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At least 19 recordsLinked to original sources
PubMed1996

Induction of micronuclei and initiation of enzyme-altered foci in the liver of female rats treated with cyproterone acetate, chlormadinone acetate, or megestrol acetate.

The synthetic anti-androgen and progestin cyproterone acetate (CPA), recently found to be genotoxic for the liver, and two structurally similar progestins, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for clastogenic and tumor-initiating activities in female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg/kg, CPA induced the maximum increase in the frequency of micronucleated hepatocytes (6.6-fold as compared to controls) when treatment was performed 3 days before partial hepatectomy and cell sampling 2 days later. Under the same experimental conditions the clastogenic potencies of CMA and MGA were 69% and 36% of that of CPA respectively. In the liver foci assay, p.o. dosing with 100 mg/kg CPA once a week for 6 successive weeks induced, as compared to controls, a significant increase in the number and area of gamma-glutamyltranspeptidase-positive foci. At the same dosage schedule the tumor-initiating activity of CMA and MGA was 7- to 10-fold lower than that of CPA. These findings suggest that the 1,2 alpha-methylene group, present in CPA but absent in both CMA and MGA, favours the activation to a reactive species and/or hinders the biotransformation to non-toxic metabolites.

2-Acetylaminofluorene↗
PubMed1996

Comparative study of DNA repair induced by cyproterone acetate, chlormadinone acetate and megestrol acetate in primary cultures of human and rat hepatocytes.

Cyproterone acetate (CPA), a synthetic progestin recently found to induce genotoxic effects in hepatocytes from female rats and from humans of both genders, and two structural analogues, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for their capacity to induce DNA repair synthesis as measured by quantitative autoradiography. Exposure of primary human hepatocytes for 20 h to concentrations of CPA, CMA and MGA ranging from 2 to 50 microM induced positive responses in cultures from donors of both genders and the amounts of DNA repair elicited by the three progestins were similar. Under the same experimental conditions substantial differences were observed in the amounts of DNA repair elicited by the three progestins in primary hepatocytes from female rats, their potency decreasing in the following order CPA > CMA > MGA, and the three compounds failed to induce DNA repair in hepatocytes from male rats. These results, which agree with previous findings, suggest that for these sex steroids extrapolation to humans of results obtained in rats might be questionable.

Animals↗
PubMed1981

Effects of hexestrol, medroxyprogesterone acetate and chlormadinone acetate on 7, 12-dimethylbenz [a] anthracene-induced rat mammary cancer in relation to estrogen receptor.

The effects of hexestrol (HXS), medroxyprogesterone acetate (MAP) and chlormadinone acetate (CMA) on 7, 12-dimethylbenz [a] anthracene-induced mammary cancer in rats were evaluated. As a result of successive intramuscular injections of HXS at dosages of 2 or 10 mg/kg or MAP at dosages of 24 or 120 mg/Kg, tumors were markedly reduced in size in all groups on day 7 approximately 14. These effects were the same regardless of the presence or absence of cytoplasmic estrogen receptors (ER) in tumors as determined by the dextran-coated charcoal method. Although such an effect was also seen with CMA, it was much less marked than the effects seen with HXS and MAP. The body weights of HXS-administered groups decreased considerably, whereas those of MAP-administered groups increased. These results may suggest that there is another endocrinological tumor-suppressing mechanism besides the mechanism involving the estrogen-ER system in large-dose administration of HXS and MAP.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Characterization of the stimulatory effect of medroxyprogesterone acetate and chlormadinone acetate on growth factor treated normal human breast epithelial cells.

OBJECTIVE: Evidence is increasing that adding progestogens to hormone replacement therapy may be more harmful than beneficial, however it is debatable whether all progestogens act equally on breast cells. Mitogenic growth factors from stromal breast tissue are important in growth-regulation of breast cells, and may modify responses to progestogens. We investigated the effect of two C-21 derivatives, medroxyprogesterone acetate (MPA) and chlormadinone acetate (CMA) on growth-factor treated normal breast epithelial cells and tried to explore the underlying mechanisms of proliferation. METHOD: MCF10A (human epithelial, estrogen- and progesterone-receptor negative normal breast cells) were incubated with MPA or CMA at 0.1 and 1 microM for 7 days with the growth factors (GFs) EGF, bFGF and IGF-I at 1pM. The same combinations, as well as growth factors alone, were also incubated with the proliferation inhibitors PD98059 and LY294002 at 1 microM for 4 days. Cell proliferation rate was measured by the ATP-assay. RESULTS: MPA 0.1 and 1 microM, and CMA 1 microM in combination with GFs both significantly increased cell proliferation rate, with MPA having the greatest effect. MPA- and CMA-induced proliferation of GF stimulated cells was blocked by both PD98059 (selective inhibitor of MAP kinases) and LY294002 (phosphatidylinositol 3-kinase inhibitor); GF stimulated cells could not be significantly reduced by any of the inhibitors used. CONCLUSION: MPA and CMA have a stimulatory effect on benign growth factor stimulated MCF10A cells, possibly via activation of MAP kinase and subsequent substrates and activation of PI3-kinase. GF induced proliferation appear to be mediated by pathways other than those investigated here. Growth factors and progestogens therefore have an additive, synergistic effect on cell proliferation, eliciting their effects via different pathways.

