Quinacrine Non-surgical Method of Voluntary Female Sterilization: Current News  
 
   
  

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QUINACRINE PELLET METHOD CLINICAL TRIALS (Continued)

Stérilization féminine, non chirurgicale avec l'emploi de quinacrine: efficacité de deux insertions de pellets de quinacrine [Nonsurgical female sterilization using quinacrine: efficacy of two insertions of quinacrine pellets].
V. Trujillo (San José Hospital, Santiago, Chile); J. Zipper (Sotero del Rio Hospital, University of Chile, Santiago); B. Viel (Chilean Academy of Medicine); M. Rivera (Sotero del Rio Hospital). Gynecology and Obstetrics 1993; 88:147-50.
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Summary: In a group of 159 women at Santiago, Chile, fertility control by means of chemical occlusion of the utero-tubular junction was assessed. Two transcervical intrauterine insertions of 216 mg of quinacrine, carried out at an interval of one month and associated with 50 mg of intrauterine diclofenac and 150 mg of intra-muscular diclofenac resulted in a pregnancy rate after 12 months of 2.1 per 100 women and a Pearl Index of 1.63 at 27 months after the sterilization process. The complications and adverse events appear to the similar to those that occur during insertion of an IUD and were minor and transient, disappearing within a few hours or at most 2 days after the procedure.

Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilization.
J. Zipper (University of Chile, Santiago; Sotero del Rio Hospital, Puente Alto, Chile); L.P. Cole, A. Goldsmith, R. Wheeler (International Fertility Research Program, Research Triangle Park, North Carolina); M. Rivera (Hospital Sotero del Rio). International Journal of Gynaecology and Obstetrics 1980; 18:275-9.
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Summary: The efficacy of transcervical insertions of quinacrine hydrochloride pellets to produce tubal occlusion has been evaluated in a study of 139 women in Santiago, Chile. At one year, the pregnancy rate was 3.1%, an acceptable rate for a nonsurgical method of female sterilization.

Overview of clinical trials with quinacrine.
J. Zipper (Hospital Sotero del Rio, Santiago, Chile); D. Edelman, L.P. Cole (International Fertility Research Program, Research Triangle Park, North Carolina); M. Rivera (Hospital Sotero del Rio).. In: Female Transcervical Sterilization: Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds., Philadelphia: Harper and Row 1983; p 172.
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Summary: Extensive research has been undertaken to develop a simple method of nonsurgical female sterilization. The intrauterine use of quinacrine hydrochloride as such a method has evolved from instillations of a solution, to the development of pellets used with a potentiating agent, and then to the use of quinacrine pellets alone. The major adverse effect of quinacrine solution administration was transient psychosis (2.0%); the use of pellets seems to have eliminated the risk of that complication (0.0%), probably because the pellet dissolves relatively slowly (< 10 minutes) within the uterine cavity, reducing the risk of rapid intravascular absorption. Animal studies were initiated to identify problems occurring if perforation occurs and quinacrine is accidentally placed in the peritoneum. At high doses, several animals died. Excessive peritoneal absorption produced a high blood level of quinacrine, leading to death, and perhaps caused by a central nervous system reaction. High doses of quinacrine when administered intraperitoneally are clearly toxic. Additional animal studies are planned to determine if, by prolonging the in utero rate of release of quinacrine, the toxic side-effects may be avoided without affecting the ability of the drug to cause tubal fibrosis.***A comparison of results from various studies conducted by Zipper shows that the pellet method of quinacrine delivery is an improvement over the solution method. Sodium thiopental does not seem to be a necessary adjunct to the procedure. But it still requires three administrations of quinacrine to be effective, thus falling short of the ultimate goal of an effective, blind, one-insertion procedure. The erratic performance of the quinacrine pellets in occluding the tubes is probably caused by the uneven distribution of the quinacrine to the tubal ostia. Improvements in the delivery of quinacrine are being explored, including the use of an IUD to deliver the quinacrine to the tubal ostia, and of a sustained-release pellet system in the hope that extended exposure of the drug will produce a higher rate of tubal closure.

