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Natural  Safe

Natural  Safe. Catherine Hammett-Stabler, PhD, DABCC Department of Pathology and Laboratory Medicine University of North Carolina. Toxicology of CAMs. CAMs Regulations Impact on healthcare Toxicology Interactions with drugs

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Natural  Safe

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  1. Natural  Safe Catherine Hammett-Stabler, PhD, DABCC Department of Pathology and Laboratory Medicine University of North Carolina

  2. Toxicology of CAMs CAMs Regulations Impact on healthcareToxicologyInteractions with drugs IdentificationDirect ToxicityAdulterants and Contaminants Inappropriate use

  3. Regulation of Herbals and Supplements • 1994: Dietary Supplement Health and Education Act (DSHEA) • classified as food products regardless of historical use • allows claims of: • affects toward structure or function of the body; • benefits related to correcting nutrient deficiency; • description of general well-being from consumption; • characterization of the mechanism of action

  4. DSHEA Manufacturer claims: allowed: “maintains cardiovascular function and a healthy circulatory system” not allowed: “reduces the risk of heart disease”

  5. US Healthcare Americans using an alternative therapy 34% in 1990 to 42% in 1997 20-40% self-report use to health care provider 18% use herbal with prescription medication Most popular herbal medicine, massage, megavitamins, folk remedies, energy healing, homeopathy US Consumers 1990 to 1997 $10.3 billion to $27-34 billion 2001 CAMs > $30 billion herbal supplements: > $5 billion Impact of CAMs JAMA 1998; 280:1569-75 www.nih.gov

  6. Utilization • Reasons for use • treatment of chronic diseases (OA/RA, BPH, depression), anxiety, pain, weight control • consistent with personal beliefs, values, philosophies • NOT dissatisfaction with conventional care • Herbals/Supplements • ginseng, ginkgo biloba, allium sativum, glucosamine, chondroitin, St. John’s wort, echinacea augustifolia, lecithin, creatine, serenoa repens

  7. 2000 AAPCC TESS Report • Essential oils • 4960 exposures • Mushrooms/other plants • 115779 exposures • Dietary supplements/herbals/homeopathic • 16929 exposures • outcomes • 7060 treated in health care facility • 641 major (required hospitalization) • 15 deaths www.aapcc.org

  8. Polypharmacy Investigations • Product • purity • Metabolic pathways • unknown • Preparation and use • oral, topical • teas, infusions, decoctions, extractions • dose, duration, frequency

  9. CAMs and Drug Interactions (TDM)

  10. Toxicology of Herbals • Product purity • identification, isolation, cultivation, harvesting, processing

  11. “a rose by any other name….” cohosh black or blue? New England: baneberry (Actaea species) Northern Appalachia: Cimicifuga racemosa Southern Appalachia: Caulophyllum thalictroides Identification

  12. Reported Misidentification

  13. (Mis)identification • 1997, FDA notified of 23 yo female presented w nausea, vomiting, lethargy, ‘sensation of irregular heatbeats’ • EKG: AV block  ? of digoxin toxicity • labs: digoxin 3.66 ng/mL (0.5-2) • Digibind not effective • abn EKG x 72 h • cholestyramine on day 5 NEJM 1998; 339:806-811

  14. Hx: oral regimen for ‘internal cleansing’ ~ 1 w pta 24 h patient symptomatic continued regimen x 2 d dc’d regimen x 1d restarted x 2d cleansing tablets: 14 herbs nutritional supplement: 11 herbs + amylase, cellulase liquid clay (hydrated bentonite) to mix w fibrous bulking power (psyllium-husk power) bowel normalizing capsules (Bifidobacterium infantis, B. bifidum, B. longum, Lactobacillus acidophilus, L. casei, L. plantarum, colostrum, fructo-oligo-saccharides) (Mis)identification

  15. (Mis)identification • Cleansing product (14 herbs) tested positive for cardiac glycosides • other products negative • HPLC/MS: lanatosides A, B,C • microscopic analysis: anatomical features of Digitalis lanata FDA investigation: German distributor  150 USA manufacturers/ distributors/ retailers

  16. Direct, dose-dependent comfrey: hepatotoxicity from pyrrolizidine alkaloids yohimbine: hypertension, anxiety Unpredictable, no simple dose relationship yohimbine: allergic dermatitis, progressive renal failure Toxicological Responses • Cumulative, long-term use • comfrey: veno-occlusive disease • Delayed (possible carcinogenic, teratogenic) • comfrey: possible carcinogen Baskin, AACC 2001; roundtables

