure of character and any error equals negligence. No one is taught what to do when medical errors do occur. Leape cites McIntyre and Popper, who said the “infallibility model” of medicine leads to intellectual dishonesty with a need to cover up mistakes rather than admit them. There are no Grand Rounds on medical errors, no sharing of failures among doctors, and no one to support them emotionally when their error harms a patient. </div> <div> Leape hoped his paper would encourage medical practitioners “to fundamentally change the way they think about errors and why they occur.” It has been almost a decade since this groundbreaking work, but the mistakes continue to soar. </div> <div> In 1995, a <I>JAMA </I>report noted, "Over a million patients are injured in US hospitals each year, and approximately 280,000 die annually as a result of these injuries. Therefore, the iatrogenic death rate dwarfs the annual automobile accident mortality rate of 45,000 and accounts for more deaths than all other accidents combined."<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(23)</FONT> </div> <div> At a 1997 press conference, Leape released a nationwide poll on patient iatrogenesis conducted by the National Patient Safety Foundation (NPSF), which is sponsored by the American Medical Association <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(AMA)</FONT>. Leape is a founding member of NPSF. The survey found that more than 100 million Americans have been affected directly or indirectly by a medical mistake. Forty-two percent were affected directly and 84% personally knew of someone who had experienced a medical mistake.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(14)</FONT> </div> <div> At this press conference, Leape updated his 1994 statistics, noting that as of 1997, medical errors in inpatient hospital settings nationwide could be as high as 3 million and could cost as much as $200 billion . Leape used a 14% fatality rate to determine a medical error death rate of 180,000 in 1994.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16)</FONT> In 1997, using Leape's base number of 3 million errors, the annual death rate could be as high as 420,000 for hospital inpatients alone. </div> <div> ONLY A FRACTION OF MEDICAL ERRORS ARE REPORTED </div> <div> In 1994, Leape said he was well aware that medical errors were not being reported.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(16)</FONT> A study conducted in two obstetrical units in the UK found that only about one-quarter of adverse incidents were ever reported, to protect staff, preserve reputations, or for fear of reprisals, including lawsuits.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(24)</FONT>. An analysis by Wald and Shojania found that only 1.5% of all adverse events result in an incident report, and only 6% of adverse drug events are identified properly. The authors learned that the American College of Surgeons estimates that surgical incident reports routinely capture only 5-30% of adverse events. In one study, only 20% of surgical complications resulted in discussion at morbidity and mortality rounds.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(25)</FONT> From these studies, it appears that all the statistics gathered on medical errors may substantially underestimate the number of adverse drug and medical therapy incidents. They also suggest that our statistics concerning mortality resulting from medical errors may be in fact be conservative figures. </div> <div> An article in <I>Psychiatric Times </I>(April 2000) outlines the stakes involved in reporting medical errors.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(26)</FONT> The authors found that the public is fearful of suffering a fatal medical error, and doctors are afraid they will be sued if they report an error. This brings up the obvious question: who is reporting medical errors? Usually it is the patient or the patient's surviving family. If no one notices the error, it is never reported. Janet Heinrich, an associate director at the U.S. General Accounting Office responsible for health financing and public health issues, testified before a House subcommittee hearing on medical errors that "the full magnitude of their threat to the American public is unknown” and "gathering valid and useful information about adverse events is extremely difficult." She acknowledged that the fear of being blamed, and the potential for legal liability, played key roles in the underreporting of errors. The <I>Psychiatric Times </I>noted that the AMA strongly opposes mandatory reporting of medical errors.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(26)</FONT> If doctors are not reporting, what about nurses? A survey of nurses found that they also fail to report medical mistakes for fear of retaliation.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(27)</FONT> </div> <div> Standard medical pharmacology texts admit that relatively few doctors ever report adverse drug reactions to the FDA.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(28)</FONT> The reasons range from not knowing such a reporting system exists to fear of being sued.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(29)</FONT> Yet the public depends on this tremendously flawed system of voluntary reporting by doctors to know whether a drug or a medical intervention is harmful. </div> <div> Pharmacology texts also will tell doctors how hard it is to separate drug side effects from disease symptoms. Treatment failure is most often attributed to the disease and not the drug or doctor. Doctors are warned, “Probably nowhere else in professional life are mistakes so easily hidden, even from ourselves.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(30)</FONT> It may be hard to accept, but it is not difficult to understand why only 1 in 20 side effects is reported to either hospital administrators or the FDA.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(31, 31a)</FONT> </div> <div> If hospitals admitted to the actual number of errors for which they are responsible, which is about 20 times what is reported, they would come under intense scrutiny.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(32)</FONT> Jerry Phillips, associate director of the FDA's Office of Post Marketing Drug Risk Assessment, confirms this number. “In the broader area of adverse drug reaction data, the 250,000 reports received annually probably represent only 5% of the actual reactions that occur.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(33)</FONT> Dr. Jay Cohen, who has extensively researched adverse drug reactions, notes that because only 5% of adverse drug reactions are reported, there are in fact 5 million medication reactions each year.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(34)</FONT> </div> <div> A 2003 survey is all the more distressing because there seems to be no improvement in error reporting, even with all the attention given to this topic. Dr. Dorothea Wild surveyed medical residents at a community hospital in Connecticut and found that only half were aware that the hospital had a medical error-reporting system, and that the vast majority did not use it at all. Dr. Wild says this does not bode well for the future. If doctors don't learn error reporting in their training, they will never use it. Wild adds that error reporting is the first step in locating the gaps in the medical system and fixing them. Not even that first step has been taken to date.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(35)</FONT> </div> <div> PUBLIC SUGGESTIONS ON IATROGENESIS </div> <div> In a telephone survey, 1,207 adults ranked the effectiveness of the following measures in reducing preventable medical errors that result in serious harm.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(36)</FONT> (Following each measure is the percentage of respondents who ranked the measure as “very effective.”) </div> <div> giving doctors more time to spend with patients (78%) </div> <div> requiring hospitals to develop systems to avoid medical errors (74%) </div> <div> better training of health professionals (73%) </div> <div> using only doctors specially trained in intensive care medicine on intensive care units (73%) </div> <div> requiring hospitals to report all serious medical errors to a state agency (71%) </div> <div> increasing the number of hospital nurses (69%) </div> <div> reducing the work hours of doctors in training to avoid fatigue (66%) </div> <div> encouraging hospitals to voluntarily report serious medical errors to a state agency (62%). </div> <div> DRUG IATROGENESIS </div> <div> Prescription drugs constitute the major treatment modality of scientific medicine. With the discovery of the “germ theory,” medical scientists convinced the public that infectious organisms were the cause of illness. Finding the “cure” for these infections proved much harder than anyone imagined. From the beginning, chemical drugs promised much more than they delivered. But far beyond not working, the drugs also caused incalculable side effects. The drugs themselves, even when properly prescribed, have side effects that can be fatal, as Lazarou's study<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(1)</FONT> showed. But human error can make the situation even worse. </div> <div> Medication Errors </div> <div> A survey of a 1992 national pharmacy database found a total of 429,827 medication errors from 1,081 hospitals. Medication errors occurred in 5.22% of patients admitted to these hospitals each year. The authors concluded that at least 90,895 patients annually were harmed by medication errors in the US as a whole.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(37)</FONT> </div> <div> A 2002 study shows that 20% of hospital medications for patients had dosage errors. Nearly 40% of these errors were considered potentially harmful to the patient. In a typical 300-patient hospital, the number of errors per day was 40.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(38)</FONT> </div> <div> Problems involving patients' medications were even higher the following year. The error rate intercepted by pharmacists in this study was 24%, making the potential minimum number of patients harmed by prescription drugs 417,908.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(39)</FONT> </div> <div> <B>Recent Adverse Drug Reactions </B></div> <div> More-recent studies on adverse drug reactions show that the figures from 1994 published in Lazarou's 1998 <I>JAMA </I>article may be increasing. A 2003 study followed 400 patients after discharge from a tertiary care hospital setting (requiring highly specialized skills, technology, or support services). Seventy-six patients (19%) had adverse events. Adverse drug events were the most common, at 66% of all events. The next most common event was procedure-related injuries, at 17%.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(40)</FONT> </div> <div> In a <I>New England Journal of Medicine </I>study, an alarming one in four patients suffered observable side effects from the more than 3.34 billion prescription drugs filled in 2002.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(41)</FONT> One of the doctors who produced the study was interviewed by Reuters and commented, "With these 10-minute appointments, it's hard for the doctor to get into whether the symptoms are bothering the patients."<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(42)</FONT> William Tierney, who editorialized on the <I>New England Journal </I>study, said “… given the increasing number of powerful drugs available to care for the aging population, the problem will only get worse.” The drugs with the worst record of side effects were selective serotonin reuptake inhibitors ( SSRIs), nonsteroidal anti-inflammatory drugs (NSAIDs), and calcium-channel blockers. Reuters also reported that prior research has suggested that nearly 5% of hospital admissions (over 1 million per year) are the result of drug side effects. But most of the cases are not documented as such. The study found that one of the reasons for this failure is that in nearly two-thirds of the cases, doctors could not diagnose drug side effects or the side effects persisted because the doctor failed to heed the warning signs.</div> <bR> <div> <B>Medicating Our Feelings </B></div> <div> Patients seeking a more joyful existence and relief from worry, stress, and anxiety often fall victim to the messages endlessly displayed on TV and billboards. Often, instead of gaining relief, they fall victim to the myriad iatrogenic side effects of antidepressant medication. </div> <div> Moreover, a whole generation of antidepressant users has been created from young people growing up on Ritalin. Medicating youth and modifying their emotions must have some impact on how they learn to deal with their feelings. They learn to equate coping with drugs rather than with their inner resources. As adults, these medicated youth reach for alcohol, drugs, or even street drugs to cope. According to <I>JAMA </I>, “Ritalin acts much like cocaine.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(43)</FONT> Today's marketing of mood-modifying drugs such as Prozac and Zoloft ® makes them not only socially acceptable but almost a necessity in today's stressful world.</div> <div> <B>Television Diagnosis </B></div> <div> To reach the widest audience possible, drug companies are no longer just targeting medical doctors with their marketing of antidepressants. By 1995, drug companies had tripled the amount of money allotted to direct advertising of prescription drugs to consumers. The majority of this money is spent on seductive television ads. From 1996 to 2000, spending rose from $791 million to nearly $2.5 billion.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(44)</FONT> This $2.5 billion represents only 15% of the total pharmaceutical advertising budget. While the drug companies maintain that direct-to-consumer advertising is educational, Dr. Sidney M. Wolfe of the Public Citizen Health Research Group in Washington, DC, argues that the public often is misinformed about these ads.