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[Liver function tests under the influence of sequential treatment using ethinyl estradiol-norethisterone acetate and ethinyl estradiol-chlormadinone acetate].

30 young healthy women were investigated during the first therapy cycle with ethinyl-estradiol-norethisterone acetate and ethinyl-estradiol-chlormadinone acetate as a sequential regime. The following laboratory data were achieved by each of the investigated group of young women: serum aminotransferase (GOT and GPT), serum alkaline phosphatase and alpha-amylase-activity in serum, serum proteins, serum cholesterol, serum bilirubin, serum ZST, serum TTT and the indocyaningreen-clearance of the liver. The serum protein pattern was determined by the paper electrophoretic method. A significant decrease of the aminotransferase GPT was viable during the sequential therapy with ethinyl-estradiol and norethisterone acetate. This viable decrease of the GPT was induced through the application of norethisterone acetate to estrogen. The alkaline phosphatase was significant lightly lower and the beta-globuline lightly elevated at the end of the therapy cycle. The sequential therapy with ethinyl-estradiol and chlormadinone acetate induced only a significant increase of the ZST in serum.

Adolescent

[Estrus synchronization in cattle using chlormadinone acetate ("Bovisynchron" Jenapharm) in the tropics. 1. On the effect of blocking the cycle using chlormadinone acetate and on the introduction of this biotechnical method in the Republic of Mali].

The oestrus synchronization in cattle is being tested as a biotechnical method supporting the implementation of the crossing programme in the Republic of Mali Using the latest results of sexual physiology, the effect is described of Bovisynchron Jenapharm (chlormadinonacetate). Bovisynchron is characterised by a high certainty of synchronization and a good toleration. It leads to a highly fertile oestrus of all animals and to a high rate of conception. An analysis of the situation in the Republic of Mali is used to discuss the advantages of this method.

Animals

A comparative study of the efficiency of hydroxyprogesterone caproate and of chlormadinone acetate in the prevention of premature labor.

The efficacy of caproate of hydroxyprogesterone and acetate of chlormadinone in preventing premature labore was compared in a controlled trial. The survey was based on 211 pregnant women with a high risk of premature delivery discovered during clinical examination. There are no significant differences between the two groups in either length of gestation, delay between the beginning of treatment and delivery or other parameters related to prematurity. The absence of evidence suggesting any significant difference between the two treatments can have three possible causes (which are discussed): the methodology, the inefficacy of the two products or the equivalent efficacy of the two products.

Chlormadinone Acetate

Serum prolactin concentrations in women treated with chlormadinone acetate.

Serum prolactin concentrations were measured serially in eight normal women who used continuous chlormadinone acetate treatment (500 mug per day) for six months as part of an investigational new drug contraceptive study. Circulating prolactin was also measured in women using several additional oral contraceptive steroid preparations including a sequential mestranol-mestranol + chlormadinone acetate regimen. No increase in basal serum prolactin concentration was produced by chlormadinone acetate treatment, either alone or when added to estrogen therapy. These results suggest that chlormadinone acetate may not alter human mammary tissue through a prolactin mechanism.

Breast

[The metabolism of 4-14C-pregnenolone in tissue sections of human ovaries and their modification by chlormadinone acetate].

In vitro incubations with slices of two normal human ovaries and 4-14C-pregnenolone as precursor were carried out to study the possibility of a direct influence of chlormadinone acetate on the metabolism of pregnenolone. In agreement with our previous studies the incubations of the ovary from the follicle phase of the cycle yields a profile of steroids different from that of the ovary from the corpus luteum phase of the cycle. Under the experimental condition chosen, the presence of enzymes of the steroidogenic pathway responsible for the synthesis of 17alpha-hydroxy-pregnenolone, DHA, androstenediol (basic metabolites) and androstenedione represents a characteristic profile of steroids of the ovaries from the follicle phase. After the addition of chlormadinone acetate to the incubation medium, the formation of androstenedione was inhibited, whereas the basic metabolites increased. The biosynthesis of progesterone, 17alpha-hydroxyprogesterone, estrone and estradiol represents a characteristic profile of steroids of the ovaries from the corpus luteum phase. After a addition of chlormadinone acetate to the incubation medium, the formation of this characteristic profile of steroids was inhibited. The influence of chlormadinone acetate on the two different profiles of steroids indicated, that chlormadinone acetate exerts an inhibitory effect on the 3beta-hydroxysteroid-dehydrogenase-delta5-4-isome

Aromatase

[Chlormadinone Acetate Reference Standard (Control 881) of National Institute of Hygienic Sciences].

