This effort by AAOM is related to the FDA's regulatory actions to aristolochic acid containing herbs. Aristolochic acid is a chemical which had been long used for its medicinal anti-inflammatory properties. It seems to block the production of prostaglandin.^11,12,14,23 However, it is harmful to the kidneys as well as cancer causing.^1,8,9,14,16 In 1993, a report appeared in the literature from the Department of Nephrology, Universite Libre de Bruselles, Belgium about 9 women, all below the age of 50, who had developed similar patterns of kidney failure. The authors had been doing an epidemiological analysis of young women who were all participating in a weight control regimen from the same medical clinic. The clinic indicated that it had used the same combination of therapy for 15 years prior to May, 1990, without problems. In May, 1990, the clinic began adding the herbs Stephania tetrandra and Magnolia officinalis to the regimen. This led to the assumption that the Chinese herbal remedy was the source of the kidney failure. However, the chemical analysis of the herbal capsules taken by the involved patients did not match the expected alkaloid patterns expected for the two herbs. It was suspected that aristolochic acid in the herb combination was the cause of the kidney problems. Later studies supported the suspicion although one study clouds the issue. In addition, other studies demonstrated an association of the slimming herb and development of urinary tract cancer in the affected patients.^{3,4,5,13,15,17,20,22}

It turned out that, due to a manufacturing error, Aristolochia fangchi (which contains aristolochic acid) was substituted for the Stephania tetrandra. This error most likely was due to the similarity of the names of the two herbs Guang Fang Ji (Aristolochia fangchi) and Han Fang Ji  (Stephania tetrandra).

Eventually, over 100 cases of kidney failure in Belgium were attributed to the herbal weight control regimen prescribed by the weight control clinic between 1990 and 1992. A few cases also appeared in France in 1994 apparently from the same error. In 1998 and 2000, several cases were reported to occur as a result of taking aristolochic containing herbs in Japan as well. However, no action was taken by the FDA in the United states until after reports of aristolochic acid containing herbal products found in United Kingdom and Canada. Following these reports, on May 16, 2000, the FDA  released a "Letter to Industry" warning manufacturers of herbal products to test their products to ensure they don't contain aristolochic acid and establish procedures for reporting adverse reactions to the herbs the FDA listed as a concern in their opinion. The letter also stated that an alert would be issued that would allow the seizure of any import that may contain any of the herbs listed as a concern to the FDA. The list contained herbs known to contain aristolochic acid [which include all herbs in the genus Aristolochia (Aristolochiaceae) and in some of the plants from the genus Asarum (Aristolochiaceae)] and 36 herbs that don't contain aristolochic acid but may be mistakenly replaced by aristolochic containing herbs.^{6,18,19,21,25,26}

On August 1, 2000, in a written response to the FDA's "Letter to Industry," the American Association Of Oriental Medicine expressed its objections to the scope of the ban because of the inclusion of herbs known to be aristolochic acid free but may accidentally be replaced by aristolochic acid containing herbs by inexperienced or untrained individuals. The American Association of Oriental Medicine response suggested allowing the herb manufacturers and qualified Chinese medical practitioners to police itself stating that errors in Belgium were most likely due to prescribing by Western medical doctors not trained in Chinese herbal medicine.¹⁰

In the petition circulated in the name of the American Association Of Oriental Medicine, it states that the FDA is visiting herb companies and demanding product recalls without receiving reports of adverse reactions. According to a personal communication to a colleague of mine, the American Association Of Oriental Medicine indicates that FDA agents have visited manufacturers of herbal formulas and practitioner's offices. The e-mail even says agents have entered at least one private home to acquire herbs. I have attempted to communicate with Laurel Eu, Public Affairs Specialist for my area to allow her to reply to the alleged actions, however, she hasn't answered my e-mail.

