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 Chinese Herbs and Dietary Supplement Regulation

by Todd Luger, L.Ac.

In 1994, congress passed legislation called the Dietary Supplement Education Health Education Act (DSHEA).  This legislation had overwhelming public support, as well as support from professional practitioners of alternative medicine, their professional organizations and their schools.  What was congress to do?  The public had spoken.  Or had they?  At the time, I remember being suspicious.  While I was concerned about losing access to certain herbs, it also occurred to me that someone with lots of money must have something to gain by this act.  Especially since it had strong Republican support, particularly from Senator Orrin Hatch of Utah, a man with personal and political interest in the Utah supplement industry.  At the time, hype being circulated around TCM schools included claims that ginseng was going to be banned for mimicking testosterone (which it does not, of course, but we were alarmed nonetheless).

The local healthfood store had mosquito netting over their supplement displays to symbolize their future difficulty of access (I guess?).  We all signed petitions and crossed our fingers, prayed to our gods or whatever.  I began to read the FDA transcripts and public commentary at this time to try and get a detached perspective.  As I looked into these documents, several things became clear.  There were definitely those who testified about the risk of supplements and recommended outright bans on anything not tested as a drug.  Others wanted to make overt disease claims on product labels.  All along, the FDA actually towed a middle ground.  In retrospect, this is hardly surprising.  The moderate Clinton administration was not about to destroy a burgeoning industry no matter what old guard liberals like Waxman and Kennedy wanted, not during the year of Newt and the contract for America, that’s for sure.  On the other hand, conservatives like Hatch were only going to go so far.  They weren’t about to support actual disease claims on products.  Given the various political and corporate interests at play here, it was thus highly unlikely that anything other than DSHEA could have resulted.

On 1/6/00, the FDA’s final rule on DSHEA was published.  The basic rule is as follows:

Permitted structure/function statements. Dietary supplement labels or labeling may, subject to the requirements in paragraphs (a) through (e) of this section, bear statements that describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans or that characterize the documented mechanism by which a nutrient or dietary ingredient acts to maintain such structure or function, provided that such statements are not disease claims under paragraph (g) of this section. If the label or labeling of a product marketed as a dietary supplement bears a disease claim as defined in paragraph (g) of this section, the product will be subject to regulation as a drug unless the claim is an authorized health claim for which the product qualifies.

The rule goes on to define what constitutes a structure-function statement versus a disease claim.  Interested parties can go on the world wide web to  http://vm.cfsan.fda.gov/~lrd/fr000106.html for the entire rule and public commentary.  But in a nutshell, it is now impermissible to mention most signs and symptoms in any way, however subtle.  Only nebulous terms like “immune support”, “improves circulation” or “restores menstrual balance” are permissible.  What would also appear to be permissible are references to other such nebulous terms such as qi, yin and yang.  This raises the issue of who DSHEA really benefits.


So Who does DSHEA really benefit?

It was suggested to me that the republican majority in congress must be preserved at all costs this fall in order to protect my patient’s access to supplements via DSHEA.  DSHEA was clearly supported mainly by rich conservatives.   The democratic party either opposes world trade agreements (like the liberal union wing of the party) or they want agreements with more accountability (like moderate clintonites say they do).  Conservatives overwhelmingly support world trade with little or no accountability (like the republican nominee, bush).  Playing a familiar laissez-faire refrain, “activists” try to paint a picture of how any further restrictions on supplements would actually harm the small business owner.  Yet, in the past five years, the vast majority of small herb businesses have been sold or folded. 

So corporate conservatives would appear to oppose labeling regulations, not to protect small herb companies, but to protect their big corporate buddies who have used DSHEA to "advertise" the smaller companies out of business, mostly via the internet.  That should tell you who is in bed with who.  So you can vote republican to protect DSHEA, but at the same time you also vote to support multinational pharmaceutical interests.  In the long term, you will have voted against the very issue you hold so dear. Not to mention, there will be even less restrictions on world use of pesticides and prison and child labor, all of which may play some role in worldwide herb production.  Perhaps most importantly to our profession, DSHEA benefits corporate supplement sales at the expense of licensed healthcare practitioners.  DSHEA hurts practitioners by allowing the public to circumvent our services in favor of bogus labeling claims that make it appear that herbalism is completely a layperson's domain and not at all the practice of medicine in its own right.  This was the biggest scam of the nineties.


Standardization

Another key isue in herb regulation is the importance of standardization in herb production.  Many in the natural healthcare field are either ignorant of what standardization actually means or willfully distort the meaning for a particular vested interest.  It has nothing to do with altering herbal synergistics.  It is just about establishing potency for safe dosing purposes.  Standardization replaces the expertise necessary to identify high quality herbs that few now possess.  And if you use prepared products, only standardization can tell you about the product.  Otherwise, you are at the manufacture's mercy.  I support this type of intelligent standardization, which is already used by major granule producers in Japan and Taiwan. 

Many people may not realize that your products have already been tested to establish levels of specific active ingredients because these are not made as label claims.  But my supplier does this and I'm glad.  How do you know that your unregulated product contains the label ingredients?  In many cases, analyses prove otherwise.  I can only surmise that this activist was attempting to protect the interests of those mass market herb companies who are currently dumping extremely low quality unstandardized product on the market, further sabotaging the practices of those who try and provide herbs of quality to their patients.  While there are still a few trustworthy companies making completely untested or nonstandardized products, how can one be sure.  You may be surprised to find that your trusted supplier has recently been sold to a large corporation and you were never notified.


Incidents and Aftermath

So why I am concerned about FDA and DSHEA. Well, several recorded incidents of adverse reactions have occurred to Chinese Herbs over the past 12 years. The incidents have typically involved multiple patients consuming the same or similar substance in most cases, rather than being isolated cases. This is significant because it allows us an opportunity to evaluate the common factors in these cases and draw our own conclusions.  The most well known of these incidents is what has come to be called Chinese Herb Nephropathy.  I have detailed the confusion surrounding this specific issue below as an illustration of herb hysteria.  Because of much hype, both mainstream physicians and the FDA are now very concerned about potential serious side effects from ALL Chinese herbs.  While it is unlike that the FDA will take any radical actions, even small moves could severely impact our ability to practice.  The use of the inflammatory term, Chinese Herb Nephropathy, is particularly misleading, as it implicates all of Chinese herbology when only a few obscure substances are actually the culprits.  Documentation of other adverse incidents are abstracted extensively in the endnotes.  The pattern is clear.  The use of Chinese herbs by laypeople or untrained physicians is inherently dangerous and should be avoided under all circumstances, yet the record of TCM professionals in this area is essentially unblemished.


Chinese Herb Nephropathy

There is currently a controversy regarding the use of Chinese herbs based upon a number of incidents of nephropathy apparently related to the ingestion of herbs from the Aristolochia genus.  There are both facts and conjecture surrounding this issue, which will hereafter be known as Chinese Herb Nephropathy (CHN).

The original incident was related to a combination diet therapy used in a Belgian weight loss clinic that involved drugs and herbs not normally combined for this purpose.  While the herbs chosen for the therapy were Stephania tetrandra (han fang ji) and Magnolia officinalis (hou po), neither of these herbs was implicated in the subsequent CHN.  Stephania was not even present; it had been substituted without knowledge of the doctors at the clinic by an herb called Aristolochia, which has a similar Chinese name (guang fang ji).  Magnolia is not known to have any toxic potential, so researchers were originally at a loss to offer any explanation.  Investigation of samples eventually revealed the presence of Aristolochic Acid (AA), a known nephrotoxin.
 