  17. Toxicity by Organ Systemhematologic • agranulocytosis • yohimbin • thrombocytopenia and leukocytosis • Dysosma pleianthum (podophyllo toxin) • platelet dysfunction • danshen, dong quai, feverfew, garlic (alliin, ajoen), ginger, ginkgo (ginkgolide B), kava kava (kavain)

  18. Toxicity by Organ Systemhepatic • hepatic necrosis, hepatitis • Jin bu huan, chaparral, germander, ma huang (ephedra), Syo-saikoto-to, valerian, kava kava, Dai-saiko-to, pennyroyal (pulegone) • veno-occlusive disease • Heliotroplum species, Borago officinalis, coltsfoot, comfrey, Jamacian bush tea, Crotalaria assamica, Sencio species, Eupatroium species (pyrrolizidine alkaloids)

  19. Toxicity by Organ Systemcardiac • hypertension, myocardial infarction, stroke • ma huang (ephedra) • arrhythmias, hypokalemia/hyperkalemia • valerian root, Ch’an su, digitalis, bitterroot, danshen, oleander (cardiac glycoside-like compounds), ginger, ginkgo • paresthesias, hypotension, acidosis, hypokalemia, ventricular tachyarrhythmia, • aconitum carmichaeli (aconite) • hypertension • yohimbe (-yohimbine), licorice (glycyrrhiza), ginseng (aglycone protopanaxytriol), ginkgo

  20. Toxicity by Organ SystemCNS • Parkinsonian symptoms (ataxia, tremor, hyphonia) • kava kava • sympathomimetic toxidrome (tremors, hyperthermia, agitation, psychosis, hallucinations, seizures, stroke) • Ma huang (ephedra), nutmeg (terpines, eugenol), wormwood (thujone) • anticholinergic toxidrome (agitation, delirium tachycardia, hyperthermia) • jimsonweed, Datura metel L (scopolamine, atropine)

  21. Toxicity by Organ Systemrenal • interstitial renal fibrosis, low mw proteinuria • Aristolochia fangchi (aristolochic acid), Tripterygium wilfordii hook, comfrey • proximal tubular injury • licorice root (glycyrrhizin), germanium supplements, Mylabris phalerata/sidae (cantharidin)

  22. Toxicity by Organ Systemmucosal membrane/skin • dermatitis • cinnamon oil (cinnamaldehyde) • blisters, mucosal swelling, erosion (progressing to oliguria, acute renal failure, hematuria, coma, death) • Mylabris phalerata/sidae (cantharidin)

  23. Signs/symptoms acute hepatitis, rashes/skin flushing, CNS stimulation, agitation, psychosis, insomnia, tremor, dizziness, hyperthermia, tachycardia, acute hypertension, arrhythmias, myocarditis, MI 140 AE reported to FDA 43 44 53 (+) (~) (-) 47% 18% CV CNS 26% 10 deaths 13 permanent disability Ephedra Haller NEJM 2000;343:1833-8

  24. Piper methysticum Forster intoxicating pepper, kawa, yangona, ava, tonga, kew Rhizome 4-8% of kavalactones Kavalactones kavain, methysticin, desmethoxyyangonin, yangonin, dihydrokavain, dihydromethysticin extensive metabolism Use So Pacific: recreational beverage; medicinal: venereal diseases, chronic cystitis Anxiety, insomnia Dose 150-500 mg std extract capsules, tincture, infusion 50 - 240 mg kavalactones bid/tid Kava kava

  25. muscle relaxant, anticonvulsant inhibition of Na and Ca channels analgesic/sedative action non-opiate pathway GABAA receptors anxiolytic/psychotropic effect inhibition of norepinephrine uptake reversible inhibition of MAO-B antithrombotic activity COX inhibition  decrease in thromboxane platelet inhibition Kava kava Pharmacological Effects

  26. Drug interactions barbiturates: increased CNS depression benzodiazepines: coma ethanol: increased hypnotic effects of both, inc kava toxicity dopamine: antagonist Toxicity low doses (65 mg/d) Parkinsonism ? blockade of dopamine receptors ? genetic high doses (>400 mg/d) liver failure unk mechanism FDA warning: March 2002 Kava kava

