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MISCELLANEOUS QUINACRINE PUBLICATIONS (Continued) Quinacrine. United States Pharmacopeia Convention (USP). United States Pharmacopeia of Drug Information (USP DI) 1997; 17th edition: p. 2489 - 2490. *NOTE: If you are unfamiliar working with PDF files Summary: The United States Pharmacopeia Convention (USP) has approved the use of quinacrine for female sterilization in American women since 1996. According to the Pharmacopeia, this decision represents the "national consensus," arrived at by a committee of medical scientists in the field who have followed the development of this method through reading the scores of peer-reviewed QS articles appearing in the literature.*** According to the Preface, "The USP DI is a comprehensive collection of clinically relevant, established information about each drug. However, it is far more than that. It is a continuous collection of the current judgments of experts in the use of drugs. The information included is the result of a planned, organized, nationwide consensus-generation system (with worldwide input). This system has been designed to involve not only the experts but all interested parties through open public review and comment."*** The USP DI represents "The National Consensus" on uses of drugs and thus appears as the title of the Foreword. It establishes the "legally recognized national standards of quality for drugs and the national consensus on the clinically relevant drug use information needed by the patient and needed by those practioners caring for the patient who is taking the medicine."***The claim of "The National Consensus" is "based on the comprehensiveness of the involvement of all interested parties, the unbiased structure of the system, and constant public access to the system." This consensus is arrived at through "an extensive expert advisory panel system reaching across the entire health field." It includes medical specialty panels, practice oriented panels, a panel of consumers and an international health advisory panel.The use of quinacrine (Atabrine) in rheumatic diseases: A reexamination. D. J. Wallace (Department of Medicine, Cedars-Mount Siani Medical Center, University of California-Los Angeles). Seminars in Arthritis and Rheumatism 1989; 18(4):282-97. *NOTE: If you are unfamiliar working with PDF files Summary: This article offers an excellent overview of the many therapeutic uses of quinacrine. Atabrine has been available for nearly 60 years. It has a variety of actions and been administered to millions of individuals. Its antirheumatic properties have been well documented but not exploited optimally for a variety of reasons. The drug is generally quite safe and could be used in low doses in lupus and rheumatoid arthritis patients as a steroid-sparing agent or synergistically with hydroxychloroquine. Its bothersome side effects should not deter the clinician from using it, because they are easy to deal with or prevent. Future studies should attempt to better characterize the immunosuppressive actions of this powerful drug, particularly in the treatment of lupus erythematosus and rheumatoid arthritis. Studies of the role of combination or single-agent antimalarial therapy in combination with other "remittive" drugs could be of great potential benefit.Atabrine hydrochloride (brand of quinacrine hydrochloride): for chemotherapy of giardiasis, tapeworm and malaria. Winthrop-Breon Laboratories, New York. Package insert from Winthrop-Breon Laboratories 1985; 6 pp. *NOTE: If you are unfamiliar working with PDF files Summary: This standard package insert prepared by a U.S. manufacturer of quinacrine (Atabrine) includes a description of the drug, actions, indications, contraindications, adverse reactions, dosage and administration, how supplied, etc.Atabrine dihydrochloride: quinacrine hydrochloride [an expanded discussion of package insert information]. Winthrop-Breon Laboratories. New York Monograph undated; . *NOTE: If you are unfamiliar working with PDF files Summary: An expanded discussion of the Winthrop-Breon package insert material, including pharmacology, therapeutics, tolerance and the safety of use during pregnancy (citing a study of 3500 pregnant women).QUINACRINE AND CANCER IN HUMANS Chemical carcinogenesis: too many rodent carcinogens. B. N. Ames, L. S. Gold (Division of Biochemistry and Molecular Biology, University of California, Berkeley). In: Proceedings of the National Academy of Sciences October 1990; 87:7772-6. *NOTE: If you are unfamiliar working with PDF files Summary: The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis), which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism, because a high proportion -- about half -- of all chemicals tested (whether natural or synthetic) are indeed rodent carcinogens. We conclude that at the low doses of most human exposures, where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed.Quinacrine hydrochloride drug eruption (tropical lichenoid dermatitis). Its early and late sequelae and its malignant potential: A review. F. Bauer, Melbourne, Victoria, Australia. Journal of the American Academy of Dermatology 1981; 4:239-248. *NOTE: If you are unfamiliar working with PDF files Summary: The totality of effects of a particular drug on patients cannot he truly assessed until many patients have taken it. In order to assess the side effects of any drug, many thousands of patients may have to he observed, and the observation may have to extend over decades. Quinacrine hydrochloride (quinacrine) was used as a malarial-suppressive drug by allied soldiers during World War II. The most commonly occurring side effect was a drug eruption. This at times led to permanent sequelae at an early stage. Further observation revealed late sequelae occurring 7 to 17 years after the war. Two of these late sequelae were observed to become malignant, and in most cases the palmar aspect was involved. This is an area which rarely shows malignant change. It has been observed that quinacrine can be instrumental in inducing skin cancers as late as 34 years after its ingestion.Quinacrine and copper, compounds with anticonceptive and antineoplastic activity. A. Dabancens, A. Guerrero (Department of Experimental Medicine, Faculty of Medicine, Universidad de Chile, Santiago), J. Zipper (Department of Physiology and Biophysics, Faculty of Medicine, Universidad de Chile, Santiago). Contraception September 1994; 50:243-51. *NOTE: If you are unfamiliar working with PDF files Summary: Changes in the evolution of a malignant transplantable tumor in mice to whom quinacrine, copper and zinc were supplied in drinking water are reported. Male AJ mice were inoculated in the right thigh with 1,000,000 TA3 or TA3 MTXR tumoral cells. Three experiments were designed with different types of tumors and different schedules of quinacrine and cations administered in drinking water. The animals that received quinacrine or quinacrine plus copper in drinking water had significantly smaller tumors and some groups had a high rate of complete tumor regression (up to 60%). Quinacrine and copper have synergistic antineoplastic activity. Zinc salts do not improve the antitumoral effect of quinacrine. The relevant fact of this experiment lies in the fact that a large number of women using IUDs with copper could occasionally be treated with quinacrine.Prevalence and standardized incidence rates of preclinical cervical pathology among 1061 women sterilized with transcervical quinacrine hydrochloride pellets. A. Dabancens (Cytopathology and Cancer Control Service, Faculty of Medicine, University of Chile); D. C. Sokal (Family Health International, Research Triangle Park, North Carolina); M. Pruyas, M. R. Rivera, J. Zipper (Sótero del Rio Hospital, Area Sur Oriente, Santiago, Chile). Fertility and Sterility 1995; 64:444-446. *NOTE: If you are unfamiliar working with PDF files Summary: Objective: To determine whether the incidence of in situ cervical carcinoma was increased among a cohort of women who received transcervical insertions of quinacrine hydrochloride pellets into the uterine cavity as a method of nonsurgical sterilization. Design: Retrospective review of Papanicolaou (Pap) test results, comparing incidence of high-grade lesions among quinacrine acceptors with a comparison population. Setting: Outpatient clinics, Santiago, Chile. Subjects: Women attending a family planning clinic (quinacrine acceptors) and a comparison population from another area of Santiago. Main Outcome Measure: Incidence of in situ cervical carcinoma. Results: During 3,668 women-years of follow-up, 8 women in the quinacrine group were found to have in situ carcinomas for an age-adjusted rate of 2.62 per 1,000 woman-years. The incidence in a comparison population was 1.62 per 1,000 woman-years, but the difference was not statistically different. Conclusions: The age-standardized incidence of in situ carcinoma among the quinacrine sterilized women was not significantly different from the rate in a comparison population of women in Santiago. However, the study has a number of limitations.Toxicological requirements for sclerosing agents or other chemicals for female sterilization. R. Heywood (St. George's