Since Aristolochic Acid is a known nephrotoxin, the problem would appear solved, but several issues remain.  Subhuti Dharmananda has pointed out that numerous people were using this combination, but only a small number became ill and only during a particular interval.  Also, that Aristolochic Acid containing herbs have apparently been used safely in Asian medicine for hundreds of years.  Perhaps the traditional Chinese prohibition on long term use of guang fang ji has protected people in the past.  It has been noted that the incidents in question did not involve traditional use of the herbs.  It has also been noted that the amount of Aristolochic Acid  present in the therapeutic mixture was exceedingly low (no more than 3-6 mg per day), much lower than would be expected to exert nephrotoxic effects and also much lower than the amounts typically present in Chinese formulae which contain this aristolochia species. 

Because of these various inconsistencies, it was initially noted that the Belgian group may have been receiving medication with an unknown contaminant other than Aristolochic Acid.  However, in recent years, reports of  AA related nephropathy have come in all over the world, including France, the Balkans, Japan, Hong Kong and Taiwan.  In none of these cases were the herbs prescribed by a fully trained and licensed practitioner of Traditional Chinese Medicine.  China itself is probably absent from this list because herbal medicine is only practiced by trained physicians in the modern People’s Republic.  Nevertheless, evidence has mounted that some patients show an acute sensitivity to AA nephrotoxins.

A number of countries have banned Stephania and Magnolia, even though they were not implicated in the CHN.  Additional regulatory recommendations run the gamut from banning AA containing herbs to banning all Chinese herbs.  Based upon the evidence gathered, the use of Chinese herbs by trained practitioners appears to be safe.  Worldwide, the only documented cluster of adverse reactions to Chinese herbs involving prescription by trained practitioners (the UK eczema incident) is now thought to be related to unavoidable allergic hypersensitivity, not general toxicity.  Work should thus be initiated on how to identify AA sensitive patients. 


The power of the FDA

Some TCM practitioners have dismissed the potential threat the FDA may pose to our practice if we do not make reasonable concessions and begin to police ourselves more thoroughly, so to speak.  It has been argued that since scope of practice in some states regulate Chinese herbology (albeit only a few like Oregon) that the FDA cannot interfere.  I think this is a grave misunderstanding of the FDA's power.  They can most certainly interfere with the legal sale of a substance under their jurisdiction.  Current federal law does put a high burden on the FDA to prove harm before they can regulate a product, which is not unreasonable given our safety record.  However, once they have passed this hurdle, their authority supersedes that of state scope of practice laws. 

For an analogy, a state medical practice act can grant a physician the right to prescribe from the entire US formulary.  But if the FDA recalls a specific drug, no doctor in ANY state can legally prescribe it any more.  The same would be true if ephedra was banned by the FDA, for example.  It would make no difference that we were previously allowed to prescribe it by state authority.  That state authority is superseded in this case.  That is why I might be inclined to work with the FDA rather than against them to protect our prescribing rights.  There is lot of support all over the political spectrum right now for industries to self regulate without government bureaucracy. 


COA requirement

The FDA is now going to require certificates of analysis for the import of certain herbs.  It is not wholly unfair that we need to be sure what we are using when potential toxicity is involved.  I think the FDA has made up its mind on this matter.  The only way we are getting han fang ji, mu xiang, mu tong and xi xin into this country is with chemical analysis of each batch to prove the absence of AA.  I have talked to the local FDA public affairs officer and this is not even open for discussion.  We can use the herbs, but we must prove their identity. The potential seriousness of this issue of herb identification was raised almost a decade ago by knowledgeable parties.  Unfortunately, this issue seems to have been dismissed as a marketing ploy by many practitioners.  Only one major Chinese herb distributor in America has made its principal mission correct species identification.  While some people have suggested just finding substitutes for herbs such as mu tong and xi xin and mu xiang, I do not find that acceptable.  In fact, it is not possible to practice shanghan lun style herbalism without using mu tong and xi xin.  The only option, it would seem, is to purchase these herbs from someone who can provide a certificate of analysis. 

Again, we need to emphasize to regulatory bodies that, while the substances may have dangers, we are the only ones trained to use them safely and our professional safety record speaks for itself.  We really have no professional interest in protecting unfettered public access to internally ingested natural medicines or protecting corporations right to push these products through barely disguised drug claims and other deceptive marketing.  Where are we going to stand on this as Professionals with an ethical responsibility to our patients?



If you can’t beat them, join them

A proposal I might actually consider supporting is that many Chinese herbs should be available only from the offices of licensed practitioners. In personal communications with the FDA, I get the impression that they are willing to work with our profession to maintain our state licensed access to Chinese herbs if we join with them to help curtail the sale of such products directly to the general public. After all, none of the cases involving AA toxicity (or ephedra deaths) involved a licensed TCM px and the FDA knows this. But we will just get stomped with the product manufacturers if we just deny the safety issues altogether.

I think we need to act now to get herb regulations that protect the consumer AND our profession. The pure libertarian stance will backfire on this issue, as the general public fully accepts the need for some regulation of medicines. If we don't help craft these regulations, we will be in a very awkward position. The regulators will regulate the herbs singly and we will see our formulas slowly dismantled under this guise of safety.


Inherent safety issues with herbs

Personally, I think most internal self medication, except for self limited ailments, is inherently unsafe, whether drug or herbal. Also, were we to gain something akin to professional prescribing control of our pharmacopoeia, then those who needed our products for chronic illness would have to visit us, not self medicate. So, manufacturer advertising would shift to directing consumers to licensed practitioners instead of to mothernature.com.  This may be a bitter pill to swallow for free traders, but worldwide, as natural medicine becomes mainstream, more regulation, not less, seems to be the rule, especially in Europe and Canada (i.e. most of the rest of the so-called industrialized world).  While in certain countries like Germany, there is a move towards MD access only to herbs, we can act now to craft something more American in spirit, achieving both wide access (by leaving most products available to the public), but also improved safety (by eliminating bogus labeling) and efficacy (by directing consumers to professionals).

It is important to remember that just because we have a great professional safety record, Chinese herbs by themselves do not. The reason they work so well in the hands of an experienced prescriber is their potency in full strength formulae.  All myths aside, this same potency has much greater (not lesser) potential to cause side effects when the herbs are misprescribed. We thus need to strongly distance ourselves from those who would indiscriminately market ma huang and eucommia and ginseng to teenage males, etc. This would be a permanent solution to this dilemma, rather than having to fight this battle over every problem herb or incident. I don't even want to give the impression that there is anything similar about what I do and what a health food store clerk does, do you? So why not just cut our losses now and join the establishment for this one?

As of this writing, the use of ma huang/herba ephedra and ban xia/rhizoma pinelliae in chinese patent medicines is effectively banned in the US.  This is because 155 deaths have occurred in the past five years due to the use of this herb in products used for weight loss, body building, energy and recreation.  Chinese Medicine has safely used ma huang and ban xia for asthma for thousands of years. There is not one adverse incident reported for these herbs when prescribed by licensed healthcare practitioners. Unfortunately a poorly crafted rule has led to the withdrawal of numerous patent medicines from the market as of 4/12/04, severely impeding the practice of chinese medicine.  Please contact the FDA and your congressional representatives to protest this infringement on your right to choose your own healthcare.  More detailed information about the rule, its effects and the professional response, including government contact info can be found HERE.

Below are references for this article and a large number of abstracts of actual adverse incidents involving chinese herbs.

References

Chen, John, Recognition and Prevention of Drug Herb Interaction, Lotus Herbs 1998

Blackwell, R. Adverse Effects Involving Certain Chinese Herbal Medicines & the Response of the Profession. J Chin Med (50) January 1996.

