Evaluation of a New Contraceptive

Transcription

1 ,. Evaluation of a New Contraceptive Aquiles J. Sobrero, M.D. To EVALUATE a new chemical contraceptive, a series of tests are employed to measure its spermicidal efficacy, harmlessness, and acceptability.5 After preliminary investigation by animal experimentation carried out by the manufacturer to exclude toxic or irritant ingredients, the preparation is subjected to laboratory tests for spermicidal efficacy. Clinical tests are then made in the human female to assess acceptability: first the "single dose" test and then the "21-day" test (daily doses for 21 consecutive days). If the preparation is found to be acceptable and nonirritating, postcoital tests are then performed to determine the degree of spermicidal activity in vivo under controlled conditions. Only when found satisfactory in all laboratory and preliminary clinical tests is a new contraceptive preparation considered ready for the field test-the final, long-range study that will measure its effectiveness in preventing pregnancy when in ordinary use. The purpose of the present communication is to report the results obtained during the investigation of a new contraceptive-an aerosol vaginal foam*-recently developed for use without a diaphragm or other occlusive device. The manufacturer describes the preparation as an oil-in-water dispersion (maintained by surface active agents) which is combined under pressure with a liquefied gas propellant, so that the liquid dispersion can be expelled as a foam into a vaginal applicator. The container is a plastic-coated glass bottle of 75-ml. capacity provided with a valve cap. From the Margaret Sanger Research Bureau of the Planned Parenthood Federation of America, New York, N. Y. Emko Vaginal Foam, The Emko Company, St. Louis 17, Mo. 518

2 Vol. II, No.5, 1960 EVALUATION OF A NEW CONTRACEPTIVE 519 The composition of the preparation, which has a ph of 7.5, is as follows: Benzyl dimethyl (2-(2-(p-l,I,3,3 tetramethylbutylphenoxy) ethoxy ) ethyl) ammonium chloride (benzethonium chloride, U.S.P.) Nonyl phenoxypolyoxyethylene ethanol Myristic acid Stearic acid Triethanolamine Glyceryl monostearate Polyoxyethylene sorbitan monooleate Polyoxyethylene sorbitan monolaurate Polyvinylpyrrolidone Polyethylene glycol (average molecular weight 600) Deionized water 0.2% 8.0% 2.0% 4.0% 2.0% 3.0% 3.0% 3.0% 1.0% 1.4% 72.4% The propellant is composed of Freon 12 (dichlorodifluoromethane CCIF2), 15 per cent by weight, and 85 per cent Freon 114 (dichlorotetra Huoroethane-CCIF 2.CCIF 2), at a pressure of kg./ sq. cm. (or 1225 mm. Hg) at 21 c., and comprises 10 per cent by weight of the contents 0 of the bottle. A transparent plastic syringe, with a circular mark to indicate the proper dose, is provided for introducing the foam into the vagina. The volume of foam is approximately 7 ml. per dose, with an average weight of 0.5 gm. LABORATORY TESTS The laboratory tests performed to estimate the spermicidal power of the foam preparation were those in routine use at the Fertility Research Laboratory of the Margaret Sanger Research Bureau.2 Seminal fluid having the following characteristics were utilized: count, 60 million or more spermatozoa per milliliter; motility, at least 60 per cent active-grade 3+ or better; morphology, at least 80 per cent normal; and resistance, 15-minute motility after mixing of seminal fluid with an equal volume of 2.8 per cent acid potassium phthalate solution. Motility of the spermatozoa was graded as follows: 0, no motion; greater than 0, slow waving of tail, without forward motion; 1, slow progressive movements-not necessarily forward motion; 2, more active, with forward

