Visvanathan, Nalini and Rao, Mohan. Women at risk: Quinacrine sterilisation, a practice that defies accepted international norms, continues in India. Frontline Vol. 14 : No. 19 : September 20 - October 3, 1997
Mulay, Shree. Quinacrine non-surgical sterilisation: troubling questions. Indian Journal of Medical Ethics July -September 2000-8(3)
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RE: Change in FHI's research strategy for female non-surgical sterilization
December 18 2006 Dear Colleagues, We would like to inform you of a change in Family Health International (FHI)'s research strategy for female non-surgical sterilization. FHI has sought to develop a product that is safe and has an effectiveness approaching that of current long-term contraceptive options, such as surgical sterilization and intrauterine devices (IUDs). To date, our research has focused on two products: quinacrine and erythromycin. Safety concerns generated by results from a recent animal study of quinacrine, combined with the results of a recent systematic review of quinacrine's effectiveness in women, have led us to cease our development of quinacrine for non-surgical sterilization. FHI will continue working on the development of erythromycin for this purpose.
With regard to quinacrine's safety, FHI has completed a battery of genotoxicity tests (in vitro tests and in animals) as well as two rodent carcinogenicity studies, one in mice and one in rats. Genotoxicity testing in cells (prokaryotic and mammalian) verified earlier results of others that quinacrine is mutagenic in vitro, although quinacrine was not clastogenic in vivo, i.e., did not cause chromosomal breaks.1
In the first of the rodent carcinogenicity studies, mice exposed to quinacrine systemically (i.e., as are humans when given quinacrine orally) did not show an increased risk of cancer at the end of the one-year observation period.2 In the recently completed rat study, quinacrine was administered directly into the rat uterus, mimicking the proposed contraceptive use in humans. The rat study showed a dose-related increase in malignant reproductive tract tumors at the end of the two-year observation period.3 The increase in tumors was only significant at the upper two doses, and not at the lowest dose. The lowest dose was approximately twice the human dose level on a mg/kg basis.
The relevance of the in vitro and animal study results to humans is unclear. Quinacrine was used widely in the 1940s for malaria treatment and prevention, and an oral toxicology study in rats found no increased risk of cancer.4 However, fewer data exist about intrauterine quinacrine administration. As previously published, FHI conducted a number of early clinical trials of quinacrine involving small numbers of women in the late 1970s and 1980s.5,,67 Since that time, FHI has conducted two long-term epidemiologic studies of women who received intrauterine quinacrine, either as part of the FHI early trials, or as part of other public or private family planning programs not funded by FHI.8,9 Neither long-term study has shown a significant increase in the risk of cancer. Since these studies had limited power to estimate cancer risk because of the relatively small number of study participants, FHI initiated and is currently completing a five-year, case-control study that should provide additional evidence about any potential association between intrauterine quinacrine administration and the risk of gynecologic cancers in women. These results should be available in mid-2007.
We have reported these recent rat study results to the U.S. Food and Drug Administration (FDA). Because women already have a variety of other contraceptive options, we believe that the potential risk of cancer outweighs the potential benefits of quinacrine as a method of contraception, and we anticipate that the FDA would reach a similar conclusion. These considerations have prompted FHI to both cancel its plans for a clinical study of quinacrine in women and to stop working to develop quinacrine as a method of non-surgical sterilization.
Ultimately, a "weight of evidence approach," based on the sum of all findings from available safety studies, will be needed to conclude whether intrauterine administration of quinacrine increases a woman's risk of cancer. While FHI will not be proceeding with quinacrine development, we still plan to convene a scientific panel in late 2007 (after results from the five-year, case-control study are available) to review results of all in vitro, animal toxicology, and human epidemiologic studies. The panel will evaluate the potential risk of cancer based on all available data. This evaluation may be useful to physicians and public health authorities if they need to address women's concerns in countries where quinacrine was used for non-surgical sterilization in the past.
Concerning quinacrine's effectiveness, FHI recently completed a systematic review of data on the effectiveness of quinacrine as used in clinical trials over the past two decades.10 Reported pregnancy rates are as high as 12.6 per 100 women, at five years after two insertions of 252 mg quinacrine, one month apart, according to the standard clinical protocol. This level of effectiveness does not satisfy our goals for a non-surgical sterilization product.
Furthermore, recent results of an FHI-sponsored animal study of a potential adjuvant to increase quinacrine's effectiveness were not promising. FHI's systematic evaluation of quinacrine reflects our dedication to (1) thoroughly studying contraceptive technologies to maximize the availability of safe and effective contraceptive options, and (2) conducting research that respects and values women's welfare. In this respect, an essential component of our non-surgical research program has been an ongoing dialogue with women's health advocates. In 2001, we formed a panel of women's health advocates, and they have regularly provided invaluable advice and input to our program. We still believe that a method of non-surgical sterilization that is safe, effective, inexpensive, and easy to administer would expand the array of contraceptive choices, especially for women who do not have access to surgical sterilization or who prefer a permanent non-surgical method. FHI will continue its efforts to develop such a product, through its current evaluation of erythromycin and consideration of other potential candidates in the future.
