Sequential oral contraception using DMAP.

PIP: A synthetic steroid, 3-desoxy-6-alpha-methyl-17-alpha-acetoxy progesterone (DMAP), was used as the progestin in a program of sequential oral administration of contraceptive tablets; indigent patients attending the postpartum clinic at the Medical College of Virginia were studied. No pregnancies occurred in 561 cycles of use. Withdrawal bleeding incidences usually occurred every 27 days, lasted 5 days, and were associated with moderate flow. The incidence of breakthrough bleeding was 3%; intermenstrual spotting, 2.4%; and nausea or vomiting, 9.5%. The endometrial changes more closely resembled those in a normal ovulatory cycle than those associated with oral contraceptive methods which utilize an estrogen-progestin mixture started on Cycle Day 5.^ieng

Dissappearance of 1 alpha-3H-chlormadinone acetate from the plasma of women.

PIP: The half-life and metabolic clearance rate of chlormadinone acetate were computed after a single iv injection of 60 to 90 mcCi 1-alpha-tritiated-chlormadinone acetate (specific activity 222 mcCi/mg) into 7 women aged 34-52 years. Plasma was extracted with acetone:MeOH for total radioactivity; then extracted with water and ether for free steroid radioactivity; then with n-butanol for conjugated steroid radioactivity; and finally extracted with chloroform:MeOH and chromatographed on thin layer with ether:benzene for specific radioactivity due to chlormadinone acetate. Blood samples were taken at .25, .5, 1, 8, 24 hours and every 24 hours for 5 days. The mean half-life of radioactivity specifically indentified as chlormadinone acetate for the first 24 hours was 2.6 hours, and after 24 hours was 81.8 hours, calculated by TAIT and BURSTEIN's method. All 4 curves, total radioactivity, conjugated steroids, free steroids, and specific activity had the same biphasic form: a rapid loss for about 24 hours, and an approaching equilibrium after 24 hours. The metabolic clearance rate was 42.61 liters per day, comparable to lynestrenol (15-30 liters) and norethynodrel. The half-life is much longer than that of progesterone (.96 and 10.7 minutes), estradiol (20 and 70 minutes), and norethynodrel (76 minutes and 45 hours). These data generate an estimate of the concentration of chlormadinone acetate in plasma of women taking .5 mg daily: about .45 ng/ml, i.e. about one-thirteenth the concentration of progesterone.^ieng

Daily chlormadinone acetate as an oral contraceptive.

PIP: 267 fertile women less than 40 years old took .5 mg of chlormadinone daily for a total of 3199 months to assess its effectiveness as an oral contraceptive. The total pregnancy rate, calculated by the Pearl Formula, was 4.5 pregnancies per 100 women years and the rate for method failure was 3.7 pregnancies per women years. The rates calculated by the life-table method were 2.5 pregnancies per 100 women for the first year and 4.1 pregnancies per 100 women for the first 24 months. All births were normal. Other disadvantages were abnormal and irregular bleeding, experienced by 107 women including 40% of all patients with histories of regular menses. Side effects other than abnormal bleeding were infrequent, with headaches as the most common (7.9%). Chlormadinone acetate was not recommended for contraceptive use at this time due to a high pregnancy rate and abnormal bleeding.^ieng

The effect of various contraceptive hormonal therapies in women with normal and diabetic oral glucose tolerance test.

PIP: The effect of various contraceptive hormonal therapies was studied in 176 women with normal and diabetic oral glucose tolerance tests (OGTTs). 160 women showed normal and 16 showed diabetic patterns on the 14th day of a control cycle, during the 3rd and 6th months of contraceptive therapy, and 3 months after having stopped medication. The women were divided into groups and fitted with a Lippes loop, treated with low doses of chlormadinone acetate, lynestrenol, and megestrol acetate or with a sequential estrogen-progestogen contraceptive containing either ethinyl estradiol or mestranol. The only groups showing modifications of OGTTs were the sequential estrogen-progestogen groups, where the OGTT curves of the normal groups became abnormal while those of the diabetic group improved. The modifications disappeared 3 months after discontinuation of the medication which can be interpreted as a direct effect of the steroids on carbohydrate metabolism.^ieng

Invluence of oral contraceptives on circulating immune response. II. Effect of progestogenic and estrogenic components.