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(45)</FONT> People want what they see on television and are told to go to their doctors for a prescription. Doctors in private practice either acquiesce to their patients' demands for these drugs or spend valuable time trying to talk patients out of unnecessary drugs. Dr. Wolfe remarks that one important study found that people mistakenly believe that the “FDA reviews all ads before they are released and allows only the safest and most effective drugs to be promoted directly to the public.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(46)</FONT></div> <div> How Do We Know Drugs Are Safe?</div> <div> Another aspect of scientific medicine that the public takes for granted is the testing of new drugs. Drugs generally are tested on individuals who are fairly healthy and not on other medications that could interfere with findings. But when these new drugs are declared “safe” and enter the drug prescription books, they are naturally going to be used by people who are on a variety of other medications and have a lot of other health problems. Then a new phase of drug testing called “post-approval” comes into play, which is the documentation of side effects once drugs hit the market. In one very telling report, the federal government's General Accounting Office "found that of the 198 drugs approved by the FDA between 1976 and 1985... 102 (or 51.5%) had serious post-approval risks... the serious post-approval risks (included) heart failure, myocardial infarction, anaphylaxis, respiratory depression and arrest, seizures, kidney and liver failure, severe blood disorders, birth defects and fetal toxicity, and blindness."<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(47)</FONT> </div> <div> NBC Television's investigative show “Dateline” wondered if your doctor is moonlighting as a drug company representative. After a yearlong investigation, NBC reported that because doctors can legally prescribe any drug to any patient for any condition, drug companies heavily promote "off label" and frequently inappropriate and untested uses of these medications, even though these drugs are approved only for the specific indications for which they have been tested.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(48)</FONT> </div> <div> The leading causes of adverse drug reactions are antibiotics <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(17%)</FONT>, cardiovascular drugs <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(17%)</FONT>, chemotherapy <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(15%)</FONT>, and analgesics and anti-inflammatory agents (15%).<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(49)</FONT> </div> <div> Specific Drug Iatrogenesis: Antibiotics</div> <div> According to William Agger, MD, director of microbiology and chief of infectious disease at Gundersen Lutheran Medical Center in La Crosse, WI, 30 million pounds of antibiotics are used in America each year.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(50)</FONT> Of this amount, 25 million pounds are used in animal husbandry, and 23 million pounds are used to try to prevent disease and the stress of shipping, as well as to promote growth. Only 2 million pounds are given for specific animal infections. Dr. Egger reminds us that low concentrations of antibiotics are measurable in many of our foods and in various waterways around the world, much of it seeping in from animal farms. </div> <div> Egger contends that overuse of antibiotics results in food-borne infections resistant to antibiotics. Salmonella is found in 20% of ground meat, but the constant exposure of cattle to antibiotics has made 84% of salmonella resistant to at least one anti-salmonella antibiotic. Diseased animal food accounts for 80% of salmonellosis in humans, or 1.4 million cases per year. The conventional approach to countering this epidemic is to radiate food to try to kill all organisms while continuing to use the antibiotics that created the problem in the first place. Approximately 20% of chickens are contaminated with <I>Campylobacter jejuni</I>, an organism that causes 2.4 million cases of illness annually. Fifty-four percent of these organisms are resistant to at least one anti-campylobacter antimicrobial agent. </div> <div> Denmark banned growth-promoting antibiotics beginning in 1999, which cut their use by more than half within a year, from 453,200 to 195,800 pounds. A report from Scandinavia found that removing antibiotic growth promoters had no or minimal effect on food production costs. Egger warns that the current crowded, unsanitary methods of animal farming in the US support constant stress and infection, and are geared toward high antibiotic use. </div> <div> In the US, over 3 million pounds of antibiotics are used every year on humans. With a population of 284 million Americans, this amount is enough to give every man, woman, and child 10 teaspoons of pure antibiotics per year. Egger says that exposure to a steady stream of antibiotics has altered pathogens such as <I>Streptococcus pneumoniae</I>, <I>Staplococcus aureus</I>, and <I>entercocci</I>, to name a few. </div> <div> Almost half of patients with upper respiratory tract infections in the U.S. still receive antibiotics from their doctor.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(51)</FONT> According to the CDC, 90% of upper respiratory infections are viral and should not be treated with antibiotics. In Germany, the prevalence of systemic antibiotic use in children aged 0-6 years was 42.9%.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(52)</FONT> </div> <div> Data obtained from nine US health insurers on antibiotic use in 25,000 children from 1996 to 2000 found that rates of antibiotic use decreased. Antibiotic use in children aged three months to under 3 years decreased 24%, from 2.46 to 1.89 antibiotic prescriptions per patient per year. For children aged 3 to under 6 years, there was a 25% reduction from 1.47 to 1.09 antibiotic prescriptions per patient per year. And for children aged 6 to under 18 years, there was a 16% reduction from 0.85 to 0.69 antibiotic prescriptions per patient per year.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(53)</FONT> Despite these reductions, the data indicate that on average every child in America receives 1.22 antibiotic prescriptions annually. </div> <div> Group A beta-hemolytic streptococci is the only common cause of sore throat that requires antibiotics, with penicillin and erythromycin the only recommended treatment. Ninety percent of sore-throat cases, however, are viral. Antibiotics were used in 73% of the estimated 6.7 million adult annual visits for sore throat in the US between 1989 and 1999. Furthermore, patients treated with antibiotics were prescribed non-recommended broad-spectrum antibiotics in 68% of visits. This period saw a significant increase in the use of newer, more expensive broad-spectrum antibiotics and a decrease in use of the recommended antibiotics penicillin and erythromycin.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(54)</FONT> A ntibiotics being prescribed in 73% of sore-throat cases instead of the recommended 10% resulted in a total of 4.2 million unnecessary antibiotic prescriptions from 1989 to 1999.</div> <div> The Problem with Antibiotics</div> <div> In September 2003, the CDC re-launched a program started in 1995 called “Get Smart: Know When Antibiotics Work.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(55)</FONT> This $1.6 million campaign is designed to educate patients about the overuse and inappropriate use of antibiotics. Most people involved with alternative medicine have known about the dangers of antibiotic overuse for decades. Finally the government is focusing on the problem, yet it is spending only a miniscule amount of money on an iatrogenic epidemic that is costing billions of dollars and thousands of lives. The CDC warns that 90% of upper respiratory infections, including children's ear infections, are viral and that antibiotics do not treat viral infection. More than 40% of about 50 million prescriptions for antibiotics written each year in physicians' offices are inappropriate.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(2)</FONT> U sing antibiotics when not needed can lead to the development of deadly strains of bacteria that are resistant to drugs and cause more than 88,000 deaths due to hospital-acquired infections.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(9)</FONT> The CDC, however, seems to be blaming patients for misusing antibiotics even though they are available only by prescription from physicians. According to Dr. Richard Besser, head of “Get Smart”: "Programs that have just targeted physicians have not worked. Direct-to-consumer advertising of drugs is to blame in some cases.” Besser says the program “teaches patients and the general public that antibiotics are precious resources that must be used correctly if we want to have them around when we need them. Hopefully, as a result of this campaign, patients will feel more comfortable asking their doctors for the best care for their illnesses, rather than asking for antibiotics."<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(56)</FONT></div> <div> What constitutes the “best care”? The CDC does not elaborate and ignores the latest research on the dozens of nutraceuticals that have been scientifically proven to treat viral infections and boost immune-system function. Will doctors recommend vitamin C, echinacea, elderberry, vitamin A, zinc, or homeopathic oscillococcinum? Probably not. The CDC's common-sense recommendations that most people follow anyway include getting proper rest, drinking plenty of fluids, and using a humidifier. </div> <div> The pharmaceutical industry claims it supports limiting the use of antibiotics. The drug company Bayer sponsors a program called “Operation Clean Hands” through an organization called LIBRA.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(57)</FONT> The CDC also is involved in trying to minimize antibiotic resistance, but nowhere in its publications is there any reference to the role of nutraceuticals in boosting the immune system, nor to the thousands of journal articles that support this approach. This tunnel vision and refusal to recommend the available non-drug alternatives is unfortunate when the CDC is desperately trying to curb the overuse of antibiotics.</div> <div> Drugs Pollute Our Water Supply </div> <div> We have reached the point of saturation with prescription drugs. Every body of water tested contains measurable drug residues. The tons of antibiotics used in animal farming, which run off into the water table and surrounding bodies of water, are conferring antibiotic resistance to germs in sewage, and these germs also are found in our water supply. Flushed down our toilets are tons of drugs and drug metabolites that also find their way into our water supply. We have no way to know the long-term health consequences of ingesting a mixture of drugs and drug-breakdown products. These drugs represent another level of iatrogenic disease that we are unable to completely measure.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(58-67)</FONT></div> <div> Specific Drug Iatrogenesis: NSAIDs</div> <div> It's not just the US that is plagued by iatrogenesis. A survey of more than 1,000 French general practitioners (GPs) tested their basic pharmacological knowledge and practice in prescribing NSAIDs, which rank first among commonly prescribed drugs for serious adverse reactions. The study results suggest that GPs do not have adequate knowledge of these drugs and are unable to effectively manage adverse reactions.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(68)</FONT> </div> <div> A cross-sectional survey of 125 patients attending specialty pain clinics in South London found that possible iatrogenic factors such as “over-investigation, inappropriate information, and advice given to patients as well as misdiagnosis, over-treatment, and inappropriate prescription of medication were common.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(69)</FONT></div> <div> Specific Drug Iatrogenesis: Cancer Chemotherapy</div> <div> In 1989, German biostatistician Ulrich Abel, PhD, wrote a monograph entitled “Chemotherapy of Advanced Epithelial Cancer.” It was later published in shorter form in a peer-reviewed medical journal.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(70)</FONT> Abel presented a comprehensive analysis of clinical trials and publications representing over 3,000 articles examining the value of cytotoxic chemotherapy on advanced epithelial cancer. Epithelial cancer is the type of cancer with which we are most familiar, arising from epithelium found in the lining of body organs such as the breast, prostate, lung, stomach, and bowel. From these sites, cancer usually infiltrates adjacent tissue and spreads to the bone, liver, lung, or brain. With his exhaustive review, Abel concluded there is no direct evidence that chemotherapy prolongs survival in patients with advanced carcinoma; in small-cell lung cancer and perhaps ovarian cancer, the therapeutic benefit is only slight. According to Abel, “Many oncologists take it for granted that response to therapy prolongs survival, an opinion which is based on a fallacy and which is not supported by clinical studies.” </div> <div> Over a decade after Abel's exhaustive review of chemotherapy, there seems no decrease in its use for advanced carcinoma. For example, when conventional chemotherapy and radiation have not worked to prevent metastases in breast cancer, high-dose chemotherapy (HDC) along with stem-cell transplant (SCT) is the treatment of choice. In March 2000, however, results from the largest multi-center randomized controlled trial conducted thus far showed that, compared to a prolonged course of monthly conventional-dose chemotherapy, HDC and SCT were of no benefit, <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(71)</FONT> with even a slightly lower survival rate for the HDC/SCT group. Serious adverse effects occurred more often in the HDC group than the standard-dose group. One treatment-related death (within 100 days of therapy) was recorded in the HDC group, but none was recorded in the conventional chemotherapy group. The women in this trial were highly selected as having the best chance to respond. </div> <div> Unfortunately, no all-encompassing follow-up study such as Dr. Abel's exists to indicate whether there has been any improvement in cancer-survival statistics since 1989. In fact, research should be conducted to determine whether chemotherapy itself is responsible for secondary cancers instead of progression of the original disease. We continue to question why well-researched alternative cancer treatments are not used.