Jin Bu Huan?

July 6, 2004

A colleague wrote asking about a formula called Jin bu huan. I have

not found a formula that is called by this name in any of my reference

texts. In Hsu's Materia Medica Jin bu huan is listed as Lycopodium

serrata. That same herb is listed under a different Chinese name in the

only other reference that mentions L. serrata, Wiseman's Dictionary of

CM. In that same dictionary Wiseman lists Jin bu huan as another name

for Stephania. In Chen and Chen's new MM it lists Jin bu huan as

another name for notoginseng.(?!) Since the question came up because

Jin bu huan is listed as one of the herbs which insurance companies will

not cover, it makes sense that it may be referring to Stephania. But

Stephania is on that same list...as Stephania. Unfortunately I don't

have the characters. Anyone want to take a stab at this?

Thanks,

Stephen Morrissey

Chinese Herbal Medicine offers various professional services, including

board approved continuing education classes, an annual conference and a

free discussion forum in Chinese Herbal Medicine.

July 6, 2004

I guess I am asleep at the wheel on the Jin bu huan formula question so

I've answered the formula part of my question below with some toxicity

citations. Perhaps it shows that I don't use (and don't recommend)

patents from China. However, the question about the " other names " for

the three different single herbs still stands if anyone wants to clarify

that part of my initial question.

Thanks!

Stephen

Arch Intern Med. 1996 Apr 22;156(8):899-903.

Related Articles, Links

Chronic hepatitis induced by Jin Bu Huan.

Picciotto A, Campo N, Brizzolara R, Giusto R, Guido G, Sinelli N,

Lapertosa G, Celle G.

Department of Internal Medicine, University of Genoa, Italy.

BACKGROUND/AIMS: Jin Bu Huan and other Chinese herbal products are

widely taken remedies. They have been developed as a natural alternative

to traditional drugs in the treatment of various ailments. Their ability

to induce several side effects such as acute hepatitis has already been

described. We report a case of chronic hepatic damage following

administration of Jin Bu Huan Anodyne tablets. METHODS: The patient, a

49-year-old man, developed biochemical signs of liver damage 2 months

after beginning Jin Bu Huan intake (3 tablets/daily) including

biopsy-proven chronic hepatitis with moderate fibrosis. Virological,

autoimmune, metabolic or other hepatotoxic causes were excluded. Liver

function impairment was resolved by discontinuing Jin Bu Huan intake.

CONCLUSIONS: This case reinforces the already known hepatotoxicity of

this product and should make us think more about the uncontrolled use of

alternative products.

Publication Types:

· Case Reports

Epidemiologic Notes and Reports Jin Bu Huan Toxicity in Children --

Colorado, 1993

The consumption of traditional ethnic remedies can have adverse health

effects, especially among children (1,2). Life-threatening bradycardia

with rapid onset and central nervous system (CNS) and respiratory

depression developed in three unrelated children in Colorado during 1993

following ingestion of Jin Bu Huan tablets, a Chinese herbal medicine

used for relieving pain. This report summarizes the investigations of

these cases.

Patient 1. A 13-month-old boy was lethargic and breathing abnormally

when found by his mother approximately 20 minutes after he ingested

approximately 60 Jin Bu Huan tablets. His initial vital signs measured

by an emergency medical team included a blood pressure of 75/50 mm Hg,

pulse of 100, and a respiratory rate of 28. The child exhibited CNS

depression and was responsive only to painful stimuli. In the emergency

department, he was lethargic, with hypotonia, and had a respiratory rate

of 44 and transient bradycardia (pulse mid 40s). He was unresponsive to

naloxone (3.8 mg), a fingerstick glucose test measured 110 mg/dL, and an

extensive toxicologic screen was negative. He was treated with activated

charcoal through an orogastric tube. He became more alert during the

next 10 hours until his physical examination and mental status were

completely normal. Follow-up indicated no permanent sequelae.