Efficacy of two insertions of 100-minute releasing quinacrine hydrochloride pellets for nonsurgical female sterilization.
J. Zipper, M. Rivera (Hospital Sotero del Rio, Santiago, Chile); L.P. Cole, E. Brown (Family Health International, Research Triangle Park, North Carolina); R.G. Wheeler (Wheeler Consulting, Product Design and Development, Greenbank, Washington). Advances in Contraception 1987; 3:255-61.
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Summary: Extensive research has been undertaken to develop a simple method of nonsurgical female sterilization. Zipper and his associates identified quinacrine hydrochloride as a drug likely to produce tubal occlusion when placed into the uterus. His early work with a solution of quinacrine led to the development of quinacrine pellets, a delivery system that was designed to bring the quinacrine into prolonged contact with the tubal ostia through extended uterine retention. Three transcervical uterine insertions of 10-minute releasing quinacrine hydrochloride pellets performed at monthly intervals have produced a 12-month pregnancy rate of 3.3 per 100 women. The ultimate goal is to develop an effective, single insertion procedure, but the performance of the quinacrine pellets in occluding tubes has necessitated more than one insertion. Family Health International developed a 100-minute extended release pellet system with the expectation that more prolonged drug exposure would produce a higher rate of tubal closure. A study of the 100-minute releasing pellet system has been conducted in Santiago, Chile. Two monthly insertions in 112 women has resulted in a 12-month pregnancy rate of 2.0 per 100 women. Postprocedure problems occurring within the first year were reported by 13% of the women; most were minor and transitory.

Non-surgical female sterilization. Review of question: experimental basis, pharmacology, toxicology, efficacy.
J. Zipper, M. Rivera, A. Dabancens (Sotero del Rio Hospital, University of Chile, Santiago). Rev fr Gynecol Obstet 1993; 88:185-90.
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Summary: Non surgical female sterilization. Use of intrauterine pellets of quinacrine and betamethasone. Review of question: experimental basis, pharmacology, toxicology, efficacy. Quinacrine produces obstruction of the region of the uterine tube by its fibroblastic granulomatous action. Factors such as the Zinc++ and Copper+ content of tubal tissue, as well as the use of anti-prostaglandins, potentiate this action. Two groups of patients were evaluated. For Group A (95 women), 180 mg of quinacrine + 0.6 mg of betamethasone were inserted into the uterine cavity, on the basis of two insertions separated by a one-month interval. Two pregnancies were found by the end of the 2nd year, the percentage failure rate being 2.2 and the Pearl index 0.58. For Group B (120 women), 216 mg of quinacrine + 1.2 mg of betamethasone were inserted into the uterine cavity, on the basis of two insertions separated by a one month interval. Two pregnancies were found by the end of the first year, the percentage failure rate being 0.59 and the Pearl index, 0.54. Iatrogenic adverse reactions associated with quinacrine only were not seen in either of these two study groups. None of the pregnancies was ectopic.

Quinacrine revised.
J. Zipper-Abragan (Department of Physiology and Biophysics, University of Chile, Santiago); A. Dabancens, A. Guerrero (Department of Experimental Medicine, University of Chile, Santiago); V. Trujillo (San José Hospital, Santiago). Human Reproduction Update 1995; 1:53-72.
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Summary: Analysis of the chemistry of quinacrine and its mechanisms of action are detailed. Clinical applications are discussed. Some concentrations in contact with the human uterine tube produce an obstructive granuloma of its lumen at the intramural portion. Two transcervical insertions of slow dissolution pellets containing 250 mg of quinacrine produce a cumulative pregnancy rate of 7% at 7 years of follow-up. The addition of antiprostaglandins to quinacrine has reduced the pregnancy rates in the first 3 years of follow-up when compared with quinacrine alone to 3% for quinacrine + diclofenac and 2% for quinacrine + betamethasone. The association of quinacrine-betamethasone-Cu during two insertions has produced a pregnancy rate of <1% in the first 3 years of follow-up. Quinacrine alone in the same period produced a 5% pregnancy rate. Any carcinogenic or toxicological assay (short-term in vitro tests or long term in vivo tests) should consider the combination of quinacrine plus the adjuvants. This research was performed by two different centers and investigators.

Quinacrine Sterilization: Development Of The Method.
JA Zipper, A Dabancens, V Trujillo (Department of Physiology and Biophysics, University of Chile, Santiago, Chile). Acta Obstetricia et Gynecologica Scandinavica 1997; Vol 76: Sup. 167:4 p.16 (Abstract).
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Summary: Starting in the mid-1960s we tested various agents, using the rat as an experimental animal for the effect of intrauterine administration on fertility. Quinacrine was finally chosen for the first clinical trial in the late 1960s as the toxicology of quinacrine had already been completed for oral use. The first clinical trials used two or three monthly transcervical instillations of a quinacrine slurry, but pregnancy failures were 9.1 per 100 women at one year using 1.5 g of quinacrine in 3 installations. There was also a worrisome side effect of cortical excitation noted in 2% of cases. In the late 1970s we changed to quinacrine as pellets that would accommodate a Copper T IUD inserter. Efficacy was improved leading to 3.1 pregnancy failures per 100 women at one year using 252 mg quinacrine for 3 monthly transcervical insertions. No case of cortical excitation has been reported for quinacrine pellets. Efficacy has been further improved by research of others using an insertion technique that assures deposit of pellets at the fundus and use of an adjuvant contraceptive for 3 months from time of last insertion. With these improvements high efficacy is achievable with even a single insertion of quinacrine 252 mg. A long-term follow-up of 1,492 women in Chile who had received quinacrine sterilization between 1971 and 1991 showed no increased risk of cancer of the uterus. Further rat studies suggest quinacrine is actually protective against experimental cancers in this species. After reviewing all accumulated data on quinacrine sterilization and reported toxicology studies the method was approved for use in Chile as an option to women requesting sterilization.