</div> <div> Drug Companies Fined</div> <div> Periodically, the FDA fines a drug manufacturer when its abuses are too glaring and impossible to cover up. In May 2002, <I>The Washington Post </I>reported that Schering-Plough Corp., the maker of Claritin, was to pay a $500 million dollar fine to the FDA for quality-control problems at four of its factories.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(72)</FONT> The indictment came after the Public Citizen Health Research Group, led by Dr. Sidney Wolfe, called for a criminal investigation of Schering-Plough, charging that the company distributed albuterol asthma inhalers even though it knew the units were missing the active ingredient. </div> <div> The FDA tabulated infractions involving 125 products, or 90% of the drugs made by Schering-Plough since 1998. Besides paying the fine, the company was forced to halt the manufacture of 73 drugs or suffer another $175 million fine. Schering-Plough's news releases told another story, assuring consumers that they should still feel confident in the company's products. </div> <div> This large settlement served as a warning to the drug industry about maintaining strict manufacturing practices and has given the FDA more clout in dealing with drug company compliance. According to <I>The Washington Post </I>article, a federal appeals court ruled in 1999 that the FDA could seize the profits of companies that violate "good manufacturing practices." Since that time, Abbott Laboratories has paid a $100 million fine for failing to meet quality standards in the production of medical test kits, while Wyeth Laboratories paid $30 million in 2000 to settle accusations of poor manufacturing practices. </div> <div> UNNECESSARY SURGICAL PROCEDURES </div> <div> In 1974, 2.4 million unnecessary surgeries were performed, resulting in 11,900 deaths at a cost of $3.9 billion.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(73,74)</FONT> In 2001, 7.5 million unnecessary surgical procedures were performed, resulting in 37,136 deaths at a cost of $122 billion (using 1974 dollars).<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(3)</FONT> </div> <div> It is very difficult to obtain accurate statistics when studying unnecessary surgery. In 1989, Leape wrote that perhaps 30% of controversial surgeries-which include cesarean section, tonsillectomy, appendectomy, hysterectomy, gastrectomy for obesity, breast implants, and elective breast implants<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(74)</FONT>- are unnecessary. In 1974, the Congressional Committee on Interstate and Foreign Commerce held hearings on unnecessary surgery. It found that 17.6% of recommendations for surgery were not confirmed by a second opinion. The House Subcommittee on Oversight and Investigations extrapolated these figures and estimated that, on a nationwide basis, there were 2.4 million unnecessary surgeries performed annually, resulting in 11,900 deaths at an annual cost of $3.9 billion.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(73)</FONT> </div> <div> According to the Healthcare Cost and Utilization Project within the Agency for Healthcare Research and Quality<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(13)</FONT>, in 2001 the 50 most common medical and surgical procedures were performed approximately 41.8 million times in the US. Using the 1974 House Subcommittee on Oversight and Investigations' figure of 17.6% as the percentage of unnecessary surgical procedures, and extrapolating from the death rate in 1974, produces nearly 7.5 million (7,489,718) unnecessary procedures and a death rate of 37,136, at a cost of $122 billion (using 1974 dollars). </div> <div> In 1995, researchers conducted a similar analysis of back surgery procedures, using the 1974 “unnecessary surgery percentage” of 17.6. Testifying before the Department of Veterans Affairs, they estimated that of the 250,000 back surgeries performed annually in the US at a hospital cost of $11,000 per patient, the total number of unnecessary back surgeries approaches 44,000, costing as much as $484 million.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(75)</FONT> </div> <div> Like prescription drug use driven by television advertising, unnecessary surgeries are escalating. Media-driven surgery such as gastric bypass for obesity “modeled” by Hollywood celebrities seduces obese people to think this route is safe and sexy. Unnecessary surgeries have even been marketed on the Internet.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(76)</FONT> A study in Spain declares that 20-25% of total surgical practice represents unnecessary operations.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(77)</FONT> </div> <div> According to data from the National Center for Health Statistics for 1979 to 1984, the total number of surgical procedures increased 9% while the number of surgeons grew 20%. The study notes that the large increase in the number of surgeons was not accompanied by a parallel increase in the number of surgeries performed, and expressed concern about an excess of surgeons to handle the surgical caseload.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(78)</FONT> </div> <div> From 1983 to 1994, however, the incidence of the 10 most commonly performed surgical procedures jumped 38%, to 7,929,000 from 5,731,000 cases. By 1994, cataract surgery was the most common procedure with more than 2 million operations, followed by cesarean section (858,000 procedures) and inguinal hernia operations (689,000 procedures). Knee arthroscopy procedures increased 153% while prostate surgery declined 29%.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(79)</FONT> </div> <div> The list of iatrogenic complications from surgery is as long as the list of procedures themselves. One study examined catheters that were inserted to deliver anesthetic into the epidural space around the spinal nerves for lower cesarean section, abdominal surgery, or prostate surgery. In some cases, non-sterile technique during catheter insertion resulted in serious infections, even leading to limb paralysis.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(80)</FONT> </div> <div> In one review of the literature, the authors found “a significant rate of overutilization of coronary angiography, coronary artery surgery, cardiac pacemaker insertion, upper gastrointestinal endoscopies, carotid endarterectomies, back surgery, and pain-relieving procedures.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(81)</FONT> </div> <div> A 1987 <I>JAMA </I>study found the following significant levels of inappropriate surgery: 17% of coronary angiography procedures, 32% of carotid endarterectomy procedures, and 17% of upper gastrointestinal tract endoscopy procedures.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(82)</FONT> Based on the Healthcare Cost and Utilization Project (HCUP) statistics provided by the government for 2001, 697,675 upper gastrointestinal endoscopies (usually entailing biopsy) were performed, as were 142,401 endarterectomies and 719,949 coronary angiographies.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(13)</FONT> Extrapolating the <I>JAMA </I>study's inappropriate surgery rates to 2001 produces 118,604 unnecessary endoscopy procedures, 45,568 unnecessary endarterectomies, and 122,391 unnecessary coronary angiographies. These are all forms of medical iatrogenesis.</div> <div> <B>MEDICAL AND SURGICAL PROCEDURES </B></div> <div> It is instructive to know the mortality rates associated with various medical and surgical procedures. Although we must sign release forms when we undergo any procedure, many of us are in denial about the true risks involved; because medical and surgical procedures are so commonplace, they often are seen as both necessary and safe. Unfortunately, allopathic medicine itself is a leading cause of death, as well as the most expensive way to die. </div> <div> Perhaps the words “health care” confer the illusion that medicine is about health. Allopathic medicine is not a purveyor of health care but of disease care. The HCUP figures are instructive,<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(13)</FONT> but the computer program that calculates annual mortality statistics for all US hospital discharges is only as good as the codes entered into the system. In email correspondence, HCUP indicated that the mortality rates for each procedure indicated only that someone undergoing that procedure died either from the procedure or from some other cause. </div> <div> Thus there is no way of knowing exactly how many people die from a particular procedure. While codes for “poisoning & toxic effects of drugs” and “complications of treatment” do exist, the mortality figures registered in these categories are very low and do not correlate with what is known from research such as the 1998 JAMA study<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(1)</FONT> that estimated an average of 106,000 prescription medication deaths per year. No codes exist for adverse drug side effects, surgical mishaps, or other types of medical error. Until such codes exist, the true mortality rates tied to of medical error will remain buried in the general statistics.</div> <div> AN HONEST LOOK AT US HEALTH CARE </div> <div> In 1978, the US Office of Technology Assessment (OTA) reported: “Only 10-20% of all procedures currently used in medical practice have been shown to be efficacious by controlled trial."<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(83)</FONT> In 1995, the OTA compared medical technology in eight countries ( Australia , Canada, France, Germany, the Netherlands, Sweden, the UK, and the US ) and again noted that few medical procedures in the US have been subjected to clinical trial. It also reported that US infant mortality was high and life expectancy low compared to other developed countries.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(84)</FONT> </div> <div> Although almost 10 years old, much of what was written in the OTA report holds true today. The report blames the high cost of American medicine on the medical free-enterprise system and failure to create a national health care policy. It attributes the government's failure to control health care costs to market incentives and profit motives inherent in the current financing and organization of health care, which includes such interests as private health insurers, hospital systems, physicians, and the drug and medical-device industries. “Health Care Technology and Its Assessment in Eight Countries” is the last report prepared by the OTA, which was disbanded in 1995. It also is perhaps the US government's last honest, detailed examination of the nation's health care system. An appendix summarizing this 60-page report follows this article. </div> <div> <B>SURGICAL ERRORS FINALLY REPORTED </B></div> <div> An October 2003 <I>JAMA </I>study from the US government's Agency for Healthcare Research and Quality (AHRQ) documented 32,000 mostly surgery-related deaths costing $9 billion and accounting for 2.4 million extra hospital days in 2000.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(85)</FONT> Data from 20% of the nation's hospitals were analyzed for 18 different surgical complications, including postoperative infections, foreign objects left in wounds, surgical wounds reopening, and post-operative bleeding. </div> <div> In a press release accompanying the study, AHRQ director Carolyn M. Clancy, MD, noted: “This study gives us the first direct evidence that medical injuries pose a real threat to the American public and increase the costs of health care.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(86)</FONT> According to the study's authors, “The findings greatly underestimate the problem, since many other complications happen that are not listed in hospital administrative data.” They added: "The message here is that medical injuries can have a devastating impact on the health care system. We need more research to identify why these injuries occur and find ways to prevent them from happening." The study authors said that improved medical practices, including an emphasis on better hand washing, might help reduce morbidity and mortality rates. In an accompanying <I>JAMA </I>editorial, health-risk researcher Dr. Saul Weingart of Harvard's Beth Israel-Deaconess Medical Center wrote, “Given their staggering magnitude, these estimates are clearly sobering.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(87)</FONT></div> <div> UNNECESSARY X-RAYS </div> <div> When x-rays were discovered, no one knew the long-term effects of ionizing radiation. In the 1950s, monthly fluoroscopic exams at the doctor's office were routine, and you could even walk into most shoe stores and see x-rays of your foot bones. We still do not know the ultimate outcome of our initial fascination with x-rays. </div> <div> In those days, it was common practice to x-ray pregnant women to measure their pelvises and make a diagnosis of twins. Finally, a study of 700,000 children born between 1947 and 1964 in 37 major maternity hospitals compared the children of mothers who had received pelvic x-rays during pregnancy to those of mothers who did not. It found that cancer mortality was 40% higher among children whose mothers had been x-rayed.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(88)</FONT> </div> <div> In present-day medicine, coronary angiography is an invasive surgical procedure that involves snaking a tube through a blood vessel in the groin up to the heart. To obtain useful information, X-rays are taken almost continuously, with minimum dosages ranging from 460 to 1,580 mrem. The minimum radiation from a routine chest x-ray is 2 mrem. X-ray radiation accumulates in the body, and ionizing radiation used in X-ray procedures has been shown to cause gene mutation. The health impact of this high level of radiation is unknown, and often obscured in statistical jargon such as, “The risk for lifetime fatal cancer due to radiation exposure is estimated to be 4 in one million per 1,000 mrem.