Patient 2. A 2 1/2-year-old girl was lethargic and breathing abnormally

when found by her mother 30-60 minutes after she ingested approximately

17 Jin Bu Huan tablets. Paramedics found the child unresponsive with

respiratory depression. An acute episode of bradycardia (pulse 30-35)

was successfully treated with atropine. Initial examination in the

emergency department indicated miotic pupils (2 mm and equal), CNS

depression, and a disconjugate gaze. Blood pressure was palpated at 100

mm Hg systolic; pulse, 100; and respiratory rate, 24. She was

unresponsive to naloxone (0.8 mg). The patient's respiratory rate

diminished, requiring intubation within 20 minutes after arrival to the

emergency department. During the next hour, the child's condition

improved, and during an episode of vomiting, she extubated herself.

Gastrointestinal decontamination treatment included performing gastric

lavage and administering activated charcoal and a cathartic. She

remained intermittently lethargic with diffuse muscle weakness until

approximately 8 hours following ingestion. Urine and serum toxicologic

screens were negative for more than 30 substances including

beta-blockers, clonidine, and opiates. She was discharged the following

day after a complete recovery. Follow-up indicated no permanent

sequelae.

Patient 3. A 23-month-old girl was lethargic when found by her parents

within 1 hour after she ingested approximately seven Jin Bu Huan

tablets. The child was transported to an emergency department 1 1/4

hours following ingestion. Her blood pressure was 94/64 mm Hg and pulse

130. Gastrointestinal decontamination consisted of performing gastric

lavage (resulting in recovery of pill fragments) and administering

activated charcoal and a cathartic. Approximately 2 hours after

ingestion, the child was awake and talkative. She was observed in the

emergency department until 5 hours following ingestion and was

discharged. Follow-up indicated no permanent sequelae.

Follow-up investigation. Analysis of Jin Bu Huan tablets retrieved from

the parents of the three children was performed at Colorado State

University using nuclear magnetic resonance and gas chromatography/mass

spectroscopy; the tablets were 36% concentrated weight-by-weight

levo-tetrahydropalmatine (L-THP), a substance present in the plant genus

Stephania but not in the genus Polygala- -the plant of origin indicated

on the product package insert (2-4). Each tablet contained 28.8 mg

L-THP; no other plant alkaloids were present in tablets tested from

multiple bottles of Jin Bu Huan. Extensive toxicologic analysis of the

Jin Bu Huan tablets and of urine and serum from patients 1 and 2 did not

detect other drugs or pharmaceutical products. As a result of this

investigation, Jin Bu Huan anodyne tablets and their active ingredient

(L-THP) were entered into the update of Poisindex Registered, an

international toxicologic data base.

Reported by: RS Horowitz, MD, RC Dart, MD, H Gomez, MD, LL Moore, B

Fulton, Rocky Mountain Poison Center, K Feldhaus, MD, Emergency Dept,

Denver General Hospital, J Brent, MD, Denver; FR Stermitz, PhD, JJ Beck,

Dept of Chemistry and Agricultural Experiment Station, Colorado State

Univ, Fort Collins; JR Alessi, DO, Walsenburg. PAGM de Smet, PhD,

Documentation and Information Center, Royal Dutch Association for

Advancement of Pharmacy, the Netherlands. Center for Food Safety and

Applied Nutrition, Food and Drug Administration. Health Studies Br, Div

of Environmental Hazards and Health Effects, National Center for

Environmental Health, CDC.

Editorial Note

Editorial Note: Traditional Chinese herbal products are widely available

in the United States. However, because they are not marketed as a drug,

these products have not been subjected to standard tests for safety and

effectiveness. Jin Bu Huan is manufactured in China, and the stated

ingredients are Polygla Chinensis L. alkaloid (30%) and starch (70%)

(5,6). The insert accompanying Jin Bu Huan anodyne tablets describes its

action to be anodyne (analgesic), sedative, antispasmodic, and hypnotic

and states it to be " a particularly good remedy for the patient

suffering from insomnia due to pain. " In addition, it lists specific

medical indications for the product including " gastric ulcer, duodenal

ulcer pains, stomachic {sic} neuralgia, pain in shrunken womb after

childbirth, nervous insomnia, spasmodic cough, etc. " Although this

product was sold as a dietary supplement in health food stores, claims

on the labeling that the product is for the treatment, prevention,

mitigation, or cure of a disease make it subject to regulation as a

drug.

The clinical presentations of and findings in the three children

described in this report are consistent with those detected in animals

exposed to L-THP (7,8). In particular, exposure of animals to L-THP

results in sedation, analgesia, neuromuscular blockade, and dopamine

receptor antagonism. These studies also have documented L-THP to be

naloxone resistant with no affinity for opiate receptors.