MISCELLANEOUS QUINACRINE PUBLICATIONS


ACOG technical bulletin: Sterilization.
American College of Obstetricians and Gynecologists. International Journal of Gynecology and Obstetrics: Technical bulletin 1996; Number 222 - April 1996 (Replaces No. 113, February 1988).
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Summary: This Technical Bulletin was developed under the direction of the Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists and aid to obstetricians and gynecologists. Summarizes sterilization procedures and new developments.

Quinacrine.
American Medical Association, Chicago, IL: Clayton, C.B., ed.. In: Guide to prescription and over-the-counter drugs; Random House 1988; p 478.
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Summary: This reference work presents in lay terms an overview of quinacrine that includes general information, information for users, possible side effects and special precautions.

The FDA does not approve uses of drugs (editorial).
J.D. Archer (American Medical Association, Chicago, Illinois). Journal of American Medical Association 1984; 252(8):1054-55.
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Summary: As a reviewer of medical manuscripts and reader of published articles, I find it frustrating to continue to find reference to "Food and Drug Administration (FDA)-approved uses of drugs"--or worse, allegations that certain uses are "not approved." For nearly two decades, through published articles, speeches, and personal communications, I have cautioned the medical profession against such diction. Perhaps the most definitive article was "Instrument or Impediment? The Regulatory Monograph in Medical Communications." The FDA cannot approve or disapprove of how a legally marketed drug is used by a physician in his practice. The agency approves of what the manufacturer may recommend about uses in its labeling (package insert) and advertising.

Camp laparoscopic sterilization deaths in Gujarat State, India, 1978-1980.
R. V. Bhatt (Department of Obstetrics and Gynaecology, Baroda Medical College) and B. M. Amin (General Hospital, Baroda, India). Asia-Oceania Journal of Obstetrics and Gynaecology 1991; 17(4):297-301.
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Summary: An early experience of camp laparoscopic sterilization in Gujarat State, India, resulted in 22 deaths among 106,500 women undergoing the operation during 1979 and 1980. Increased risk of death was seen when larger numbers of procedures were performed by year or month of year. The least experienced surgeons had the highest case fatality rate. Improvised settings (i.e., school buildings) exacerbated the risk of death, as did advanced age, and, to a lesser extent, high parity. Errors in clinical judgment were identified in some fatal procedures. A system of health audit of large sterilization programs is needed.

Pharmacokinetics of quinacrine after intrapleural instillation in rabbits and man.
S. Bjorkman; L.O. Elisson; J. Gabrielsson (University of Lund, Malmo, Sweden). Journal of Pharmacy and Pharmacology 1989; 160-3.
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Summary: Quinacrine was given by intrapleural instillation or intravenous infusion to 10 rabbits. The uptake of quinacrine from the pleural space was rapid and complete. The mean absorption half-life was approximately 7 minutes. Similar absorption characteristics generally applied in man.

Quinacrine (Atabrine): mode of action [bactericidal].
J. Ciak; F.E. Hahn (Walter Reed Army Institute of Research, Washington, DC). Science 1967; 156:655-56.
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Summary: Quinacrine blocks DNA synthesis. This drug is bactericidal.

Complications of interval laparoscopic tubal sterilization.
F. Destefano, J.R. Greenspan, R.C. Dicker, H.B. Peterson, L.T. Strauss, G.L. Rubin (U.S. Department of Health and Human Services, Atlanta, Georgia). Obstetrics and Gynecology 1983; 61:153-158.
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Summary: In 1978, the Centers for Disease Control initiated a multi-center prospective study to assess the safety of the various female sterilizing operations and the ways in which they could be made safer. During the first 31 months, 3500 women who underwent interval laparoscopic tubal sterilization by electrocoagulation or Silastic banding without other concurrent operations were enrolled in the study. When a standard definition of complications was used, the overall rate of an intraoperative or postoperative complication was 1.7 per 100 women. Several patients' factors increased the risk of complications twofold or more: diabetes mellitus, previous abdominal or pelvic surgery, lung disease, a history of pelvic inflammatory disease, and obesity. There was a fivefold difference in complication rates between procedures performed under general anesthesia and those done under local anesthesia.