A One-Year Neonatal Mouse Carcinogenesis Study of Quinacrine Dihydrochloride
Aida M. Cancel A1, Thomas Smith A2, Ursula Rehkemper A2, John E. Dillberger A3, David Sokal A1, R. Michael McClain A4 A1 Family Health International, Research Triangle Park, North Carolina, USA; A2 Covance Laboratories, Harrogate, North Yorkshire, England; A3 J. Dillberger, LLC, Nashville, Indiana, USA; A4 McClain Associates, Randolph, New Jersey, USA
Abstract:
Quinacrine is an acridine derivative under investigation for its use in nonsurgical female sterilization. Safety issues regarding the carcinogenic potential of quinacrine have been raised because it is mutagenic and clastogenic in vitro. The objective of the study was to evaluate the carcinogenic potential of quinacrine dihydrochloride (quinacrine) in neonatal mice treated with single intraperitoneal doses on postpartum days 8 and 15 and observed for 52 weeks. Neonatal Crl: CD-1 mice of each sex were randomly allocated into four treatment groups (0, 10, 50, and 150 mg/kg), dosed twice with quinacrine suspended in carboxymethylcellulose, observed for 52 weeks post dose, and then euthanized, necropsied, and subjected to a full histopathological examination. In male mice, tumor incidence was not significantly increased at any site at any dose level. In female mice, the incidence of benign uterine endometrial stromal polyps was slightly greater at the mid and high dose (=50 mg/kg), as was the incidence of endometrial hyperplasia. The incidence of polyps in these groups was not significantly greater than in controls by pair-wise comparison but was significantly greater (p= .042) by the linear trend test. The authors conclude that quinacrine administered twice to neonatal mice may have enhanced or accelerated the development of endometrial hyperplasia and uterine stromal polyps at higher doses. Because uterine stromal polyps are a commonly observed benign tumor in older mice, the significance of this finding is unclear and will require a weight of evidence evaluation for a conclusion on the carcinogenic potential of quinacrine.
Keywords: Carcinogenesis, Endometrial Stromal Polyps, Neonatal Mouse, Quinacrine, Uterus ^^^^^^^^^^^^^^^ For additional information about this study, please feel free to contact us.
Sincerely,
David Sokal, MD Scientist, Clinical Research Division Family Health International (FHI) PO Box 13950 Research Triangle Park, NC 27709, USA Office - direct: 919-405-1466 FHI gen'l phone: 919-544-7040 ext. 232
Karen E. Haneke, MS Program Manager, Nonsurgical Sterilization Product Development Family Health International (FHI) PO Box 13950 Research Triangle Park, NC 27709, USA Phone: 919-544-7040 ext. 530
1 Clarke JJ, Sokal DC, Cancel AM, et al. Re-evaluation of the mutagenic potential of quinacrine dihydrochloride dehydrate. Mutat Res 2001;494(1-2):41-53. 2 Cancel AM, Smith T, Rehkemper U, et al. A one-year neonatal mouse carcinogenesis study of quinacrine dihydrochloride. Int J Toxicol 2006;25(2):109-118. 3 A manuscript describing the study is being prepared for publication. 4 Fitzhugh OG, Nelson AA, Calvery HO. The chronic toxicity of quinacrine (atabrine). J Pharmacol Exp Ther 1945;85:207-221. 5 Laufe LE, Sokal DC, Cole LP, et al. Phase I prehysterectomy studies of the transcervical administration of quinacrine pellets. Contraception 1996;54:181-186. 6 Zipper J, Cole LP, Rivera M, et al. Efficacy of two insertions of 100-minute releasing quinacrine hydrochloride pellets for non-surgical female sterilization. Adv Contraception 1987;3[3]:255-261. 7 Sokal DC, Zipper J, King T. Transcervical quinacrine sterilization clinical experience. Int J Gynaecol Obstet 1995;51[1]:S57-69. 8 Sokal DC, Dabancens A, Guzman-Serani R, et al. Cancer risk among women sterilized with transcervical quinacrine in Chile—An update through 1996. Fertil Steril 2000;74:169-171. 9 Sokal D, Hieu DT, Weiner DH, et al. Long-term follow-up after quinacrine sterilization in Vietnam. Part II: Interim safety analysis. Fertil Steril 2000;74:1092-1101. 10 A manuscript describing the review is being prepared for publication.
RE: Change in FHI's research strategy for female non-surgical sterilization