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

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Teratologic and mutagenic studies with intrauterine quinacrine hydrochloride.
D.A. Blake, N.H. Dubin, M.C. Diblasi, T.H. Parmley, G. Stetten, T.M. King (The Johns Hopkins University School of Medicine, Baltimore, Maryland).. In: Female Transcervical Sterilization, Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds., Philadelphia, Harper and Row 1983; p 71.
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Summary: The mutagenicity studies were performed primarily to corroborate what was already published for quinacrine (i.e., it is a direct-acting frameshift mutagen in bacterial systems). As noted in the review of the literature, quinacrine has much less mutagenic activity in eukaryotic cells and no clear mutagenic activity in mammalian systems. It is particularly noteworthy that no chromosomal abnormalities could be detected in the peripheral lymphocytes of cynomolgus monkeys that had received quinacrine by intrauterine or intravenous injection. Within the limitations of such extrapolations, from these studies quinacrine would appear to have little potential for inducing fetal malformations when administered by intrauterine injection. The embryolethal effect is expected for direct-acting mutagens.

Pharmacokinetic studies on quinacrine following intrauterine administration to cynomolgus monkeys.
N.H. Dubin, D.A. Blake, M.C. DiBlasi, T.H. Parmley, T.M. King (The Johns Hopkins University School of Medicine, Baltimore, Maryland). Fertility and Sterility 1982; 38:735-40.
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Summary: Recent efforts have been made to develop a chemical oviductal occluding agent. Intrauterine quinacrine has been used in certain areas of the world with moderate success in effecting tubal closure. This report presents the pharmacokinetics of a quinacrine solution (30 mg) as administered to cynomolgus monkeys via the intrauterine route, compared with intravascular injection. The data show rapid transfer of the drug from the uterine to the vascular compartment and uptake by almost all tissues examined. Although plasma concentrations disappear within 24 hours, levels can be detected in most tissues for at least 1 week following intrauterine injection. After 28 days, however, tissue levels of the drug are absent or near the limit of detection.

Effect of intrauterine and intravascular quinacrine administration on histopathology, blood chemistry, and hematology in cynomolgus monkeys.
N.H. Dubin, J.D. Strandberg, C.F. Craft, T.H. Parmley, D.A. Blake, T.M. King (The Johns Hopkins University School of Medicine, Baltimore, Maryland). Fertility and Sterility 1982; 38:741-7.
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Summary: Histopathologic features, blood chemistry, and hematologic features were studied in cynomolgus monkeys following intravascular or intrauterine administration of a 30-mg solution of quinacrine hydrochloride. Intrauterine quinacrine administration resulted in extensive necrosis of the endometrial surface, and lesions which obliterated the cornual areas of the uterus were observed at 24 hours after treatment. Necrosis was also observed on occasion in the ampulla or isthmic portion of the tube. Evidence of repair of the reproductive tract was seen 7 and 28 days following treatment. No lesions were observed in any nonreproductive organ examined, whether quinacrine was administered by the intrauterine or intravascular route. Blood chemistry data revealed moderate and transient increases in serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and lactic dehydrogenase (LDH). No other blood chemistry or hematologic changes were noted that could be attributed to quinacrine administration. For the conditions described in these studies, intrauterine administration of quinacrine appears to be a safe procedure. However, the potential toxicity of the drug is discussed.

Pharmacology of quinacrine hydrochloride with emphasis on its use as a tubal occluding agent.
N.H. Dubin, T.H. Parmley, M.C. Diblasi, R.B. Ghodgaonkar, M.T.M. Jiffry, D.A. Blake, T.M. King (The Johns Hopkins University School of Medicine, Baltimore, Maryland).. In: Female Transcervical Sterilization: Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds., Philadelphia, Harper and Row 1983; p 60.
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Summary: An intensified program for identification of synthetic antimalarial drugs was conducted in Germany during the 1920s. Quinacrine was one of 12,000 synthetic chemicals found to be effective in treating malaria and was widely used prior to World War II. Quinine remained the chief antimalarial drug, however, until the Japanese invasion of the South Pacific cut supplies and expanded US production of quinacrine became imperative, increasing from a prewar level of 1200 lb/year to almost one ton/day. Much of the pharmacologic knowledge about quinacrine was acquired from observations and studies made during that time. Quinacrine is a bright yellow crystalline powder. The metabolic rate of quinacrine is incompletely understood. In humans, urinary products include the unmetabolized form as well as the O-demethylated derivative, the side-chain-cleaved amine derivative, and an O-demethylated side-chain-cleaved amine. The pharmacokinetics of quinacrine has been studied primarily in regard to ingestion of the drug. Because the mode of administration may alter the absorption of a drug and its distribution, we investigated the pharmacokinetic properties of quinacrine following intrauterine injection. Besides its use in the management of malaria, quinacrine has been used to treat tapeworm infection, cutaneous leishmaniasis, and lupus erythematosus and to control neoplastic effusions in the pleural and peritoneal cavities.