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(89)</FONT> </div> <div> Dr. John Gofman has studied the effects of radiation on human health for 45 years. A medical doctor with a PhD in nuclear and physical chemistry, Gofman worked on the Manhattan Project, discovered uranium-233, and was the first person to isolate plutonium. In five scientifically documented books, Gofman provides strong evidence that medical technology-specifically x-rays, CT scans, and mammography and fluoroscopy devices-are a contributing factor to 75% of new cancers. In a nearly 700-page report updated in 2000, “Radiation from Medical Procedures in the Pathogenesis of Cancer and Ischemic Heart Disease: Dose-Response Studies with Physicians per 100,000 Population,”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(90)</FONT> Gofman shows that as the number of physicians increases in a geographical area along with an increase in the number of x-ray diagnostic tests performed, the rate of cancer and ischemic heart disease also increases. Gofman elaborates that it is not x-rays alone that cause the damage but a combination of health risk factors that include poor diet, smoking, abortions, and the use of birth control pills. Dr. Gofman predicts that ionizing radiation will be responsible for 100 million premature deaths over the next decade. </div> <div> In his book, “Preventing Breast Cancer,” Dr. Gofman notes that breast cancer is the leading cause of death among American women between the ages of 44 and 55. Because breast tissue is highly sensitive to radiation, mammograms can cause cancer. The danger can be heightened other factors including a woman's genetic makeup, preexisting benign breast disease, artificial menopause, obesity, and hormonal imbalance.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(91)</FONT> </div> <div> Even x-rays for back pain can lead someone into crippling surgery. Dr. John E. Sarno, a well-known New York orthopedic surgeon, found that there is not necessarily any association between back pain and spinal x-ray abnormality. He cites studies of normal people without a trace of back pain whose x-rays indicate spinal abnormalities and of people with back pain whose spines appear to be normal on x-ray.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(92)</FONT> People who happen to have back pain and show an abnormality on x-ray may be treated surgically, sometimes with no change in back pain, worsening of back pain, or even permanent disability. Moreover, doctors often order x-rays as protection against malpractice claims, to give the impression of leaving no stone unturned. It appears that doctors are putting their own fears before the interests of their patients.</div> <div> UNNECESSARY HOSPITALIZATION</div> <div> Nearly 9 million (8,925,033) people were hospitalized unnecessarily in 2001.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(4)</FONT> In a study of inappropriate hospitalization, two doctors reviewed 1,132 medical records. They concluded that 23% of all admissions were inappropriate and an additional 17% could have been handled in outpatient clinics. Thirty-four percent of all hospital days were deemed inappropriate and could have been avoided.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(93)</FONT> The rate of inappropriate hospital admissions in 1990 was 23.5%.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(94)</FONT> In 1999, another study also found an inappropriate admissions rate of 24%, indicating a consistent pattern from 1986 to 1999.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(95)</FONT> The HCUP database indicates that the total number of patient discharges from US hospitals in 2001 was 37,187,641,<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(13)</FONT> meaning that almost 9 million people were exposed to unnecessary medical intervention in hospitals and therefore represent almost 9 million potential iatrogenic episodes.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(4)</FONT> </div> <div> WOMEN'S EXPERIENCE IN MEDICINE </div> <div> Dr. Martin Charcot (1825-1893) was world-renowned, the most celebrated doctor of his time. He practiced in the Paris hospital La Salpetriere. He became an expert in hysteria, diagnosing an average of 10 hysterical women each day, transforming them into “iatrogenic monsters” and turning simple “neurosis” into hysteria.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(96)</FONT> The number of women diagnosed with hysteria and hospitalized rose from 1% in 1841 to 17% in 1883. Hysteria is derived from the Latin “hystera” meaning uterus. According to Dr. Adriane Fugh-Berman, US medicine has a tradition of excessive medical and surgical interventions on women. Only 100 years ago, male doctors believed that female psychological imbalance originated in the uterus. When surgery to remove the uterus was perfected, it became the “cure” for mental instability, effecting a physical and psychological castration. Fugh-Berman notes that US doctors eventually disabused themselves of that notion but have continued to treat women very differently than they treat men.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(97)</FONT> She cites the following statistics:</div> <div> Thousands of prophylactic mastectomies are performed annually. </div> <div> One-third of US women have had a hysterectomy before menopause. </div> <div> Women are prescribed drugs more frequently than are men. </div> <div> Women are given potent drugs for disease prevention, which results in disease substitution due to side effects. </div> <div> Fetal monitoring is unsupported by studies and not recommended by the CDC.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(98)</FONT> It confines women to a hospital bed and may result in a higher incidence of cesarean section.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(99)</FONT> </div> <div> Normal processes such as menopause and childbirth have been heavily “medicalized.” </div> <div> Synthetic hormone replacement therapy (HRT) does not prevent heart disease or dementia, but does increase the risk of breast cancer, heart disease, stroke, and gall bladder attack.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(100)</FONT> </div> <div> As many as one-third of postmenopausal women use HRT.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(101,102)</FONT> This number is important in light of the much-publicized Women's Health Initiative Study, which was halted before its completion because of a higher death rate in the synthetic estrogen-progestin <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(HRT)</FONT> group.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(103</FONT></div> <div> Cesarean Section </div> <div> In 1983, 809,000 cesarean sections (21% of live births) were performed in the US, making it the nation's most common obstetric-gynecologic (OB/GYN) surgical procedure. The second most common OB/GYN operation was hysterectomy (673,000), followed by diagnostic dilation and curettage of the uterus (632,000). In 1983, OB/GYN procedures represented 23% of all surgery completed in the US.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(104)</FONT> </div> <div> In 2001, cesarean section is still the most common OB/GYN surgical procedure. Approximately 4 million births occur annually, with 24% (960,000) delivered by cesarean section. In the Netherlands, only 8% of births are delivered by cesarean section. This suggests 640,000 unnecessary cesarean sections-entailing three to four times higher mortality and 20 times greater morbidity than vaginal delivery<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(105)</FONT>-are performed annually in the US. </div> <div> The US cesarean rate rose from just 4.5% in 1965 to 24.1% in 1986. Sakala contends that an “uncontrolled pandemic of medically unnecessary cesarean births is occurring.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(106)</FONT> VanHam reported a cesarean section postpartum hemorrhage rate of 7%, a hematoma formation rate of 3.5%, a urinary tract infection rate of 3%, and a combined postoperative morbidity rate of 35.7% in a high-risk population undergoing cesarean section.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(107)</FONT></div> <div> <B>NEVER ENOUGH STUDIES </B></div> <div> Scientists claimed there were never enough studies revealing the dangers of DDT and other dangerous pesticides to ban them. They also used this argument for tobacco, claiming that more studies were needed before they could be certain that tobacco really caused lung cancer. Even the American Medical Association (AMA) was complicit in suppressing the results of tobacco research. In 1964, when the Surgeon General's report condemned smoking, the AMA refused to endorse it, claiming a need for more research. What they really wanted was more money, which they received from a consortium of tobacco companies that paid the AMA $18 million over the next nine years during which the AMA said nothing about the dangers of smoking.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(108)</FONT> </div> <div> The <I>Journal of the American Medical Association (JAMA)</I>, "after careful consideration of the extent to which cigarettes were used by physicians in practice," began accepting tobacco advertisements and money in 1933. State journals such as the <I>New York State Journal of Medicine </I>also began to run advertisements for Chesterfield cigarettes that claimed cigarettes are "Just as pure as the water you drink… and practically untouched by human hands." In 1948, <I>JAMA </I>argued "more can be said in behalf of smoking as a form of escape from tension than against it… there does not seem to be any preponderance of evidence that would indicate the abolition of the use of tobacco as a substance contrary to the public health."<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(109)</FONT> Today, scientists continue to use the excuse that more studies are needed before they will support restricting the inordinate use of drugs.</div> <div> <B>ADVERSE DRUG REACTIONS </B></div> <div> The Lazarou study<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(1)</FONT> analyzed records for prescribed medications for 33 million US hospital admissions in 1994. It discovered 2.2 million serious injuries due to prescribed drugs; 2.1% of inpatients experienced a serious adverse drug reaction, 4.7% of all hospital admissions were due to a serious adverse drug reaction, and fatal adverse drug reactions occurred in 0.19% of inpatients and 0.13% of admissions. The authors estimated that 106,000 deaths occur annually due to adverse drug reactions. </div> <div> Using a cost analysis from a 2000 study in which the increase in hospitalization costs per patient suffering an adverse drug reaction was $5,483, costs for the Lazarou study's 2.2 million patients with serious drug reactions amounted to $12 billion.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(1,49)</FONT> </div> <div> Serious adverse drug reactions commonly emerge after FDA approval of the drugs involved. The safety of new agents cannot be known with certainty until a drug has been on the market for many years.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(110)</FONT> </div> <div> <B>BEDSORES</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Over one million people develop bedsores in U.S. hospitals every year. It's a tremendous burden to patients and family, and a $55 billion dollar healthcare burden. <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(7)</FONT> Bedsores are preventable with proper nursing care. It is true that 50% of those affected are in a vulnerable age group of over 70. In the elderly bedsores carry a fourfold increase in the rate of death. The mortality rate in hospitals for patients with bedsores is between 23% and 37%. <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(8)</FONT> Even if we just take the 50% of people over 70 with bedsores and the lowest mortality at 23%, that gives us a death rate due to bedsores of 115,000. Critics will say that it was the disease or advanced age that killed the patient, not the bedsore, but our argument is that an early death, by denying proper care, deserves to be counted. It is only after counting these unnecessary deaths that we can then turn our attention to fixing the problem.</div> <div> <B>MALNUTRITION IN NURSING HOMES </B></div> <div> The General Accounting Office <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(GAO)</FONT>, a special investigative branch of Congress, cited 20% of the nation's 17,000 nursing homes for violations between July 2000 and January 2002. Many violations involved serious physical injury and death.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(111)</FONT> </div> <div> A report from the Coalition for Nursing Home Reform states that at least one-third of the nation's 1.6 million nursing home residents may suffer from malnutrition and dehydration, which hastens their death. The report calls for adequate nursing staff to help feed patients who are not able to manage a food tray by themselves.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(11)</FONT> It is difficult to place a mortality rate on malnutrition and dehydration. The Coalition report states that malnourished residents, compared with well-nourished hospitalized nursing home residents, have a fivefold increase in mortality when they are admitted to a hospital. Multiplying the one-third of 1.6 million nursing home residents who are malnourished by a mortality rate of 20%<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(8,14)</FONT> results in 108,800 premature deaths due to malnutrition in nursing homes.