J. Zipper

Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilization.

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.

Human Fertility Control by Transvaginal Application of Quinacrine on the Fallopian Tube

A suspension of the cytotoxant quinacrine is instilled into the endometrial cavities to occlude the proximal fallopian tube of women. Rat experiments had shown that obstruction of the uterus occurred because of hyperplasia of the endometrium increased with dose and was reversible with exogenous estradiol or progesterone. One group of 85 patients received up to 3 doses with 2 ml of 250 mg quinacrine-HCl in water suspension. Group B (37 patients) received up to 2 treatments with 4 ml of a 1 gm suspension. Suspensions were given with a biopsy cannula with an attached 10 ml syringe endometrially within 1 min 3 or 4 days after the menstrual flow. If patency of the tubes were verified by CO2 insufflation or hysterosalpingography treatment was stopped. Biopsies were studied histologically from 4 patients who subsequently had salpingectomy and 20 others. Sixty out of 85 in Group A (24 after 1 dose) were occluded and pregnancy rate was 8.6 per 100 woman-years after 2 years. Menstruation was normal. Occlusion and histologic changes took place in the cornual tube lessening for 2-3 mm. Occlusion occurred in 24/37 in Group B after 1 dose and 5/9 who had 2 doses. Pregnancies appeared only in those whose tubes remained patent. No peritonitis pain or ectopic pregnancies were recorded. Rat experiments point to the acridine nucleus as the active moeity since proflavine but not chloroquine or riboflavine produced hyperplasia of the endometrium.

Alterations in fertility induced by unilateral intrauterine instillation of cytotoxic compounds in rats

Abstract 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.

Transvaginal chemical sterilization: Clinical use of quinacrine plus potentiating adjuvants

Abstract Six years of experience with the use of transvaginal quinacrine as an obliterating agent of the intramural portion of the fallopian tube are presented. Fifteen different forms of treatment using various dosages of quinacrine, alone as well as a combination of quinacrine with several other pharmacological agents were studied. The purpose of these studies was to increase the rate of tubal obstruction, with 1 or 2 instillations of solution. The total experience is based on 638 patients who received treatment according to a prefixed plan. There was a total of 14,677 women months of observation and 437 patients were diagnosed as having tubal obstruction with CO2 insufflation. Out of this group of 437, 50 pregnancies were observed, none of them ectopic, for a Pearl Index of 4. 10. The most effective treatment regimen, quinacrine + xylocaine, with and without epinephrine, after the second instillation had an obstruction rate of 94%. Most of the pregnancies in obstructed patients occurred in the first year and appeared to be due to incomplete obstruction of the oviduct.

Quinacrine sterilization: a retrospective

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.

Pregnancy rates among Chilean women who had non-surgical sterilization with quinacrine pellets between 1977 and 1989.

We describe cumulative pregnancy probabilities among women who underwent quinacrine pellet sterilization in Chile between 1977 and 1989 (N = 1492). We interviewed the women or relatives in 1991-93 and 1994-96, and reviewed hospital records. Mean follow-up was 9.6 years (median 9 years). We recorded 120 pregnancies, including 40 that went to term or near-term. There were nine adverse outcomes in eight infants: one fetal death at 18 weeks gestation; three infants born prematurely; one stillbirth (placental infarct); and four infants with birth defects. There was no clustering of any particular kind of birth defect. For two insertions, the 10-year cumulative pregnancy probability was 8.9 (95% confidence interval 3. 7, 14.1). For 3 insertions, the 10-year rate was 7.0 (4.4, 9.5). For women who were under 35 years at insertion, the 10-year rate was 10. 7 (7.4, 14.1). For women who were 35 or older at insertion, the 10-year rate was 3.1 (0.6, 5.7). The pregnancy rate varied little for 2 vs. three insertions, but the rate did vary significantly by age, with women who received quinacrine at 35 years or older 0.3 (0. 2, 0.5) times as likely to become pregnant as younger women. The 10-year cumulative ectopic pregnancy probabilities for women with two and three insertions of quinacrine were 0.9 (<0.1, 2.6) and 0.5 (<0.1, 1.2), respectively. Pregnancy rates after quinacrine insertion are higher than after surgical sterilization, but ectopic pregnancy rates appear similar.