3 520 SOBRERO Fertility & Sterility motion; 3, good forward motion; and 4, very active-fastest observed speed in vitro. By one dilution technic-a modification of the test devised by Brown and Gamble1-the highest dilution of the foam which immobilized the spennatozoa within 20 seconds when mixed manually for 10 seconds 5 with an equal volume of semen was determined against 26 semen specimens. The median spermicidal value was found to be at the S/5 dilution, or one part of foam in 4 parts of physiologic saline solution. This value corresponds to a ratio of foam, saline, and semen of 1:4:5. By a second dilution technic-a modification of the test devised by Sander and Cramer 4 -the highest dilution of foam which immobilized the spermatozoa within 20 seconds when mixed electromagnetically for 10 seconds with one-fifth part of semen was investigated (also against 26 semen specimens). The median spennicidal value obtained with this technic was S/25, or one part of foam in 24 of saline, the ratio of foam, saline, and semen being 1:24:5. Bya third laboratory test-the titration technic of Mende and Berliner3- the median value of volumes of semen in which the spermatozoa were immobilized within 20 seconds by 0.05 ml. of undiluted foam in 8 trials was found to be 4-6 volumes, or one volume of foam to 4-6 of semen. The results of the laboratory tests are summarized in Table l. Single-Dose Test CLINICAL TESTS Speculum observations made at 5 minutes after application of the advised dose (7 ml.) of the foam, and again at 30 minutes, showed the cervix fully covered in all of 8 cases. No complaints of discomfort were expressed, nor were there any signs of local irritation. 21-Day Test The 12 women participating in this test had undergone similar tests of several vaginal contraceptive products, and were therefore able to give attention to the several considerations involved in the choice of a satisfactory preparation. Each was instructed to insert one dose of the foam deep into the vagina daily, beginning at the end of menstruation and continuing for 21 consecutive days. Vaginal examinations were made with a

4 Vol. 11, No.5, 1960 EVALUATION OF A NEW CONTRACEPTIVE 521 TABLE 1. Spermicidal Values Dilution tests Titration test Modified Modified Brown-Gamble Sander-C ramer Mende-Berliner Electro- Mixing (for 10 sec.) Manual magnetic Manual Volumes Semen 1 1 Variable Foam 1 Diluted foam 1 5 Number of trials Values (at 20 sec.) Range S/2-S/10 S/10-S/ X Median S/5 S/ X Ratios Foam Diluent" 4 24 Sement The diluent used was physiologic saline solution, 0.9% NaCI; all dilutions were prepared by volume. t Semen quality standard: Count, 60 million or more spermatozoa per milliliter; motility, at least 60% with good forward motion; morphology, at least 80% normal; resistance, motility continued for 15 minutes after mixing of seminal fluid with an equal volume of 2.8% acid potassium phthalate solution. speculum before the test, twice weekly during the testing period, and after its completion. No irritation or burning on application of the foam or during coition was reported by these subjects. There was no increase in moisture at the vulva after application of the foam, and no complaints of "leakage" when application was made without subsequent intercourse. In each examination, the cervix and vagina were found normal, and a small amount of a white, watery fluid was observed in the upper part of the vagina. No change in vaginal cytology was found upon comparison of specimens obtained (by the Papanicolaou technic) prior to the test with those obtained after the final application of foam. Postcoital Test Observations were made at the time in the cycle presumed to be that of ovulation, as indicated by the basal body temperature curve of previous months, on 22 women of reproductive age and with ovulatory menstrual