Chlormadinone acetate was tested for the preparation of the "Chlormadinone Acetate Reference Standard (Control 881)". Analytical data obtained were as follows: loss on drying, 0.00%; infrared spectrum, 1740, 1715, 1658, 1604, 1587, 1256, 1244 cm-1; ultraviolet spectrum, lambda max = 284 nm; absorbance, E1cm1% (284 nm) = 539-549; optical rotation, [alpha]D20: -12.1 degrees; melting point, 214.6 degrees C; thin-layer chromatography, contaminants were not detected until 300 micrograms; high-performance liquid chromatography, one contaminant was detected. On the basis of the above results, this material was authorized as the National Institute of Hygienic Sciences Reference Standard (Control 881).

Chlormadinone Acetate

The metabolic fate of chlormadinone acetate in the baboon.

The metabolic fate of chlormadinone acetate (17alpha-acetoxy-6-chloro-4, 6-pregnadiene-3, 20-dione; CAP) was studied in intact and biliary fistula baboons. The steroid was labeled with 3H at position 1 and with 14C at the carboxyl moiety of the 17alpha-acetate, thus affording the opportunity to ascertain the loss of the 17alpha-acetoxy group and the fate of both labels. The averages of the radioactivity excreted, given as percentages of the amounts injected, and the standard deviations were as follows: In the urine of intact animals after 6 hours, 5.7 +/- 0.2% and 5.5 +/- 0.7% of the 3H and 14C were recovered, respectively. After 6 days, there was 17.5% of the 3H and 16.2% of the 14C in the urine plus 15.3% of the 3H and 16.4% of the 14C in the feces. In baboons with biliary fistulas, the total radioactivity excreted was 7.8 +/- 0.7% of the 3H and 11.6% of the 14C in the urine, and 30.9 +/- 4.4% of the 3H and 30.7% of the 14C in the bile after 6 hours. Glucosiduronates were the predominant conjugates in the urine and bile. The similarity in the urinary excretion of radioactivity in the first 6 hours in intact and biliary fistula animals, the relatively low excretion of radioactivity in the bile and after 6 days in the urine, and the low fecal excretion suggest that the metabolites of CAP are not involved in an extensive enterohepatic circulation in the baboon. Deacetylation of the 17alpha-acetate in CAP was detected in the early collection periods of the urine and bile and constituted a very small percentage of the injected compound. No significant oxygenation of CAP at position 1 was detected. The metabolism of CAP is discussed and compared to our previously reported data on the metabolism of progesterone, ethynodiol diacetate and medroxyprogesterone acetate and the data on other progestogens reported in the literature. It appears that the excretion of CAP is significantly slower in the baboon than that of the other progestogens. The amounts of glucosiduronates of CAP and/or its metabolites formed in vivo are less than those formed with the other progestogens. Also, the extent of deacetylation of the 17alpha-acetate of CAP is much less than that of the 3beta-acetate of ethynodiol diacetate.

Animals

Improvement of intractable idiopathic epilepsy with chlormadinone acetate. A case report.

A 10-year-old boy with idiopathic epilepsy refractory to treatment from age 4 and with clinical signs of hyperandrogenism was treated with chlormadinone acetate (24 mg/day) during two alternate periods of 3 months. The administration of chlormadinone was associated with a marked clinical and electroencephalographic improvement as well as a concomitant decrease in the levels of plasma testosterone and delta4 androstenedione. No changes in plasma gonadotropins were observed. Placebo had no effect neither in seizures nor in the concentration of hormones in the plasma. Since chlormadinone acetate is not a very potent gonadotropin inhibitor in males, it is suggested that the clinical and electroencephalographic improvement associated with the use of this compound, might be the consequence of a decrease in the plasma levels of androgens, mainly testosterone.