House, Huntingdon, Cambridge, United Kingdom). International Journal of Gynecology and Obstetrics 1995; 51(Suppl):S41-S45. *NOTE: If you are unfamiliar working with PDF files Summary: There are no guidelines regulating the technologies available for Fallopian tube occlusion. Generally accepted regulatory requirements cannot be applied directly to the safety assessment of these technologies. The more appropriate guidelines are those regulating medical devices. Each method has to be evaluated on its own merits taking into consideration the duration of contact with tissue and the chemical and physical composition of the occlusive agents.The Wellcome Trust population initiative. B.M.Ogilvie, I.G.Scott. Human Reproduction, 12 National Supplement, The British Journal of Fertility and Sterility 1997; 2(2). pp. 95-98. *NOTE: If you are unfamiliar working with PDF files Summary: On the 7 December 1995 the Trust convened a meeting of a small group of independent experts who had reviewed the existing clinical and toxicological data on quinacrine. The group discussed the nature of the toxicological evaluations that would be needed for an adequate risk-benefit analysis of its clinical use. After considering a report on the group's deliberations the Population Studies Panel indicated its willingness to receive research proposals addressing the safety of the method, noting that prehysterectomy studies of quinacrine pharmacodynamics would be constructive, and that they could be taken forward without additional data from animal studies. The consensus of the Panel was that the Trust should not actively promote long-term animal studies.Cancer risk among women sterilized with transcervical quinacrine in Chile: an update through 1996. D.C. Sokal, A. Dabancens, R. Guzman-Serani, J. Zipper (Family Health International, Research Triangle Park, North Carolina 27709, USA). Fertil Steril Jul;74(1):169-71 2000; Jul;74(1):169-71. *NOTE: If you are unfamiliar working with PDF files Summary: OBJECTIVE: To determine whether further follow-up of a cohort of Chilean women would demonstrate an increased risk of invasive cancer associated with quinacrine sterilization. DESIGN: Cohort study. Cancer cases were evaluated using cohort analyses. SETTING: Santiago and Valdivia, Chile. SUBJECT(S): Fourteen hundred ninety-two women who received transcervical quinacrine pellets for contraceptive sterilization between 1977 and 1989. METHOD(S): Interviews and reviews of medical records. MAIN OUTCOME MEASURE(S): Age- and site-specific incidence of invasive cancers. RESULT(S): During 13,444 person-years of follow-up, 25 invasive cancers were identified, including 8 new cases. This compares with 21.9 expected cancers, based on age-specific rates from the Cali, Colombia, cancer registry. Eight cases of cervical cancer were observed, compared with the 6.3 expected. Since the initial study's confirmation of a single case of leiomyosarcoma, no other noncervical uterine cancers have been diagnosed. The number of observed person-years gives an expectation of 0.62 noncervical uterine cancers. One case of ovarian cancer was diagnosed, compared with the 0.99 expected. CONCLUSION(S): Rates of cancer among women exposed to intrauterine quinacrine are not significantly different from population-based rates.Cancer risk among women sterilized with transcervical quinacrine hydrochloride pellets, 1977 to 1991. D. C. Sokal (Family Health International, Research Triangle Park, North Carolina); J. Zipper (Sótero del Rio Hospital, Santiago, Chile); R. Guzman-Serani (Escuela de Medicina, Universidad Austral de Chile); T. E. Aldrich (Department of Epidemiology, University of North Carolina at Chapel Hill). Fertility and Sterility 1995; 64:325-34. *NOTE: If you are unfamiliar working with PDF files Summary: To determine whether a cluster of 8 cancers among 572 women who had received transcervical quinacrine hydrochloride was a random occurrence or evidence of an increased risk of cancer, a retrospective cohort study was designed, using interviews and reviews of medical records. Cancer cases were evaluated by means of cohort analyses and space-time cluster methods. The study included 1492 women from Santiago and Valdivia, Chile, who had received transcervical quinacrine pellets for sterilization between 1977 and 1989. The main outcome to be measured was age- and site-specific incidence of invasive cancers. A total of 802 women were interviewed. From 1 to 14 years of data were available on 600 of the noninterviewed women from their clinic records. During 7852 woman-years of follow-up, 17 invasive cancers were identified, compared with 11.8 expected, based on age-specific rates from the Cali, Colombia cancer registry. Five cases of cervical cancer were observed, compared with the 3.96 expected. Only one other uterine cancer was observed, a leiomyosarcoma, compared with 0.2 or 0.3 other uterine cancers expected. The occurrence of an unusual cluster was confirmed, but no evidence was found of excess cancer risk associated with quinacrine pellet sterilization. However there was a single provocative observation (the leiomyosarcoma), and surveillance of the cohort is continuing.Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. R. W. Tennant, et al (Cellular and Genetic Toxicology Branch, Toxicology Research and Testing Division, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina). Science 1987; 236:933-41. *NOTE: If you are unfamiliar working with PDF files Summary: Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays.An evaluation of the mutagenicity and carcinogenicity of quinacrine. R.R. Tice (Genetic Toxicology Integrated Laboratory Systems, Research Triangle Park, North Carolina); J. Griffith (Environmental Health and Epidemiology, Inc., Raleigh, North Carolina); L. Recio (Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina). Unpublished report of Family Health International June 22, 1990; 32pp. *NOTE: If you are unfamiliar working with PDF files Summary: Quinacrine is a direct acting mutagen in prokaryotic organisms. The mutagenic activity results from the ability of this aminoacridine derivative to intercalate into DNA, which results in frame-shift mutations. There is a surprising lack of information, especially from recently conducted studies, on its genotoxicity in eukaryote assay systems. Quinacrine has been reported to induce sister chromatid exchanges, chromosomal aberrations and morphologic transformation in cultured mammalian cells. However, these positive results lack independent verification. The existing data from in vivo mammalian systems, although largely limited to bone marrow micronucleus studies, is negative. Studies to comprehensively evaluate the effect of quinacrine treatment on levels of DNA damage in the cells of patients have not been reported. Among the various aminoacridine compounds evaluated for genotoxicity, either in vitro or in vivo, quinacrine is less potent than, for example, acridine orange and proflavine. Thus, although carcinogenicity studies on quinacrine have not been conducted, cancer bioassays conducted on acridine orange and proflavine have not been able to convincingly demonstrate carcinogenic activity. This comparison would suggest that the carcinogenic risk from quinacrine may be, at the very worst, quite small.***The general conclusion is that because of its mutagenic activity, the possibility exists that quinacrine may pose a carcinogenic risk to humans, necessitating concern and continued monitoring. However, the lack of positive in vivo data and, considering the extent of medicinal use, the lack of relevant human data suggests that the risk for cancer may be quite small. Recommendations for increasing the mutagenicity/carcinogenicity data base for quinacrine are suggested.Quinacrine: sclerosing agent of the utero-tubal junction in women, with anticarcinogenic actions in transplanted tumors in mice. J. Zipper (Department of Physiology and Biophysics, Faculty of Medicine, University of Chile and Sotero del Rio Hospital, Santiago, Chile); A. Dabancens, A. Guerrero (Department of Experimental Medicine, Faculty of Medicine, University of Chile, Santiago, Chile); V. Trujillo (San Jose Hospital, Santiago, Chile). International Journal of Gynecology and Obstetrics 1995; 51(Suppl):S47-S55. *NOTE: If you are unfamiliar working with PDF files Summary: Quinacrine, an acridine derivative that was in widespread use as an anti-malarial, has been shown to have both sclerosant and anticarcinogenic actions. The sclerosant action of quinacrine has been used to produce occlusion of the Fallopian tube in both experimental animals and women, and several clinical studies are reviewed. Both actions of quinacrine are potentiated by steroidal and non-steroidal antiprostaglandins as well as by ionic copper. Combinations of quinacrine with antiprostaglandin drugs, and also with copper, improved the efficacy of quinacrine when used for female sterilization and reduced side effects. A review of the experimental and epidemiological evidence suggests that quinacrine has no carcinogenic effects.WHO AND QS Quinacrine family planning method. (Letter) Response to Editorial of April 23, 1994. G. Benagiano (Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland). Lancet 