Breast↗
PubMed2005

Pure red cell aplasia in a prostate cancer patient treated with leuprolide acetate and chlormadinone acetate.

Pure red cell aplasia (PRCA) is characterized by anemia with reticulocytopenia but with normal leukocyte and platelet counts, and a bone marrow with a selective absence of erythroid precursor cells. Drug-induced PRCA is a rare secondary form of PRCA, and is usually acute and fully reversible by the withdrawal of the causative drugs. We report a rare case of PRCA in a prostate cancer patient treated with combined androgen blockade (CAB) consisted of leuprolide acetate as a luteinizing hormone-releasing hormone agonist and chlormadinone acetate as an antiandrogen. This case demonstrated that these drugs could be a cause of PRCA, and suggests that regular close monitoring for anemia is needed in prostate cancer patients treated with these drugs.

Adenocarcinoma↗
PubMed1995

DNA-damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver.

The synthetic progestin cyproterone acetate (CPA) has been recently shown to elicit DNA repair synthesis in cultured rat hepatocytes and to form adducts with rat hepatocyte DNA in vitro and in vivo. In the present study we have examined the genotoxic potential of the structural analogues of CPA, chlormadinone acetate (CMA) and megestrol acetate (MGA) in rat liver cells. CPA strongly induced DNA repair synthesis in hepatocyte cultures from females but not from males. In contrast, CMA and MGA (2-50 microM) did not detectably increase repair synthesis in cultured hepatocytes from either gender. CMA and MGA, however, caused the formation of DNA adducts detectable by the 32P-postlabelling technique. At a concentration of 30 microM, between 30 and 50 adducts/10(9) nucleotides were found with MGA and CMA in cultured hepatocytes of female rats, and between 5 and 20 adducts/10(9) nucleotides were found in hepatocytes of males. By comparison, 30 microM CPA has been found to produce 1670 adducts/10(9) nucleotides in hepatocytes from female rats. CMA and MGA also induced low levels of DNA adducts in vivo. When female rats were treated with 100 mg/kg of CMA or MGA per os, the adduct levels were 2 and 19 adducts/10(9) nucleotides respectively. The results indicate that both CMA and MGA show some genotoxicity in rat liver cells, which is, however, much lower than that for CPA. Our findings further suggest that the high genotoxicity of CPA is associated with the presence of the 1,2 alpha-methylene group, which is absent in CMA and MGA.

Animals↗
PubMed2006

Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate.

BACKGROUND: Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). MATERIALS AND METHODS: Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. RESULTS: Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 h after single dosing and 36-39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. CONCLUSIONS: The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature.

Adolescent↗
PubMed1980

[The in vivo metabolism of chlormadinone acetate in guinea pig and the uptake of testosterone-3 H and chlormadinone acetate-3 H in prostate of castrated male rat (author's transl)].

The metabolic fate and distribution of the anti-androgenic agent, 17 alpha-acetoxy-6-chloropregna-4, 6-diene-3, 20-dione (chlormadinone acetate, CMA), was investigated using guinea-pigs and rats. In order to elucidate the metabolic outcome, chlormadinone acetate was labelled with 3H at position C-1 and with deuterium at methyl moiety of the 17alpha-acetate. Guineapigs were maintained for 7 days on a diet containing 1% chlormadinone acetate having a ratio of d2/d0=1 and then for 1 day on a diet containing 1% chlormadinone acetate having radioactivity. The isolation and purification of the urinary and fecal metabolites were usually carried out in the manner shown in Fig. 1 and 2. The metabolites identified were as follows: the parent drug, monohydroxychlormadinone acetate having the additional hydroxy function in the steroid skeleton, 15 beta-hydroxy, 2 alpha-, 2 beta-hydroxy and unknown position, dihydroxy chlormadinone acetate, 2 alpha-, 3 beta-dihydroxy, 2 alpha-, 3 alpha-dihydroxychlormadinone acetate. Further, three dechlornated and reduced metabolites were also isolated from urine and feces. These were 17 a-acetoxy-5a-pregnane-3 beta-ol-20-one and its isomer, and 17-acetoxy-5 beta-pregnane-2 beta, 3 beta, 15a-triol-20-one. But 3 beta-hydroxychlormadinone acetate possessd with anti-androgenic activity, one of the main metabolites in humans and rats, was not found in the excreta of the guinea-pigs. However, the main metabolite on the prostate of the guinea-pigs and rats and 3 beta-hydroxychlormadinone acetate. Chlormadinone acetate causes regression of the seminal vesicle and prostate in oral administration to a mammalian. It was therefore hypothesized that chlormadinone acetate might inhibit the uptake and retention of testosterone in these tissues. To elucidate this hypothesis, the accumulation of testosterone-3H and chlormadinone acetate-3H in several organs was determined on castrated rats and normal rats, respectively. When 1.0 muM of testosterone-3H was given to the castrated rats, a maximal accumulation of radioactivity resulted in seminal vesicle and prostate at 15 approximately 120 min. While the treatment of chlormadinone acetate significantly prevented the accumulation of testosterone-3H in the seminal vesicle and prostate, but levels in fat and muscle were not evident. In addition, to prove the accumulation of chlormadinone acetate in androgen target tissues, 3 muM of chlormadinone acetate-3H was similarly administered to castrated rats. The uptake of chlormadinone acetate on the target organs was higher than that in normal rats at 5 approximately 30 min.