CFR: Code of Federal Regulations: The clinical investigation of an off-label use of a drug such as quinacrine that is lawfully marketed in the United States.
FDA. Food and Drug Administration: Code of Federal Regulation (4-1-96 Edition); 312.1-2 p. 72.
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Summary: States the conditions under which an IND is unnecessary in order to undertake a clinical investigation of an approved drug. The use of quinacrine to achieve sterilization meets these conditions.

Quinacrine.
L.S. Goodman; A. Gilman. In: The Pharmacological Basis of Therapeutics. Second Edition. New York, Macmillan 1960; pp 1167-73.
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Summary: Standard textbook presentation of the pharmacology, toxicology, and therapeutics of drugs, including quinacrine, written for physicians and medical students. Highly detailed.

Chlorination alone won't control giardiasis.
R.P. Handler. Health officer, Town of Altamont, New York, Letter to the Editor. New York Times June 6, 1994; .
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Summary: The most effective and best tolerated drug for giardiasis is quinacrine. Unfortunately, it is no longer obtainable in the U.S. Its manufacturer lost its source of raw material. Other sources are available to overseas manufacturers. FDA has not approved them. Action by FDA is critically important.

Mepacrine and pregnancy.
F. Humphreys, JM Marks. British Journal of Dermatology 1988; 118:452.
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Summary:

An Agent for the Palliative Treatment of Neoplastic Effusions: Quinacrine Hydrochloride.
Council on Drugs. Journal of the American Medical Association March 28, 1966; Vol 195, No 13.
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Summary: Quinacrine hydrochloride is often effective in the palliation of recurrent pleural effusions and ascites associated with certain neoplastic diseases. Adverse reactions are mild and transient.

Regulation of investigational drugs: unapproved uses of approved drugs - role of Food and Drug Agency (FDA).
D. Kessler, Commissioner. The New England Journal of Medicine 1989; 320:285-6.
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Summary: The FDA's newly articulated policy permits physicians to explore new uses of approved drugs without submitting an IND. A physician may treat patients with an approved drug for indications not included on the drug's approved label, subject to possible malpractice action. According to the new FDA regulations, a different issue arises if a physician uses a drug not to treat but to investigate an unapproved use of an approved drug. Under the new regulation, investigations of the use of approved drugs differing from the approved use only in doses, routes of administration, or types of populations treated are exempt from IND requirements if two conditions are met: if the investigation does not substantially increase the associated risks, and if the sponsor does not intend to present the data to the FDA in support of new uses or changes in the drug's approved labeling or promotional materials.

Letters to the Editor.
E. Kessel (Department of Public Health and Preventive Medicine, Oregon Health Sciences University, Portland, Oregon). American Journal of Obstetrics and Gynecology December 1996; p. 1675.
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Summary: Ectopic pregnancy. Discusses findings of Peterson et al (American Journal of Obstetrics & Gynecology) that 32.9% of surgical female sterilization failures ended in ectopic pregnancies. Suggests quinacrine non-surgical method. Very low ectopic rate associated with it.***H. B. Peterson (Centers for Disease Control and Prevention, Atlanta, Georgia): Response to Kessel. Mentions concerns raised because quinacrine method is not approved for use in USA and WHO recommended resolution of toxicologic issues.

Sterilant action of quinacrine [How does it produce infertility in women?].
E. Patek (Karolinska Institute, Huddinge University Hospital, Sweden). Fertility and Sterility 1977; 28:692.
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Summary: What is the mode of action and degree of effectiveness of the chemosterilant quinacrine for achieving tubal occlusion for sterilization in women? Quinacrine hydrochloride, mainly used as an antimalarial agent, has been used as a nontoxic chemosterilant in transvaginal procedures in the human female. Clinical experiments indicate that quinacrine acts as a powerful obstructive agent exclusively on the epithelium of the intramural portion of the tube, without altering the histology of the endometrium. The precise mechanism of quinacrine's obstructive action on the mucosa of the uterotubal junction is unknown. One possible mode of action is that it binds to epithelial DNA, thus forming a clot of granulomatous tissue, as quinacrine is known to form adhesions when used in the control of neoplastic effusions. Zinc is known to inhibit quinacrine-DNA binding. The human endometrium, rich in zinc, is unaffected by quinacrine, whereas the tubal cornua, with little zinc, promote the obstruction by quinacrine-DNA bonding. The procedure is effective in 90% of cases with two instillations of quinacrine. Further studies are essential to find agents that will potentiate the action of quinacrine on the human Fallopian tube epithelium.***See also (in English): Quinacrine Hydrochloride: review and mode of action of an antimalarial, used as an occlusive agent for transvaginal human sterilization.