As part of this investigation, the Rocky Mountain Poison Center found

Jin Bu Huan tablets for sale in health food stores in the Denver

metropolitan area. The investigation has not detected evidence of

pharmaceutical contamination of this product. However, its potential

toxicity may result from a combination of factors, including the extreme

potency of L-THP, the misidentification of the plant from which the

product was derived, the false and potentially misleading medical

claims, the availability of the product, and lack of childproof

packaging.

The public health implications associated with the use of herbal

products in the United States are potentially great because many persons

use such herbs and other unconventional products. For example, a recent

study of the prevalence and frequency of use of unconventional therapy

in the United States indicated that 3% of adult respondents reported

using an herbal medicine during the preceding year (9). In addition, a

study in the United States of dietary supplement advertising indicated

that 22% of these products did not list ingredients in their

advertisements (10). The investigation of the three cases in this report

does not provide an adequate basis for assessing the health impact of

these products; however, the severity of the adverse health effects in

these three cases underscores the potential health risks associated with

use of these herbal and other botanical products.

To prevent cases of unintentional poisoning associated with herbal and

other botanical products, such products should be sold in childproof

packaging and kept in childproof containers, and parents should be

informed about the potential toxicity of these products. In addition,

accurate labeling of the active ingredient is critical to enable prompt

and proper medical treatment for unintentional poisoning.

References

1.CDC. Lead poisoning associated with use of traditional ethnic remedies

-- California, 1991-1992. MMWR 1993;42:521-4.

2. De Smet PAGM, Elferink F, Verpoorte R. Left-turning

tetrahydropalmatine in Chinese tablets {Dutch}. Ned Tijdschr Geneeskd

1989;133:308.

3. Ghosal S, Chauhan RPS, Srivastava RS. Structure of chinensin: a new

lignan lactone from Polygala chinensis. Phytochemistry 1974;13:2281-4.

4. Tomita M, Kozuka M, Uyeo S. Studies on the alkaloids of

menispermaceous plants, CCXXII: alkaloids of Stephania rotunda loureiro

(suppl 1) {Japanese}. J Pharm Soc Jap 1966;86:460-6.

5. Zhen-Gang W, Gan-Zhong L. Advances in natur al products in China.

Trends in Pharmacological Sciences 1985;6:423-6.

6. Ding GS. Important Chinese herbal remedies. Clin Ther 1987;9:345-57.

7. Lui GQ, Algeri S, Garattini S. D-L-tetrahydropalmatine as monoamine

depleter. Arch Int Pharmacodyn Ther 1982;258:39-50.

8. Marcenac F, Jin GZ, Gonon F. Effect of L-tetrahydropalmatine of

dopamine release and metabolism in the rat striatum. Psychopharmacology

1986;89:89-93.

9. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco

TL. Unconventional medicine in the United States. N Engl J Med

1993;328:246-52. 10. Philen RM, Ortiz DI, Auerback SB, Falk H. Survey of

advertising for nutritional supplements in health and bodybuilding

magazines. JAMA 1992;268:1008-11.

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Case report:

Jin bu huan—not so benign herbal medicine

Miriam Divinsky, MD, CCFP, FCFP

Jin bu huan (JBH) is most likely a benign Chinese herbal medicine that

has been in use for a long time. It became a poisoned pharmaceutical

when marketed as “anodyne tablets” in the 1990s. Though now banned in

Canada and the United States, it is still causing hepatitis.

Case description

A 45-year-old white woman consulted her family physician regarding 4 to

6 weeks of nausea and mild pruritus, followed by 2 to 3 days of white

stools. She was a smoker with a history of mild asthma, migraine, and

back pain attributed to spondylolisthesis* and had last seen her doctor

16 months previously for a complete physical examination.

At this visit, physical findings included a 7-kg weight loss; mild sinus

tachycardia; a palpable but non-goitrous thyroid; some spider nevi; and

tenderness on palpation of her liver, the border of which was felt 3 cm

below the costal margin. She had no history of viral exposure, and there

was no reason to suspect alcohol abuse. Results of urinalysis and

abdominal ultrasound were normal, but liver enzymes were consistent with

a diagnosis of hepatitis: aspartate aminotransferase was 656 U/L,

alanine aminotransferase was 1785 U/L, and bilirubin was 46 µmol/L, all

markedly elevated, while alkaline phosphatase was 115 U/L, the upper

limit of normal. Hemoglobin and white blood cell counts were within

normal limits, with mild lymphocytosis (48% compared with 32%

neutrophils) and normal smear results.