Androstenedione

A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.

Three low dose progestogens, chlormadinone acetate (0-5 mg), megestrol acetate (0-5 mg) in oil, and norethisterone (0-35 mg), taken daily, were employed as oral contraceptives in postnatal women who desired to postpone their next pregnancy for up to a year. In a lower and middle social class population net pregnancy rates (life table) were five to six per 100 woman-years, of which about half were due to failure to take the tablets. Side effects other than menstrual disturbance were few. Norethisterone was the least likely of the three preparations to lead to discontinuation because of disturbance of menstruation. There were three ectopic gestations amongst 35 pregnancies in 4500 women-months of use. Ninety-five patients with varicose veins, 15 with a history of thrombophlebitis and 23 with a history of liver disease took progestogens without relevant untoward effects.

Adult

[Dysfunctional uterine bleeding. Hormonal management with chlormadinone acetate].

In 138 patients with uterine dysfunctional bleeding a hormonal treatment with chlormadinone acetate, was given. The dosage varied according to four therapeutic stages: hemostatic, maintenance, consolidation and observation. Patients were placed in three groups: Group I, adolescents, Group II, reproductive life, Group III, premenopausal. In 51.9% of the patients there was endometrial hyperplasia, proliferative in 26.6% and secretory in 14.1%. Good results were obtained in all four therapeutic stages.

Adult

[Use of chlormadinone acetate (CAP) in bovine reproduction (author's transl)].

The results obtained with chlormadinone acetate (CAP) in the treatment of dairy cattle with inactive ovaries (anoestrus) and during the puerperium are reported. CAP was administered to eighteen animals with inactive ovaries for fourteen days. Oestrus occurred in fourteen animals within from one to four days after treatment had been completed. Insemination during this oestrus resulted in pregnancy in five animals. CAP was also administered to sixty animals on three farms for fourteen days during the puerperium, treatment starting on the twelfth day post partum. This was done for the purpose of improving subsequent fertility. However, as regards the interval between parturition and first insemination, the conception rate following the first insemination and the interval between parturition and conception, there were no detectable differences between the treated groups and the controls in the same herds (Table 1).

Anestrus

Prevention of estrus in the queen with chlormadinone acetate administered orally.

The possibility of estrus prevention in the queen by the oral administration of chlormadinone acetate was examined. The animals used were 29 mature and 15 immature queens. For 16 mature females, 4-12.5 mg was given daily by mouth for 7 days every 3 months. Ten of the 16 queens given this treatment came into estrus within 4 months of the first treatment. For 28 females including the immature, 2-12.5 mg was given once a week throughout the experiment. This treatment prevented estrous activity for at least 1 year. In the queens in this study, the side effects were not observed excepting an increase in body weight during treatment. Our results showed that oral administration of this drug weekly is safe and reliable for long-range prevention of estrus in queens.

Administration, Oral

[Enzyme histochemical studies on the rat adrenal cortex, ovary, uterus and vagina following chlormadinone acetate administration, especially cholinesterase activity in myometrium and endometrium].

1. Female albino rats were treated with a total of 28 mg of chlormadinone acetate (CMA) for 28 days. In the adrenal cortex, the ovary, the vagina, and the uterus the activities of 3-beta-ol-steroiddehydrogenase, of dl-beta-OH-butric acid dehydrogenase, of alcaline and acid phosphatases, of DPN-diaphorase, of ATP-ase, and of non-specific esterases do not differ from untreated controls. 2. In the external muscle layer of the myometrium strong cholinesterase (ChE) activity was induced by C.M.A. A corresponding high ChE activity is normally found in immature rats or in estrus. 3. Furthermore, by treatment with CMA, ChE activity was induced in the tubular glands of the endometrium. This activity is found in the small parts of glomerate glandular terminals only but not in the rest of the glandular epithelium, nor in the epithelium of the cavum. It could be demonstrated that a corresponding ChE activity normally appears in the second third of pregnancy. The ChE activity induced by CMA was considerably higher and more widespread than during normal pregnancy. 4. It is concluded that in the endometrial glands a development similar to pregnancy is initiated by CMA. But development stops at the stage of ChE activity, thus leading to accumulation of ChE active cells.

