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Traditional Chinese Medicine-Related Poisonings in Hong Kong

EAPCCT International Congress 2008. Traditional Chinese Medicine-Related Poisonings in Hong Kong. Dr. Tony MAK MBChB, MBA, FRCPA, FRCPath Consultant Chemical Pathologist Toxicology Reference Laboratory Hospital Authority Hong Kong, CHINA. Hong Kong Population: 7 millions

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Traditional Chinese Medicine-Related Poisonings in Hong Kong

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  1. EAPCCT International Congress 2008 Traditional Chinese Medicine-Related Poisonings in Hong Kong Dr. Tony MAK MBChB, MBA, FRCPA, FRCPath Consultant Chemical Pathologist Toxicology Reference Laboratory Hospital Authority Hong Kong, CHINA

  2. Hong Kong • Population: 7 millions • >95% are Chinese • Traditional Chinese Medicine (TCM) • a common alternative mode of healthcare • related poisonings • Toxicology Reference Lab • Founded in 2004 • TCM-related poisoning referrals: ~100/year

  3. Origin of Serious Side Effects Huxtable RJ: • Plant: toxicity unknown • Toxin is added to a non-toxic herb • Non-toxic herb: misidentified or substituted Our experience?

  4. Acute Confusion • F/26, skin problem  herbalist • Herbal broth, 1 hour: • Acute confusion • dry skin • full urinary bladder • dilated pupils • pulse 129  Anticholinergic toxidrome

  5. Acute Confusion • Urine & blood – analysis (LCMSMS): • atropine and scopolamine Linshaohua (Campsis radicans (L.) Seem) Not anticholinergic

  6. Linshaohua • (Campsis radicans (L.) Seem): • NOT anticholinergic ✘ • Yangjinhua • (Dantura metel L. ): • Anticholinergic

  7. Acute Confusion • Confusing • Yangjinhua • (Dantura metel L.) : • Anticholinergic as • Linshaohua • (Campsis radicans (L.) Seem): • NOT anticholinergic • Known >20 yrs in Hong Kong! • Substitution

  8. A “new” anticholinergic herb • F/48, herbal broth, 3 hours: • Full blown anticholinergic toxidrome Urine: atropine scopolamine anisodamine

  9. A “new” anticholinergic herb Cangshu  no anticholinergic herb

  10. A “new” anticholinergic herb • Cangshu (Rhizoma Atractylodis) • for bone pain, stomachache • NOT anticholinergic

  11. Cangshu(Rhizoma Atractylodis) • NOT anticholinergic • But, such poisoning noted since 1999 • In one series: 8% affected • Herb - contaminated by • Scopolia Japonica Maxim.(anticholinergic) • Contamination

  12. Anticholinergic Poisoning • 17 cases seen in 4 years • 9 cases: Cangshu(Rhizoma Atractylodis) • 4 cases: Yangjinhua(Dantura metel L.) • Others: contamination • NONE: deliberately prescribed • Contamination / substitution

  13. A cluster of kidney failure cases • F/55, carcinoma of the uterus • Operation: 2 yr before present problem • Rapidly deteriorating renal function: • Apr 02 Jun 03 Mar 04 Reference Range • Urea 4.0 9.5 H 28.4 H2.7 - 6.8 mmol/L • Creatinine 76 94 H 475 H44 – 80 umol/L • Taking herbs regularly since operation

  14. A cluster of kidney failure cases • 5 similar cases • Prolonged usage of herbs • Impaired renal function • 1 also had urothelial carcinoma • Aristolochic acid (AA) nephropathy? • AA was detected in the herbs

  15. No nephrotoxic herb in all formulae Baiyin

  16. Baiyin (Solanum lyratum Thunb) • Clearing the “heat” • Strengthening the “wetness” • Reducing poisoning • NOT toxic • Xungufeng (Aristolochia mollissima Hance) • Driving out the “wind” • Reducing the “wetness” • Juvenating the “blood” • Clearning the “channels” • Contains AA! Both are also known as “white furry ivy”!

  17. A cluster of kidney failure cases • All baiyin in Hong Kong was xungufeng • Error for decades! • 1 clinic: >200 patients were affected • All AA-containing herbs were banned • AA Nephropathy: Hong Kong variation • Substitution

  18. Sudden death after herbs • M/48 • Carcinoma of the oesophagus • Operation in Beijing • Herbal medicine as supplementary therapy • Purchased one item in Hong Kong • Took the herbs once, immediately: • abdominal pain, diarrhoea • BP 105/55 • slow atrial fibrillation (41/min) • ventricular tachycardia • cardiac arrest, died.

  19. Dry toad skin

  20. Sudden death after herbs • Dry toad skin • from bufo bufo gargarizans or bufo melanostictys • Contains bufotoxins

  21. Sudden death after herbs • Bufotoxins • >20 digoxin-like substances • Comparing to digoxin: • Weaker ionotropic effect, shorter duration • Usages in TCM: • Sore throat • Cough / asthma • Heart failure • Malignancy

  22. Sudden death after herbs • Screening: digoxin immunoassay of blood =63 nmol/L(1.3-2.6) • This can’t be real!

  23. Sudden death after herbs • ?Substitution of: • Dry toad skinby • Chansu(secretion from the glands of toads) • Both contain bufotoxins, however, • Potency 200 times difference! • Recommended dosage: • Dry toad skin: 3.1- 6.2 grams • Chansu: 0.016 - 0.032 grams