Quinacrine as a method of female sterilization.
T. M. King (President, Family Health International, Research Triangle Park, North Carolina). Association for Voluntary Surgical Contraception (AVSC) offices in New York City (unpublished) December 2, 1993; 11pp.
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Summary: A short review of human toxicology information on quinacrine. Animal toxicology studies completed in the 1970s and early 1980s are furnished.

Histologic changes following intrauterine administration of quinacrine hydrochloride.
T.H. Parmley, N.H. Dubin, J. Strandberg (The Johns Hopkins University School of Medicine, Baltimore, Maryland); L.E. Laufe (The University of Texas, Health Sciences Center at San Antonio, Texas).. In: Female Transcervical Sterilization: Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds., Philadelphia, Harper and Row 1983; p 89.
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Summary: Intrauterine administration of quinacrine effectively occludes the central portion of the Fallopian tube in a certain proportion of cases. The factors that determine the frequency with which this occurs are still unclear, but intrauterine chemical sterilization with this or a similar agent seems promising.


ANIMAL STUDIES

Toxic effects of quinacrine hydrochloride in rhesus monkeys.
H. Chandra, B. Malaviya (Central Drug Research Institute, Lucknow, India. Contraception 1981; 24:269-74.
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Summary: The toxic effects of intraperitoneal, intrauterine and intravenous administration of quinacrine hydrochloride solution were evaluated in female adult rhesus monkeys (Macaca mulatta). A single intraperitoneal injection of 400 mg and above resulted in the development of toxic manifestations leading to death of monkeys. Intrauterine instillation of 500 mg of quinacrine was well tolerated and did not produce any toxic effects. However, intravenous injection of 100 mg and 75 mg was lethal to the animals.

Comparative effects of intrauterine instillation of analogues of quinacrine and tetracycline on uterine morphology in the rat.
N.H. Dubin, T.H. Parmley, R.B. Ghodgaonkar, B. Pharm, T.M. King (The Johns Hopkins University School of Medicine, Baltimore, Maryland). Contraception 1984; 29:553-59.
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Summary: Currently, intrauterine instillation of quinacrine hydrochloride is used to induce closure of the uterotubal junction in women, thus constituting a chemical method of sterilization. Questions regarding the safety of this drug have been raised. The purpose of the present study is to screen other drugs for their sterilizing potential by comparing quinacrine-induced changes in uterine morphology in the rat which have previously been correlated with decreased fertility with the changes induced by other drugs. The drugs tested include quinacrine-like compounds, namely chloroquine, primaquine and trimethoprim; and tetracycline and its analogues which are known sclerosing agents. The quinacrine-like drugs were relatively ineffective in producing uterine lesions similar to those of quinacrine, but like quinacrine, chloroquine and primaquine showed some toxicity. Tetracycline and its analogues produced quinacrine-like morphologic changes in the rat uterus and showed no toxicity for the doses tested. These results prompt further testing of tetracycline and its analogues as sterilizing agents.

Controlled delivery systems for quinacrine for female sterilization.
R.L. Dunn, D.R. Cowsar (Southern Research Institute, Birmingham, Alabama); D.H. Lewis (Stolle Research and Development Corporation, Birmingham, Alabama).. In: Female Transcervical Sterilization: Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds., Philadelphia, Harper and Row 1983; p 128.
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Summary: The results from this study show that modified monolithic delivery systems can be prepared from quinacrine or quinacrine dihydrochloride with polycaprolactone, a totally biodegradable polymer. These systems, in the form of coaxial fibers or rods, can be designed to give almost zero-order release of quinacrine dihydrochloride for various times, ranging from several days to several weeks. Although the fibers are limited in the quantity of drug they deliver, owing to size and flexibility, both systems provide an effective method of delivering quinacrine at a controlled rate to the Fallopian tubes.

The chronic toxicity of quinacrine (Atabrine).
O. G. Fitzhugh, A. A. Nelson, H. O. Calvery (Division of Pharmacology, Food and Drug Administration, Federal Security Agency, Washington, DC). Journal of Pharmacologic Experimental Therapy 1945; Volume 85, pp. 207-21.
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Summary: This investigation was undertaken to demonstrate differences in response to the toxic action of quinacrine when administered for the approximate lifetime of albino rats on high and low protein diets. Though this study was not undertaken for the purpose of determining carcinogenesis in rats administered quinacrine for their lifetime, the findings do offer some reassurance. 144 rats were given quinacrine continuously in their diet at one of four levels for their lifetime. At the higher levels, quinacrine was very toxic and none of the rats survived until the end of the experiment. No cancers were observed.