Biologic Changes Induced by Unilateral Intrauterine Instillation of Quinacrine in the Rat and Their Reversal by Either Estradiol or Progesterone

Quinacrine had previously been found to induce alterations in the en dometrium of the rat and also had been safely employed in humans for its carcinostatic effect. Single injections of from 5 to 40 mg in a .2 ml aqueous suspension were instilled into the right uterine horn of each rat. The animals were mated at different intervals daily vaginal smears made and implantation sites and corpora lutea recorded on Days 9 or 10 after coitus. In another group a search for blastocysts was made on Day 5 after injections of 20 mg or 40 mg. In a third group either estradiol benzoate 50 mcg or progestogen 500 mcg was injected at varying times from 24 hours to 28 days after the quinacrine. Animals were sacrificed 10 days after the last hormone injection. Doses of quinacrine below 20 mg did not alter the fertility of the rats. With larger doses there was a gradual time-related recovery with regard to the number of implantations. This recovery paralleled restoration of uterine patency. Another antimalarial drug chloroquine had no effect on implantation rates. Microscopic studies of some uterine horns of rats treated with 20 mg of quinacrine showed a proliferative reaction and complete obstruction of the lumen. Quinacrine crystals were observed within the mass of foreign-body giant cells and stroma cells for as long as 90 days. These changes after 20 mg reversed spontaneously after 3 months but those after 40 mg doses persisted. Use of talc powder as a particulate matter did not produce any tissue reaction. This action of quinacrine was prevented by either estrogen or progestogen when injected within a short time after quinacrine instillation. In these cases the uterine lumina were patent and the uterine epithelium showed typical changes induced by either estrogen or progestogen. Also the luminal patency was restored when the hormones were administered when obstructed uteri were present.

Copper determination and localization in different morphologic components of human endometrium during the menstrual cycle in copper intrauterine contraceptive device wearers

Comparisons were made of endometrial biopsies performed at random during the 4 phases of the menstrual cycle and after different periods of use on women wearing TCU-120 sq.mm IUD devices, users of plain T devices (minus Cu), and patients without IUDs to determine the localization of Cu delivered by the IUD and the leukocytic infiltration rate. Cu was found to localize in the secretory vacuoles of the endometrial epithelial cells during the progestational phase and was absent during the estrogenic phase indicating that a rise in Cu concentration is progesterone-dependent. No Cu was detected 7 or more days after extraction of the device. No increase in leukocytic infiltration was found in TCU-120 sq.mm device wearers suggesting that the contraceptive mechanism of Cu is not related to leukocyte concentration.

25 years of quinacrine sterilization experience in Chile: review of 2,592 cases.

Objectives: To assess short‐term side effects, long‐term risks and efficacy of quinacrine sterilization (QS) in Chile. Methods: Review experience of 2,592 cases sterilized with 2 or 3 transcervical insertions of 252 mg quinacrine as pellets since 1977; review the Chilean pre‐clinical experience and epidemiological studies on cervical, endometrial and other cancers. Results: Among 2,592 women who underwent QS, the total number of pregnancies was 119 (4.6%); 59 (49.5%) were carried to term with no birth defects related to QS. Nine cases were ectopic pregnancies. The ectopic pregnancy risk per 1,000 woman‐years was 0.41, similar to that for surgical sterilization. The cumulative life‐table pregnancy rates per 100 women at 10 years varied from 5.2 to 6.9. Mild and transient side effects were reported in 13.5% of quinacrine intrauterine insertions and pelvic inflammatory disease was diagnosed in 4 cases (0.15%). Long‐term follow‐up of quinacrine‐sterilized patients shows no increased risk of cervical, endometrial or other cancer. Conclusions: QS efficacy at 10 years is comparable to widely accepted tubal clip and single point bipolar electrocoagulation laparoscopic procedures. QS has a low risk of serious, immediate side effects. No long‐term risks have been identified after 25 years of use.

FOUR YEARS EXPERIENCE WITH THE Cu7 200 DEVICE- ENDOUTERINE COPPER IN FERTILITY CONTROL

Four years of experience with the Cu7 200 device have been completed. The 516 initial women studied accumulated a total of 17,554 months of observation. The most relevant events were: the net annual pregnancy rates, in four successive years of observation, were 2.3, 1.8, 2.1 and 0.9; rates for expulsions were 4.7 0.8, 0.0, and 0.4; and rates for bleeding/pain were 1.6, 2.1, 1.1, and 0.9, respectively, for each year. The quantitative gravimetric analysis of the remaining copper on the device, after four years of use, indicated that the loss of the metal is less than 30% of the original material; therefore the contraceptive activity of the device will continue for some years more. The mechanism of action of endouterine copper is discussed.