Hospital Authority Toxicology Service Annual Conference 2011Herbs and Alternative Medicine-Related problems

Proprietary Chinese MedicinePoisoning in Hong Kong

Dr Jones CM ChanPWH Poison Treatment Centre香港威爾斯親王醫院中毒治療中心

陳俊文醫生

5 March 2011

Introduction

Use of proprietary Chinese Medicine (pCM) is common, even in pregnant women (Chan TY 1994)

Some may present to hospital with adverse drug events after useClinicians are not familiar with the action or unwanted reaction related to pCM

Adverse Events Related to pCM in HK 2004 – 2005

ClobetasolA topical cream (膚康)

TriptolideMultiglycosides Tripterygii Wilfordii Capsule (雷公籐多甙膠囊 )

Strychnine, brucineUnnamed pills containing Semen Strychni (馬錢子) Chlorpromazine Texiao Shushen Jiaonang (特效舒神膠囊) Tetrahydropalmatine and diclofenacUnnamed herbal pills SulfamethazineA herbal powder (珍珠末) RosiglitazoneA product for regulating blood glucose (苦樂康)

Betamethasone"Lii San Lian" Snakes' Bones Rheumatic Capsules (特效李三連蛇骨風濕丸)

AnthraquinoneA slimming agent: Belly Cut (消腩丸) FenfluramineA slimming agent: (常青春纖之素膠囊) SibutramineA slimming agent: (康婷纖維素)N-nitrosofenfluramineA slimming agent: Supreme Quick Slim ( 健美素)

Toxic componentspCM

http://www.cmchk.org.hk/news/adverse_events_2004_5_english.pdf

Problems with pCM

WMW470文字方塊

WMW470文字方塊

WMW470文字方塊

Prince of Wales Hospital Poison Treatment Centre (PWHPTC)

Functions as the tertiary referral centre for treatment of patients with poisoning

Provides expert information and consultative services on the management of poisoning

A multi-disciplinary team of doctors, nurses and pharmacists led by a Consultant Toxicologist (Prof. Thomas Chan)

Questions

How safe is proprietary Chinese medicine in HK?

What kinds of pCM are more commonly associated with adverse drug effect?

SourceBranded or unnamedListed as herbal ingredientPrescribed or over-the-counter

Methods

Retrospective review of all clinical consultations related to use of pCM

Study period: Jan 2007 to Dec 2010

Exclusion: consultations related to use of traditional CM, fake pharmaceuticals, non-medicinal health product, or intentional overdose with pCM

Definition of proprietary Chinese Medicine中成藥是在中醫藥理論指導下，以中藥飲片為原料，按規定的處方和標準製成具有一定規格的劑型，可直接用於防治疾病的製劑。

pCM are Chinese medicinal materials (herbs, animals, minerals, or combination) which have been formulated into finished products in the form of capsules, tablets, pills, powders, mixtures, etc.

國家中醫藥管理局 中成藥臨床應用指導原則 2010年6月www.satcm.gov.cn/file2010/20100630152349.doc 2010-6-30

Definition of proprietary Chinese Medicine中成藥具有特定的名稱和劑型，在標籤和說明書上註明了批准文號、品名、規格、處方成分、功效和適應證、用法用量、禁忌、注意事項、生產批號、有效期等內容 。

For diagnostic, treatment, prevention or alleviation for any disease or symptoms; or for regulating or enhancing health

國家中醫藥管理局 中成藥臨床應用指導原則 2010年6月www.satcm.gov.cn/file2010/20100630152349.doc 2010-6-30

Definition of Serious ADR

ADR that:DeathLife threatening conditionProlonged hospitalizationDisabilityOr required intervention to prevent permanent impairment or damage

Results

Total 62 consultations related to use of pCMor suspected pCM12 cases were excluded

3 Health product2 traditional Chinese medicine7 drug adulterated with pharmaceuticals for erectile dysfunction

50 cases included for analysis

Patients

62% had chronic illnesses (HT, DM, CVS disease, COPD, stroke, malignancy, organ impairment) on medications

50 patients

31 MalesMean age = 64.5 yrs (24 – 90)

19 FemalesMean age = 55.3 yrs (0.17 – 83)

Presenting Problems

0

2

4

6

8

10

12

Liver CNS CVS Blood Endo Psychi GI Kidney Skin Respi Allergy

Reasons for use of pCM

3 (6%)Urinary problems

7 (14%)Otherse.g. DM, HT, SLE, insomnia, sliming, ect.

