Transcript Pulseless VT after herbs

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
✦ >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
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?
Acute Confusion
✦ F/26, skin problem  herbalist
✦ Herbal broth, 1 hour:
✦ Acute confusion
✧
dry skin
✧ full urinary bladder
✧ dilated pupils
✧ pulse 129
 Anticholinergic toxidrome
Acute Confusion
✦ Urine & blood – analysis (LCMSMS):
✧ atropine and scopolamine
Linshaohua
(Campsis radicans (L.) Seem)
Not anticholinergic
Linshaohua
(Campsis radicans (L.) Seem):
NOT anticholinergic
✘
Yangjinhua
(Dantura metel L. ):
Anticholinergic
Acute Confusion
✦ Confusing
as
Yangjinhua
(Dantura metel L.) :
Anticholinergic
Linshaohua
(Campsis radicans (L.) Seem):
NOT anticholinergic
✦ Known >20 yrs in Hong Kong!
✏ Substitution
A “new” anticholinergic herb
✦ F/48, herbal broth, 3 hours:
✦ Full blown anticholinergic toxidrome
Urine: atropine
scopolamine
anisodamine
A “new” anticholinergic herb
Cangshu
 no anticholinergic herb
A “new” anticholinergic herb
✦ Cangshu (Rhizoma Atractylodis)
✧ for bone pain, stomachache
✦ NOT anticholinergic
✦ Cangshu (Rhizoma Atractylodis)
✦ NOT anticholinergic
✦ But, such poisoning noted since 1999
✦ In one series: 8% affected
✦ Herb - contaminated by
✦ Scopolia Japonica Maxim. (anticholinergic)
✏ Contamination
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
A cluster of kidney failure cases
✦ F/55, carcinoma of the uterus
✦ Operation: 2 yr before present problem
✦ Rapidly deteriorating renal function:
Urea
Creatinine
Apr 02 Jun 03 Mar 04
4.0
9.5 H 28.4 H
76
94 H 475 H
Reference Range
2.7 - 6.8 mmol/L
44 – 80 umol/L
✦ Taking herbs regularly since operation
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
No nephrotoxic herb
in all formulae
Baiyin
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”!
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
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.
Dry toad skin
Sudden death after herbs
✦ Dry toad skin
✦ from bufo bufo gargarizans or bufo melanostictys
✦ Contains bufotoxins
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
Sudden death after herbs
✦ Screening: digoxin immunoassay of blood
=
63 nmol/L
(1.3-2.6)
✦ This can’t be real!
Sudden death after herbs
✦ ?Substitution of:
✦ Dry toad skin by
✦ 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
Sudden death after herbs
✦ If substituted,
✦ Theoretical serum conc. of digoxin?
✧ Cross reactivity with immunoassay (TDx) 1.4%
✧ Chansu 2g/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 was 63 nmol/L
Yes, substitution is likely!
✏ Substitution
✏ Poor dispensing standard
(1.3-2.6)
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
Fuzi 9 grams
Bradycardia after herbs
✦ Urine analysis: hypaconitine
✦ Aconitine poisoning, mild
✦ Cardiac toxicity, neurotoxicity
✦ Fuzi (Radix Aconiti Lateralis) 9 g was prescribed
✦ Recommended dosage < 15 g
✦ Yet still poisonous
✦ Active ingredient: 10 times difference!
✏ Poor standardisation of herbs
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
jixueteng
guizhi
chuanniuxi
gancao
chuanwu
baishao
weilingxian
wujiapi
caowu
fuzi
chuanduan
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
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
Pulseless VT after herbs
✦ 2 months later
✦ Took another decoction of the same formula
✦ Immediately:
✧ weakness, sweating, vomiting
✦ Attended Accident & Emergency Dept
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!
Pulseless VT after herbs
✦ Analysis:
✧ Herbal broth remains & urine
✧ Found yunaconitine
✧ an aconitum alkaloid from caowu
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
Pulseless VT after herbs
✦ Aconite herb was
✧ NOT prescribed
✧ NOT intentionally dispensed
✧ but present by mistake
Pulseless VT after herbs
✦ What could be the mistake?
✧ harvest?
✧ manufacturing?
✧ herb processing?
✧ transportation?
✧ storage?
✧ dispense?
✧ ….
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
Proprietary
Chinese Medicine
Mixture of extracts
Adulteration
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.
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
N-nitroso-fenfluramine
✦ Fenfluramine (banned)
Fenfluramine
✦ NNF – an analogue
✦ Singapore, the UK, Japan
N-nitrosofenfluramine
N-nitroso-fenfluramine
Fenfluramine
Heart valve defects
Pulmonary HT
No liver toxicity
N-nitrosofenfluramine
??
??
Liver toxicity ++++
Hong Kong Med J. 2007;13:216-20.
What is drug analogue?
✦ Existing drug – structurally modified
 Same or better pharmacology effects?
What is drug analogue?
✦ Similar structure ≠ similar effects
Paracetamol
Phenacetin
carcinogenicity & nephrotoxicity
Drug testing process
Preclinical Testing
Phase 1 Clinical Trial
Phase 2 Clinical Trial
Phase 3 Clinical Trial
Post marketing surveillance
Drug testing process
✦ Efficacy
✦ Quality
✦ Safety
Lesson learned from thalidomide
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
Viagra-like drug analogues
O
O
O
N
N
HN
S
N
N
N
O
Acetildenafil
- Drug analogue
Sildenafil (Viagra)
- Registered drug
O
N
O
N
HN
N
N
N
O
Viagra-like drug analogues
✦ Local survey
✦ 26 “purely herbal” impotence products
✦ 14 (53.8%) contained various
viagra-like chemicals!
 Can become a disaster!
Hong Kong Med J. 2007;13:359-63.
J Pharm Biomed Anal. 2008;46:804-7.
Concluding remarks
✦ Efficacy ✔
✦ Quality ?
✧ Quality of prescribing?
✧ Cumulative toxicity
✧ Quality of dispensing?
✧ Substitution
✧ Knowledge of toxicity
✧ Quality of herbs?
✧ Standardisation
✧ Contamination
✧ Adulteration
✦ Safety? Still a long way to go….
Thank you.