Results of screening for hepatitis A, B, and C were negative.

Thyroid-stimulating hormone was undetectable and thyroglobulin antibody

was negative, but microsomal antibody was slightly elevated at 177 U/L.

Creatinine, blood sugar, uric acid, international normalized ratio

(INR), serum albumin, and amylase levels were all normal. Specialist

recommendations of blood tests to search for a cause of hepatitis

included a VDRL test, Epstein-Barr virus, and cytomegalovirus antibody

tests, antinuclear factor, antismooth muscle antibody, ceruloplasmin,

and ferritin, which were all normal except for a “reactive” high

ferritin level of 1349 µg/L.

The patient was advised to avoid both alcohol and large doses of

acetaminophen. Stools and results of blood tests returned to normal over

the course of the next 6 weeks. Meanwhile the free thyroxine confirmed

hyperthyroidism (47 pmol/L), and a subsequent 24-hour radioactive iodine

uptake scan confirmed Graves disease.

During the search for the cause of her hepatitis, the patient reported

that her son’s grandfather was visiting from Asia but was well and had

no history of infection. On a review of medications, she reported having

taken JBH for anxiety and insomnia (possibly symptoms of her undiagnosed

Graves disease). Jin bu huan is available as a tea or pill from

herbalists in Chinatown in Toronto, Ont. Our patient, however, took a

formulation that was banned in Canada and the United States in 1994.

Discussion

The decision to ban JBH Anodyne tablets followed reports of toxicity

after both acute and chronic use from the Centers for Disease Control in

1993.3,4 A literature search from 19945 to 2000 revealed discussion of

the cause and mechanism of these reactions as well as suggestions for

preventive measures.

It is now known that JBH Anodyne contains levo-tetrahydro-palmatine, a

“sedating dopamine receptor antagonist and calcium channel antagonist,”

structurally similar to hepatotoxic pyrrolizidine alkaloids known to

cause poisonings in Africa, Asia, and the West Indies.6 Not only were

the ingredients of the JBH tablets mislabelled but

levo-tetrahydro-palmatine is naloxone-resistant. As well, the pill

containers were not childproof, and no list of potential side effects

was included.

In 1996, Blackwell7 emphasized another unique issue: preparation of the

“medicine” involved extracting a single chemical from a traditional

herb, a non- traditional, untested method that proved unsafe. Despite

naming the manufacturer and publicizing the drug’s ban in North America,

use of JBH anodyne persists.

Since 1993 in North America, awareness has increased about the potential

toxicity of JBH. In the lay press, books and periodicals have cautioned

readers against its use.8-12 In fact, there is now a recognized list of

herbal remedies that might cause liver toxicity: borage (suspected),

chaparral tea, coltsfoot, comfrey, Crotalaria (apparently contaminated

with pyrrolizidine alkaloids), germander (skullcap), mate tea, mistletoe

(suspected), pennyroyal oil, sassafras, Senecio (groundsel), valerian

(suspected), megadose vitamin A, and willow bark (theoretical—contains

salicin, which is structurally different from acetylsalicylic acid and

therefore unlikely to cause Reye’s syndrome. No clinical adverse effects

have been reported). But there is also an equally long list of

allopathic prescription drugs that can do the same: allopurinol,

erythromycin, fluoroquinolones, halothane, isoniazid, isotretinoin,

ketoconazole, nefazodone, nicotinic acid, nitrofurantoin, nonsteroidal

anti-inflammatory drugs (NSAIDs), oral contraceptives, statins,

tetracyclines, tricyclic antidepressants, trimethoprim-sulfamethoxazole,

and valproate.13

Patients see alternative remedies as safer, and Blackwell reminds us

that most historical remedies are safe:

We should remember that adverse effects from Chinese herbs are rare. In

Hong Kong, where the use…is both widespread and unregulated, it has been

shown that only 0.2% of the general medical admissions to the Prince of

Wales Hospital were due to adverse reactions to Chinese medicine, as

compared to 4.4% of admissions caused by Western pharmaceuticals.7

Patients anticipate our disapproval when they report using alternative

remedies. This will diminish only if we remember to include

nonjudgmental questions, such as “Have you found any herbs or vitamins

to be helpful?” and acknowledge how influenced we all are (doctors and

patients) by anecdotal evidence (ie, patients by personal recovery

stories and doctors by side effect “horror” stories). Proving efficacy

is an important long-term project, but documenting safety is an

immediate and more realistic need.

