herbal medicine, massage, megavitamins, folk remedies

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
Impact of CAMs

• 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 gt 30 billion
• herbal supplements gt 5 billion

JAMA 1998 2801569-75 www.nih.gov
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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. Johns wort,
  echinacea augustifolia, lecithin, creatine,
  serenoa repens

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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
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Investigations

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

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CAMs and Drug Interactions (TDM)
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Toxicology of Herbals

• Product purity
• identification, isolation, cultivation,
  harvesting, processing

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Identification

• a rose by any other name.
• cohosh
• black or blue?
• New England baneberry (Actaea species)
• Northern Appalachia Cimicifuga racemosa
• Southern Appalachia Caulophyllum thalictroides

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Reported Misidentification
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(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 339806-811
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(Mis)identification

• Hx oral regimen for internal cleansing 1 w
  pta
• 24 h patient symptomatic
• continued regimen x 2 d
• dcd 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)

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(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
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Toxicological Responses

• Direct, dose-dependent
• comfrey hepatotoxicity from pyrrolizidine
  alkaloids
• yohimbine hypertension, anxiety
• Unpredictable, no simple dose relationship
• yohimbine allergic dermatitis, progressive renal
  failure

• Cumulative, long-term use
• comfrey veno-occlusive disease
• Delayed (possible carcinogenic, teratogenic)
• comfrey possible carcinogen

Baskin, AACC 2001 roundtables
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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)

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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)

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Toxicity by Organ Systemcardiac

• hypertension, myocardial infarction, stroke
• ma huang (ephedra)
• arrhythmias, hypokalemia/hyperkalemia
• valerian root, Chan 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

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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)

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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)

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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)

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Ephedra

• Signs/symptoms
• acute hepatitis, rashes/skin flushing, CNS
  stimulation, agitation, psychosis, insomnia,
  tremor, dizziness, hyperthermia, tachycardia,
  acute hypertension, arrhythmias, myocarditis, MI

Haller NEJM 20003431833-8
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Kava kava

• 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

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Kava kava Pharmacological Effects

• 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

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Kava kava

• 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 (gt400 mg/d)
• liver failure
• unk mechanism
• FDA warning March 2002

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Kava kavaToxicity

• 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

• Treatment
• biperiden,
• L-dopa/ carbidopa
• support, transplant

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Adulterants and Contaminants

• 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

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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

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PC-SPES

• PC-SPES (International Medical Research, aka
  Botaniclab, Brea, CA)
• 320-mg caps 4-9 q d
• Reishi, Baikal Skullcap, Rabdosia, Dyers 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
• 1200 dilution estrogenic activity ? 1nM
  estradiol
• ? testosterone (25-494 ng/dL) ? PSA
  gynecomastia, breast tenderness ? libido
• thrombosis (venous, pulmonary)
• hematuria, bruising, ? PT, ? fibrinogen, ?
  platelets

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• 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

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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

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Chinese Herbal Medicines

• April 2001 FDA recalls gt 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

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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

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Aristolochic Acid Toxicity

• Histological
• tubular atrophy
• cortical interstitial fibrosis
• preservation of glomeruli and medullary tubules

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Inappropriate Use

• 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

arsenic trioxide treatment of acute
promeylocytic leukemia
patient taking potassium arsenic prescribed by
herbalist
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Our roles
Remember its not nice to mess with Mother
Nature.

• Collect data
• detailed patient history, dose/frequency/preparati
  on
• product(s) involved / collect products
• manufacturer info, lot numbers, etc

• Communicate MedWatch (FDA)

• Stay informed FDA, NIH, CDC websites

• Educate health care providers and patients