Quinacrine hydrochloride: Review and mode of action of an antimalarial, used as an occlusive agent for transvaginal human sterilization.
E. Patek. (Department of Obstetrics and Gynecology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden). Acta Obstetricia et Gynecologia Scandinavica (Copenhagen) 1979; 58:561-4.
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Summary: Quinacrine hydrochloride, mainly used as an antimalarial, has been used as a nontoxic chemosterilant in a transvaginal procedure in the human female. Clinical experiments indicate that Quinacrine acts as a powerful obstructive agent exclusively on the epithelium of the intramural portion of the tube without altering the histology of the endometrium. The precise mechanism of Quinacrine's obstructive action on the mucosa of the uterotubal junction is unknown. Its possible mode of action is binding to epithelial DNA thus forming a clot of granulomatous tissue, as Quinacrine is known to form adhesions when used in the control of neoplastic effusions. Zinc is known to inhibit Quinacrine-DNA binding. The human endometrium, rich in Zinc is unaffected by Quinacrine, whereas the tubal cornua, with little Zinc promote the obstruction by Quinacrine DNA bondage. The procedure is effective in 90 per cent of the cases with two instillations of Quinacrine. Further studies are essential to find agents that would potentiate the action of Quinacrine on the human Fallopian tube epithelium.

Detailed description of Atabrine (quinacrine).
PDR. Physicians' Desk Reference 1993; .
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Summary: This standard reference work includes an entry for Atabrine, the Sanofl Winthrop brand name for quinacrine. It describes the drug, its actions, indications, contraindications, offers warnings and precautions and discusses adverse reactions, dosage and administration.

The safty and efficacy of tubal sterilization: an international overview.
H.B. Peterson, I. Lubell, F. DeStefano, H.W. Ory (Family Planning Evaluation Division, Centers for Disease Control, Atlanta, Georgia, and The Association for Voluntary Sterilization, Inc., New York, NY, USA). International Journal of Gynaecology and Obstetrics 1983; 21:139-144.
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Summary: body

The risk of pregnancy after tubal sterilization: Findings from the U.S. Collaborative Review of Sterilization.
H. B. Peterson, Z. Xia, J. M. Hughes, L. S. Wilcox, L. R. Tylor, J. Trussell. American Journal of Obstetrics and Gynecology April 1996; 174:1161-70.
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Summary:

The risk of ectopic pregnancy after tubal sterilization.
H. B. Peterson, Z. Xia, J. M. Hughes, L. S. Wilcox, L. R. Tylor, J. Trussell. The New England Journal of Medicine March 13, 1997; Vol. 336 Number 11: 762-67.
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Summary: Although pregnancy after sterilization is uncommon, it can occur and maybe ectopic. Using the data from the U.S. Collaborative Review of Sterilization to estimate the risk of ectopic pregnancy in women who have undergone the common types of tubal sterilization, the authors analyzed the follow-up data of 10,685 cases. Using cumulative life-table probabilities and proportional-hazards analysis the 10-year cumulative probability of ectopic pregnancy for all methods combined was 7.3 per 1000 procedures. The cumulative probability varied substantially according to the method used and the women's age. A complete analysis is provided.

Reversal of sterilization due to application of quinacrine by means of transcervical tubal catheterization.
A. S. Thurmond (Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, Oregon); M. K. Jones (Department of Radiology, Kaiser Sunnyside Medical Center, Portland, Oregon); B. Mullick (Indian Rural Medical Association, Calcutta, India); E. Kessel (Department of Public Health and Preventive Medicine, Oregon Health Sciences University, Portland, Oregon). Journal of Vascular and Interventional Radiology 1995; 6:147-9.
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Summary: The establishment of tubal patency is necessary for subsequent conception, but it does not guarantee conception. The postprocedure salpingograms of the two tubes that were successfully recanalized demonstrated patent tubes, which is a promising finding. However, the microscopic findings are unknown, and the patients may have developed pelvic adhesions or other factors affecting fertility since their prior deliveries. The occurrence of a normal intrauterine pregnancy in these two women would help establish the usefulness of transcervical catheterization in the reversal of sterilization. If pregnancy did not occur, this finding would, unfortunately, be inconclusive because of the small number of patients.

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