  27. Signs/symptoms CNS: hypophonia, generalised tremor, changes in sleep, altered gait/balance liver: nausea, vomiting, fatigue, jaundice, hepatitis, cirrhosis, liver failure Laboratory  HVA   AST, ALT, -GT, bilirubin Kava kavaToxicity • Treatment biperiden, L-dopa/ carbidopa support, transplant

  28. California DHS 1998: 1-2% SFPCC calls related to herbals/supplements 5 y investigative program Asian patent medicines screen for undeclared ingredients/contaminants GC/MS, LC/MS, atomic absorption APMs 260 Heavy metals 95 Undeclared pharmaceuticals 17 Lead 24 Mercury 35 Arsenic 36 litharge (lead oxide) realgar (arenic sulfide) cinnabar (mercuric sulfide) Haller, Congressional Testimony, www.FDA.gov Ko. Clin Toxicol 1999;37:697-708 Adulterants and Contaminants

  29. Identified Adulterants and Contaminants • steroids:prednisolone, hydrocortisone, triamcinolone, methyltestosterone • benzodiazepines:diazepam, estazolam, chlordiazepoxide • heavy metals:mercury, lead, arsenic, antimony, cadmium • analgesics and NSIADs:acetaminophen, aspirin, indomethacin, mefanamic acid • other drugs and chemicals:hydrochlorothiazide, digitalis, caffeine, scopolamine, atropine, strychnine, carbamazepine, phenytoin, valproic acid, dipyrone, diacetyldiphenolisatin

  30. PC-SPES • PC-SPES (International Medical Research, aka Botaniclab, Brea, CA) • 320-mg caps; 4-9 q d • Reishi, Baikal Skullcap, Rabdosia, Dyer’s Woad, Mum, Saw Palmetto, San-Qi Ginseng, Licorice • “with documented anti-tumor, anti-viral, immune stimulating activity” • ~30-40% prostate cancer patients use CAMs • HPLC/MS: estrogenic organic compounds • 1:200 dilution estrogenic activity  1nM estradiol •  testosterone (25-494 ng/dL);  PSA; gynecomastia, breast tenderness;  libido • thrombosis (venous, pulmonary) • hematuria, bruising,  PT,  fibrinogen,  platelets

  31. 2 Feb 02; FDA recall D-198-2 • “The product contains the undeclared prescription drug: Warfarin” • company voluntarily recalled product • suggested the compound found was a phytocoumarin • previous questions of contamination with alprazolam and DES • BotanicLab closed 1 June 02 • NCCAM has 4 clinical studies on-hold

  32. Continued Mystery • 33 yo female • 3/01  5/01/01 • ~2 w hx: joint swelling, sore throat, myalgias, fever, nausea, sob • multisystem organ failure • renal, liver, respiratory • ~ 3 w hx of herbal and supplement use, some discarded • scleromyxedema

  33. Chinese Herbal Medicines • April 2001 FDA recalls > 20 products • diet and skin care products • Green Kingdom Akebia Extract; Temple of Heaven Chinese Herbs Radix aristolochiae; Qualiherb Chinese Herbal Formulas Dianthus; Formulas Ba Zheng San • Joint Ease & Verified Quality Brand Joint Comfort Complex; Rheumixx; BioSlim Doctor's Natural Weight Loss System Slim Tone Formula; Prostatin; Virginia Snake Root

  34. Chinese Herbal Medicines • Aristolochic acid • nephrotoxic and potential carcinogen • found in Aristolochia, Bragantia, Asarum species • Clinical presentation • headaches, hypertension • proteinuria,  urea nitrogen/creatinine, anemia, pancytopenia, negative autoimmune serology

  35. Aristolochic Acid Toxicity • Histological • tubular atrophy • cortical interstitial fibrosis • preservation of glomeruli and medullary tubules

  36. 74 yo male referred progressive weakness, anemia, fatigue, renal failure transformation of chronic myelomonocytic leukemia to acute myelogenous leukemia hx of herbal and naturopathic medications heavy metal screen: arsenic 940 ug/L Inappropriate Use arsenic trioxide: treatment of acute promeylocytic leukemia patient taking potassium arsenic prescribed by herbalist

  37. Our roles Remember: “it’s not nice to mess with Mother Nature….” • Educate health care providers and patients • Collect data: • detailed patient history, dose/frequency/preparation • product(s) involved / collect products • manufacturer info, lot numbers, etc • Communicate: MedWatch (FDA) • Stay informed: FDA, NIH, CDC websites

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