Laboratory Investigation of Traditional Chinese Medicine ... · Pyrrolizidine alkaloids containing...
Transcript of Laboratory Investigation of Traditional Chinese Medicine ... · Pyrrolizidine alkaloids containing...
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Laboratory Investigation of
Traditional Chinese Medicine Related Poisonings
Dr Tony MAK Consultant Pathologist
Hospital Authority Toxicology Reference Lab Hong Kong
HA Convention 2016: Master Class 10
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The “Usual” Toxins ✦ More well defined ✦ Better studied ✦ Part of the medical school curriculum ✦ Assay commercially available ✦ Western drugs: Paracetamol, glibenclamide… ✦ Drugs of abuse: Morphine, amphetamines… ✦ Heavy metals: Lead, mercury…
✦ Investigation of TCM-related poisoning… ✦ Need some new approaches ✦ My lab started this journey since 2004
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Knowledge Gap
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Knowledge Gap
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Knowledge Gap
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雞血藤
威靈仙
川牛膝
甘草
川斷
五加皮 附子
製草烏
白芍
川烏
桂枝
Knowledge Gap
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雞血藤
威靈仙
川牛膝
甘草
川斷
五加皮 附子
製草烏
白芍
川烏
桂枝
✏ Transcribe TCM formulae
Knowledge Gap
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Transcribing TCM Formulae
製川烏 (Chuenwu) 製草烏 (Caowu)
熟附 (Fuzi)
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The complexity of herbs as a poison ✦ The “usual” poisons:
✦ Relatively well-defined
Paracetamol Morphine Paraquat
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✦ Herbs:
✦ Not pure compounds, but ✧ a complex mixture of compounds! ✧ TCM: uses multiple herbs each time
Toxin: which compound in which herb? ✏ Identify herbs morphologically ✏ Develop assay in-house
The complexity of herbs as a poison
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Herb Identification
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熟附片 (Fuzi)
Herbs Identification
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Biochemical Investigations
✦ No commercial assays ✦ Everything was developed in-house
✦ What to develop? A big question!
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Biochemical Investigations
✦ Detecting 22 toxic plant alkaloids at once
✦ Testing for other individual toxin as indicated ✦ Developing new assay for specific cases
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Our Approach ✦ History ✦ Clinical features / toxidrome ✦ Specimens: ✧ Biological samples ✧ Herbs (raw / remnant) ✧ Herbal broth ✧ Herbal prescription ✧ Proprietary CMs ✧ Fresh plants
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Better Worked up Problems
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Aconite Poisoning ✦ As traditional Chinese medicine: ✧ Caowu (草烏, A. kusnezoffii) ✧ Chuenwu (川烏 A. carmichaeli) ✧ Fuzi (附子 A. carmichaeli)
✦ Narrow therapeutic index ✦ Widely used by TCM practitioners ✦ Toxidrome: ✧ GI ✧ Neurological ✧ Cardiovascular
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✦ Most common in HK ✦ 70% of the severe TCM-poisoning cases* ✦ In-patient mortality rate: 5.5%*
*Chan TYK (1994, 2009)
Aconite Poisoning
Authors No. of cases Where Lin CC 17 in 10 year Taiwan
Tai YT 17 in 4 year HK
Chan TY 22 in 8 year HK
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TRL Since 2004
✧ Hx of aconite herb used ✧ Compatible clinical features ✧ +/- Review of prescription ✧ + Idenfication of herbs ✧ + Analytical confirmation
~ 10 cases per year
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✦ M/20 ✦ Low back pain
✦ Took decoction of a composite formula: ✧ 川牛膝, 杜仲, 杞子, 知母, 川斷, 白芥子, ✧ 蒼術, 白術, 防風, 淫羊藿, 百花蛇, 枳殼, ✧ 白芍, 威靈仙, 茯苓, 狗脊, 春砂仁
✦ No problem after the 1st dose
Hidden aconite poisoning
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✦ 2 months later ✦ Same formula
✦ Immediately: ✧ weakness, sweating, vomiting
✦ Attended Accident & Emergency Dept
Hidden aconite poisoning
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✦ In A&E: ✧ impaired consciousness ✧ in shock, BP unmeasurable ✧ ECG ventricular tachycardia ✧ cardioversion: unsuccessful ✧ amiodaron given ✧ intubated, ICU ✧ pulseless ventricular tachycardia ✧ prolonged resuscitation ✧ temporarily pacemarker ✧ survived!
Hidden aconite poisoning
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✦ Analysis: ✧ Herbal broth remains & urine
✧ Found yunaconitine
✧ an aconitum alkaloid from caowu(草烏)
Hidden aconite poisoning
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✦ Source of the aconite herb? ✧ No problem 2/12 ago ✧ No aconite herb in the formula
✦ A dose of unused herbs kept by the patient: ✧ No aconite herb was identified
Hidden aconite poisoning
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✦ Aconite herb was ✧ NOT prescribed
✧ NOT intentionally dispensed
✧ but present by mistake
Hidden aconite poisoning
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✦ Mistake: which stage? ✧ harvest? ✧ manufacturing? ✧ herb processing? ✧ transportation? ✧ storage? ✧ dispense? ✧ ….