PIP: Female mice were treated with chlormadinone acetate (.25 mcg or 6.25 mcg), megestraol acetate (.25 mcg or 6.25 mcg), ethynodiol diacetate (.5 mcg or 12.5 mcg), norgestrel (.25 mcg or 6.25 mcg) or norethynodrel (2.5 mcg or 62.5 mcg) and studied to determine what effect these progestagens had on circulating tetanus antibody titers. None of the progesterones affected the immune response to tetanus toxoid. Mice given ethinyl estradiol or mestranol had enhanced circulating antibody titers. It is conlcuded that combination oral contraceptives act to diminish antibody response as a result of the combined potency of the estrogen and progesterone components.^ieng

[Influence of chlormadinonacetate on the rat ovary (author's transl)]. / Einfluss von Chlormadinonacetat auf das Rattenovar

PIP: Effects of chlormadinone acetate on the ovary were studied in 20 female Wistar rats. Chlormadinone was started on the 1st day of diestrus and given for 20 days; animals were killed 24 hours after the last administration. Examination of ovary sections revealed hyperplastic interstitial gland, a decreased number of corpora lutea and an increased number of atretic follicules. Histochemical studies indicated increased interstitial gland activity and full activity of atretic follicules.^ieng

Hydrocarbons in human cervical mucus and the effect of oral contraception.

PIP: 8 women, 2 taking C-Quens, 2 on Ovral, 1 on Ovulen-21, and 3 controls not taking oral contraceptives, were tested for several menstrual cycles for composition of hydrocarbons in cervical mucus and for the cyclic variation. Results show that hydrocarbons definitely decreased during contraceptive usage. The major saturated hydrocarbons definitely decreased during contraceptive usage. The major saturated hydrocarbons in cervical mucus were in the range of carbons-15-38. The most prominent unsaturated hydrocarbon was squalene. The variations of hydrocarbon composition were small, except for the twofold increase of the carbon-28 peak in the premenstrual sample of a woman on Ovral. Compositional cyclic variations of hydrocarbons occur, and, with the decrease observed in those taking oral contraceptives, it is suggested that they are partly influenced by hormonal activity. It is concluded that hydrocarbons may play a role in determining cervical mucus viscosity.^ieng

[Concentration of estrone, estradiol and estriol in the blood of pregnant sheep after induction of estrus with chlormadinone acetate and medroxyprogesterone acetate]. / Chlormadinonacetátom a medroxyprogesterón-acetátom

The radioisotopic method of 131J-labelled albumin was employed to determine the distribution of acidic proteinase activity in some organs and tissues of chickens. The highest enzymatic activities were found in intestine wall, in pancreas, and in liver. Considerably lower activities were ascertained in kidneys, brain, lungs, and heart. The different proportions of these enzymes in homogenates and supernatant fractions (106 000 g) testify to a lack of uniformity in the solubility of cathepsins in the organs tested. The tested organs, with the exception of pancreas, did not show any enzymatic activity of neutral proteinases.

PIP: Estrus was artificially induced in 10 Merino sheep by a vaginal swab administration of 30 mg of chlormadionone acetate (in 5 animals for 13 days) or of 60 mg of medroxyprogesterone acetate (in 5 animals for 17 days), both on a background administration of 750 IU pregnant mare's serum gonadotropin. After impregnation in this condition, the levels of esterone, estradiol, and estriol were determined. A progressive increase was found in the levels of all 3 of these hormones over the course of the pregnancy, in both groups. Comparison of estrogen concentrations showed that the use of the 2 progesterone derivatives did not affect the endocrine ciruclation of the mother and the fetus during pregnancy.

[Continuous microdoses of chloramadinone during lactation]. / Microdosis contínua de clormadinona durante la lactancia.

PIP: Progesterones and estrogens normally inhibit milk production. 50 lactating mothers, who had received no steroid since giving birth, were given daily doses of chlormadinone .5 mg from 5 to 40 days postpartum. Mothers and babies were seen every 2 weeks for 8 weeks and then every month. Milk production lasted an average of 5.7 months, with 7 women continuing from 7 to 10 months. On the average, the younger mothers produced more milk; the older ones recommenced menstruation sooner. Several supplemented their milk with other nourishment from the 2nd or 3rd month. The babies gained well, following closely the average gain, according to the Mexican Pediatric Academy. The chlormadinone was 100% effective as a contraceptive and milk production was good.^ieng

[Studies on the contraceptive effect of chlormadinone]. / Badania nad efektywnoscia antykoncepcyjna chlormadinonu.