1994; 344:689. *NOTE: If you are unfamiliar working with PDF files Summary: No "WHO critique of Hieu's paper" exists. We do have on file the confidential review by a staff scientist made in a private capacity for the editor of another journal which we cannot make public. This was made clear by Dr. Francis Webb in his letter to Ms. Linda Demers, the UN Population Fund (UNFPA) country director for Vietnam. I remind you that an official WHO position is only given out after approval of the document through the appropriate channels. Indeed, in Dr. Webb's letter the only reference to a "WHO position" is contained in a sentence that reads "WHO's position is that further clinical research is not justified until various toxicological issues have been resolved."Sterilization by Quinacrine. (Letter) (On the 25-27 July 1994 World Health Organization meeting on quinacrine). G. Benagiano (Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland). Lancet 1994; 344:689. *NOTE: If you are unfamiliar working with PDF files Summary: Report to Benagiano of experts' meeting in Geneva on technological advances in nonsurgical sterilization: The outcome of this consultation substantiates the statement on WHO's position: further clinical research is not justified until various toxicological issues have been resolved. The high standards of safety demanded in the testing and use of contraceptives should apply whether the subjects recruited to the studies are from the developed or developing world.Frittering of utopian WHO. T. R. Choudhury. Indian Medical Tribune, New Delhi 1992; . *NOTE: If you are unfamiliar working with PDF files Summary: A research report seriously criticizes WHO's spending patterns and points out that it has failed to be an effective promoter of health throughout the world.WHO lacks transparency: members cautious . I.R. Choudhury, New Delhi. Indian Medical Tribune February 15, 1995; . *NOTE: If you are unfamiliar working with PDF files Summary: Sweden, discontented with the working of WHO, has decided to slash its funding by 50% from current contributions. Sweden finds WHO to be inefficient and unprofessional in its approach towards fund utilization. Lack of transparency and apparent reluctance by WHO to discuss with member states the issues and steps required to carry out decided reforms. A working system has to be upgraded to carry out the international health work for which it was established. An urgent need exists to prevent further losses in prestige of the organization.Quinacrine: of medicine, politics and vested interests -- where is the woman in the equation?. E.B. Conant (Canisius College, Buffalo, New York). Speak Out Magazine of the PRO-CHOICE NETWORK OF WESTERN NEW YORK 1995; Summer. *NOTE: If you are unfamiliar working with PDF files Summary: Quinacrine has been used widely and safely for decades, but is suddenly controversial when used to control fertility. The debate among international health agencies, and private researchers has ignored the woman patient. Quinacrine is still prescribed for various medical conditions. The author describes its use for female sterilization, and cites the clinical trials that have been mounted since the 1970s, especially the Vietnamese study reported in the Lancet in 1993. She relates how the Association of Voluntary Surgical Contraception, who have the most to lose if a chemical displaces their method. Then an officer of the WHO raised the specter of quinacrine causing cancer, although no cancer has been found in any follow-up studies. Conant states that the well-known Catholic influence within WHO has made it historically resistant to family planning initiatives. Oppositional groups, despite the lack of substantiation of their claims, have brought the trials to a standstill in Vietnam, where the women had been very well satisfied with this alternative to childbirth mortality and morbidity that is safer and more accessible than surgery.Fighting the parasites of poverty: public research, private industry, and tropical diseases. T. Godal (Director, UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Disease, Geneva). Science 1994; 264(June 24):1864-6. *NOTE: If you are unfamiliar working with PDF files Summary: Although 90% of the global disease burden occurs in the tropics, where a billion people live in absolute poverty, only about 5% of global research and development investment is directed to reducing that burden. Dedicated scientists, supported with some private foundation funding and national and international agencies and programs, have made an important contribution. But products have not been