2 (4%)Stroke prevention

3 (6%)Erectile dysfunction

3 (6%)Cardiovascular problems

3 (6%)Respiratory problems

12 (24%)Pain relief

17 (34%)Health promotion / supplement

Number (%)Reason

Outcome

Overall 17 (34%) ADR related to pCM were found

4/17 (24%) of these ADRs were serious (1 anoxic brain damage, 1 prolonged hosp stay, 1 intensive care support, 1 pacemaker insertion)1 (6%) died (anoxic brain damage)

Source, Brand and Ingredient of the pCM

50 pCM

22 OTC HK(44%)

100% Branded

86% herbal9% pharmaceutical

2% unknown

18 OTC outside HK(36%)

94% Branded

89% herbal6% mixed

6% unknown

4 Prescribed HK(8%)

50% branded

100% herbal

5 Prescribed outside HK(10%)

60% branded

60% herbal40% unknown

1 Unknown(2%)

0% branded

100% unknown

Overall (N = 50)Listed ingredients:

Herbal: 42 (84%)Pharmaceutical: 2 (4%)Mixed: 1 (2%)Unknown: 5 (10%)

Adverse Drug Reaction and the Over-The-Counter pCM

40 OTC pCM

22 from HK 18 from outside HK

22 branded 17 branded 1 Unknown

19 herbal5 ADR

2 pharmaceutical0 ADR

1 unknown0 ADR

15 herbal9 ADR

1 mixed0 ADR

1 unknown1 ADR

1 unknown1 ADR

Adverse Drug Reaction and the prescribed pCM

9 prescribed pCM

4 prescribed HK 5 prescribed outside HK

2 branded 4 branded 1 unknown

2 herbal0 ADR

3 herbal0 ADR

1 unknown0 ADR

1 unknown1 ADR

2 unknown

2 herbal0 ADR

Characteristics pCM that are more likely associated with ADR

4.25 (1.1 – 16.6)OTC HK vs OTC from outside HK

0.75 (0.03 – 17.5)Prescribed HK vs Prescribed from outside HK

1.39 (0.3 – 7.1)Herbal vs Unknown

6.64 (0.6 – 69.6)Branded vs Unnamed

0.48 (0.09 – 2.6)OTC vs Prescribed

Odds Ratio (95% CI)Characteristics

The cause of ADR related to pCM

Among 17 ADR:

9 (53%) undeclared pharmaceuticals adulterants (Prednisolone, NSAID, OHA, Sildenafil, Sibutramine)2 (12%) undeclared toxic herbs (aconitum alkaloids)6 (35%) listed herbal ingredients (地龍,蜈蚣,大黃,蒼耳子)

Among 33 unrelated cases:

3 (11%) had undeclared pharmaceuticals (sildenafil, indomethacin, phenobarbital)

Case 1: Hypoglycaemia

M/91History of DM on diet control, HT, old pTB, and CA sigmoid with surgery doneTaken his son’s OHA (胰島排毒膠囊 , 淨血穩糖膠囊, 北京同仁堂金匱腎氣丸 bought OTC from China) for better glycaemic control for 2 daysPresented with decreased general condition and fall, and subsequently developed 4 limbs twitchingFound low Haemostix in the ambulanceGiven dextrose infusion with improvement

Ingredient胰島排毒膠囊(云香疳，雪莲，肉从容，茯苓，黄连，山查，灵芝袍子油，车前草，等二十多种草本植物提取的排毒因子),

淨血穩糖膠囊(大叶海藻，深海珍珠母，鱼脑石，叶海龙，鲍鱼壳，海带等二十多种海洋生物免疫活性汰)

Drug analysis

Analysis by Toxicology Reference Lab (TRL) [Techniques: HPLC-DAD, LC-MS/MS]

胰島排毒膠囊 (phenformin, glibenclamide, berberine)

淨血穩糖膠囊 (prednisone acetate, tadalafil, forsythin)

Ching CK, et al. Hong Kong Med J 2008

Case 2: Coma

M/76History of COPDPresented with coma and collapse at home, 17:30 Completely well 11 hours agoOn arrival to AED, GCS was E1V1M1Managed as respiratory failure with artificial ventilationNoted persistent hypoglycaemia in the ICU, managed with dextrose infusionAfter stabilization, he admitted that he had taken 三體牛鞭動力膠囊,壯陽滋陰,新喘寧散 for erectile dysfunction and chest problems

Case 2:

三體牛鞭動力膠囊

(黄牛鞭,鹿茸、人参、五味子、刺五加、枸杞子、黄芪、免丝子、淫羊藿、肉苁蓉、龙眼肉、蛇床子)

Urine toxicology screening by HPLC:Glibenclamide metabolites and unidentified substance

Drug Analogs

Poon WT, et al. Hong Kong Med J 2007

Case 3: Pulmonary hypertension

F/34Good past healthPresented with on and off chest discomfort and dizzinessThree episodes of syncope in the past 2 monthsNo family history of cardiac diseaseNo sign and symptom of thyrotoxicosis

Case 3ECG: right axis deviation, ST depression over V1-V5

Case 3

Echocardiogram: severe pulmonary hypertension with right ventricular failure and secondary TRD-dimer level – normalV/Q scan: no evidence of PETSH = 0.01 mIU/L (Ref: 0.3 – 4.2)FT4 = 16.6 pmol/L (Ref: 12 – 22)FT3 = 2.8 pmol/L (Ref: 2.8 – 7.1)