Toxic and antifertility effects of quinacrine hydrochloride in rats.
A.A. Joseph, Fred A. Kincl (Laboratory for Reproduction, Brookdale Hospital Centers, Brooklyn, New York). American Journal of Obstetrics and Gynecology 1974; 119:978-81.
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Summary: A single instillation of an aqueous suspension containing 40 mg of quinacrine hydrochloride into the uterine horns of adult rats prevented implantation for at least 4 weeks. A suboptimal dose of 5 mg could be potentiated by the addition of epinephrine or metaraminol. In some animals, the use of the quinacrine hydrochloride suspension resulted in atrophy and necrosis of the treated uterine horn, a constriction of the lower colon which blocked the propulsion of intestinal contents, and death.

Chemical occlusion of monkey oviducts with quinacrine: antagonism and reversal with estrogen.
B. Malaviya, H. Chandra, A.B. Kar (Central Drug Research Institute, Lucknow, India). Contraception 1975; 12:31-6.
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Summary: The effect of estrogen on quinacrine induced tubal occlusion was studied in rhesus monkeys (Macaca mulatta). The results suggest that estradiol dipropionate, when given at a dose of 1 mg per animal intramuscularly daily for 5 days commencing from day 2 of instillation (Day 1 = day of quinacrine instillation), antagonizes the action of quinacrine in producing tubal occlusion. It was further observed that estrogen treatment from days 16 to 20 reversed the already established tubal occlusion in monkeys.

Evaluation of slow-release quinacrine pellets in the pig.
L.J.D. Zaneveld (University of Illinois at the Medical Center, Chicago, Illinois); A. Goldsmith (Program for Applied Research on Fertility Regulation, Northwestern University Medical School, Chicago, Illinois).. In: Female Transcervical Sterilization: Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds., Philadelphia: Harper and Row 1983; p 122.
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Summary: The slow release of quinacrine appears to result in much lower nonreproductive tissue levels of quinacrine than the acute administration of quinacrine and should therefore be less toxic. Since high levels of quinacrine can be released from the slow-release pellets, it can be expected that, in the primate or the woman, the slow release of quinacrine from the pellets should effectively obstruct the uterotubal junction (UTJ), while causing minimal, if any, side-effects.

Lack of tubal occlusion by intrauterine quinacrine and tetracycline in the primate.
L.J.D. Zaneveld (University of Illinois at the Medical Center, Chicago, Illinois); A. Goldsmith (Program for Applied Research on Fertility Regulation, Northwestern University Medical School, Chicago, Illinois). Contraception 1984; 30:161-7.
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Summary: The effects of slow- and fast-releasing quinacrine pellets and tetracycline tablets on the genital tracts of 20 cynomolgus monkeys were evaluated. After surgical implantation of the pellets, the primates were observed for three months. No signs of toxic effects of the drugs were observed during the three-month period and on autopsy. Histopathological evaluation of the Fallopian tubes, cervix, ovaries and uterus (except the endometrium) indicated they were all within normal limits. In no case were the uterotubal junctions obstructed. Endometrial changes were more frequent for quinacrine-tested monkeys. The results of the study point to the need for additional research regarding the optimal dose and duration of quinacrine administration.

Alterations in fertility induced by unilateral intrauterine instillation of cytotoxic compounds in rats.
J.A. Zipper, M. Medel, R. Prager (Instituto de Fisiologia, Escuela de Medicina, Universidad de Chile, and Hospital Barros Luco, Santiago, Chile). American Journal of Obstetrics and Gynecology 1968; 101:971-78.
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Summary: Cytotoxic agents, cadmium, iodoacetate, thio-TEPA, podophyllin, colchicine, and alcohol, were instilled in one uterine horn of the rat to observe their subsequent effect on fertility. Cadmium and iodoacetate interfere with implantation in both horns without altering ovulation for periods of 1 to 2 months. Thio-TEPA produces a unilateral effect for periods of 2 months. With alcohol this unilateral effect is prolonged. In every group histologic changes are detailed. Reversibility is complete in every group except the alcohol group.