Dharmananda, S. Drugs in Imported Chinese Herb Products. ITM START 1996 Nov.  Institute for Traditional Medicine, Portland, OR

Dharmananda, S. How Clean and Pure are Chinese Herbs? ITM START 1993.  Institute for Traditional Medicine, Portland, OR 

Dharmananda, S. The Strange Story of Stephania. ITM START 1996: Institute for Traditional Medicine, Portland,OR  

Interactions software, Chinese Herbs Group. Integrative Medical Arts. 1/00



Bupleurum/InterferonAbstracts

Ishizaki T, Sasaki F, Ameshima S, Shiozaki K, Takahashi H, Abe Y, Ito S, Kuriyama M, Nakai T, Kitagawa M. Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis. Eur Respir J 1996 Dec;9(12):2691-2696.

Abstract: We report four cases of acute pneumonitis due either to interferon, or a herbal drug, "Sho-saiko-to", or both in combination, in patients with chronic active hepatitis, focusing on its pathogenesis and response to prednisolone therapy. These cases shared common clinical features: fever, dry cough, dyspnoea, hypoxaemia, diffuse infiltrates both on chest radiography and chest computed tomography, restrictive pulmonary functional impairment, and alveolitis on examination of transbronchial lung biopsy, all of which suggest acute interstitial pneumonia. Furthermore, lymphocytosis was observed in association with the dominant CD8+ T-cell subset in bronchoalveolar lavage fluid. A lymphocyte stimulation test using peripheral blood was positive to interferon in one case and to Sho-saiko-to in another. All patients responded to oral prednisolone therapy. Peripheral soluble interleukin-2 receptor levels decreased in parallel with improvement in the clinical course. All patients were free of symptoms with a follow-up of 1-3 yrs. We conclude that interferon- and/or Sho-saiko-to-induced acute pneumonitis may be due to allergic-immunological mechanisms rather than toxicity, and that peripheral levels of soluble interleukin-2 receptor appear to be good markers of disease activity.


Kakumu S, et al. Effects of TJ-9 Sho-saiko-to (kampo medicine) on interferon gamma and antibody production specific for hepatitis B virus antigen in patients with type B chronic hepatitis. Int J Immunopharmacol. 1991; 13(2-3): 141-146.

Abstract: To examine whether Sho-saiko-to (kampo medicine) could modulate the immune response of immunocompetent cells to hepatitis B virus (HBV)-associated antigens, we investigated in vitro interferon gamma (IFN-gamma) and antibody (antibody to HB core and e antigens; anti-HBc and anti-HBe) production by peripheral blood mononuclear cells (PBMC) from eight patients with chronic active hepatitis (CAH) (four with HBeAg and four with anti-HBe) in the presence of recombinant HBcAg and purified HBeAg. IFN-gamma and antibody production were measured using ELISA and RIA, respectively. PBMC from both HBeAg and anti-HBe positive patients generated significantly increased IFN-gamma and antibody (anti-HBc and anti-HBe) production in the culture containing Sho-saiko-to (TJ-9) in a dose-dependent manner in comparison with those of medium alone culture. Similarly, when various concentrations of TJ-9 were added to the HBV antigen-stimulated cultures, TJ-9 was found to enhance both IFN-gamma and antibody production dose-dependently. These results indicate that TJ-9 is able to modulate both cellular and humoral immune responses specific for HBV-associated antigens. These findings also may account for, at least in part, the efficacy of TJ-9 treatment for type B chronic hepatitis.


Kawakita T, Nakai S, Kumazawa Y, Miura O, Yumioka E, Nomoto K. Induction of interferon after administration of a traditional Chinese medicine, xiao-chai-hu-tang (shosaiko-to). Int J Immunopharmacol 1990;12(5):515-521.

Abstract: We examined the ability of a traditional chinese herbal medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to) to induce IFN in mice. A maximum activity (105 units/ml) of interferon (IFN) appeared in the serum of mice 16 h after intraperitoneal (i.p.) treatment with 250 mg/kg of shosaiko-to. Addition of polymyxin B did not abrogate the ability of shosaiko-to to induced serum IFN. The IFN was identified as IFN-alpha/beta by neutralizing test using anti-IFN alpha/beta antibodies. Pretreatment of mice with carrageenan suppressed the IFN induction by shosaiko-to, whereas the IFN induction by shosaiko-to was impaired neither in mice treated with anti-asialo-GM1 antibody nor in T-cell-deficient athymic nude mice. IFN was produced in vitro by spleen cells obtained from shosaiko-to treated mice. Moreover, spleen cells from untreated mice could also produce IFN when they were cultured with shosaiko-to. Additionally, serum IFN was also induced by the adoptive transfer of spleen cells from shosaiko-to treated mice to normal mice. On the other hand, peroral administration of shosaiko-to also induced IFN-alpha/beta in the serum. While IFN activity induced by i.p. administration of shosaiko-to declined after repeated treatments, the activity induced by its peroral administration did not decline during a long term treatment. These results showed that shosaiko-to is an IFN-alpha/beta inducer capable of repeated peroral administration.


Matsushima T. [Drug-induced pneumonitis and related diseases]. Nippon Naika Gakkai Zasshi 1997 Mar 10;86(3):457-62. [Article in Japanese] (Review)


Matsuura K, Kawakita T, Nakai S, Saito Y, Suzuki A, Nomoto K. Role of B-lymphocytes in the immunopharmacological effects of a traditional Chinese medicine, xiao-chai-hu-tang (shosaiko-to). Int J Immunopharmacol 1993 Feb;15(2):237-243.

Abstract: We previously reported that a traditional Chinese medicine, Xiao-chai-hu-tang (Japanese name: Shosaiko-to), induced interferon (IFN) activity in the serum of mice after intraperitoneal (i.p.) administration. In the present study in which murine spleen cells were cultured in vitro with Shosaiko-to, B-cells isolated by anti-immunoglobulin-coated plates were confirmed to generate IFN in response to Shosaiko-to stimulation. IFN activity was induced in the serum after i.p. administration of Glycyrrhizae radix, Scutellariae radix, Bupleuri radix and Pinelliae tuber which are included in Shosaiko-to as its constituent. Such an IFN-inducing activity was confirmed to exist in methanol-insoluble fractions of these extracts derived from Shosaiko-to and these constituents but not in methanol-soluble fractions. These four extracts as well as Shosaiko-to, induced interleukin 6 (IL-6) in the serum after the administration. In in vitro stimulation of spleen cells, Shosaiko-to and extracts of Glycyrrhizae radix, Bupleuri radix and Pinelliae tuber showed mitogenic activity, but an extract of Scutellariae radix with in vivo IFN-inducing activity did not. B-cells appear to participate in the immunopharmacological effects of Shosaiko-to through mitogenic activity, IFN induction and the effect of IL-6.


Murakami K, Okajima K, Sakata K, Takatsuki K. [A possible mechanism of interstitial pneumonia during interferon therapy with sho-saiko-to]. Nihon Kyobu Shikkan Gakkai Zasshi 1995 Apr;33(4):389-394. [Article in Japanese]

Abstract: Interstitial pneumonia has been reported to be a side effect of treatment with interferon, and Sho-saiko-to (Xiao-Chai-Hu-Tang) may enhance this side effect. It is well known that activated neutrophils are important mediators of pulmonary fibrosis, so we studied the effects of interferon and Sho-saiko-to on neutrophil activation. Homogenized lung myeloperoxidase (MPO) activity was assayed after intraperitoneal injection of interferon with or without pretreatment with Sho-saiko-to. Although Sho-saiko-to alone did not change the lung MPO content, MPO in the lung was significantly increased by interferon administration. The increase was enhanced further by pretreatment with Sho-saiko-to. When the accumulated neutrophils are activated by some cytokines, such as TNF alpha or IL-1 beta from monocytes/macrophages, they may damage lung tissue. We therefore studied the effects of Sho-saiko-to and interferon on TNF alpha production in freshly isolated human monocytes. Sho-saiko-to increased the production of TNF alpha, but interferon did not. In addition, Sho-saiko-to significantly increased the production of TNF alpha by monocytes stimulated by lipopolysaccharide. Taken together, these data indicate that interferon causes neutrophils to accumulate in the lung. Sho-saiko-to alone may not injure lung tissue, but it increases the effect of interferon. When stimulated by some antigen, Sho-saiko-to may overstimulate the neutrophils. Granulocytes elastase and oxygen radicals released from activated neutrophils may damage lung tissue. The fibroblasts that repair the damaged tissue may increase the risk of pulmonary fibrosis.