Case 3Patient reported history of taking some slimming pills for 6 months to prepare for her wedding

Listed ingredients:•黃蓍•決明子•荷葉•菊花•杞子•山楂•萊菔子

Case 3Analysis by Toxicology Reference Lab (TRL) [Techniques: HPLC-DAD, GCMS, LC-MS/MS, LC-MS-IT-TOF]

Fenfluramine → pulmonary hypertension and valvular heart diseaseSibutramineEphedra alkaloids (ephedrine, pseudoephedrine)CaffeineNifedipinePhenolphthalein

Case 3

Animal thyroid tissue→ abnormal thyroid function

Patient’s clinical condition remained stablePlanned for repeat echocardiogram to evaluate the progress

Case 4. Vent fibrillation and cardiogenic shock

F/82NSNDGood past health except chronic low back painRecent increase of back painTook a proprietary Chinese medicine (張真人山茯丸) bought from mainland China

Case 4

Case 4

Took 1/3 sachet (10 tablets) of the PCM at 7pmAttended Emergency Department 1 hours later for chest discomfort and sweatingOn arrival, BP 81/57 mmHg, pulse rate 72/minClinically in cardiogenic shock

Case 4First ECG

→ DC cardioversion 50J, 100J

Case 4

But…

Case 4Repeated defibrillation, intravenous amiodarone infusionIntubated and ICU care? Aconite poisoningHowever, the listed ingredients: 山藥、佛手、干姜、魚腥草、金銀花、木瓜、桃仁、小茴、小薊、薤白、薏苡仁、蒲公英、烏梢蛇 should not contain aconitineAconitum alkaloids found in urine and product → undeclared aconite herb in product

“Hidden” Aconite Poisoning

From March 2004 to May 2006, 10 laboratory confirmed cases of aconite poisoning4 cases had NO aconite herb listed in the written prescriptionYunaconitine was the aconitum alkaloid detected in all cases (urine samples + some herbal booth/remnants)? Contamination ? Quality control problem

Poon WT, et al. Hong Kong Med J 2006

Conclusion34% of this case series had problems associated with the use of pCM

• 24% of ADR were serious• 6% of ADR were fatal

High risk pCM:1. Over-the-counter drug bought from outside HK2. Used for indication out of the standard (e.g. weight

reduction, erectile dysfunction)

The main cause for pCM related ADR is due to undeclared pharmaceuticals and undeclared toxic herbs (65%)

Classification of pCM

1. 解表劑2. 瀉下劑3. 和解劑4. 清熱劑5. 祛暑劑6. 溫裡劑7. 表裡雙解8. 補益劑9. 安神劑10.開竅劑

11.固澀劑12.理氣劑13.理血劑14.治風劑15.治燥劑16.祛濕劑17.祛痰劑18.止咳平喘劑19.消導化積劑20.殺蟲劑

國家中醫藥管理局 中成藥臨床應用指導原則 2010年6月www.satcm.gov.cn/file2010/20100630152349.doc 2010-6-30

Known problems of proprietary Chinese Medicine

Same name, different formulaeSame formula, different namesSimilar names, different formulae (may not be interchangeable)

新編中成葯手冊 第二版

Documented causes of toxicity related to pCM

Pharmaceutical adulterantsUndeclared toxic herbsHeavy metal contamination: from processing machinery, or from accumulation during cultivation from soil contamination, or from the coating of ‘丹’ in illegal pCM

High risk components

Acontinum alkaloid: 川烏,草烏,附子,關白附Arsenic: 雄黄,砒霜Mercury: 朱砂,白降丹,紅升丹Lead: 狗皮膏Bufotoxin: 蟾酥Croton: 巴豆,巴豆霜Strychnine: 馬錢子

新編中成葯手冊 第二版

The Chinese Medicines Board reminded members of the public to note the following when using Chinese proprietary medicines:

1. PCM is a type of medicine and should be used with caution.2. The use of any medicine (including PCM) may have side effect.3. Should get a clear idea of one’s need before taking any medicine

arbitrarily.4. Natural product may not be safe. Members of the public should

be careful about this point.5. Even PCM will have interacting effects with other medicine.

Patients should inform their healthcare providers about one’s history of taking medicines.

6. Keep all medicines, including PCM, out of the reach of children.7. Study carefully the label and instruction insert of the PCM. Don’t

buy medicines from dubious source8. Seek medical advice promptly if adverse reaction arises or

symptoms persist after the use of PCM.

Summary

pCM can cause adverse effects especially those with undeclared ingredients or adulterated with western medicines

Registration system recently introduced in HK can improve quality and safety of pCM

Products from outside HK remain a concern

Frontline healthcare professionals should be vigilant

Acknowledgement

Chief Pharmacist Office, HAHOToxicology Reference Laboratory, PMH