PIP: The investigations covered 80 women receiving oral contraceptives (43 Chlormadinone and 37 Femigen). The chlormadinone preparation was ingested in a daily dose of 0.5 mg in 43 women, through 351 months with a coefficient of gestations of 6.8 (technique fault 3.4), with a minimum of side effects, without apparent influence on body weight and arterial blood pressure. This preparation caused disturbances of the cycle length (18.4% of cycles) and spotting in the course of the cycle (13.7% of cycles); however, 71% of cycles were free of these disturbances. It was demonstrated that an important role in the mechanism of contraception is played by the changes in cervical mucus and in the endometrium. The Femigen preparation was used by 37 women through 450 months with full contraceptive efficacy (coefficient of gestations, 4.3, due to technique faults, 0). It caused numerous and sometimes troublesome side effects which were observed in 65.1% of cycles in the first 5 months of administration and reduced in the following months to 52.4% of the cycles. While intermenstrual spotting (10.9% of cycles) and amenorrhea (12.4% of cycles) were due to the drug, it did not induce alterations in body weight or blood pressure. The observations suggest that the administration of chlormadinone preparations in a daily dose of 0.5 mg as luteal supplementation is a safe and usable technique of oral contraception, especially when the classic technique is poorly tolerated or contraindications exist as to the administration of estrogen-progestagen compositions. (Author's modified)^ieng

[Effect of ovosiston on the thrombelastogram]. / Wplyw preparatu ovosiston na tromboelastogram.

PIP: 26 women using Ovosiston as a contraceptive and 22 women using it as a therapeutic agent were administered thromboelastograms during the 1st and 2nd halves of the menstrual cycle. Results were compared with those taken from 20 healthy women. A significant increase in the maximal elasticity of the clot in the 2nd half of the cycle was revealed in those using Ovosiston as a contraceptive as compared with the control group. Those using Ovosiston as a therapeutic agent for hypothrombosis showed a normalization of the thromboelastographic patterns of blood clotting.^ieng

[Femigen forte and mite preparations in contraception and gynecologival disorders]. / Femigen forte i mite w antykoncepcji i ogólnje praktyce ginekologicznej.

PIP: Femigen forte (chlormadinone 3 mg + mestranol .1 mg) was administered to 90 women and Femigen mite (chlormadinone 2 mg + .084 mg of mestranol) was administered to 43 women, both groups aged 19-47 years, as a contraceptive and as therapy for endometriosis, dysmenorrhea, irregular and profuse menstruations, in the incipient phase of climax, and in diagnostics. Both drugs were observed to be 100% effective as contraceptives. Side effects such as nausea, intermenstrual bleedings, and absence of menstruation were most often observed with Femigen forte; about 30% of these users. Most side effects occurred in the first 2 cycles. Those using Femigen mite showed almost no side effects. No increase in the concentration of blood glucose was noted with either preparation. The effect of these drugs on the vaginal lining and on the endometrium was weak. No thromboembolic complications were observed. The low-dose preparation was recommended more for contraception. An estrogenic content of about .05 mg creates the same effect and decreases the occurrence of side effects.^ieng

[Effects of gestagens on the early phases of pregnancy in cattle--clinical experiences. I. Studies on the prevention of embryonic death]. / Gestagen-Wirkungen auf frühe Phasen der Gravidität des Rindes--Klinische Erfahrungen. 1. Versuche zur Embryonaltod-Verhütung

PIP: Effects of chlormadinone acetate (CAP) on early gestation and embryonal death were studied in 177 cows. CAP (10 mg) was administered daily on Days 14-23 after service or insemination. CAP at the dose level and timing chosen had no adverse effect on gestation but seemed to have caused an insignificant increase of conceptions from inseminations before treatment. The CAP effect on increasing conceptions after treatm ent was less pronounced. The luteolytic effect CAP exerts in cycling animals seems to have ceased as soon as animals had conceived. An unexpected high percentage of repeat breeding cows had conceived at the last insemination or service before treatment: 52.9% in the CAP, and 46.7% in the placebo group. A total of 62.1 (CAP) and 61.2 (placebo) an imals became pregnant from service before, during, or immediately after treatment. Findings are discussed in terms of bovine reproduction and animal husbandry.^ieng

[Regulation of stress-free nonlaying periods using chlormadinone acetate]. / Steuerung stressloser Legepausen mittles Chlormadinonacetat

PIP: Nonlaying intervals were induced in 6 group of 30 hens with chlormadinone acetate (CAP), with a 7th groups serving as a control. 3 groups were treated for 10 days and 3 for 20 days, each group getting a different dosage of CAP. 1.2% of the hens were lost per month in the control group, with losses in the other 6 groups ranging from .6 to 1.7%/month. The length of the nonlaying period corresponded in 5 groups to the dosage and length of CAP treatment. The groups treated with the lowest daily dosages in the 10- and 20-day groups did not experience a complete nonlaying interval. The CAP treatment caused thickening of the egg shells but did not alter the weight of the eggs. The hens treated with CAP lost most of their feathers during the treatment. The longer, more concentrated dosage of CAP caused egg production to decrease more quickly, a prolonged nonlaying interval, and a higher rate of egg production following the nonlaying interval.^ieng

[Excretion of 17-hydroxycorticosteroids under the effect of combined preparations containing separate progestagens: ethynodiol diacetate and chlormadinone]. / Wydalanie 17-hydroksykortykosterydów pod wplywem kombinowanych preparatów zawierajacych odrebne progestageny: dwuoctan etinodiolu i chloramadinon.