</div> <div> Nosocomial Infections </div> <div> The rate of nosocomial infections per 1,000 patient days rose from 7.2 in 1975 to 9.8 in 1995, a 36% jump in 20 years. Reports from more than 270 US hospitals showed that the nosocomial infection rate itself had remained stable over the previous 20 years, with approximately five to six hospital-acquired infections occurring per 100 admissions, a rate of 5-6%. Due to progressively shorter inpatient stays and the increasing number of admissions, however, the number of infections increased. It is estimated that in 1995, nosocomial infections cost $4.5 billion and contributed to more than 88,000 deaths, or one death every 6 minutes.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(9)</FONT> The 2003 incidence of nosocomial mortality is quite probably higher than in 1995 because of the tremendous increase in antibiotic-resistant organisms. Morbidity and Mortality Report found that nosocomial infections cost $5 billion annually in 1999,<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(10)</FONT> representing a $0.5 billion increase in just four years. At this rate of increase, the current cost of nosocomial infections would be around $5.5 billion.</div> <div> <B>Outpatient Iatrogenesis </B></div> <div> In a 2000 <I>JAMA </I>article, Dr. Barbara Starfield presents well-documented facts that are both shocking and unassailable.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(12)</FONT> The U.S. ranks 12th of 13 industrialized countries when judged by 16 health status indicators. Japan, Sweden, and Canada were first, second, and third, respectively. More than 40 million people in the US have no health insurance, and 20-30% of patients receive contraindicated care. </div> <div> Starfield warns that one cause of medical mistakes is overuse of technology, which may create a "cascade effect" leading to still more treatment. She urges the use of ICD (International Classification of Diseases) codes that have designations such as "Drugs, Medicinal, and Biological Substances Causing Adverse Effects in Therapeutic Use" and "Complications of Surgical and Medical Care" to help doctors quantify and recognize the magnitude of the medical error problem. Starfield notes that many deaths attributable to medical error today are likely to be coded to indicate some other cause of death. She concludes that against the backdrop of our poor health report card compared to other Westernized countries, we should recognize that the harmful effects of health care interventions account for a substantial proportion of our excess deaths. </div> <div> Starfield cites Weingart's 2000 article, “Epidemiology of Medical Error,” as well as other authors to suggest that between 4% and 18% of consecutive patients in outpatient settings suffer an iatrogenic event leading to:</div> <div> 116 million extra physician visits </div> <div> 77 million extra prescriptions filled </div> <div> 17 million emergency department visits </div> <div> 8 million hospitalizations </div> <div> 3 million long-term admissions </div> <div> 199,000 additional deaths </div> <div> $77 billion in extra costs<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(112)</FONT> </div> <div> <B>Unnecessary Surgeries </B></div> <div> While some 12,000 deaths occur each year from unnecessary surgeries, results from the few studies that have measured unnecessary surgery directly indicate that for some highly controversial operations, the proportion of unwarranted surgeries could be as high as 30%.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(74)</FONT> </div> <div> MEDICAL ERRORS: A GLOBAL ISSUE </div> <div> A five-country survey published in the <I>Journal of Health Affairs </I>found that 18-28% of people who were recently ill had suffered from a medical or drug error in the previous two years. The study surveyed 750 recently ill adults. The breakdown by country showed the percentages of those suffering a medical or drug error were 18% in Britain, 23% in Australia and in New Zealand, 25% in Canada, and 28% in the US.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(113)</FONT> </div> <div> <B>HEALTH INSURANCE </B></div> <div> The Institute of Medicine recently found that the 41 million Americans with no health insurance have consistently worse clinical outcomes than those who are insured, and are at increased risk for dying prematurely <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(114)</FONT>.</div> <div> When doctors bill for services they do not render, advise unnecessary tests, or screen everyone for a rare condition, they are committing insurance fraud. The US GAO estimated that $12 billion dollars was lost to fraudulent or unnecessary claims in 1998, and reclaimed $480 million in judgments in that year. In 2001, the federal government won or negotiated more than $1.7 billion in judgments, settlements, and administrative impositions in health care fraud cases and proceedings.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(115)</FONT></div> <div> WAREHOUSING OUR ELDERS </div> <div> One way to measure the moral and ethical fiber of a society is by how it treats its weakest and most vulnerable members. In some cultures, elderly people lives out their lives in extended family settings that enable them to continue participating in family and community affairs. American nursing homes, where millions of our elders go to live out their final days, represent the pinnacle of social isolation and medical abuse.</div> <div> In America, approximately 1.6 million elderly are confined to nursing homes. By 2050, that number could be 6.6 million.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(11,116)</FONT> </div> <div> Twenty percent of all deaths from all causes occur in nursing homes.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(117)</FONT> </div> <div> Hip fractures are the single greatest reason for nursing home admissions.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(118)</FONT> </div> <div> Nursing homes represent a reservoir for drug-resistant organisms due to overuse of antibiotics.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(119)</FONT> </div> <div> Presenting a report he sponsored entitled "Abuse of Residents is a Major Problem in U.S. Nursing Homes" on July 30, 2001, Rep. Henry Waxman <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(D-CA)</FONT> noted that “as a society we will be judged by how we treat the elderly." The report found one-third of the nation's approximately 17,000 nursing homes were cited for an abuse violation in a two-year period from January 1999 to January 2001.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(116)</FONT> According to Waxman, “the people who cared for us deserve better." The report suggests that this known abuse represents only the “tip of the iceberg” and that much more abuse occurs that we aware of or ignore.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(116a)</FONT> The report found:</div> <div> Over 30% of US nursing homes were cited for abuses, totaling more than 9,000 violations. </div> <div> 10% of nursing homes had violations that caused actual physical harm to residents or worse. </div> <div> Over 40% <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(3,800)</FONT> of the abuse violations followed the filing of a formal complaint, usually by concerned family members. </div> <div> Many verbal abuse violations were found. </div> <div> Occasions of sexual abuse. </div> <div> Incidents of physical abuse causing numerous injuries such as fractured femur, hip, elbow, wrist, and other injuries. </div> <div> Dangerously understaffed nursing homes lead to neglect, abuse, overuse of medications, and physical restraints. In 1990, Congress mandated an exhaustive study of nurse-to-patient ratios in nursing homes. The study was finally begun in 1998 and took four years to complete.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(120)</FONT> A spokesperson for The National Citizens' Coalition for Nursing Home Reform commented on the study: “They compiled two reports of three volumes each thoroughly documenting the number of hours of care residents must receive from nurses and nursing assistants to avoid painful, even dangerous, conditions such as bedsores and infections. Yet it took the Department of Health and Human Services and Secretary Tommy Thompson only four months to dismiss the report as `insufficient.'”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(121)</FONT> Although preventable with proper nursing care, bedsores occur three times more commonly in nursing homes than in acute care or veterans hospitals.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(122)</FONT>. </div> <div> Because many nursing home patients suffer from chronic debilitating conditions, their assumed cause of death often is unquestioned by physicians. Some studies show that as many as 50% of deaths due to restraints, falls, suicide, homicide, and choking in nursing homes may be covered up.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(123,124)</FONT> It is possible that many nursing home deaths are instead attributed to heart disease. In fact, researchers have found that heart disease may be over-represented in the general population as a cause of death on death certificates by 8-24%. In the elderly, the overreporting of heart disease as a cause of death is as much as twofold.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(125)</FONT> </div> <div> That very few statistics exist concerning malnutrition in acute-care hospitals and nursing homes demonstrates the lack of concern in this area. While a survey of the literature turns up few US studies, one revealing US study evaluated the nutritional status of 837 patients in a 100-bed subacute-care hospital over a 14-month period. The study found only 8% of the patients were well nourished, while 29% were malnourished and 63% were at risk of malnutrition. As a result, 25% of the malnourished patients required readmission to an acute-care hospital, compared to 11% of the well-nourished patients. The authors concluded that malnutrition reached epidemic proportions in patients admitted to this subacute-care facility.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(126)</FONT> </div> <div> Many studies conclude that physical restraints are an underreported and preventable cause of death. Studies show that compared to no restraints, the use of restraints carries a higher mortality rate and economic burden.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(127-129)</FONT> Studies have found that physical restraints, including bedrails, are the cause of at least 1 in every 1,000 nursing-home deaths.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(130-132)</FONT> </div> <div> Deaths caused by malnutrition, dehydration, and physical restraints, however, are rarely recorded on death certificates. Several studies reveal that nearly half of the listed causes of death on death certificates for elderly people with chronic or multi-system disease are inaccurate.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(133)</FONT> Even though 1 in 5 people die in nursing homes, an autopsy is performed in less than 1% of these deaths.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(134)</FONT>.</div> <div> Overmedicating Seniors</div> <div> Dr. Robert Epstein, chief medical officer of Medco Health Solutions Inc. (a unit of Merck & Co.), conducted a study in 2003 of drug trends among the elderly.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(135)</FONT> He found that seniors are going to multiple physicians, getting multiple prescriptions, and using multiple pharmacies. Medco oversees drug-benefit plans for more than 60 million Americans, including 6.3 million seniors who received more than 160 million prescriptions. According to the study, the average senior receives 25 prescriptions each year. Among those 6.3 million seniors, a total of 7.9 million medication alerts were triggered: less than one-half that number, 3.4 million, were detected in 1999. About 2.2 million of those alerts indicated excessive dosages unsuitable for seniors, and about 2.4 million alerts indicated clinically inappropriate drugs for the elderly. Reuters interviewed Kasey Thompson, director of the Center on Patient Safety at the American Society of Health System Pharmacists, who noted: “There are serious and systemic problems with poor continuity of care in the United States .” He says this study represents only “the tip of the iceberg” of a national problem. </div> <div> According to <I>Drug Benefit Trends </I>, the average number of prescriptions dispensed per non-Medicare HMO member per year rose 5.6% from 1999 to 2000, - from 7.1 to 7.5 prescriptions. The average number dispensed for Medicare members increased 5.5%, from 18.1 to 19.1 prescriptions.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(136)</FONT> The total number of prescriptions written in the US in 2000 was 2.98 billion, or 10.4 prescriptions for every man, woman, and child.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(137)</FONT> </div> <div> In a study of 818 residents of residential care facilities for the elderly, 94% were receiving at least one medication at the time of the interview. The average intake of medications was five per resident; the authors noted that many of these drugs were given without a documented diagnosis justifying their use.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(138)</FONT> </div> <div> Seniors and groups like the American Association for Retired Persons <FONT SIZE="1" COLOR="#000000" FACE="Arial" >(AARP)</FONT> are demanding that prescription drug coverage be a basic right.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(139)</FONT> They have accepted allopathic medicine's overriding assumption that aging and dying in America must be accompanied by drugs in nursing homes and eventual hospitalization. Seniors are given the choice of either high-cost patented drugs or low-cost generic drugs. Drug companies attempt to keep the most expensive drugs on the shelves and suppress access to generic drugs, despite facing stiff fines of hundreds of millions of dollars levied by the federal government.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(140,141)</FONT> In 2001, some of the world's largest drug companies were fined a record $871 million for conspiring to increase the price of vitamins.