5 522 SOBRERO Fertility & Sterility cycles. Each woman had had two or more previous routine postcoital tests reported "excellent" when made without a contraceptive, and the husband's seminal fluid had been classified as "good" (i.e., of the standard set forth above). A postcoital test is considered excellent at the Margaret Sanger Research Bureau when the endocervical mucus is found to contain 15 or more motile spermatozoa per dry high-power field (X 400) with motility of Grade 3 or better. In lo of the 48 "excellent" routine postcoital tests performed (all within 4 hours after sexual relations) before the study, the endocervical mucus specimens were found to be teeming with spermatozoa too numerous for counting. Each woman was instructed to introduce gently into the vagina, as deep as possible, the plastic syringe applicator with a full dose of the foam, and then to withdraw the applicator about half an inch before pushing its plunger to deposit the foam in the upper part of the vagina. She was instructed to have coitus at any time within the hour after application. The subsequent postcoital tests were performed within 4~~ hours after coitus, except for 5 cases, in which the interval was from 8 to 11 hours. A sample of fluid was obtained from the vagina by means of forceps, and after thorough wiping of the upper vagina and cervix, another specimen was taken from the endocervical mucus by suction with a I-m!. glass "tuberculin" syringe. These samples were forthwith examined for spermatozoa in at least 40 dry high-power fields (44 X objective, lo X ocular), and record made of the numbers of nonmotile and motile spermatozoa seen and the degree of motility, if any. Thirty-two postcoital tests were performed during the evaluation of the aerosol foam-once in 14 women, twice in 6 women, and 3 times in 2 women. FINDINGS Subjective Most of the women estimated that intravaginal ejaculation occurred within 30 minutes after application of the foam; 2 reported intervals of 40 and 45 minutes respectively. Female orgasm was reported in 10 of the 32 trials. In response to direct questioning, no instance of any burning, itching, or irritation prior to, during, or after intercourse was reported, nor any unfavorable reaction by a husband.

6 Vol. 11, No.5, 1960 EVALUATION OF A NEW CONTRACEPTIVE 523 In eight instances, "leakage" after withdrawal was reported, but it was not unusual in amount or in color. Objective In the 32 postcoital tests performed after the use of the contraceptive vaginal foam, no motile spermatozoa were seen in any of the vaginal specimens. Of the 32 specimens of endocervical mucus, 29 contained no motile spermatozoa. In 2 cases, one motile spermatozoon was seen, with motility rated as slightly greater than zero (the tail just barely waving, with no forward motion). In 1 case a total of three motile spermatozoa was found in more than 40 high-power dry fields-each spermatozoon with motility slightly greater than zero. In each of these last three instances, coitus occurred without female orgasm within 30 minutes of the application of the foam.... DISCUSSION By the three routine laboratory technics applied, it was found that the contraceptive aerosol foam had satisfactory spermicidal activity in vitro. The single-dose test as well as the 21-day test showed that the aerosol foam was highly acceptable clinically and aesthetically. In postcoital tests, after use of the aerosol vaginal foam there was almost complete absence of motile spermatozoa in the endocervical specimens in contrast to the findings in the preliminary postcoital tests when, in the absence of a contraceptive, the endocervical mucus had been found teeming with motile spermatozoa. This indicated high spermicidal effectiveness in vivo. The report of "leakage" after withdrawal or arising, in eight of the 32 tests, is of no greater incidence than ordinarily noted after coitus without contraceptive. SUMMARY An aerosol vaginal foam found to have spermicidal power in vitro was used in a single-dose test in 8 women and in a 21-day test in 12 women; none showed any subjective or objective evidence of local discomfort or irritation. Thirty-two postcoital tests were performed after use of the foam in 22

7 ( 524 SOBRERO Fertility & Sterility selected couples of reproductive age, all of whom had had previous excellent postcoital test results, and good semen analyses. In contrast to the results of the postcoital tests when no contraceptive was employed, neither vaginal nor endocervical specimens were found to contain motile spermatozoa in 29 of the 32 postcoital tests that followed the use of the foam. In three postcoital tests, one to three spermatozoa, feebly motile and without forward motion, were seen in the endocervical mucus specimens after a search of more than 40 dry high-power fields. The aerosol contraceptive vaginal foam studied appears to possess a high degree of spermicidal activity in vivo. REFERENCES 1. BROWN, R. L., and C. J. GAMBLE. A method of testing the relative spermicidal effectiveness of contraceptives, and its application to ten commercial products. Human Fertility 5:97, MACLEOD, J., SOBRERO, A. J., and INGLIS, W. Spermicidal values of commercial contraceptives. In preparation. 3. MILLMAN, N. A critical study of methods of measuring spermicidal action. Ann. New York Acad. Sc. 54:815, SANDER, F. V., and CRAMER, S. D. A practical method for testing the spermicidal action of chemical contraceptives. Human Fertility 6: 134, SOBRERO, A. J. Laboratory evaluation of spermicidal agents. In preparation. f.