Nakagawa A, Yamaguchi T, Takao T, Amano H. [Five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both]. Nihon Kyobu Shikkan Gakkai Zasshi 1995 Dec;33(12):1361-1366. [Article in Japanese]

Abstract: We encountered five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both. In all 5 cases the underlying disease was chronic hepatitis or liver cirrhosis caused by hepatitis C virus. Interferon-alpha alone was administered in one case, Sho-saiko-to alone was administered in two cases, and both were administered in two cases. Bronchoalveolar lavage was done in 4 cases. In three cases, lymphocytosis and abnormally low CD4/8 ratios were found on examination of bronchoalveolar lavage fluid. In the only case in which interferon-alpha alone was given the percentage of neutrophils in bronchoalveolar lavage fluid was abnormally high, and the adult respiratory distress syndrome developed. Lymphocyte stimulation tests were done in four cases, and in all four cases the only positive results were against Sho-saiko-to or against interferon-alpha. The frequency of drug-induced pneumonitis among patients with chronic hepatitis or liver cirrhosis was 0.7% in those given only Sho-saiko-to, 0.5% in those given only interferon-alpha, and 4.0% in those given both interferon-alpha and Sho-saiko-to. Therefore, pneumonitis due to Sho-saiko-to and to interferon-alpha is more likely to occur if these two drugs are given simultaneously.


Sugiyama, H, Nagai, M, Kotajima, F, Yoshizawa, A, Kamimura, M, Horiuchi T, Kudo K, Kabe J, Hayashi, S, Umeda, N. A case of interstitial pneumonia with chronic hepatitis C following interferon-alfa and sho-saiko-to therapy. Arerugi 1995 Jul;44(7):711-714 [Article in Japanese]



Chinese Herb Nephropathy Abstracts
 
Bieler CA, Stiborova M, Wiessler M, Cosyns JP, van Ypersele de Strihou C, Schmeiser HH.  32P-post-labelling analysis of DNA adducts formed by aristolochic acid in tissues from patients with Chinese herbs nephropathy.Carcinogenesis 1997 May;18(5):1063-7
Abstract:  Recently, we reported that aristolochic acid (AA) a naturally occurring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). Indeed, we identified the principal aristolochic acid-DNA adduct in the kidney of five such patients. We now extend these observations and demonstrate the presence of additional AA-DNA adducts by the 32P-post-labelling method not only in the kidneys, but also in a ureter obtained after renal transplantation. Using the nuclease P1 version of the assay not only the major DNA adduct of aristolochic acid, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), but also the minor adducts, 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)-aristolactam II (dA-AAII) were detected, and identified by cochromatographic analyses with TLC and HPLC. Quantitative analyses of six kidneys revealed relative adduct levels from 0.7 to 5.3/10(7) for dA-AAI, from 0.02 to 0.12/10(7) for dG-AAI and 0.06 to 0.24/ 10(7) nucleotides for dA-AAII. The detection of the dA-AAII adduct is consistent with the occurrence of aristolochic acid II (AAII) in the herb powder imported under the name of Stephania tetrandra and confirms that the patients had indeed ingested the natural mixture of AAI and AAII. 32P-post-labelling analyses of further biopsy samples of one patient showed the known adduct pattern of AA exposure not only in the kidney, but also in the ureter, whereas in skin and muscle tissue no adduct spots were detectable. In an attempt to explain the higher level of the dA-AAI adduct compared to the dG-AAI adduct level in renal tissue even 44 months after the end of regimen, the persistence of these two purine adducts was investigated in the kidney of rats given a single oral dose of pure AAI. In contrast to the dG-AAI adduct, the dA-AAI adduct exhibited a lifelong persistence in the kidney of rats. Our data demonstrate that AA forms DNA adducts in human tissue by the same activation mechanism(s) reported from animal studies. Thus, the carcinogenic/mutagenic activity of AA observed in animals could also be responsible for the urothelial cancers observed in two of the CHN patients.

Cosyns JP, Jadoul M, Squifflet JP, De Plaen JF, Ferluga D, van Ypersele de Strihou C.  Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994 Jun;45(6):1680-8
Abstract:  Rapidly progressive interstitial renal fibrosis has recently been reported in young women who have been on a slimming regimen including Chinese herbs. We examined four nephroureterectomies performed in three patients prior to or at the time of transplantation to determine the nature and topography of the kidney and urinary tract lesions in Chinese herbs nephropathy (CHN). Extensive, hypocellular, interstitial sclerosis, tubular atrophy and global sclerosis of glomeruli decreasing from the outer to the inner cortex, including the columns of Bertin, were observed in the four kidney specimens, together with severe fibromucoid to fibrous intimal thickening, mainly of interlobular arteries, normal or collapsed residual glomeruli, and mild to moderate atypia and atypical hyperplasia of the urothelium. In addition, bilateral pelvi-ureteric sclerosis was observed in one case. With the exception of the latter, these lesions are very similar to those described in Balkan endemic nephropathy (BEN). The clinical presentation of the patients was also similar to that observed in BEN: normal blood pressure, aseptic leukocyturia, low grade low molecular weight proteinuria, early and severe anemia. In conclusion, on morphological and clinical grounds, CHN appears similar to BEN. A common etiologic agent, aristolochic acid, is suspected. The known carcinogenic potential of this compound, taken together with our finding of multiple foci of cellular atypia of the urothelium suggest that CHN patients should undergo a regular follow-up for urothelial malignancy.
 

Cosyns JP, Jadoul M, Squifflet JP, Wese FX, van Ypersele de Strihou C.  Urothelial lesions in Chinese-herb nephropathy.Am J Kidney Dis 1999 Jun;33(6):1011-7
Abstract:  Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.


Cosyns JP, Goebbels RM, Liberton V, Schmeiser HH, Bieler CA, Bernard AM.  Carcinoma in the forestomach but no interstitial nephropathy in rats.  Arch Toxicol 1998 Nov;72(11):738-43
Abstract:  Chinese herbs nephropathy (CHN), a rapidly progressive interstitial fibrosis of the kidney, has been described in approximately 100 young Belgian women who had followed a slimming regimen containing some Chinese herbs. In 4 patients multifocal transitional cell carcinomas (TCC) were observed. Aristolochic acid (AA), suspected as the causal factor of CHN, is a well known carcinogen but its ability to induce fibrosis has never been demonstrated. The objective of this study was to evaluate the latter using doses of AA, durations of intoxication and delays of sacrifice known to yield tumours in rats. We also tested the hypothesis that a possible fibrogenic role of AA was enhanced by the other components of the slimming regimen. Male and female rats were treated orally with 10 mg isolated AA/kg per day for 5 days/week, or with approximately 0.15 mg AA/ kg per day 5 days/week contained in the herbal powder together with the other components prescribed in the slimming pills for 3 months. The animals were killed respectively 3 and 11 months later. At sacrifice, animals in both groups had developed the expected tumours but not fibrosis of the renal interstitium. Whether the fibrotic response observed in man is due to species and/or strain related differences in the response to AA or to other factors, remains to be determined. Interestingly, despite the addition of fenfluramine and diethylpropion, two drugs incriminated in the development of valvular heart disease, no cardiac abnormalities were observed.
 