PIP: 28 women were treated with .1 mg of mestranol + 3 mg of chlormadinone and 25 were treated with .1 mg of mestranol + 1 mg of ethynodiol diacetate. Examinations of the excretion of 17-corticosteroids in the urine were made and compared between the 2 groups. In the group treated with mestranol + chlormadinone here was no change in the excretion of 17-OHCS. The group of women treated with mestranol + ethynodiol diacetate showed a significant decrease of approximately 37%. The difference in the effects of these preparations is thought to be caused by their different chemical structure.^ieng

[Influence of contraceptives on the carbohydrate metabolism in female diabetics]. / Zur Frage der Beeinflussung des Kohlenhydratstoffwechsels bei Diabetikerinnen durch Ovulationshemmer.

PIP: The effects of Eugynon (5 patients), Anovlar (2), Aconcen (1), Noracycline (1), and estirona (1 patient) on insulin requirements, glycosuria, and metabolism quality were studied in 10 diabetic women. Insulin requirements were unchanged in 7 patients and increased slightly in 3. Metabolic quality declined appreciably in 2 patients, slightly in 2, remained unchanged in 3, and improved in 2 patients. Glycosuria decreased in 3 patients, but increased in 7. No conclusions could be drawn concerning specific ovulation inhibiting preparations. It is suggested that in women with irregular cycles, regularization of the hormonal cycle may improve metabolic function.^ieng

[Oral contraception and gynecologic therapy]. / Orale Kontrazeption und gynäkologische Therapie.

PIP: Clinical experiences with the use of Aconcen as a contraceptive (269 women) and in the treatment of ovarian dysfunction, dysmenorrhea, andometriosis, and other disorders (181 women) is reported. Contraceptive efficiency was 100%. Therapeutic results were generally good. Side effects included spotting and breakthrough bleeding, nausea, headache, loss of libido, breast swelling, and weight gain. 21 women discontinued treatment because of side effects.^ieng

[Preclinical research--toxicology]. / Präklinische Untersuchungen--Toxikologie

The different steps of the toxicological testing of new drugs are shortly described. Furthermore it is discussed that only 60-70% of the drug induced adverse reactions in man can be predicted by the experimental methods being available at present. Special problems exist in evaluating the results of reproductive-toxicological, carcinogenicity and mutagenicity tests. These problems are illustrated by some experimental and clinical examples.

PIP: Toxicological testing of new drugs is briefly described. Only 60-70 % of the adverse drug reactions in human beings can be predicted by presently available experimental methods. Special problems exist in the evaluation of reproductive-toxicity, carcinogenicity, and mutagenicity tests. The example of the carcinogenic effect of chlormadinone acetate, when given to beagles at doses 2-25x greater than the human therapeutic dose, is cited, in addition to several examples of antineoplastic agents .

The metabolism of antifertility steroids. The in virto metabolism of chlormadinone acetate.

PIP: The isolation and identification of the major in vitro metabolites of chlormadinone acetate are reported. Human, rabbit, and rat liver incubations were employed in the isolation and identification, and male rat liver preparations were used to study the effect of phenobarbital stimulation on the formation of these metabolites. The metabolic pathway was influenced by the microsomal stimulating property of phenobarbital. 2alpha-hydroxychlormadinone was the major metabolite from the incubation of phenobarbital-stimulated rabbit and male rat liver. 17alpha-acetoxy-6-chloro-3beta-hydroxypregna-4,6-diene-20-one was the major metabolite from the incubation of unstimulated human and male rat liver. It was concluded that the 2alpha-hydroxychlormadinone acetate was demostrated only as a consequence of phenobarbital treatment.^ieng

[Influence of chlormadinone acetate on hypothalamic differentiation in male rats]. / Einfluss von Chlormadinonazetat auf die Hypothalamusdifferenzierung männlicher Ratten.

PIP: The effect of chlormadinone acetate on adult male rats during the hypothalamic differentiation phase was studied. Psychic intersexuality with increased male and increased female sexual behavior was observed both before and after postpuberal castration and sex hormone replacement. Organ weights of testes, seminal vesicles, and ventral prostrates were normal, but penis and adrenal gland weights were significantly smaller. Body growth was also significantly reduced compared with control animals. The effects of chlormadinone acetate on androgen-dependent brain differentiation are discussed and compared with analogous effects of cyproterone acetate and orchidectomy.^ieng