In an attempt to determine the FDA pattern of how it handles this type of thing with substances other than herbs, I investigated how it handled the recent PPA (phenylpropanolamine) controversy. PPA is a drug that was found commonly in over the counter cough/cold medicines and appetite suppressants. From 1973 until 2000, there were 30 published cases of hemorrhagic stroke after taking PPA or PPA containing drugs. A final Yale University School of Medicine study reported in May 2000, convinced the FDA that enough evidence existed to issue a warning that PPA was not safe for over-the-counter use and that it was taking steps to have it removed from all over-the-counter medications. Also, in a letter to manufacturers on November 3, 2000, the FDA warned that it was taking action to remove PPA from prescription drugs as well.^7,24,27 So, from this it wouldn't seem that the ban on the aristolochic acid containing herbs is any more extreme (other than the ban on herbs that can be misidentified with aristolochic acid containing herbs). Whether the FDA agents entered manufacturing facilities or private residences of manufacturers or physicians to seize any PPA products I cannot tell from my investigations.

I have mixed feelings about both positions in this herb regulation issue as it relates to the aristolochic acid ban. On the one side I respect the American Association Of Oriental Medicine's concern that herbs that are common components to herb formulas which have no toxic ingredients are banned on the basis of guilt by association due to name or relationship to toxin containing herbs. But I can also respect the FDA concern that it needs to act to prevent what it feels is a potential problem when such a problem has occurred in the neighboring country of Canada. However, a better control measure might be to ensure that all manufacturers be properly trained and licensed. This would allow the greatest access to useful herbs and ensure the expertise to prevent the problem that occurred in Belgium. We, as consumers, must make our decision based on knowledge rather than emotion. Hopefully this article helps to supply some of the knowledge needed to make an informed decision. If you decide you wish to express a desire to limit the FDA's scope of it's ban of the non-toxic herbs, you may use the copy of the petition from the AAOM by clicking this link.

Abel G, Schimmer O

2. Petition
DEFEND MY ACCESS TO HERBS

American Association Of Oriental Medicine

3. Carcinogenesis 1997 May;18(5):1063-7
32P-post-labelling analysis of DNA adducts formed by aristolochic acid in tissues from patients with Chinese herbs nephropathy.

Bieler CA, Stiborova M, Wiessler M, Cosyns JP, van Ypersele de Strihou C, Schmeiser HH

Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany.

4. Arch Toxicol 1998 Nov;72(11):738-43
Chinese herbs nephropathy-associated slimming regimen induces tumours in the forestomach but no interstitial nephropathy in rats.

Cosyns JP, Goebbels RM, Liberton V, Schmeiser HH, Bieler CA, Bernard AM

Department of Pathology, ANPS 1712 Catholic University of Louvain Medical School, Cliniques Universitaires St. Luc, Brussels, Belgium.

5. Am J Kidney Dis 1999 Jun;33(6):1011-7
Urothelial lesions in Chinese-herb nephropathy.

Cosyns JP, Jadoul M, Squifflet JP, Wese FX, van Ypersele de Strihou C

Departments of Pathology, Nephrology, Renal and Pancreatic Transplantation, and Urology, Universite Catholique de Louvain, Brussels, Belgium. cosyns@anps.ucl.ac.be

6. J Ethnopharmacol 1999 Feb;64(2):185-9
Quantitative analysis of aristolochic acids, toxic compounds, contained in some medicinal plants.

Hashimoto K, Higuchi M, Makino B, Sakakibara I, Kubo M, Komatsu Y, Maruno M, Okada M

Central Research Laboratories, Tsumura and Company, Ibaraki, Japan.

7.  N Engl J Med 2000 Dec 21;343(25):1826-32
Phenylpropanolamine and the risk of hemorrhagic stroke.
http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3647b1_tab19.doc

Kernan WN, Viscoli CM, Brass LM, Broderick JP, Brott T, Feldmann E, Morgenstern LB, Wilterdink JL, Horwitz RI

8. Arch Toxicol 1987 Feb;59(5):328-31
Acute toxicity of aristolochic acid in rodents.

Mengs U

9. Arch Toxicol 1993;67(5):307-11
Renal toxicity of aristolochic acid in rats as an example of nephrotoxicity testing in routine toxicology.

Mengs U, Stotzem CD

Toxicology and Experimental Pathology, Madaus AG, Koln, Germany.

10. Letter to Christine Lewis, Ph.D., Director, Office of Nutritional Products, Labeling and Dietary Supplements, US Food and Drug Administration, Center for Food Safety and Applied Nutrition 2000 August 1; http://www.aaom.org/currentevents/fda/aao mres.html

AAOM Herb Committee Responds to FDA Aristolochia Ban

Molony, David Lisc. Ac., Dipl. Ac. & C. H. (NCCAOM), Executive Director AAOM
 

11. Immunopharmacology 1993 Jul-Aug;26(1):1-9
Effect of aristolochic acid on arachidonic acid cascade and in vivo models of inflammation.