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(142)</FONT> </div> <div> Current AARP recommendations for diet and nutrition assume that seniors are getting all the nutrition they need in an average diet. At most, AARP suggests adding extra calcium and a multivitamin and mineral supplement.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(143)</FONT> </div> <div> Ironically, studies also indicate underuse of proper pain medication for patients who need it. One study evaluated pain management in a group of 13,625 cancer patients, aged 65 and over, living in nursing homes. While almost 30% of the patients reported pain, more than 25% received no pain relief medication, 16% received a mild analgesic drug, 32% received a moderate analgesic drug, and 26% received adequate pain-relieving morphine. The authors concluded that older patients and minority patients were more likely to have their pain untreated.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(144)</FONT> </div> <div> <B>WHAT REMAINS TO BE UNCOVERED </B></div> <div> Our ongoing research will continue to quantify the morbidity, mortality, and financial loss due to:</div> <div> X-ray exposures (mammography, fluoroscopy, CT scans). </div> <div> Overuse of antibiotics for all conditions. </div> <div> Carcinogenic drugs (hormone replacement therapy,* immunosuppressive and prescription drugs). </div> <div> Cancer chemotherapy<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(70)</FONT> </div> <div> Surgery and unnecessary surgery (cesarean section, radical mastectomy, preventive mastectomy, radical hysterectomy, prostatectomy, cholecystectomies, cosmetic surgery, arthroscopy, etc.). </div> <div> Discredited medical procedures and therapies. </div> <div> Unproven medical therapies. </div> <div> Outpatient surgery. </div> <div> Doctors themselves. </div> <div> * Part of our ongoing research will be to quantify the mortality and morbidity caused by hormone replacement therapy (HRT) since the 1940s. In December 2000, a government scientific advisory panel recommended that synthetic estrogen be added to the nation's list of cancer-causing agents. HRT, either synthetic estrogen alone or combined with synthetic progesterone, is used by an estimated 13.5 to 16 million women in the US.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(145)</FONT> The aborted Women's Health Initiative Study (WHI) of 2002 showed that women taking synthetic estrogen combined with synthetic progesterone have a higher incidence of ovarian cancer, breast cancer, stroke, and heart disease, with little evidence of osteoporosis reduction or dementia prevention. WHI researchers, who usually never make recommendations except to suggest more studies, advised doctors to be very cautious about prescribing HRT to their patients.<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(100,146-150)</FONT> </div> <div> Results of the “Million Women Study” on HRT and breast cancer in the UK were published in medical journal <I>The Lancet </I>in August 2003. According to lead author Prof. Valerie Beral, director of the Cancer Research UK Epidemiology Unit: "We estimate that over the past decade, use of HRT by UK women aged 50-64 has resulted in an extra 20,000 breast cancers, estrogen-progestagen (combination) therapy accounting for 15,000 of these.”<FONT SIZE="1" COLOR="#000000" FACE="Arial" >(151)</FONT> We were unable to find statistics on breast cancer, stroke, uterine cancer, or heart disease caused by HRT used by American women. Because the US population is roughly six times that of the UK, it is possible that 120,000 cases of breast cancer have been caused by HRT in the past decade</div> <bR> <div> OFFICE OF TECHNOLOGY ASSESSMENT (OTA)</div> <div> Health Care Technology and Its Assessment in Eight Countries, 1995.</div> <div> General Facts </div> <div> In 1990, US life expectancy was 71.8 years for men and 78.8 years for women, among the lowest rates in the developed countries. </div> <div> The 1990 US infant mortality rate in the US was 9.2 per 1,000 live births, in the bottom half of the distribution among all developed countries. </div> <div> Health status is correlated with socioeconomic status. </div> <div> Health care is not universal. </div> <div> Health care is based on the free market system with no fixed budget or limitations on expansion. </div> <div> Health care accounts for 14% of the US GNP ($800 billion in 1993). </div> <div> The federal government does no central planning, though it is the major purchaser of health care for older people and some poor people. </div> <div> Americans are less satisfied with their health care system than people in other developed countries. </div> <div> US medicine specializes in expensive medical technology; some large US cities have more magnetic resonance image (MRI) scanners than most countries. </div> <div> Huge public and private investments in medical research and pharmaceutical development drive this “technological arms race.” </div> <div> Any efforts to restrain technological developments in health care are opposed by policymakers concerned about negative impacts on medical-technology industries. </div> <div> Hospitals </div> <div> In 1990, the US had 5,480 acute-care hospitals, 880 specialty (psychiatric, long-term care, and rehabilitation) hospitals, and 340 federal (military, veterans, and Native American) hospitals, or 2.7 hospitals per 100,000 population. </div> <div> In 1990, the average length of stay for 33 million admissions was 9.2 days. The bed occupancy rate was 66%. Lengths of stay were shorter and admission rates lower than other countries. </div> <div> In 1990, the US had 615,000 physicians, or 2.4 per 1,000 population; 33% were primary care (family medicine, internal medicine, and pediatrics) and 67% were specialists. </div> <div> In 1991, government-run health care spending totaled $81 billion. </div> <div> Total US health care spending rose to $752 billion in 1991 from $70 billion in 1950. Spending grew five-fold per capita. </div> <div> Reasons for increased healthcare spending include: </div> <div> The high cost of defensive medicine, with an escalation in services solely to avoid malpractice litigation. </div> <div> US health care based on defensive medicine costs nearly $45 billion per year, or about 5% of total health care spending, according to one source. </div> <div> The availability and use of new medical technologies have contributed the most to increased health care spending, argue many analysts. These costs are impossible to quantify. </div> <div> The reasons government attempts to control health care costs have failed include: </div> <div> Market incentive and profit-motive involvement in the financing and organization of health care, including private insurers, hospital systems, physicians, and the drug and medical-device industries. </div> <div> Expansion is the goal of free enterprise. </div> <div> Health-Related Research and Development </div> <div> The US spends more than any other country on health-related R&D. </div> <div> In 1989, the federal government spent $9.2 billion on R&D, while private industry spent an additional $9.4 billion. </div> <div> Total US R&D expenditures rose 50% from 1983 to 1992. </div> <div> NIH receives about half of US government R&D funding. </div> <div> NIH spent more on basic research ($4.1 billion in 1989) than for clinical trials of medical treatments on humans ($519 million in 1989). </div> <div> Most of the clinical trials evaluate new treatment protocols for cancer and complications of AIDS, and do not study existing treatments, even though their effectiveness is in many cases unknown and questionable. </div> <div> In 1990, the NIH had just begun to do meta-analysis and cost-effectiveness analysis. </div> <div> Pharmaceutical and Medical-Device Industries </div> <div> About two-thirds of the industry's $9.4 billion budget went to drug research; device manufacturers spent the remaining one-third. </div> <div> In addition to R&D, the medical industry spent 24% of total sales on promoting their products and 15% of total sales on development. </div> <div> Total marketing expenses in 1990 were over $5 billion. </div> <div> Many products provide no benefit over existing products. </div> <div> Public and private health care consumers buy these products. </div> <div> If health care spending is perceived as a problem, a highly profitable drug industry exacerbates the problem. </div> <div> Controlling Health Care Technology </div> <div> The FDA ensures the safety and efficacy of drugs, biologics, and medical devices. </div> <div> The FDA does not consider costs of therapy. </div> <div> The FDA does not consider the effectiveness of a therapy. </div> <div> The FDA does not compare a product to currently marketed products </div> <div> The FDA does not consider nondrug alternatives for a given clinical problem. </div> <div> It costs $200 million in development costs to bring a new drug to market. AIDS-drug interest groups forced new regulations that speed up the approval process. </div> <div> Such drugs should be subject to greater post-marketing surveillance requirements. As of 1995, these provisions had not yet come into play. </div> <div> Many argue that reductions in the pre-approval testing of drugs open the possibility of significant undiscovered toxicities. </div> <div> Health Care Technology Assessment </div> <div> Failure to evaluate technology was a focus of a 1978 report from OTA with examples of many common medical practices supported by limited published data (10-20%). </div> <div> In 1978, Congress created the National Center for Health Care Technology (NCHCT) to advise Medicare and Medicaid. </div> <div> With an annual budget of $4 million, NCHCT published three broad assessments of high-priority technologies and made about 75 coverage recommendations to Medicare. </div> <div> Congress disbanded NCHCT in 1981. The medical profession opposed it from the beginning. The AMA testified before Congress in 1981 that “clinical policy analysis and judgments are better made-and are being responsibly made-within the medical profession. Assessing risks and costs, as well as benefits, has been central to the exercise of good medical judgment for decades.” </div> <div> The medical device lobby also opposed government oversight by NCHCT. </div> <div> Examples of Lack of Proper Management of HealthCare </div> <div> Treatments for Coronary Artery Disease </div> <div> Since the early 1970s, the number of coronary artery bypass surgeries (CABGS) has risen rapidly without government regulation or clinical trials. </div> <div> Angioplasty for single vessel disease was introduced in 1978. The first published trial of angioplasty versus medical treatment was done in 1992. </div> <div> Angioplasty did not reduce the number of CABGS, as was promoted. </div> <div> Both procedures increase in number every year as the patient population grows older and sicker. </div> <div> Rates of use are higher in white patients and private insurance patients, and vary greatly by geographic region, suggesting that use of these procedures is based on non-clinical factors. </div> <div> As of 1995, the NIH consensus program had not assessed CABGS since 1980 and had never assessed angioplasty. </div> <div> RAND researchers evaluated CABGS in New York in 1990. They reviewed 1,300 procedures and found 2% were inappropriate, 90% were appropriate, and 7% were uncertain. For 1,300 angioplasties, 4% were inappropriate and 38% uncertain. Using RAND methodologies, a panel of British physicians rated twice as many procedures “inappropriate” as did a US panel rating the same clinical cases. The New York numbers are in question because New York State limits the number of surgery centers, and the per-capita supply of cardiac surgeons in New York is about one-half of the national average. </div> <div> The estimated five-year cost is $33,000 for angioplasty and $40,000 for CABGS. Angioplasty did not lower costs, due to its high failure rates. </div> <div> Computed Tomography (CT) </div> <div> The first CT scanner in the US was installed at the Mayo Clinic in 1973. By 1992, the number of operational CT scanners in the US had grown to 6,060. By comparison, in 1993 there were 216 CT units in Canada . </div> <div> There is little information available on how CT scans improve or affect patient outcomes </div> <div> In some institutions, up to 90% of scans performed were negative. </div> <div> Approval by the FDA was not required for CT scanners, nor was any evidence of safety or efficacy. </div> <div> Magnetic Resonance Imaging (MRI) </div> <div> MRIs were introduced in Great Britain in 1978 and in the US in 1980. By 1988, there were 1,230 units and by 1992 between 2,800 and 3,000. </div> <div> A definitive review published in 1994 found less than 30 studies of 5,000 that were prospective comparisons of diagnostic accuracy or therapeutic choice. </div> <div> The American College of Physicians assessed MRI studies and rated 13 of 17 trials as “weak,” i.e., lacking data concerning therapeutic impact or patient outcomes. </div> <div> The OTA concluded: “It is evident that hospitals, physician-entrepreneurs, and medical device manufacturers have approached MRI and CT as commodities with high-profit potential, and decision-making on the acquisition and use of these procedures has been highly influenced by this approach. Clinical evaluation, appropriate patient selection, and matching supply to legitimate demand might be viewed as secondary forces.” </div> <div> Laparoscopic Surgery </div> <div> Laparoscopic cholecystectomy was introduced at a professional surgical society meeting in late 1989. By 1992, 85% of all cholecystectomies were performed laparoscopically. </div> <div> There was an associated increase of 30% in the number of cholecystectomies performed. </div> <div> Because of the increased volume of gall bladder operations, their total cost increased 11.4% between 1988 and 1992, despite a 25.1% drop in the average cost per surgery. </div> <div> The mortality rate for gall bladder surgeries did not decline as a result of the lower risk because so many more were performed. </div> <div> When studies were finally done on completed cases, the results showed that laparoscopic cholecystectomy was associated with reduced inpatient duration, decreased pain, and a shorter period of restricted activity. But rates of bile duct and major vessel injury increased and it was suggested that these rates were worse for people with acute cholecystitis. No clinical trials had been done to clarify this issue. </div> <div> Patient demand, fueled by substantial media attention, was a major force in promoting rapid adoption of these procedures. </div> <div> The major manufacturer of laparoscopic equipment produced the video that introduced the procedure in 1989. </div> <div> Doctors were given two-day training seminars before performing the surgery on patients. </div> <div> Infant Mortality </div> <div> In 1990, the US ranked 24th in infant mortality of 38 developed countries with a rate of 9.2 deaths per 1,000 live births. </div> <div> US black infant mortality is 18.6 per 1,000 live births, compared to 8.8 for whites. </div> <div> Screening for Breast Cancer </div> <div> Mammography screening in women under 50 has always been a subject of debate. </div> <div> In 1992, the Canadian National Breast Cancer Study of 50,000 women showed that mammography had no effect on mortality for women aged 40-50. </div> <div> The National Cancer Institute (NCI) refused to change its recommendations on mammography. </div> <div> The American Cancer Society decided to wait for more studies on mammography. </div> <div> In December 1993, NCI announced that women over 50 should have routine screenings every one to two years but that younger women would derive no benefit from mammography. </div> <div> Summary </div> <div> The OTA concluded: “There are no mechanisms in place to limit dissemination of technologies regardless of their clinical value.” </div> <div> Shortly after the release of this report, the OTA was disbanded. </div> <div> References </div> <div> Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. <I>JAMA </I>. 