 
Levi M, Guchelaar HJ, Woerdenbag HJ, Zhu YP.  Acute hepatitis in a patient using a Chinese herbal tea--a case report.Pharm World Sci 1998 Feb;20(1):43-4
Abstract:  A case is presented of reversible acute hepatitis in a patient using a Chinese herbal tea. Upon identification of the tea mixture Aristolochia species, including A. debilis, which contains the highly toxic aristolochic acid, could be identified. We conclude that the acute hepatitis as described in this patient is most likely to be caused by (one of) the active ingredients of the Chinese herbal tea. Furthermore, this case illustrates that so-called natural products can cause unexpected severe adverse reactions.
 
 
Lord GM, Tagore R, Cook T, Gower P, Pusey CD. Nephropathy caused by Chinese herbs in the UK.Lancet 1999 Aug 7;354(9177):481-2
Abstract:  The use of Chinese herbal remedies is increasing in the UK. We report the presence of a nephrotoxic compound in herb samples,which led to end-stage renal failure in two patients. We suggest that use of these products is regulated more tightly.

 

Mengs U.  Tumour induction in mice following exposure to aristolochic acid. Arch Toxicol 1988;61(6):504-5
Abstract:  After treatment for 3 weeks with aristolochic acid (AA) in daily doses of 5.0 mg/kg mice were kept under observation for approximately 1 year. During this period papillomatous changes occurred in the forestomach. At a later stage, squamous cell carcinomas were observed in all the animals. In one case, an adenocarcinoma was found in the glandular stomach. In addition, malignant lymphomas were found, as well as adenomas of the kidneys, carcinomas of the lungs, and haemangiomas of the uteri.
 

Mengs U.  Acute toxicity of aristolochic acid in rodents.Arch Toxicol 1987 Feb;59(5):328-31
Abstract:  The acute toxic effects of aristolochic acid (AA) were tested in rats and mice of both sexes. Oral or intravenous administration in high doses was followed by death from acute renal failure within 15 days. Histologically, the predominant features were severe necrosis affecting the renal tubules, atrophy of the lymphatic organs and large areas of superficial ulceration in the forestomach, followed by hyperplasia and hyperkeratosis of the squamous epithelium. The LD50 ranged from 56 to 203 mg/kg orally or 38 to 83 mg/kg intravenously, depending on species and sex.
 

Sekita S, Kamakura H, Yasuda I, Hamano T, Satake M.  Aristolochic acids in herbal medicines.  Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku 1998;(116):195-6
Abstract:  Aristolochic acids are nitrophenanthrenes with a carboxylic acid fanction which have been found only among the Aristolochiaceae. In 1993, rapidly progressive interstitial renal fibrosis has been reported in women have been on a slimming regimen including Chinese herbal medicines in Belgium. In Japan, at the Kansai district, several cases of Chinese herbs nephropathy have been reported quite recently. In both cases, aristolochic acids was detected in the Chinese herbal medicines taken by the patients. We have Asiasarum Root, a species of Aristolochiaceae, in Japanese Pharmacopoeia. Therefore, we quantitatively analysed aristolochic acids in these herbal medicines and related plants.
 

Stengel B, Jones E.  End-stage renal insufficiency associated with Chinese herbal consumption in France.Nephrologie 1998;19(1):15-20
Abstract:  In May 1994 in Toulouse, there were two cases of end-stage renal failure (ESRF) related to Chinese herbs similar to those incriminated in the case series reported in Belgium in 1992-93, they led to an epidemiologic investigation aimed at evaluating the risk linked to these plants in France. Studies carried out by the Pharmacy Inspection showed that powders labelled Stephania Tetrandra, but consisting instead of Aristolochia Fangji and containing aristolochic acid, were sold in France between 1989 and May 1994. A systematic attempt to ascertain cases of ESRF associated with ingesting Chinese herbs was carried out by analysing data from the ERA-EDTA Registry of ESRF as well as from the French adverse drug reaction monitoring system. Registry data showed no significant increase over previous years in the number of new ESRF cases caused by tubulo-interstitial nephritis (TIN) between 1990 and 1993. In eight regions of France, the files of 85 ESRF cases were examined, and all patients whose nephropathy began after 1989 were interviewed using a very detailed questionnaire. No association with Chinese herb use was found in any of these cases. In 1996, two new ESRF cases were reported in Nice; the regional adverse drug reaction monitoring center considered the relationship with Aristolochia Fangji to be as possible (I2) for one case and dubious (I1) for the other. Despite a lack of sensitivity of the methods used to detect cases, it seems clear that no phenomenon as extensive as that observed in Belgium occurred in France, although the same drugs prescribed at the same doses have been widely distributed in our country. A possible explantation for the difference in the number of cases in Belgium and France is that of an unrecognised factor, promoting the toxicity of aristolochic acid or peculiar to the Belgian clinic and causative. The precautionary principle led the authorities to ban Stephania Tetrandra and Aristolochia Fangji from the market permanently.
 
 
Stiborova M, Frei E, Breuer A, Bieler CA, Schmeiser HH.  Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs nephropathy.Exp Toxicol Pathol 1999 Jul;51(4-5):421-7
Abstract:  Aristolochic acid (AA) a naturally occuring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). We identified AA-specific DNA adducts in kidneys and in a ureter obtained from CHN patients after renal transplantation. AA is a plant extract of aristolochia species containing AA I as the major component. Aristolactams are the principal detoxication metabolites of AA, which were detected in urine and faeces from animals and humans. They are activated by cytochrome P450 (P450) and peroxidase to form DNA adducts. Using the 32P-postlabelling assay we investigated the formation of DNA adducts by aristolactam I in these two activation systems. A combination of two independent chromatographic systems (ion-exchange chromatography TLC and reversed-phase HPLC) with reference compounds was used for the identification of adducts. Aristolactam I activated by peroxidase led to the formation of several adducts. Two major adducts were identical to adducts previously observed in vivo. 7-(deoxyguanosin-N2-yl)aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI) were formed in DNA during the peroxidase-mediated one-electron oxidation of aristolactam I. Aristolactam I activated by P450 led to one major adduct and four minor ones. Beside the principal AA-DNA adducts identified recently in the ureter of one patient with CHN, an additional minor adduct was detected, which was found to have indistinguishable chromatographic properties on TLC and HPLC from the major adduct formed from aristolactam I by P450 activation. Thus, this minor AA-adduct might be evolved from the AAI detoxication metabolite (aristolactam I) by P450 activation. These results indicate a potential carcinogenic effect of aristolactam I in humans.
 
 
Tanaka A, Nishida R, Sawai K, Nagae T, Shinkai S, Ishikawa M, Maeda K, Murata M, Seta K, Okuda J, Yoshida T, Sugawara A, Kuwahara T.  Traditional remedy-induced Chinese herbs nephropathy showing rapid deterioration of renal function. Nippon Jinzo Gakkai Shi 1997 Dec;39(8):794-7
Abstract:  A 19-year-old female was referred to our hospital for azotemia and anemia. She had been taking a health food for atopic dermatitis for about three years. Urinalysis showed proteinuria, glycosuria and microscopic hematuria. Generalized aminoaciduria was observed. Moreover, severe anemia, azotemia, hypokalemia and hypophosphatemia were also observed. Renal biopsy specimen disclosed hypocellular interstitial fibrosis and degeneration of the proximal tubular epithelial cells. No remarkable changes were observed in the glomeruli. Aristolochic acid was detected in the health food. From these findings, she was diagnosed as having Chinese herbs nephropathy (CHN). Although consumption of the food intake was stopped, her renal function deteriorated rapidly. Previously, we reported that certain kinds of Chinese herbal drugs contain aristolochic acid and that the drugs should be prohibited if aristolochic acid is identified. However, we experienced a patient of CHN arising from traditional remedy, which was not proved to be safe. It should be awared that health foods may contain aristolochic acid.
 
