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Objective: To trace development of quinacrine sterilization (QS)., Methods: Review of published reports., Results: The high prevalence of septic abortion among high parity women in Santiago, Chile, motivated Zipper to find a safe, inexpensive method of non-surgical female sterilization. Various cytotoxic drugs were tried in rats. Because quinacrine was already accepted for intrapleural injection it was chosen for the first clinical trial. A slurry consisting of quinacrine and xylocaine was instilled into the uterine cavity with a transcervical syringe. Reasonable efficacy was noted and a limited scar of the intramural tube demonstrated. However, a side effect of cortical excitation and reports of 3 deaths ended this approach. Zipper and Wheeler hypothesized that the difficulty was due to rapid absorption of quinacrine under pressure and designed a pellet form that dissolves slowly and could be delivered transcervically using a modified IUD inserter. A standard protocol of 252 mg in seven 36 mg pellets placed at the uterine fundus on two occasions a month apart has now been widely used with considerable evidence for safety and efficacy. Indeed, protection is greater than 98% at 2 years of use., Conclusion: QS is ready for widespread use, especially where surgical sterilization is not safely available or when women are poor candidates for surgery or have such a fear of surgery that they will not seek surgical sterilization.

Quinacrine sterilization (QS) involves transcervical insertion of quinacrine pellets using a modified Copper TIUD inserter. Pellets are placed at the fundus in the proliferative phase of the menstrual cycle. Efficacy is presently estimated at 1 pregnancy failure per 100 women at 2 years. Early complications are lower for QS than surgical sterilization and this is also true for risk of ectopic pregnancy with newer insertion protocols. The risk of birth defects is very low, when estimated from a model with reasonable assumptions for probability of insertion in a pregnant uterus or within 30 days of conception, probability of such exposed pregnancy being carried to term, and probability of quinacrine exposure to the fetus causing a birth defect. Although quinacrine is a mutagen it is unlikely to be a carcinogen. Concentrations of quinacrine in the uterus after transcervical insertion are higher than for oral administration for only a matter of a few hours, although this brief exposure is adequate to cause injury to the tubal epithelium, leading to inflammation and an occluding scar. Oral administration of quinacrine is accepted as non-carcinogenic. Each site of use of QS must make its own risk/benefit assessment. The benefits of any contraceptive that can raise contraceptive prevalence is greatest for developing countries.

100000 quinacrine nonsurgical female sterilizations have been completed over the past decade involving transcervical insertion of quinacrine (252 mg) as pellets by one, two or three monthly insertions. No deaths have been reported and serious complications are far fewer than for surgical sterilization. Side-effects are mild and transient. Efficacy has improved from 3 pregnancy failures per 100 women at one year to approximately 1 by improved insertion technique and use of adjuvants. Long-term follow-up of early cases in Chile shows no increased risk of cancer for this method. The main advantage of quinacrine sterilization is its ability to raise contraceptive prevalence and thereby reduce maternal mortality and morbidity, especially in rural and urban slum areas of developing countries. It should be made available as an option to well informed women everywhere as an economical and safe permanent family planning method.

To investigate relative efficacy of intrauterine diclofenac and ibuprofen as adjuvants to intrauterine quinacrine for nonsurgical sterilization, a total of 900 women were systematically allocated to 2 monthly insertions of pellets of diclofenac (75 mg) or ibuprofen (55.5 mg) as adjuvants to intrauterine quinacrine (216 mg) in a rural private practice in West Bengal, India. All women were prescribed oral contraceptives for three months from first insertion. In the middle of the study increased care was taken to insert pellets at the fundus. There was no statistically significant difference found in cumulative life-table pregnancy failure rates at 36 months for women receiving diclofenac (2.7 +/- 0.82) or ibuprofen (3.4 +/- 0.89). Taking care to insert pellets at the fundus resulted in a decline of failures at 24 months from 4.4 +/- 0.92 to zero. Intrauterine administration of pellets of quinacrine (216 mg) plus diclofenac (75 mg) or ibuprofen (55.5 mg) with 3 months' oral contraception provides acceptable efficacy if pellets are inserted to the fundus.

Two preliminary single-insertion clinical trials of the quinacrine pellet method of non-surgical female sterilization were compared. Both trials used transcervical application of quinacrine, 252 mg, and diclofenac, 75 mg, as pellets. In the first trial (21 April 1992 to 17 February 1993), 58 women received oral contraceptives for three months. In the second trial (19 February 1993 to 25 May 1994), 229 women received medroxyprogesterone acetate, 150 mg IM, at the time of quinacrine insertion. At 18 months, the life-table pregnancy failure rate per 100 women of the first trial was 8.6 (SE 3.7), whereas the failure rate for the medroxyprogesterone acetate group was 0.5 (SE 0.5), p<0.05. There were no serious complications or side-effects in either group. Larger confirming trials with random allocation and long-term systematic follow-up are needed to determine whether a single injection of medroxyprogesterone improves the efficacy of quinacrine.