Acid Phosphatase

Morphometric investigations on endocrine glands. V. Changes in the testes of Wistar rats after application of chlormadinone acetate and norethisterone acetate.

In growth inhibiting tests of rat testes the tubular diameter and, somewhat less sensitive, the nuclear volume of the Leydig cell follow the weight changes. Chlormadinone acetate shows antigonadotropic activity only at high doses and a dose-dependent antiandrogenic activity. The dose-weight curve under norethisterone acetate has a minimum at 4.2 mg/rat/14 days; higher doses seem to be accompanied by androgenic efficiency.

Animals

The influence of chlormadinone acetate treatment on the concentration of some steroids in the blood, on the ovarian activity, and on the sexual behaviour of the mare.

The effect of orally administered chlormadinone acetate (CAP), 10 mg daily for a period of 16 days, was investigated in the case of four mares with an irregular oestrous pattern accompanied by low ovarian activity (group 1), four mares which did not show oestrous symptoms at all and which had also low ovarian activity (group 2), and two ovariectomized and two ovario-hysterectomized mares (group 3). In all mares of group 1 and in the two ovariectomized mares of group 3 oestrus symptoms became apparent during treatment. Two mares of group 2 came into heat 8 and 11 days after the cessation of treatment. The two other mares of group 2 and the ovario-hysterectomized mares of group 3 showed no oestrous symptoms at all. In all except the two ovario-hysterectomized mares the progesterone concentration was found to increase in the peripheral blood from less than 1 ng/ml up to at least 4-6 ng/ml. In the mares which came into oestrus this progesterone increase occurred about three days before symptoms of heat became apparent. It is assumed that the uterus played an important role in the increase of the progesterone concentration in the blood during or after CAP treatment. A similar rise of the progesterone level was also found in the ovariectomized mares, indicating that this progesterone did not originate in the ovaries.

Anestrus

The effects of new steroidal anti-androgen, TZP-4238, and chlormadinone acetate on the pituitary, prostate and adrenal gland of the rat: histopathological and immunocytochemical studies.

The atrophic effects of a synthetic steroidal anti-androgen, TZP-4238, on the pituitary, prostate and adrenal gland of rats were investigated. Male Sprague-Dawley rats were divided into three experimental groups. Group 1 consisted of controls. Groups 2 and 3 received chlormadinone acetate (CMA) 50 mg/kg/day and TZP-4238 10 mg/kg/day p.o., respectively, for 3 weeks. CMA (Group 2) produced marked atrophy of the prostate. Furthermore, CMA caused marked atrophy of the adrenal gland. Histopathologically, the remarkable atrophy was observed in the adrenal cortical cells of zonae fasciculata and reticularis. The most striking ultrastructural alterations were noted in the mitochondria. In addition, intramitochondrial localization of glutathione-peroxidase (GSH-PO) which effectively reduces the lipid peroxides, was less than that in the controls. In the anterior pituitary gland, CMA induced a reduction in the size of ACTH cells. TZP-4238 (Group 3) produced marked atrophy of the prostate. However, TZP-4238 exerted no effect on the adrenal gland or anterior pituitary ACTH cells. In addition, the present histopathological study showed that TZP-4238 or CMA exerted no effect on the testes or anterior pituitary LH cells. Therefore, it is suggested that TZP-4238 causes atrophy of the prostate without any significant histopathological changes in the adrenal glands or anterior pituitary ACTH cells under the present experimental conditions. We further speculated that TZP-4238 had a more potent anti-prostatic effect than CMA and TZP-4238 had a less inhibitory influence than CMA on the pituitary-adrenal axis.

Adrenal Glands