 

Tanaka A, Shinkai S, Kasuno K, Maeda K, Murata M, Seta K, Okuda J, Sugawara A, Yoshida T, Nishida R, Kuwahara T.  Chinese herbs nephropathy in the Kansai area: a warning report. Nippon Jinzo Gakkai Shi 1997 May;39(4):438-40
Abstract:  In 1993, Vanherweghem and his associates reported cases of rapidly progressive renal interstitial fibrosis in young women who were administered a slimming regimen including Chinese herbs. Subsequently, similar cases have been reported. In Japan, especially in the Kansai area, several cases of Chinese herbs nephropathy have already been reported. We experienced a patient suffering from Chinese herbs nephropathy (CHN), and further detected aristolochic acids from the Chinese herbs taken by the patient. Aristolochic acids are known to be causative agents of CHN. The danger of CHN should be noted as soon as possible and drugs containing aristolochic acids should be prohibited.
 
 
 
Vanherweghem JL. A new form of nephropathy secondary to the absorption of Chinese herbs Bull Mem Acad R Med Belg 1994;149(1-2):128-140
Abstract:  .An outbreak of rapidly progressive renal failure was observed in Belgium in 1992-1993 and was related to a slimming regimen involving chinese herbs, namely Stephania tetrandra and Magnolia officinalis. Seventy one cases were registered on january 1994, 35 of whom being on renal replacement therapy. Renal failure has been progressing in most of the cases despite the withdrawal of the exposure to the chinese herbs. Renal biopsies showed an extensive interstitial fibrosis with loss of tubes, predominantly in the outer cortex. Chemical analyses of the chinese herbs powdered extracts delivered in Belgium demonstrated a misidentification between Stephania tetrandra and another chinese herb, Aristolochia Fang-chi, potentially nephrotoxic. These observations indicate the need of intensive search of nephrotoxins in cases of interstitial nephritis of unknown origin. Also, they underline the necessity of the introduction of measures allowing the control of correct identification of herbs preparations.
 
 
Vanherweghem LJ.  Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium.J Altern Complement Med 1998 Spring;4(1):9-13
Abstract:  At least 100 cases of extensive interstitial fibrosis of the kidneys were observed in Belgium in women who had followed a weight-loss regimen that included the use of Chinese herbs. The possible relation between the renal disease and these Chinese herbs was investigated. It was shown that the prescribed Chinese herb called Stephania tetrandra was, in fact, inadvertently replaced by another Chinese herb, namely Aristolochia fangchi in the powdered extracts delivered in Belgium and in France. The development of renal disease in about 100 patients exposed to the so-called Stephania tetrandra stresses the need for more stringent control of herbal medicine.

 

Violon C.  Belgian (Chinese herb) nephropathy: why?J Pharm Belg 1997 Jan-Feb;52(1):7-27
Abstract:  During the last years several patients with renal failure were admitted in Brussels hospitals. The progressive interstitial fibrosis with tubular atrophy seen in these patients has been ascribed to the slimming therapy preceding the pathology. The nephropathy was remarkable with regard to its extensive fibrotic process and the rapidity of its evolution. The ingestion of Aristolochia fangchi instead of the prescribed Stephania tetrandra, one of the components of the slimming therapy, was put forward as hypothesis for the etiology of the nephropathies in the literature. Questions however remain unanswered: Why have certain persons, among thousands similarly treated including ingestion of Aristolochic acids, not withstood the treatment? Why is there no correlation between the length of treatment and the occurrence nor the degree of illness? Last but not least: Is it in the actual conditions possible to be confident again in slimming treatments as the concerned one? We made an overview of the pharmacological action and possible (nephro) toxicity of the known components of the concerned therapy. Concerning the Chinese plants we have described and commented on the procedures for quality control actually at disposal and the difficulties in differentiation between resembling species and possible substitute herbs. We have described largely the traditional and medicinal use of the involved Chinese plants as to evaluate their implication in the nephrotoxicity. The elements of the therapy possibly relevant in the etiology of the disease are mentioned. The overview shows that different elements of the therapy are hazardous. Attention is caught to the danger of the use of (Chinese) herbs of unknown origin when nor the indications nor the form of preparation--in this case decoctions--are respected and when the quality cannot be assured, due to lack of (official) operating procedures. Medicinal plants as those implied contain secondary metabolites (bis)-benzylisoquinoline-alkaloids, dihydroxy-diallyl-biphenyls, aristolochic acids) with strong pharmacological (and possibly toxic) actions. Attention is caught to the danger of alternative therapies as mesotherapy. Products are injected which are not proved safe for this administration way. The administration during long periods of cocktails with anorectics (fenfluramine and diethylpropion) in association with a diuretic, a tranquilizer, plants with laxative and atropinergic action are alike to be at the origin of susceptibility in the excretion system. Under these circumstances exposure to any toxic product might cause renal failure. Several years have passed after the scientific reports of the first nephropathy cases in Belgium. We are afraid that prohibiting (temporarily) three Chinese herbs (Stephania tetrandra, Aristolochia fangchi and Magnolia officinalis) does not provide enough safety in order to assume responsibilities for common health care. Keeping in mind that these treatments were not meant to cure any disease but only for slimming, we ask Belgian authorities to regulate strictly the use of (Chinese) herbal medicines, the products and practices in alternative practices as mesotherapy and cocktail-treatments.



Poisoning and Adulteration Abstracts

But PP. Herbal poisoning caused by adulterants or erroneous substitutes. J Trop Med Hyg 1994 Dec;97(6):371-374.

Abstract:  Six cases of herbal poisoning involving six patients in Hong Kong, Taipei and Kuala Lumpur are reported. The sources of poisoning were identified as adulterants (Podophyllum emodi) or erroneous substitutes (Datura metel). In cases of suspected herbal poisoning, it is recommended that the prescriptions, herbal residues and herb samples should be collected for pharmacognostical and chemical analysis to substantiate the cause of poisoning. Insofar as it is possible, an estimate of the amount of herbs consumed should also be obtained, to establish whether the amount of toxin present is sufficient to account for the symptoms.

 
Chan TY, Critchley JA.  Usage and adverse effects of Chinese herbal medicines. Hum Exp Toxicol 1996 Jan;15(1):5-12.

Abstract:  The great majority of Chinese herbal preparations are safe, and in the past, some useful Western drugs have been derived from these herbs. Nearly all serious poisonings are due to the few preparations containing aconitine, podophyllin or anticholinergics or else proprietary preparations containing dangerous Western drugs or heavy metals. Both medical professionals and the general public should be alerted to the potential toxicity of herbal remedies. There should be frequent monitoring of Chinese herbal medicines or their derivatives, such as some Chinese proprietary medicines, for undeclared Western drugs and heavy metals. Mothers should be discouraged from treating their children with herbal or proprietary medicines. There should be continuing efforts to collect safety information on these widely used products.


Chan TY, Lee KK, Chan AY, Critchley JA. Poisoning due to Chinese proprietary medicines. Hum Exp Toxicol 1995 May;14(5):434-436.