developed to make practical new tools to control parasites and their vectors. Research is not enough. The author cites successful smallpox campaign; decline in polio, etc. Systematic search for way of delivery efficiently and to affected communities is called for. ***Lists three basic requirements to overcome pharmaceutical market problems. (1) Commitment by all parties to keep costs at lowest possible levels. Public sector must not overregulate the private sector in which it should invest on a pragmatic basis. (2) Private sector to undertake research, development and supply on a break-even or defined profit basis. (3) Willingness on all sides to fund innovative institutional arrangements. ***Public sector can identify means for reducing development costs and promote more appropriate analysis of the public risks and benefits of introducing new medical products. We can make use of existing products where much of the toxicology or even registration is complete. Drugs already in human use would be such candidates. It is essential to make appropriate risk-benefit analyses in tackling these problems. The debate on one global drug development standard is misguided. The only standard is one in each local case, the rational, and political, analysis of risk against benefit.WHO in crisis. F. Godlee, assistant editor. British Medical Journal 1994; 309:1424-8. *NOTE: If you are unfamiliar working with PDF files Summary: Media attention has been focused on the leadership of the World Health Organization, rather than on the real factors that limit WHO's effectiveness. These factors relate to the organization's structure and also to its current priorities, methods, and management. This article examines the objectives and strategy of WHO in view of financial constraints and donor countries' demands; WHO's stated goal of integrated primary health care; staff morale; and the growing dislocation between the regions and headquarters.WHO in retreat: is it losing its influence?. F. Godlee, assistant editor. British Medical Journal 1994; 309:1491-5. *NOTE: If you are unfamiliar working with PDF files Summary: WHO says it has three main functions: to set normative standards; to provide technical advice and assistance on medical matters; and to advocate changes in health policy. During its 46 year history the first two functions have been a constant and uncontroversial backbone through which WHO has earned its reputation for scientific excellence. The third function, advocacy, came to the fore with the launch of Health for All in 1977, after which WHO took a key role in influencing international health policy. WHO's friends and critics alike now say that the organization is losing its influence and retreating into its technical and biomedical shell. This article maps the changes in WHO's approach over the past 46 years and considers whether fears about its loss of influence are justified.The regions -- too much power, too little effect. F. Godlee, assistant editor. British Medical Journal 1994; 309:1566-70. *NOTE: If you are unfamiliar working with PDF files Summary: WHO's regional offices make it structurally one of the most decentralized of all United Nations agencies. But at what cost and to what effect? This article argues that too often the regions give only the illusion of decentralization while wresting power from WHO's governing body and prolonging the time taken for resources to reach the point of need.WHO at country level -- a little impact, no strategy. F. Godlee, assistant editor. British Medical Journal 1994; 309:1636-9. *NOTE: If you are unfamiliar working with PDF files Summary: The acid test of WHO's effect on the world's health is its impact at country level. Unless it has an impact there, all of its declarations, its debates at the World Health Assembly, its conferences, its pamphlets, its political maneuvering in Geneva and the regions, all of these come to nothing. Working as it does through national governments, WHO insists that it has no role in directly managing or delivering health care. Judging WHO's impact in individual countries is therefore difficult -- its approaches are largely indirect, and initiatives may take years to bear fruit. But from the meagre resources that WHO makes available at country level it is clear why its country operations are criticized as the weakest link in an already weak chain of influence from its headquarters in Geneva to the people in its member states. Poorly funded, undertrained, and with no clear strategy to follow, its staff at country level stand little chance of making an impact.WHO AND QS (Continued on Next Page) |