Physicians are encouraged to participate in the voluntary reporting

program of the new federal Natural Health Products Directorate

(http://www.hc-sc.gc.ca/hpb-dgps/therapeut)at Health Canada. In November

1998, the Standing Committee on Health tabled its report on Natural

Health Products, which included recommendations that mandatory reporting

of adverse reactions be required from the industry, but voluntary

reporting only from practitioners and the public. Its working principles

included a goal for standards of quality but a clear statement that

safety is its primary concern. Health professionals and consumers can

now use the toll-free adverse drug reaction line (866) 234-2345 or fax

(866) 678-6789 or can call Ottawa directly at (613) 957-0337 or fax

(613) 957-0335.

Conclusion

This case study is meant to inform physicians about a benign Chinese

herbal remedy that became a manufactured poison. Though banned in 1994,

JBH might still be available in Canada. It is not listed in the new

Canadian Medical Association’s reference book on herbs.14

Acknowledgment

I thank Judy Kornfeld, MLS, and Professor Janice Newton for their

invaluable help with the literature search.

Competing interests

None declared

Correspondence to: Dr Miriam (Mimi) Divinsky, 597 Parliament St, Suite

203, Toronto, ON M4X 1W3

References

1. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco

TL. Unconventional medicine in the United States. Prevalence, costs, and

patterns of use. N Engl J Med 1993;328(4):246-52.

2. Verhoef MJ, Sutherland LR, Brkich L. Use of alternative medicine by

patients attending a gastroenterology clinic. Can Med Assoc J

1990;142(2):121.

3. Centers for Disease Control. Jin bu huan toxicity in

children—Colorado, 1993 [Epidemiologic Notes and Reports]. MMWR Morb

Mortal Wkly Rep 1993;42(33):633-5.

4. Centers for Disease Control. Jin bu huan toxicity in adults—Los

Angeles, 1993 [Epidemiologic Notes and Reports]. MMWR Morb Mortal Wkly

Rep 1993;42(47):920-2.

5. Woolf GM, Petrovic LM, Rojter SE, Wainwright S, Villamil FG, Katkov

WN, et al. Acute hepatitis associated with the Chinese herbal product

jin bu huan. Ann Intern Med 1994;121(10):729-35.

6. Larrey D. Hepatotoxicity of herbal remedies. J Hepatol 1997;26 (Suppl

1):48-9.

7. Blackwell R. Adverse events involving certain Chinese herbal

medicines and the response of the profession. J Chinese Med. Available

from: http://acupuncture.com/Herbology/Toxic.htm. Accessed 2002 Apr 17.

8. Cassileth BR. The alternative medicine handbook. New York, NY: Norton

and Co; 1998.

9. Fugh-Berman A. Alternative medicine. What works. Baltimore, Md:

Williams and Wilkins; 1997.

10. Mills S, Bone K. Principles and practice of phytotherapy. New York,

NY: Churchill Livingstone; 2000.

11. Healers or quacks? Therapies once viewed as fringe are becoming

mainstream. Macleans 1995;108(Sep 25):34-9.

12. Get the most from the East Asian culture. Flare 1995;17(9):138,140.

12. Lee WM. Drug-induced hepatotoxicity. N Engl J Med

1995;333(17):1118-27.

13. Chandler F, editor. Herbs: everyday reference for health

professionals. Ottawa, Ont: Canadian Pharmacists Association and the

Canadian Medical Association; 2000.

*Two of these symptoms, headache and back pain, are among the five most

common conditions for which patients use unconventional therapies.

Anxiety is a third.1,2

Dr.Divinsky is a family physician and Lecturer in the Department of

Family and Community Medicine at the University of Toronto in Ontario.

Stephen [stephen]

Tuesday, July 06, 2004 5:11 PM