Abstract:  1. To determine the toxic potentials of those Chinese proprietary medicines (CPM) which are commonly used for self-poisoning by adults in Hong Kong, all patients admitted to four of the eight general medical wards at the Prince of Wales Hospital between January 1988 and December 1993 were retrospectively studied. 2. There were 54 women and 17 men with their age ranging from 15 to 86 years. Twenty-three subjects (32%) also took alcohol, chemicals or drugs. Of the 51 subjects (72%) who had taken topical medicaments, 22 had no symptoms while 28 had minor features of gastrointestinal irritation (n = 26), mild (n = 2) or severe (n = 1) salicylate poisoning. Of the 17 subjects (24%) who had taken CPM tablets/capsules, nine had mild symptoms including nausea/vomiting and drowsiness. The three remaining patients (4%) who had ingested liquid CPM preparations were asymptomatic. Elevated plasma salicylate or paracetamol concentrations (> 0.1 mmol l-1) were found in some patients who had taken topical medicaments and CPM tablets/capsules, respectively. All the 71 patients completely recovered. 3. Most of the CPM used for self-poisoning in Hong Kong were of low to moderate toxicity except for those containing wintergreen oil (methyl salicylate).

 

Chan TY, Tomlinson B, Tse LK, Chan JC, Chan WW, Critchley JA.  Aconitine poisoning due to Chinese herbal medicines: a review. Vet Hum Toxicol 1994 Oct;36(5):452-455.

Abstract:  Both "chuanwu", the main root of Aconitum carmichaeli, and "caowu", the root of A kusnezoffii, are believed to possess anti-inflammatory, analgesic and cardiotonic effects and have been used in Chinese materia medica mainly for the treatment of musculoskeletal disorders. They contain the highly toxic C19 diterpenoid alkaloids of aconitine, mesaconitine and hypaconitine. After ingestion, patients may present with signs and symptoms that are typical of aconitine poisoning. Death may occur from ventricular arrhythmias, which are most likely to occur within the first 24 h. Management of aconitine poisoning is essentially supportive. There are no adequate studies in humans to indicate the most effective treatment of the ventricular arrhythmias. All clinicians should be alerted to the potential toxicity of "chuanwu" and "caowu".


Chan TY. The prevalence use and harmful potential of some Chinese herbal medicines in babies and children. Vet Hum Toxicol 1994 Jun;36(3):238-240.

Abstract:  This article reviews the prevalence use of Chinese herbal medicines (CHM) in Chinese pregnant women, babies and children living in Hong Kong and the harmful potential of some CHM and Chinese proprietary medicines (CPM) in babies and children. The use of CHM appears to be common amongst Chinese pregnant women. The possible effects of these herbs on the fetus and baby and their overall safety are not known. This practice should be discouraged since there is suggestion that maternal consumption of CHM might increase the risk of neonatal jaundice. Both "chuen-lin" and "yin-chen" can displace bilirubin from their serum protein binding and increase the risk of hyperbilirubinaemia. These herbs should not be given to the neonates. The use of CPM-containing undeclared drugs of high toxicity or lead, arsenic and mercurial compounds should be banned. The medical profession and the general public should be alerted to the harmful potential of some of the CHM and CPM. There should be continuing efforts to collect information on the safety of these compounds.


Chan TY, Tomlinson B, Critchley JA.  Aconitine poisoning following the ingestion of Chinese herbal medicines: a report of eight cases. Aust N Z J Med 1993 Jun;23(3):268-271

Abstract:  BACKGROUND: Traditional Chinese medicines often contain 'chuanwu' and 'caowu', the roots of certain Aconitum species which are thought to have an anti-inflammatory effect in many conditions. Excessive amounts of these materials, which contain diterpene alkaloids particularly aconitine, can produce toxic effects and occasional fatalities. AIMS: This study was conducted to document the adverse effects related to these herbal medicines which resulted in hospital admission and to determine the outcome in these patients. METHODS: A retrospective survey was conducted of patients admitted to the Prince of Wales Hospital, Hong Kong with suspected adverse effects from Chinese herbal medicines containing chuanwu or caowu over a two year period from 1989 to 1991. RESULTS: Eight patients were identified with features of mild to moderate intoxication including nausea and vomiting, paraesthesiae or numbness in the mouth and extremities, hypotension and ventricular extrasystoles. The management of aconitine poisoning is essentially supportive and in-hospital observation with ECG monitoring should be continued for at least 24 hours because of the risk of cardiovascular collapse and ventricular arrhythmias. The medical profession and general public should be alerted to the potential toxicity of these herbs and their usage should be controlled by legislation in Hong Kong as it is in some other countries.

 

Chan TY, Chan JC, Tomlinson B, Critchley JA.  Chinese herbal medicines revisited: a Hong Kong perspective Lancet 1993 Dec 18-25;342(8886-8887):1532-1534.

Abstract:  Chinese herbal medicines (CHM) and Chinese proprietary medicines (CPM) are widely used by people of Chinese origin throughout the world. Although the use of these medicinal materials rarely causes significant toxic effects, cases of severe and even fatal poisoning have occurred after medication with herbs containing aconitine, podophyllin, and anticholinergic substances. Furthermore, CHM and CPM are often adulterated with substituted herbs, heavy metals, and western medicines; such contamination can have important clinical consequences. In Hong Kong, surveillance and legislation are required to control the use of some of these herbal preparations. In other countries, medical practitioners should also be aware of the possibility that these herbal-medicine-related remedies may cause significant clinical problems in their Chinese patients.

 
Ernst E. Harmless Herbs? A review of the Recent Literature. Am J Med 1998 Feb104(2):170-178

 
Ferguson JE, Chalmers RJ, Rowlands DJ.  Reversible dilated cardiomyopathy following treatment of atopic eczema with Chinese herbal medicine.

Br J Dermatol 1997 Apr;136(4):592-593

Abstract:  Chinese herbal medicines are increasingly being used as an alternative treatment for chronic skin disease. Most patients and many doctors remain insufficiently aware of their potential toxicity. We report a patient with eczema who developed a severe cardiomyopathy following a 2-week course of Chinese herbal medicine. The connection between the two conditions was not made until 2 weeks after presentation when the patient was specifically asked if she had ingested any unusual substances. The belief that herbs, as natural products available without prescription, are harmless, is commonplace and patients may not consider them worthy of mention during a standard medical history.
 

Horowitz RS, Feldhaus K, Dart RC, Stermitz FR, Beck JJ.  The clinical spectrum of Jin Bu Huan toxicity. Arch Intern Med 1996 Apr 22;156(8):899-903

Abstract:  Herbal medications and other nontraditional medical therapies are becoming increasingly popular in the United States. We describe three children and three adults in whom severe toxic effects developed after ingestion of a Chinese herbal medication, jin bu huan, which is sold as Jin Bu Huan Anodyne Tablets. Jin bu huan produced distinct clinical syndromes after acute ingestion in children and long-term use in adults. A single, acute ingestion in children rapidly produced life-threatening neurologic and cardiovascular manifestations, while long-term jin bu huan use in adults was associated with hepatitis. Jin bu huan contains levo-tetrahydropalmatine, a potent neuroactive substance. The constituents of jin bu huan are misidentified on the package, resulting in significant delay in identifying the plant alkaloid responsible for its toxicity. Although perceived as innocuous, jin bu huan may produce major health effects. The highly concentrated formulation, the lack of childproof packaging, and the product insert listing indications for the treatment of serious medical conditions may all contribute to the development of toxic reactions.

 

Huang WF, Wen KC, Hsiao ML. Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol 1997 Apr;37(4):344-350.