1998 Apr 15;279(15):1200-5. </div> <div> Rabin R. Caution about overuse of antibiotics. <I>Newsday </I>. September 18, 2003 .</div> <div> 2a. Centers for Disease Control and Prevention. CDC antimicrobial resistance and antibiotic resistance-general information. Available at: http://www.cdc.gov/drugresistance/community/. Accessed December 13, 2003 . </div> <div> For calculations detail, see “Unnecessary Surgery.” Sources: HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville , MD. Available at: http://www.ahrq.gov/data/hcup/hcupnet.htm . Accessed December 18, 2003 . US Congressional House Subcommittee Oversight Investigation. <I>Cost and Quality of Health Care: Unnecessary Surgery </I>. Washington , DC : Government Printing Office;1976. Cited in: McClelland GB, Foundation for Chiropractic Education and Research. Testimony to the Department of Veterans Affairs' Chiropractic Advisory Committee. March 25, 2003 . </div> <div> For calculations detail, see “Unnecessary Hospitalization.” Sources: HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville , MD. Available at: http://www.ahrq.gov/data/hcup/hcupnet.htm . Accessed December 18, 2003 . Siu AL, Sonnenberg FA, Manning WG, et al. Inappropriate use of hospitals in a randomized trial of health insurance plans. <I>N Engl J Med </I>. 1986 Nov 13;315(20):1259-66. Siu AL, Manning WG, Benjamin B. Patient, provider and hospital characteristics associated with inappropriate hospitalization. <I>Am J Public Health </I>. 1990 Oct;80(10):1253-6. Eriksen BO, Kristiansen IS, Nord E, et al. The cost of inappropriate admissions: a study of health benefits and resource utilization in a department of internal medicine. <I>J Intern Med </I>. 1999 Oct;246(4):379-87. </div> <div> U.S. National Center for Health Statistics. National Vital Statistics Report, vol. 51, no. 5, March 14, 2003 . </div> <div> Thomas, EJ, Studdert DM, Burstin HR, et al. Incidence and types of adverse events and negligent care in Utah and Colorado. Med Care. 2000 Mar;38(3):261-71. Thomas, EJ, Studdert DM, Newhouse JP, et al. Costs of medical injuries in Utah and Colorado . <I>Inquiry </I>. 1999 Fall;36(3):255-64. [Two references.] </div> <div> Xakellis GC, Frantz R, Lewis A. Cost of pressure ulcer prevention in long-term care. <I>Am Geriatr Soc </I>. 1995 May;43(5):496-501. </div> <div> Barczak CA, Barnett RI, Childs EJ, Bosley LM. Fourth national pressure ulcer prevalence survey. <I>Adv Wound Care </I>. 1997 Jul-Aug;10(4):18-26. </div> <div> Weinstein RA. Nosocomial Infection Update. <I>Emerg Infect Dis </I>. 1998 Jul-Sep;4(3):416-20. </div> <div> Fourth Decennial International Conference on Nosocomial and Healthcare-Associated Infections. Morbidity and Mortality Weekly Report. February 25, 2000 , Vol. 49, No. 7, p.138. </div> <div> Burger SG, Kayser-Jones J, Bell JP. Malnutrition and dehydration in nursing homes: key issues in prevention and treatment. National Citizens' Coalition for Nursing Home Reform. June 2000. Available at: http://www.cmwf.org/programs/elders/burger_mal_386.asp. Accessed December 13, 2003 . </div> <div> Starfield B. Is US health really the best in the world? <I>JAMA </I>. 2000 Jul 26;284(4):483-5. Starfield B. Deficiencies in US medical care. <I>JAMA </I>. 2000 Nov 1;284(17):2184-5. </div> <div> HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville , MD. Available at: http://www.ahrq.gov/data/hcup/hcupnet.htm . Accessed December 18, 2003 . </div> <div> Nationwide poll on patient safety: 100 million Americans see medical mistakes directly touching them [press release]. McLean , VA : National Patient Safety Foundation; October 9, 1997 . </div> <div> The Society of Actuaries Health Benefit Systems Practice Advancement Committee. <I>The Troubled Healthcare System in the US </I>. September 13, 2003 . Available at: http://www.soa.org/sections/troubled_healthcare.pdf. Accessed December 18, 2003 . </div> <div> Leape LL. Error in medicine. <I>JAMA </I>. 1994 Dec 21;272(23):1851-7. </div> <div> a.Brennan TA, Leape LL, Laird NM , et al. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. <I>N Engl J Med </I>. 1991 Feb 7;324(6):370-6. </div> <div> Campbell EG, Weissman JS, Clarridge B, Yucel R, Causino N, Blumenthal D. Characteristics of medical school faculty members serving on institutional review boards: results of a national survey. <I>Acad Med </I>. 2003 Aug;78(8):831-6. </div> <div> Possible conflict of interest within medical profession. HealthDayNews. August 15, 2003 . </div> <div> World Health Organization. Press Release Bulletin #9. December 17, 2001 . </div> <div> Angell M. Is academic medicine for sale? <I>N Engl J Med </I>. 2000 May 18;342(20):1516-8. </div> <div> McKenzie J. Conflict of interest? Medical journal changes policy of finding independent doctors [transcript]. ABC News. June 12, 2002 . </div> <div> Crossen C. <I>Tainted Truth: The Manipulation of Fact in America </I>. New York , NY : Simon & Schuster; 1994. </div> <div> Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. <I>JAMA </I>. 1995 Jul 5;274(1):29-34. </div> <div> Vincent C, Stanhope N, Crowley-Murphy M. Reasons for not reporting adverse incidents: an empirical study. <I>J Eval Clin Pract </I>. 1999 Feb;5(1):13-21. </div> <div> Wald H, Shojania KG. Incident reporting. In: Shojania KG, Duncan BW, McDonald KM, et al, eds. <I>Making Health Care Safer: A Critical Analysis of Patient Safety Practices </I>. Rockville , MD : Agency for Healthcare Research and Quality; 2001:chap 4. Evidence Report/Technology Assessment No. 43. AHRQ publication 01-E058. </div> <div> Grinfeld MJ. The debate over medical error reporting. <I>Psychiatric Times </I>. April 2000. </div> <div> King G III, Hermodson A. Peer reporting of coworker wrongdoing: A qualitative analysis of observer attitudes in the decision to report versus not report unethical behavior. <I>Journal of Applied Communication Research </I>. 2000;(28), 309-29. </div> <div> Gilman AG, Rall TW, Nies AS , Taylor P. Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York , NY : Pergamon Press; 1996. </div> <div> Kolata G. New York Times News Service. Who cares when our drugs fail? <I>San Diego Union-Tribune </I>. October 15, 1997 :E-1,5. </div> <div> Melmon KL, Morrelli HF, Hoffman BB, Nierenberg DW, eds. <I>Melmon and Morrelli's Clinical Pharmacology: Basic Principles in Therapeutics </I>. 3rd ed. New York , NY : McGraw-Hill, Inc., 1992. </div> <div> Moore TJ, Psaty BM, Furberg CD. Time to act on drug safety <I>. JAMA </I>. 1998 May 20, 279 (19):1571-3.</div> <div> 32 a.Cullen DJ, Bates DW, Small SD, Cooper JB, Nemeskal AR , Leape LL. The incident reporting system does not detect adverse drug events: a problem for quality improvement. <I>Jt Comm J Qual Improv </I>. 1995 Oct;21(10):541-8. </div> <div> Bates DW. Drugs and adverse drug reactions: how worried should we be? <I>JAMA </I>. 1998 Apr 15;279(15):1216-7. </div> <div> Dickinson, JG. FDA seeks to double effort on confusing drug names. <I>Dickinson 's FDA Review </I>. 2000 Mar;7(3):13-4. </div> <div> Cohen JS. <I>Overdose: The Case Against the Drug Companies </I>. New York , NY : Tarcher-Putnum; 2001. </div> <div> Stenson J. Few residents report medical errors, survey finds. Reuters Health. February 21, 2003 . </div> <div> Survey by Henry J. Kaiser Family Foundation, Harvard School of Public Health. Methodology: Fieldwork conducted by ICR - International Communications Research, April 11- June 11, 2002 </div> <div> Bond CA, Raehl CL, Franke T. Clinical pharmacy services, hospital pharmacy staffing, and medication errors in United States hospitals. <I>Pharmacotherapy </I>. 2002 Feb;22(2):134-47. </div> <div> Barker KN, Flynn EA, Pepper GA, Bates DW, Mikeal RL. Medication errors observed in 36 health care facilities. <I>Arch Intern Med </I>. 2002 Sep 9;162(16):1897-903. </div> <div> LaPointe NM , Jollis JG. Medication errors in hospitalized cardiovascular patients. <I>Arch Intern Med </I>. 2003 Jun 23;163(12):1461-6. </div> <div> Forster AJ, Murff HJ, Peterson JF, Gandhi TK, Bates DW. The incidence and severity of adverse events affecting patients after discharge from the hospital. <I>Ann Intern Med </I>. 2003 Feb 4;138(3):161-7. </div> <div> Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. <I>N Engl J Med </I>. 2003 Apr 17;348(16):1556-64. </div> <div> Medication side effects strike 1 in 4. Reuters. April 17, 2003 . </div> <div> Vastag B. Pay attention: ritalin acts much like cocaine. <I>JAMA </I>. 2001 Aug 22-29;286(8):905-6. </div> <div> Rosenthal MB, Berndt ER, Donohue JM, Frank RG, Epstein AM. Promotion of prescription drugs to consumers. <I>N Engl J Med </I>. 2002 Feb 14;346(7):498-505. </div> <div> Wolfe SM. Direct-to-consumer advertising-education or emotion promotion? <I>N Engl J Med </I>. 2002 Feb 14;346(7):524-6. </div> <div> Ibid. </div> <div> US General Accounting Office. <I>Report to the Chairman, Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government Operations, House of Representatives: FDA Drug Review Postapproval Risks 1976-85 </I>. Washington , DC : US General Accounting Office; 1990:3. </div> <div> Drug giant accused of false claims. MSNBC News. July 11, 2003 . Available at: http://msnbc.com/news/937302.asp?0sl=-42&cp1=1. Accessed December 17,2003 . </div> <div> Suh DC , Woodall BS, Shin SK , Hermes-De Santis ER. Clinical and economic impact of adverse drug reactions in hospitalized patients. <I>Ann Pharmacother </I>. 2000 Dec;34(12):1373-9. </div> <div> Egger WA. Antibiotic resistance: unnatural selection in the office and on the farm. <I>Wisconsin Medical Journal </I>. August 2002. </div> <div> Nash DR, Harman J, Wald ER, Kelleher KJ. Antibiotic prescribing by primary care physicians for children with upper respiratory tract infections. <I>Arch Pediatr Adolesc Med </I>. 2002 Nov;156(11):1114-9. </div> <div> Schindler C, Krappweis J, Morgenstern I, Kirch W. Prescriptions of systemic antibiotics for children in Germany aged between 0 and 6 years. <I>Pharmacoepidemiol Drug Saf </I>. 2003 Mar;12(2):113-20. </div> <div> Finkelstein JA, Stille C, Nordin J, et al. Reduction in antibiotic use among US children, 1996-2000. <I>Pediatrics </I>. 2003 Sep;112(3 Pt 1):620-7. </div> <div> Linder JA, Stafford RS. Antibiotic treatment of adults with sore throat by community primary care physicians: a national survey, 1989-1999. <I>JAMA </I>. 2001 Sep 12;286(10):1181-6. </div> <div> Drug resistance page. Centers for Disease Control and Prevention website. Available at: http://www.cdc.gov/drugresistance/community/. Accessed December 17, 2003 . </div> <div> Available at: http://www.health.state.ok.us/program/cdd/ar/. Accessed December 17, 2003 . </div> <div> Available at: http://www.librainitiative.com/life/en/libra_initiative.html. Accessed December 17, 2003 . </div> <div> Ohlsen K, Ternes T, Werner G, et al. Impact of antibiotics on conjugational resistance gene transfer in Staphylococcus aureus in sewage. <I>Environ Microbiol </I>. 2003 Aug;5(8):711-6. </div> <div> Pawlowski S, Ternes T, Bonerz M, et al. Combined in situ and in vitro assessment of the estrogenic activity of sewage and surface water samples. <I>Toxicol Sci </I>. 2003 Sep;75(1):57-65. Epub 2003 Jun 12. </div> <div> Ternes TA, Stuber J, Herrmann N, et al. Ozonation: a tool for removal of pharmaceuticals, contrast media and musk fragrances from wastewater? <I>Water Res </I>. 2003 Apr;37(8):1976-82. </div> <div> Ternes TA, Meisenheimer M, McDowell D, et al. Removal of pharmaceuticals during drinking water treatment. <I>Environ Sci Technol </I>. 2002 Sep 1;36(17):3855-63. </div> <div> Ternes T, Bonerz M, Schmidt T. Determination of neutral pharmaceuticals in wastewater and rivers by liquid chromatography-electrospray tandem mass spectrometry. <I>J Chromatogr A </I>. 2001 Dec 14;938(1-2):175-85. </div> <div> Golet EM, Alder AC, Hartmann A, Ternes TA, Giger W. Trace determination of fluoroquinolone antibacterial agents in urban wastewater by solid-phase extraction and liquid chromatography with fluorescence detection. <I>Anal Chem </I>. 2001 Aug 1;73(15):3632-8. </div> <div> Daughton CG, Ternes TA. Pharmaceuticals and personal care products in the environment: agents of subtle change? <I>Environ Health Perspect </I>. 1999 Dec;107 Suppl 6:907-38. </div> <div> Hirsch R, Ternes T, Haberer K, Kratz KL. Occurrence of antibiotics in the aquatic environment. <I>Sci Total Environ </I>. 