Pharmacological agents that potentiate or inhibit the occlusive action of quinacrine in the rabbit tube and rat uterus.
J. Zipper, S. Insunza (School of Medicine, University of Chile, Santiago, Chile).. In: Female Sterilization: Prognosis for Simplified Outpatient Procedures. (Proceedings of a workshop held at Airlie, Virginia, December 2-3, 1971): Duncan CW, Falb RD, Speidel JJ, eds., New York: Academic Press 1972; p 151-8.
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Summary: The precise mechanism of action of quinacrine as an occlusive agent in the intramural region of the human Fallopian tube and the rat uterus is unknown, as is the reason for its lack of occlusive effect in the rabbit tube. As a working hypothesis, we have postulated that "binding" of quinacrine to DNA is the essential factor in this process and that this binding is dependent upon the zinc concentration in the endometrium. The findings with Zn and Cu are in total agreement with the initial hypothesis, as are the experiments with chelating agents in the rabbit tube. The diverse actions of sodium and potassium cations is difficult to explain as are the estrogenic effects induced by Xylocaine when it is combined with quinacrine in the rat. Epinephrine and metaproterenol are adrenergic beta agents that inhibit uterine motility, which is associated with an increase in cyclic adenosine 3, 5-monophosphate and an increased glucose production from glycogen. Norepinephrine activates alpha receptors, but its catabolic effects on glycogen are slight. Our observation that both drugs act in a very similar way, although epinephrine is somewhat less effective, could be regarded as a problem exclusively of dose. The fact that metaproterenol acts differently than epinephrine in the rat is difficult to explain in this stage of investigation, but preliminary studies in the rabbit indicate that in this species they both potentiate the action of quinacrine.

Biologic changes induced by unilateral intrauterine instillation of quinacrine in the rat and their reversal by either estradiol or progesterone.
J.A. Zipper, R. Prager, M. Medel (University of Chile, Santiago, Chile). Fertility and Sterility 1973; 24:48-53.
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Summary: Intrauterine instillation of a suspension of quinacrine in the rat has been shown to induce a giant cell foreign body reaction in the endometrium and a consequent obstruction of the lumen. There is a long lasting decrease in fertility subsequent to this obstruction. This effect can be inhibited or reversed by either estradiol benzoate or progesterone.


PREHYSTERECTOMY STUDIES

Quinacrine-induced pathologic changes in the Fallopian tube.
R.V. Bhatt (Medical College and S.S.G. Hospital, Baroda, India); A. Aparicio, L.E. Laufe (International Fertility Research Program, Research Triangle Park, North Carolina); T.H. Parmley, T.M. King (The Johns Hopkins University School of Medicine, Baltimore, Maryland). Fertility and Sterility 1980; 33:666-7.
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Summary: Sterilization has become the single most prevalent method of family planning on an international scale. It is estimated that approximately 80 million surgical sterilization procedures have been performed since the early 1950s, and the majority of these have been female. The demand for female sterilization is growing, and there is a clear need for a safe and effective nonsurgical method to terminate fertility. A transcervical chemical method is most desirable as it eliminates the need for surgery and thus could be a major contribution to family planning programs. For the past decade, Zipper and his associates have been exploring the use of intrauterine quinacrine, a sclerosing agent, for the tubal ostia. Early experiments using multiple instillations of a quinacrine solution produced an unacceptably high pregnancy rate until the three instillations were completed. Recently, Zipper et al have employed quinacrine pellets delivered through a modified intrauterine device (IUD) inserter. By compacting the quinacrine into pellets to delay solution time and delivering 250 mg of these quinacrine pellets postmenstrually for 3 consecutive months, they have eliminated the pregnancies which occurred between the instillations of quinacrine solution. The pregnancy rate postinstillation has no significant difference for either the quinacrine solution or the quinacrine pellets. It is of interest to note that in over 400 patients to date no ectopic pregnancy has occurred.

Histopathologic changes in the cornual portion of the Fallopian tube following a single transcervical insertion of quinacrine hydrochloride pellets.
A.A. El-kady (Boulak El-Dakrour Hospital, Giza, Egypt); M.M. Mansy (Kasr El-Aini Faculty of Medicine, Cairo University, Egypt); H.S. Nagib (Boulak El-Dakrour Hospital, Giza, Egypt); E. Kessel (Oregon Health Sciences University, Portland, Oregon). Advances in Contraception 1991; 7:1-9.
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Summary: To study the sequence of histopathologic changes taking place in the cornual portion of the Fallopian tube subsequent to exposure to quinacrine, 252 mg were inserted transcervically in 12 women awaiting hysterectomy for non-malignant conditions of the uterus. All patients who underwent surgery within ten days of insertion were found to have necrosis of the epithelial lining and an acute inflammatory reaction. Later on, the changes observed included progressive absorption of the inflammatory cellular exudate, progressive fibrosis, with partial or almost complete occlusion of the lumen, and failure of regeneration of the epithelial lining. Our results support other studies indicating that quinacrine can effectively produce tubal fibrosis and occlusion.