 Abstract: The adulteration by synthetic therapeutic substances of traditional Chinese medicines has been reported on various occasions and has been a public health concern in Taiwan over the past several years. A large-scale effort was initiated in 1992 to screen traditional Chinese medicines that were suspected of adulteration with synthetic therapeutic substances. The term "adulteration" refers to traditional Chinese medicines that are tested and found to contain chemical substances not prescribed or labeled as part of the intended use. A total of 2,609 samples were collected by eight major general hospitals in Taiwan. Samples were collected through physicians' referrals during patients visits. The samples were analyzed by hospital pharmacists following the established standard procedures in comparison to references by thin-layer chromatography. An average of 23.7% (n = 618) of the samples collected from the eight hospitals were adulterated. Four samples with either a rheumatoid or an antiinflammatory indication contained six different kinds of adulterants. More than half (52.8%) of the adulterated traditional Chinese medicines contained two or more adulterants. The sources of adulterated samples and their claimed indications, as well as the most frequently detected synthetic therapeutic substances, are presented in this report. The controversies regarding the combination of synthetic therapeutic substances and traditional Chinese medicines without adequate labeling should be resolved through regulatory actions for better safety of drug use.

 

Kang-Yum E, Oransky SH.  Chinese patent medicine as a potential source of mercury poisoning. Vet Hum Toxicol 1992 Jun;34(3):235-238.

Abstract:  This research is an effort to create an awareness. of the potential hazards of some Chinese patent medicines which contain mercurial ingredients. This should be of consideration when screening symptomatic patients who are of Asian ethnic background or other users of these medicines. This research discusses reported cases of mercury poisoning related to the use of Chinese patent medicines and the potential toxicity of cinnabar (red mercuric sulfide) and calomel (mercurous chloride), 2 mercurials commonly used in these medicines. A list of mercurial-containing Chinese patent medicines available on the open market in North America has been compiled, together with their traditional uses and mercurial contents and is presented as a quick reference for Specialists in Poison Information. This class of medicine may not pose a problem when used appropriately; however, its misuse, abuse, overdosage and improper storage can lead to serious mercury poisoning.

 

Jin bu huan toxicity in adults--Los Angeles, 1993.MMWR Morb Mortal Wkly Rep 1993 Dec 3;42(47):920-922.

Abstract:  Jin Bu Huan (JBH) is a traditional Chinese herbal product used as a sedative and analgesic. During 1993, public health and health-care providers in Colorado reported three children with unintentional overdoses of JBH that caused central nervous system and respiratory depression with rapid onset of life-threatening bradycardia. Subsequently, the first cases of acute hepatitis attributed to use of JBH were diagnosed in three women in Los Angeles during July and August 1993. Patients 1 and 2 were referred to a Los Angeles hepatology clinic by their physicians; patient 3 was identified by patient 2. All three patients had purchased JBH at the same health-food store. This report summarizes the investigation of these cases.

 

MMWR  Jin bu huan toxicity in children--Colorado, 1993.Morb Mortal Wkly Rep 1993 Aug 27;42(33):633-636.

Abstract:  The consumption of traditional ethnic remedies can have adverse health effects, especially among children. 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.

 

Picciotto A, Campo N, Brizzolara R, Giusto R, Guido G, Sinelli N, Lapertosa G, Celle G.

Chronic hepatitis induced by Jin Bu Huan. J Hepatol 1998 Jan;28(1):165-167.

Abstract:  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.

 

Ries CA, Sahud MA.Agranulocytosis caused by Chinese herbal medicines. Dangers of medications containing aminopyrine and phenylbutazone. JAMA 1975 Jan 27;231(4):352-355.

Abstract:  Four non-Chinese patients, middle-aged or older, developed agranuloctyosis while taking Chinese herbal medicines for relief of arthritis and back pain. All four developed life-threatening infections with bacterial sepsis; one died. The herbal medicines were shown to contain substantial amounts of undeclared aminopyrine and phenylbutazone, drugs that are well-known causes of agranulocytosis. These Chinese herbal medicines are widely available over the counter throughout the United States.

 

Tie B, Qi W, Chen G. Determination of soluble mercury contents in Chinese traditional patent medicines for children. Chung Kuo Chung Yao Tsa Chih 1990 Oct;15(10):602-604, 639.

Abstract:  Soluble mercury contents in Baochi San, Xiaoer Zhibon Ding and Xiaoer Baishou Dan have been determined using dithizone method. This method has the advantages of short digestion time, clear digestion end point, simple operation and reproducible results. The recovery rate ranges from 98.4 to 103%. The data obtained can be used as a reference for controlling soluble mercury contents in Chinese traditional patent medicines containing cinnabar.

 

Woolf GM, Petrovic LM, Rojter SE, Wainwright S, Villamil FG, Katkov WN, Michieletti P, Wanless IR, Stermitz FR, Beck JJ, et al.  Acute hepatitis associated with the Chinese herbal product jin bu huan. Ann Intern Med 1994 Nov 15;121(10):729-735.

Abstract:  OBJECTIVE: To describe the hepatotoxicity associated with ingestion of the Chinese herbal product Jin Bu Huan Anodyne Tablets (Lycopodium, serratum) and to propose possible mechanisms of injury. DESIGN: Retrospective analysis. SETTING: Academic hepatology units and private practice facilities. PATIENTS: Seven previously healthy patients. MEASUREMENTS: Clinical, laboratory, radiologic, and histologic studies. RESULTS: Acute hepatitis occurred after a mean of 20 weeks (range, 7 to 52 weeks) of Jin Bu Huan ingestion and resolved in six patients within a mean of 8 weeks (range, 2 to 30 weeks); another patient is currently improving. Hepatitis was associated with symptoms of fever, fatigue, nausea, pruritus, and abdominal pain and with signs of jaundice and hepatomegaly. Biopsy specimens showed that one patient had hepatitis with eosinophils (consistent with a drug reaction) and the other had mild hepatitis, moderate fibrosis, and microvesicular steatosis. Decreasing the Jin Bu Huan dose in one patient improved liver test results. Reusing Jin Bu Huan in two other patients caused abrupt recrudescence of hepatitis. CONCLUSION: Jin Bu Huan can cause liver injury. Although the hepatotoxic mechanisms are not defined, they may include hypersensitive or idiosyncratic reactions or direct toxicity to active metabolites. Hepatotoxicity caused by herbal products underscores the toxicity caused by herbal products underscores the importance of national surveillance programs and quality control of the manufacture of these products.

Comments: Ann Intern Med 1994 Nov 15;121(10):803-804;Ann Intern Med 1995 Apr 15;122(8):636


Zhang ZW, Watanabe T, Shimbo S, Higashikawa K, Ikeda M.  Lead and cadmium contents in cereals and pulses in north-eastern China Sci Total Environ 1998 Sep 18;220(2-3):137-145

Abstract:  It is known that, unlike Japanese, Koreans or southern Chinese who depend on rice as a major source of energy for daily life, people in north-eastern China rely not only on rice, but on wheat and other cereals and to a lesser extent also on pulses. Cereal and pulse samples were collected from open markets in north-eastern China, and analyzed by inductively-coupled plasma spectrometry (ICP-MS) for two potentially hazardous heavy metals--lead (Pb) and cadmium (Cd). The average Pb level in cereals (31.3 ng Pb/g as a geometric mean) and that of pulses (25.7 ng Pb/g) were similar to each other with no significant difference. Among the cereals, Pb contents were higher in foxtail millet (54.3 ng/g) and lower in maize (35.4 ng Pb/g; grain and flour in combination), wheat flour (28.8 ng Pb/g) and rice flour (22.7 ng Pb/g). Lead levels in two important types of pulses, kidney bean and soybean (24.6 and 30.8 ng Pb/g, respectively), were comparable to the levels in rice and wheat. In contrast, Cd levels were substantially higher in pulses (55.7 ng Cd/g) than in cereals (9.2 ng Cd/g), and among the pulses, Cd in soybean (55.7 ng Cd/g) was significantly higher than that in kidney bean (23.8 ng Cd/g). The possible public health implication of the Pb and Cd levels, especially the high Pb level in foxtail millet (54.3 ng Pb/g) and the high Cd level in soybean (73.5 ng Cd/g), is discussed.

 

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