1999 Jan 12;225(1-2):109-18. </div> <div> Ternes TA, Stumpf M, Mueller J, Haberer K, Wilken RD , Servos M. Behavior and occurrence of estrogens in municipal sewage treatment plants-I. Investigations in Germany , Canada and Brazil . <I>Sci Total Environ </I>. 1999 Jan 12;225(1-2):81-90. </div> <div> Hirsch R, Ternes TA, Haberer K, Mehlich A, Ballwanz F, Kratz KL. Determination of antibiotics in different water compartments via liquid chromatography-electrospray tandem mass spectrometry. <I>J Chromatogr A </I>. 1998 Jul 31;815(2):213-23. </div> <div> Coste J, Hanotin C, Leutenegger E. Prescription of non-steroidal anti-inflammatory agents and risk of iatrogenic adverse effects: a survey of 1072 French general practitioners. <I>Therapie </I>. 1995 May-Jun;50(3):265-70. </div> <div> Kouyanou K, Pither CE, Wessely S. Iatrogenic factors and chronic pain. <I>Psychosom Med </I>. 1997 Nov-Dec;59(6):597-604. </div> <div> Abel U. Chemotherapy of advanced epithelial cancer-a critical review. <I>Biomed Pharmacother </I>. 1992;46(10):439-52. </div> <div> Schulman KA, Stadtmauer EA, Reed SD , et al. Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. <I>Bone Marrow Transplant </I>. 2003 Feb;31(3):205-10. </div> <div> Kaufman, M. Drugmaker to pay FDA $500 million. Manufacturing problems found at schering-plough <I>. The Washington Post </I>. May 18, 2002 :A01. </div> <div> US Congressional House Subcommittee Oversight Investigation. <I>Cost and Quality of Health Care: Unnecessary Surgery </I>. Washington , DC : Government Printing Office;1976. Cited in: McClelland GB, Foundation for Chiropractic Education and Research. Testimony to the Department of Veterans Affairs' Chiropractic Advisory Committee. March 25, 2003 . </div> <div> Leape LL. Unnecessary surgery. <I>Health Serv Res </I>. 1989 Aug;24(3):351-407. </div> <div> McClelland GB, Foundation for Chiropractic Education and Research. Testimony to the Department of Veterans Affairs' Chiropractic Advisory Committee. March 25, 2003 . </div> <div> Coile RC Jr. Internet-driven surgery. <I>Russ Coiles Health Trends </I>. 2003 Jun;15(8):2-4. </div> <div> Guarner V. Unnecessary operations in the exercise of surgery. A topic of our times with serious implications in medical ethics. <I>Gac Med Mex </I>. 2000 Mar-Apr;136(2):183-8. </div> <div> Rutkow IM. Surgical operations in the United States : 1979 to 1984. <I>Surgery </I>. 1987 Feb;101(2):192-200. </div> <div> Rutkow IM. Surgical operations in the United States . Then (1983) and now (1994). <I>Arch Surg </I>. 1997 Sep;132(9):983-90. </div> <div> Linnemann MU, Bulow HH. Infections after insertion of epidural catheters. <I>Ugeskr Laeger </I>. 1993 Jul 26;155(30):2350-2 </div> <div> Seres JL, Newman RI . Perspectives on surgical indications. Implications for controls. <I>Clin J Pain </I>. 1989 Jun;5(2):131-6. </div> <div> Chassin MR, Kosecoff J, Park RE, et al. Does inappropriate use explain geographic variations in the use of health care services? A study of three procedures. <I>JAMA. </I>1987 Nov 13;258(18):2533-7. </div> <div> Office of Technology Assessment, US Congress. <I>Assessing the Efficacy and Safety of Medical Technologies. </I>Washington DC : Office of Technology Assessment, US Congress; 1978. </div> <div> Tunis SR, Gelband H. Health care technology in the United States . <I>Health Policy </I>. 1994 Oct-Dec;30(1-3):335-96. </div> <div> Zhan C, Miller M. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. <I>JAMA </I>. 2003;290:1868-1874. </div> <div> Injuries in hospitals pose a significant threat to patients and a substantial increase in health care charges [press release]. Rockville , MD : Agency for Healthcare Research and Quality. October 7, 2003 . http://www.ahrq.gov/news/ress/pr2003/injurypr.htm. </div> <div> Weingart SN, Iezzoni LI. Looking for medical injuries where the light is bright. <I>JAMA </I>. 2003 Oct 8 ;290(14):1917-9. </div> <div> MacMahon B. Prenatal x-ray exposure and childhood cancer. <I>J Natl Cancer Inst </I>. 1962 May;28:1173-91. </div> <div> Health Physics Society. Available at: http://hps.org/publicinformation/ate/q1084.html. Accessed December 17, 2003 . </div> <div> Gofman JW. <I>Radiation from Medical Procedures in the Pathogenesis of Cancer and Ischemic Heart Disease: Dose-Response Studies with Physicians per 100,000 </I>Population. San Francisco , CA : CNR Books; 1999. </div> <div> Gofman J W. <I>Preventing Breast Cancer: The Story of a Major, Proven, Preventable Cause of This Disease </I>. 2nd ed. San Francisco , CA : CNR Books; 1996. </div> <div> Sarno JE. <I>Healing Back Pain: The Mind-Body Connection </I>. Warner Books; 1991. </div> <div> Siu AL, Sonnenberg FA, Manning WG, et al. Inappropriate use of hospitals in a randomized trial of health insurance plans. <I>N Engl J Med </I>. 1986 Nov 13;315(20):1259-66. </div> <div> Siu AL, Manning WG, Benjamin B. Patient, provider and hospital characteristics associated with inappropriate hospitalization. <I>Am J Public Health </I>. 1990 Oct;80(10):1253-6. </div> <div> Eriksen BO, Kristiansen IS, Nord E, et al. The cost of inappropriate admissions: a study of health benefits and resource utilization in a department of internal medicine. <I>J Intern Med </I>. 1999 Oct;246(4):379-87. </div> <div> Showalter E. <I>Hystories: Hysterical Epidemics and Modern Media </I>. New York , NY : Columbia University Press; 1997. </div> <div> Fugh-Berman A. Alternative healing. In: Smith B, Steinem G, Mink G, Navarro M, and Mankiller W, eds. The Reader's Companion to U.S. Women's History. New York , NY : Houghton Mifflin; 1998. Available at: http://college.hmco.com/history/readerscomp/women/html/wh_001200_alternativeh.htm . </div> <div> Thacker SB, Stroup D, Chang M. Continuous electronic heart rate monitoring for fetal assessment during labor (Cochrane Review). In: The Cochrane Library, issue 1, 2003. Oxford : Update Software. </div> <div> Cole C. Admission electronic fetal monitoring does not improve neonatal outcomes <I>. J Fam Pract </I>. 2003 Jun;52(6):443-4. </div> <div> Nelson HD, Humphrey LI, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. <I>JAMA </I>. 2002 Aug 21;288(7):872-81. </div> <div> Nelson HD. Assessing benefits and harms of hormone replacement therapy: clinical applications. <I>JAMA </I>. 2002 Aug 21;288(7):882-4 </div> <div> Fletcher SW, Colditz GA. Failure of estrogen plus progestin therapy for prevention. <I>JAMA </I>. 2002 Jul 17;288(3):366-8. </div> <div> Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. <I>JAMA </I>. 2002 Jul 17;288(3):321-33. </div> <div> Rutkow IM. Obstetric and gynecologic operations in the United States , 1979 to 1984. <I>Obstet Gynecol </I>. 1986 Jun;67(6):755-9. </div> <div> <I>Family Practice News </I>. February 15, 1995 : 29. </div> <div> Sakala C. Medically unnecessary cesarean section births: introduction to a symposium. <I>Soc Sci Med </I>. 1993 Nov;37(10):1177-98. </div> <div> VanHam MA, van Dongen PW, Mulder J. Maternal consequences of cesarean section. A retrospective study of intra-operative and postoperative maternal complications of cesarean section during a 10-year period. <I>Eur J Obstet Reprod Biol </I>. 1997 Jul;74(1):1-6. </div> <div> Weiner J. Smoking and cancer: the cigarette papers: how the industry is trying to smoke us all <I>. The Nation </I>. January 1, 1996 :11-18. </div> <div> Tobacco.org. Tobacco timeline. Available at: http://www.tobacco.org/resources/history/tobacco_history.html. Acccessed December 16, 2003 . </div> <div> Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. 2002. Timing of new black box warnings and withdrawals for prescription medications. <I>JAMA </I>. 2002 May 1;287(17):2215-20. </div> <div> Injuryboard.com. General Accounting Office study sheds light on nursing home abuse. July 17, 2003 . Available at: http://www.injuryboard.com/view.cfm/Article=3005. Accessed December 17, 2003 . </div> <div> Weingart SN, McL Wilson R, Gibberd RW, Harrison B. Epidemiology of medical error. <I>West J Med </I>. 2000 Jun;172(6):390-3. </div> <div> Blendon R, Schoen C, et al. Five nation survey exposes flaws in the U.S. health care system. <I>Health Affairs </I>. May/June 2002. </div> <div> Institute of Medicine . <I>Care Without Coverage: Too Little, Too Late </I>. May 21, 2002 . <I>A Shared Destiny: Community Effects of Uninsurance </I>. March 6, 2003 . </div> <div> US Department of Health and Human Services and US Department of Justice. Health Care Fraud and Abuse Control Program Annual Report for FY 1998. April 1999. Health Care Fraud and Abuse Control Program Annual Report for FY 2001. April 2002. </div> <div> Abuse of residents is a major problem in U.S. nursing homes [transcript]. CNN television. July 30, 2001</div> <div> 117 a. Available at: http://www.house.gov/waxman. Accessed December 17, 2003 . </div> <div> Mitka M. Unacceptable nursing home deaths unautopsied. <I>JAMA </I>. 1998 Sep 23-30;280(12):1038-9 </div> <div> New data is in on North Carolina 's nursing home residents. Medical Review of North Carolina, Inc. July 21, 2003 . </div> <div> Weinstein RA. Nosocomial infection update. <I>Emerg Infect Dis </I>. 1998 Jul-Sep;4(3):416-20. </div> <div> Centers for Medicare & Medicaid Services. <I>Report to Congress: Appropriateness of Minimum Nurse Staffing Ratios In Nursing Homes: Phase II Final Report </I>. December 24, 2001 . </div> <div> Consumer group criticizes Thompson letter dismissing report on dangerous staffing levels in nursing homes [news release]. Washington , DC : National Citizens' Coalition for Nursing Home Reform. March 22, 2002 . </div> <div> Bergstrom N, Braden B, Kemp M, Champagne M, Ruby E. Multi-site study of incidence of pressure ulcers and the relationship between risk level, demographic characteristics, diagnoses and prescription of preventive interventions <I>. J Am Geriatr Soc </I>. 1996 Jan;44(1):22-30. </div> <div> Miles SH. Concealing accidental nursing home deaths. <I>HEC Forum </I>. 2002 Sep;14(3):224-34. </div> <div> Corey TS, Weakley-Jones B, Nichols GR 2nd, Theuer HH. Unnatural deaths in nursing home patients. <I>J Forensic Sci </I>. 1992 Jan;37(1):222-7. </div> <div> Lloyd-Jones DM, Martin DO, Larson MG, Levy D. Accuracy of death certificates for coding coronary heart disease as the cause of death. <I>Ann Intern Med </I>. 1998 Dec 15;129(12):1020-6. </div> <div> Thomas DR , Zdrowski CD, Wilson MM, et al. Malnutrition in subacute care. <I>Am J Clin Nutr </I>. 2002 Feb;75(2):308-13. </div> <div> Robinson BE. Death by destruction of will. Lest we forget. <I>Arch Intern Med </I>. 1995 Nov 13;155(20):2250-1. </div> <div> Capezuti E, Strumpf NE, Evans LK, Grisso JA, Maislin G. The relationship between physical restraint removal and falls and injuries among nursing home residents <I>. J Gerontol A Biol Sci Med Sci </I>. 1998 Jan;53(1):M47-52. </div> <div> Phillips CD, Hawes C, Fries BE. Reducing the use of physical restraints in nursing homes: will it increase costs? <I>Am J Public Health </I>. 1993 Mar;83(3):342-8. </div> <div> Miles SH, Irvine P. Deaths caused by physical restraints. <I>Gerontologist </I>. 1992 Dec;32(6):762-6. </div> <div> Annas GJ. The last resort-the use of physical restraints in medical emergencies. <I>N Engl J Med </I>. 1999 Oct 28;341(18):1408-12. </div> <div> Parker K, Miles SH. Deaths caused by bedrails. <I>J Am Geriatr Soc </I>. 1997 Jul;45(7):797-802. </div> <div> Miles SH. Concealing accidental nursing home deaths. <I>HEC Forum </I>. 2002 Sep;14(3):224-34. </div> <div> Katz PR, Seidel G. Nursing home autopsies. Survey of physician attitudes and practice patterns. <I>Arch Pathol Lab Med </I>. 1990 Feb;114(2):145-7. </div> <div> Overmedication of U.S. seniors. Reuters Health. May 21, 2003 . </div> <div> Average number of prescriptions by HMOs increases. <I>Drug Benefit Trends </I>. 2002 Sep 12;14(8). </div> <div> Kaiser Family Foundation. <I>Prescription Drug Trends </I>. November 2001. </div> <div> Williams BR, Nichol MB, Lowe B, Yoon PS, McCombs JS, Margolies J. Medication use in residential care facilities for the elderly. <I>Ann Pharmacother </I>. 1999 Feb;33(2):149-55. </div> <div> AARP. Medicare and prescription drugs. Available at: http://www.aarp.org/prescriptiondrugs. Accessed December 16, 2003 . </div> <div> California reaches $100 million multi-state settlement with drug giant Mylan over alleged price-fixing scheme [press release]. Sacramento , CA : Office of the Attorney General, Department of Justice, State of California ; July 12, 2000 . </div> <div> Attorney general reaches settlement with drug giant. WRAL News. March 7, 2003 . Available at: . <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>http://www.wral.com/money/2026364/detail.html </U></FONT>. Accessed December 16, 2003 . </div> <div> Blowing the final whistle. The Observer. November 25, 2001 . Available at: http://education.guardian.co.uk/businessofresearch/comment/0,9976,606260,00.html. Accessed December 16, 2003 . </div> <div> AARP. Are food supplements for me. Available at: http://www.aarp.org/Articles/a2003-03-07-supplements.html. Accessed December 16,2003 . </div> <div> Bernabei R, Gambassi G, Lapane K, et al. Management of pain in elderly patients with cancer. SAGE study group. Systematic assessment of geriatric drug use via epidemiology. <I>JAMA </I>. 1998 Jun 17;279(23):1877-82. </div> <div> Associated Press. Panel names estrogen as carcinogen. <I>The Washington Post </I>. December 16, 2000 :A05. </div> <div> Estrogen hikes ovarian cancer risk. MSNBC staff and wire reports. July 16, 2002 . Grady D. Study recommends NOT using hormone therapy for bone loss. <I>New York Times </I>. October 1, 2003 . </div> <div> Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. <I>JAMA </I>. 2003 Oct 1;290(13):1739-48. </div> <div> Chlebowski RT, Hendrix SL, Langer RD , et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized trial. <I>JAMA </I>. 2003 Jun 25;289(24):3243-53. </div> <div> Wassertheil-Smoller S, Hendrix SL, Limacher M, et al <B>. </B>Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. <I>JAMA </I>. 2003 May 28;289(20):2673-84. </div> <div> Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative memory study: a randomized controlled trial. <I>JAMA </I>2003;289:2651-62 . </div> <div> Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. <I>Lancet </I>. 2003 Aug 9;362(9382):419-27. </div> <bR> <bR> <bR> <bR> <bR> <bR> <bR> </td> </tr></table></body>