Quinacrine IUDs.
L.E. Laufe (The University of Texas, Health Sciences Center at San Antonio, San Antonio, Texas); R.G. Wheeler (International Fertility Research Program, Research Triangle Park, North Carolina).. In: Female Transcervical Sterilization: Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds., Philadelphia: Harper and Row 1983; p 115.
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Summary: As our interest in the further development of the concept of chemical sterilization with quinacrine was pursued, we realized that we must determine the exact pathologic changes induced by quinacrine. In 1980, Bhatt and associates reported on the quinacrine-induced pathologic changes in Fallopian tubes. This limited study was accomplished by inserting one application of 250 mg quinacrine pellets into the uterine cavity of 23 women awaiting hysterectomies; therefore, 46 tubes were studied. The changes induced by quinacrine were documented, and in about 50% of the cases an obstructive lesion commensurate with tubal closure was induced. As a result of this study, a concept was developed to provide a better delivery system of quinacrine to attempt to ensure a more accurate application of the drug to the tubal ostia and to reduce the delivery system to a single event. At that time, studies were initiated using the IUD as a vector for delivering quinacrine. Requirements for these studies were that the participants were awaiting an elective hysterectomy and had no distortion of the uterine body such as myomas and no severe endometrial disturbances. Most of the hysterectomies were in women with prolapse or a premalignant lesion of the cervix. To date, 72 women have been studied. No patient has had any adverse reaction.

Phase I prehysterectomy studies of the transcervical administration of quinacrine pellets.
L. E. Laufe (formerly of the University of Texas Health Science Center at San Antonio, retired), D. C. Sokal, L. P. Cole (Family Health International, Research Triangle Park, North Carolina), D. Shoupe (Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles), R. S. Schenken (Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas). Contraception 1996; 54:181-6.
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Summary: To determine the safety of transcervical administration of quinacrine pellets as a method of voluntary female sterilization, three noncomparative Phase I clinical trials of the administration of 250 mg quinacrine were carried out in 21 women who were scheduled to undergo hysterectomy 24 hours or one month later. Detailed results are presented for one of the trials using 10-min pellets. Six of 10 women had minor transitory complaints during the postinsertion 24-hour follow-up period. Five women reported pelvic/abdominal cramping, one experienced headache, and one experienced dizziness. Blood chemistry values were not adversely influenced by the quinacrine. The average plasma level of quinacrine peaked at 3 hours, 36.1 ng/ml, slightly lower than the value observed 4 hours after oral administration of 200 mg in a previous study. An average of 27% of the administered dose was recovered in tampons. Quinacrine was detected in the plasma of two women at the four/six-week visit. Selected results are presented from two other trials that were halted because of slow recruitment. The transcervical administration of 250 mg of 10-minute quinacrine pellets was well tolerated. However, based on recent mutagenicity testing and meetings with regulatory officials, it appears unlikely that the use of quinacrine for nonsurgical sterilization could be approved in the United States or Europe.

Clinico-pathological study of Fallopian tubes after transcervical insertion of quinacrine hydrochloride pellets.
R.N. Merchant (B.Y.L. Nair Hospital and T.N. Medical College, Bombay, India); V.M. Doctor (Breach Candy Hospital, Bombay, India); S.S. Thaku (B.Y.L. Nair Hospital and T.N. Medical College, Bombay, India); M. Sinha (Breach Candy Hospital, Bombay, India); C.L. Jhaveri (Indian Fertility Research Program, Bombay, India); E. Kessel (International Federation for Family Health, Chapel Hill, North Carolina); S.D. Mumford (Center for Research on Population and Security, Research Triangle Park, North Carolina). Advances in Contraception 1986; 2:79-90.
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Summary: This study lends support to others indicating the apparent safety and effectiveness of multiple transcervical insertions of quinacrine hydrochloride as pellets in 240 mg dosage to achieve permanent sterilization. In order to study the effects of the number of quinacrine pellet insertions and the site of placement of the pellets in the uterus of prehysterectomy volunteers, a scoring system of histological changes in the Fallopian tube was designed. Quinacrine pellets were deposited at the fundus using a straight inserter in 16 women, and at the cornua using a curved inserter in 17 others. Each group had at least five women receiving one, two or three insertions at one-week intervals. Results indicate that neither the number of insertions nor the place of deposition of the pellets affects the degree of tubal inflammation and fibrosis.

PREHYSTERECTOMY STUDIES (Continued on Next Page)

  
         
 
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