Moreno JJ

Departamento de Ciencias Fisiologicas, Fac. Farmacia, Univ. Barcelona, Spain.

12. Placenta 1998 Nov;19(8):631-41
Prostaglandin production by guinea-pig placenta and other uterine tissues during mid-pregnancy.

Norman SJ, Poyser NL

Department of Pharmacology, University of Edinburgh Medical School, UK.

13. N Engl J Med 2000 Jun 8;342(23):1686-92
Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)

Nortier JL, Martinez MC, Schmeiser HH, Arlt VM, Bieler CA, Petein M, Depierreux MF, De Pauw L, Abramowicz D, Vereerstraeten P, Vanherweghem JL

Department of Nephrology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium. jnortier@ulb.ac.be

14. Mutat Res 1988 Dec;206(4):447-54 Evaluation of the mutagenic and cytostatic potential of aristolochic acid (3,4-methylenedioxy-8-methoxy- 10-nitrophenanthrene-1-carboxylic acid) and several of its derivatives.

Pezzuto JM, Swanson SM, Mar W, Che CT, Cordell GA, Fong HH

Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago 60612.

15. Nephrol Dial Transplant 1997 Jan;12(1):81-6
Chinese herbs nephropathy presentation, natural history and fate after transplantation.

Reginster F, Jadoul M, van Ypersele de Strihou C

University of Louvain Medical School, Cliniques Universitaires St-Luc, Department of Nephrology, Bruxelles, Belgium.

16. Cancer Lett 1993 Jul 30;71(1-3):83-7
Induction of hepatic nodules in the rat by aristolochic acid.

Rossiello MR, Laconi E, Rao PM, Rajalakshmi S, Sarma DS

Department of Pathology, University of Toronto, Ontario, Canada.

17. Cancer Res 1996 May 1;56(9):2025-8
Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy.

Schmeiser HH, Bieler CA, Wiessler M, van Ypersele de Strihou C, Cosyns JP

Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany.
 

18. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku 1998;(116):195-6
[Aristolochic acids in herbal medicines].

[Article in Japanese]

Sekita S, Kamakura H, Yasuda I, Hamano T, Satake M

19. Nephrologie 1998;19(1):15-20
[End-stage renal insufficiency associated with Chinese herbal consumption in France].

[Article in French]

Stengel B, Jones E

INSERM U 170, Villejuif. stengel@vjf.inserm.fr

20. Exp Toxicol Pathol 1999 Jul;51(4-5):421-7
Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs nephropathy.

Stiborova M, Frei E, Breuer A, Bieler CA, Schmeiser HH

Department of Biochemistry, Charles University, Prague, The Czech Republic.

22. Lancet 1993 Feb 13;341(8842):387-91
Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs.

Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R, et al

Department of Nephrology, Universite Libre de Bruselles, Belgium.

23. Inflammation 1988 Dec;12(6):549-61
Edema-inducing activity of phospholipase A2 purified from human synovial fluid and inhibition by aristolochic acid.

Vishwanath BS, Fawzy AA, Franson RC

Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0614.

24. Letter 2000 November 03
FDA Letter to Manufacturers of Drug Products Containing Phenylpropanolamine  http://www.fda.gov/cder/drug/infopage/ppa/ppaltr.pdf

U.S. Food and Drug Administration • Center for Drug Evaluation and Research

25. Letter 2000 May 16
Letter to Industry  http://vm.cfsan.fda.gov/~dms/ds-botl1.html

U.S. Food and Drug Administration • Center for Drug Evaluation and Research

26. Attachment to Letter to Industry updated 2000 May 30
Listing of Botanical Ingredients of Concern http://vm.cfsan.fda.gov/~dms/ds-bot2.html

U.S. Food and Drug Administration • Center for Drug Evaluation and Research

27. Drug Information 2001 February 05
Phenylpropanolamine (PPA) Information Page http://www.fda.gov/cder/drug/i nfopage/ppa/default.htm

U.S. Food and Drug Administration • Center for Drug Evaluation and Research