Objective: To determine the effect on tubal closure of intrauterine quinacrine by dose and time from administration., Design and Participants: Subjects included 33 women of reproductive age who were awaiting hysterectomy for nonmalignant conditions at a Bombay, India medical college. Ten women received 252 mg quinacrine as pellets using a modified Copper-T IUD inserter followed by hysterectomy within 6 weeks, and 23 women received 324 mg quinacrine followed by hysterectomy 6 to 20 weeks post-insertion. Hysterosalpingograms were done before insertion, prior to surgery and on the fresh surgical specimen. The uteri and tubes were subjected to histology studies, including grading of tubal damage. For study of dose, an additional 7 women receiving 100 mg quinacrine (and previously reported) were included., Main Outcome Measure: Tubal closure rates by hysterosalpingogram and tubal histology., Results and Conclusion: Tubal closures were directly related to quinacrine dose and length of insertion-hysterectomy interval. For the 252 mg quinacrine dose, 55.0% of intramural tubal segments and 5.9% of isthmic segments showed histologic evidence of closure. For the 324 mg dose, all intramural tubal segments and 58.8% of isthmic segments showed histologic evidence of closure. Clinical conditions, such as dysfunctional uterine bleeding, were associated with lower tubal closure rates. Multivariate discriminant analysis showed quinacrine dose to be more important than quinacrine-hysterectomy interval.

Objective: To investigate the rates of tubal occlusion, pregnancy, and side effects of repeated, monthly transcervical insertions of 252 mg quinacrine as pellets., Design: Clinical trial among 159 reproductive age women receiving two monthly transcervical insertions of 252 mg of quinacrine followed by hysterosalpingograms (HSGs) 1 month after last insertion and an additional monthly insertion among women without evidence of bilateral tubal occlusion. Contraception of women's choice provided until bilateral tubal occlusion achieved, and surgical sterilization provided for women failing to achieve bilateral tubal occlusion after third quinacrine insertion. Women were followed for at least 24 months for evidence of pregnancy or side effects., Results: Among the 159 women completing the protocol, 73% had evidence of bilateral tubal occlusion by HSGs after two insertions of quinacrine pellets and 94% after a third insertion. These 149 women were followed for 24 months without a pregnancy failure or serious side effect., Conclusion: Transcervical applications of quinacrine as pellets have potential for safe, effective, inexpensive, and easily deliverable female sterilization.

Much evidence suggests that demand for sterilization is a function of supply of surgical sterilization services in less-developed countries. If such services were greatly expanded, the number of procedures performed would grow dramatically. While the prevalence of sterilization is estimated to increase from 23.5% to 28.8% of married women of reproductive age in the 1990s, there will actually be 106,432,000 more couples of reproductive age at the end of this decade than at its beginning who use either no method or a far less effective method with much lower continuation rates than sterilization--nearly a 20% increase. To achieve a mean sterilization prevalence of 47% of married women of reproductive age in the less-developed world, as now seen in the Republic of Korea and Puerto Rico, the number of sterilizations would need to be more than double the current projection for the 1990s: 328,429,000 rather than 159,000,000. The quinacrine pellet method for nonsurgical female sterilization offers hope that this enormous shortfall in sterilization services can be overcome in this decade.

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.

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 women. 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.

The transcervical quinacrine pellet method developed by Zipper and co-workers is potentially a much needed safe, inexpensive, and effective non-surgical method of female sterilization. This method utilizes an intrauterine device inserter to deposit 250 mg of quinacrine hydrochloride as pellets in the uterine cavity. No complications or side effects, other than temporary pain and oligomenorrhea, have been reported. Tetracycline has an established track record for safety. It also has been reported to have properties similar to quinacrine as a sclerosing agent, with potential as a non-surgical method using the quinacrine insertion technique. To expand the experience with quinacrine and to study tetracycline as an alternative, studies were undertaken under the auspices of the Indian Rural Medical Association in Calcutta, India. During the period 14 August, 1979 to 28 June, 1984, 414 women received three insertions of 200 mg of quinacrine. There were 29 failures and a three-year life table failure rate of 8.5. During the period 25 April, 1984 to 28 December 1984, 55 women received three insertions of 200 mg of tetracycline. By 1 June, 1986 there were 32 failures among the 55 cases for a failure rate of 58%. A more recent study using a single dose of 1000 mg of tetracycline also produced unacceptably high failure rates.