  24. Sudden death after herbs • If substituted, • Theoretical serum conc. of digoxin? • Cross reactivity with immunoassay (TDx) 1.4% • Chansu2g/10mL=1.45 mmol/L digoxin equiv (TDx) • Volume of distribution of digoxin = 5 L/kg, assuming 60 kg BW • = 48 nmol/L • Measured “digoxin” level was63nmol/L(1.3-2.6) • Yes, substitution is likely! • Substitution • Poor dispensing standard

  25. Bradycardia after herbs • F/83 • Hypertension, diabetes, heart failure • Took one dose of herbal broth • weakness, generalized discomfort • perioral numbness • BP 139/45 • pulse 30/min in atrial fibrillation

  26. Fuzi9 grams

  27. Bradycardia after herbs • Urine analysis: hypaconitine • Aconitine poisoning, mild • Cardiac toxicity, neurotoxicity • Fuzi(Radix Aconiti Lateralis)9g was prescribed • Recommended dosage < 15 g • Yet still poisonous • Active ingredient: 10 times difference! • Poor standardisation of herbs

  28. Perioral numbness • M/52, took a herbal broth • 30 min later: perioral numbness • Spread to all 4 limbs • Symptom subsided after 5 hours • Aconitine alkaloids were found in urine • Another aconitine poisoning, mild

  29. jixueteng guizhi chuanniuxi chuanwu gancao baishao weilingxian caowu wujiapi fuzi chuanduan

  30. Perioral numbness • Fuzi (Radix Aconiti Lateralis)9 grams • Chuanwu(Radix Aconiti)9 grams • Caowu(Radix Aconiti Kusnezoffii)9 grams • The 3 most commonly used aconite herbs • All 3 were used simultaneously! • Individually not excessive • Cumulatively: overdose • Prescription standard • Dispensing standard

  31. Pulseless VT after herbs • M/20 • Low back pain • Took decoction of a composite formula: • chuanniuxi, chuanduan, cangzhu, baishao, • weilingxian, baijiezi, baizhu, duzhong, gouji, • zhimu, yinyanghuo, zhiqiao,fuling • No problem after the 1st dose

  32. Pulseless VT after herbs • 2 months later • Took another decoction of the same formula • Immediately: • weakness, sweating, vomiting • Attended Accident & Emergency Dept

  33. Pulseless VT after herbs • In A&E: • impaired consciousness • in shock, BP unmeasurable • ECG  ventricular tachycardia • cardioversion: unsuccessful • amiodaron given • intubated, ICU  pulseless VT • prolonged resuscitation • temporarily paced • survived!

  34. Pulseless VT after herbs • Analysis: • Herbal broth remains & urine • Found yunaconitine • an aconitum alkaloid from caowu

  35. Pulseless VT after herbs • Source of the aconite herb? • No problem 2/12 ago • No aconite containing herb in the formula • A dose of unused herbs kept by the patient: • No aconite herb was identified

  36. Pulseless VT after herbs • Aconite herb was • NOT prescribed • NOT intentionally dispensed • but present by mistake

  37. Pulseless VT after herbs • What could be the mistake? • harvest? • manufacturing? • herb processing? • transportation? • storage? • dispense? • ….

  38. Pulseless VT after herbs • “Hidden” aconitine poisoning • Isolated? • 9 cases in 4 years! • Indications: variable; no common herb • Low back pain, abdomenal pain… • One x stabilizing the fetus! • Quality of herbs • Random contamination J Anal Toxicol. 2006;30:426-33 Hong Kong Med J 2006;12:456-9

  39. Proprietary Chinese Medicine Mixture of extracts Adulteration

  40. Commonly found adulterants • Antidiabetic drugs • glibenclamide, phenformin, rosiglitazone … • Corticosteroids • prednisolone, dexamethasone…. • Slimming agents • sibutramine, phentermine • tiratricol (T3 analogue) • fenfluramine/N-nitroso-fenfluramine • animal thyroid tissue • Impotence medication • Sildenafil, tadalafil, “analogues” Hong Kong Med J. 2007;13:359-63. Hong Kong Med J. 2007;13:216-20. Hong Kong Med J. 2008;14:50-4.

  41. N-nitroso-fenfluramine • F/33 • Weight reduction • Took Jianmeisu (a PCM) x 6 weeks • Claimed: 12 benign herbs • Fulminant hepatic failure! • Saved by liver transplantation • N-nitroso-fenfluramine was found

  42. N-nitroso-fenfluramine • Fenfluramine (banned) • NNF – an analogue • Singapore, the UK, Japan Fenfluramine N-nitroso-fenfluramine

  43. N-nitroso-fenfluramine Fenfluramine N-nitroso-fenfluramine Heart valve defects Pulmonary HT No liver toxicity ?? ?? Liver toxicity++++ Hong Kong Med J. 2007;13:216-20.

  44. What is drug analogue? • Existing drug – structurally modified • Same or better pharmacology effects?

  45. What is drug analogue? • Similar structure ≠ similar effects Paracetamol Phenacetin carcinogenicity & nephrotoxicity

  46. Drug testing process Long-term toxicity Toxicity Preclinical Testing Cell-culture Carcinogenic Phase 1 Clinical Trial Dosage Animal studies Phase 2 Clinical Trial Teratogenic Drug interactions Phase 3 Clinical Trial Post marketing surveillance Efficacy Idiosyncratic

  47. Drug testing process • Efficacy • Quality • Safety

  48. Lesson learned from thalidomide

  49. Viagra-like drug analogues • Young man • Took cPM for erectile dysfunction • “Pure herbal”, “not-containing viagra” • Presented with unsteady gait • Analysis: no viagra was found • But a “viagra-like” chemical • Acetildenafil

  50. Viagra-like drug analogues Acetildenafil - Drug analogue Sildenafil (Viagra) - Registered drug

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