Hidden aconite poisoning
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✦ “Hidden” aconite poisoning ✦ Isolated? ✦ 52 cases in 5 years ✦ 1/3 were “hidden” Quality of herbs: a BIG problem
Hidden aconite poisoning
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5-Year Review ✦ How common?
✦ How severe?
✦ Why poisoning?
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Why poisoning
Reason No. % Overdose 17
Hidden Aconite Poisoning 17 Inadequately processed herbs 7 Dispensing error 2 Ingestion of externally used herb 1
✏ Quality of prescribing ✏ Quality of herbs
✏ Quality of dispensing
98%
2%
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Analytical findings J Anal Toxicol. 2006 Sep;30(7):426-33.
Hong Kong Med J. 2006 Dec;12(6):456-9.
Drug Safety 2012 Jul 1;35(7):575-87.
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Other Better Worked up
Problems
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Other better worked up problems ✦ Anticholinergic TCM herbs ✧ Datura metel (洋金花); ✧ Atractylodes lancea (蒼朮)
✦ Aristolochic acid nephropathy ✧ Aristolochia mollissima Hance (尋骨風)
✦ TCM-related heavy metal poisonings ✧ Lead ✧ Mercury ✧ Arsenic…
✦Adulteration of proprietary CM ✧ Many!
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Emilia sonchifolia 一點紅 ✦ M/10m, healthy all along ✦ Took herbal broth x 3 months ✦ Presented with: ✧ Ascites, pleural effusion, hepatomegaly ✧ Thrombosed right hepatic vein ✧ Budd-Chiari syndrome ✧ Recovered after stopping exposure
✦ The herb: ✧ Identified to be E. sonchifolia
✧ Senkirkine was detected in the plant ✧ a pyrrolizidine alkaloid
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Pyrrolizidine alkaloids containing herbs ✦ Present in many herbs, e.g.
✧ Senecio scandens 千里光 ✧ Farfugium japonicum 蓮蓬草 ✧ Gynura divaricata 白背三七 ✧ Heliotropium indicum 大尾搖 ✧ …
✦ Notoriously hepatotoxic ✧ P-450: highly reactive metabolites ✧ Binds to protein, DNA, RNA ✧ Induce acute/chronic toxicities ✧ Liver: principally affected ✧ Budd-Chiari syndrome
✦ All can be found in HK
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Emilia sonchifolia 一點紅
Hong Kong Med J 2013;19:553-5
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Teucrium viscidum 山藿香 ✦ F/51, back pain ✧ Back pain, consulted a herbalist ✧ prescribed “鬼見愁” x 3 days ✧ Nausea, vomiting, tea-colour urine ✧ Increased ALT ✧ Typical acute hepatitis picture ✧ Gradually recovered after 2 months
✦ The herb: ✧ Identified to be T visidum 山藿香 ✧ Teucvin was detected hepatotoxic
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Teucrium viscidum 山藿香
Clin Tox 2008; 46: 819-822
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Hepatotoxic Proprietary CM ✦ 火把花根片 ✧ Triptolide (雷公藤甲素)
驅白巴布期片 ✧ Psoralen (補骨脂素)
Jianmeisu (健美素) ✧ Ingredient?
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Jianmeisu (健美素)
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✦ 2004 ✦ F/33 ✦ Weight reduction ✦ Took Jianmeisu x 6 weeks ✦ Sold >100 boxes/month in HK ✦ Claimed: 12 benign TCM herbs
Jianmeisu (健美素)
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Jianmeisu (健美素)
✦ Fulminant hepatic failure! ✦ Saved by liver transplantation ✦ Cause of liver failure?? ✦ Idiosyncratic reaction to a herb? ✦ TRL found N-nitroso-fenfluramine (NNF) ✦ NNF – an analogue of fenfluramine ✦ Department of Health: banned the product
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Fenfluramine
N-nitroso-fenfluramine
Jianmeisu (健美素)
✦ Fenfluramine ✦ Banned slimming agent ✦ NNF – an analogue ✦ Singapore, UK ✦ Japan >800 cases
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Heart valve defects Pulmonary HT No liver toxicity Appetite suppressant
Fenfluramine
N-nitroso-fenfluramine
N-nitroso-fenfluramine
?? ?? Liver toxicity ++++ Appetite suppressant x
Jianmeisu (健美素)
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Poorly Worked up Problems
Many!
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Herb Hepatotoxic? ✦ Herbs with “known” hepatotoxins ✧ Some are known
✦ Herbs without known hepatotoxin ✧ Far more ✧ Causally related? Clin Tox 2011; 49: 34-39
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Conclusions
✦ TCM-related poisonings ✦ A very difficult problem ✦ Need some new approaches ✦ Cracked some hard nuts ✦ Lab investigation: infancy ✦ Collaboration is most welcome!
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Thank you!