Animals↗
PubMed1976

[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↗
PubMed2001

Comparison of histological compositions and apoptosis in canine spontaneous benign prostatic hyperplasia treated with androgen suppressive agents chlormadinone acetate and finasteride.

PURPOSE: Chlormadinone acetate and finasteride are androgen suppressive agents clinically used for benign prostatic hyperplasia but their mechanism for inducing prostatic atrophy differs. We investigated the effect of these androgen suppressive agents on prostatic histology and apoptosis using the spontaneous canine benign prostatic hyperplasia model. MATERIALS AND METHODS: Animals were treated with oral chlormadinone acetate or finasteride for 25 weeks. The prostatic volumes were analyzed every 5 weeks. Prostatic androgen and estrogen concentrations, histological composition and apoptosis were determined at the end of treatment. Apoptosis was measured by in situ labeling of 3' hydroxy ends of the DNA breaks using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling method. RESULTS: There was a similar volume reduction effect with 0.3 mg./kg. chlormadinone acetate daily and 1 mg./kg. finasteride daily. Chlormadinone acetate decreased testosterone and dihydrotestosterone but finasteride decreased only dihydrotestosterone in the prostate gland. The concentration ratio of estradiol-to-total androgen in the prostate was significantly increased in finasteride treated canines. Chlormadinone acetate and finasteride decreased the epithelial and stromal components. The extent of apoptosis observed in the prostate was significantly higher in the chlormadinone acetate group compared to that of the control and finasteride groups. CONCLUSIONS: Although a similar effect of chlormadinone acetate and finasteride was observed in the induction of prostatic regression and composition of the histological components, the sustained increase in apoptosis was observed only in chlormadinone acetate treated canines. We suggest that different intraprostatic endocrine environments created by chlormadinone acetate or finasteride, which have different intraprostatic testosterone levels and estradiol-to-androgen ratios, may be responsible for the different outcomes in the extent of apoptosis.

Androgen Antagonists↗
PubMed1975

[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↗
PubMed1980

Binding of chlormadinone acetate to cytosol from human benign prostatic hypertrophy.

Chlormadinone acetate was bound to cytosol from the human benign prostatic hypertrophy in a high affinity fashion. The kd and number of maximum binding site of the binding were 5.4 +/- 0.7 X 10(-9) M and 67.9 +/- 5.8 fmol/mg protein, respectively. When compared with the binding to dihydrotestosterone, the Kd for chlormadinone acetate was greater. The number of maximum binding site for chlormadinone acetate was observed to be smaller than that for dihydrotestosterone, but these two values were not different statistically. The binding of chlormadinone acetate was inhibited significantly by the addition of R 1881 or cyproterone acetate. However, dihydrotestosterone revealed itself to be a weak inhibitor of the binding. The cytosol prelabelled with chlormadinone acetate was not bound to the nuclei of the human prostate.

Androgen Antagonists↗
PubMed2004

Evaluation of genotoxic potential of synthetic progestin chlormadinone acetate.

The genotoxicity study of a synthetic progestin chlormadinone acetate, was carried out on mouse bone marrow cells using sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) as parameter, chlormadinone acetate was studied at three different doses, i.e. 5.62, 11.25 and 22.50 mg/kg body weight and was found to be non-genotoxic at 5.62 mg/kg body weight. But at 11.25 and 22.50 mg/kg of body weight chlormadinone acetate increases SCE (P < 0.001) and CA (P < 0.01) at significant level compared to normal control. The results suggests a genotoxic and cytotoxic effect of chlormadinone acetate in mouse bone marrow cells.

Animals↗
PubMed1994

[Antiovulatory action of chlormadinone acetate].

Antiovulatory action of chlormadinone acetate (5 mg twice daily from day 7 to day 25) has been assessed in 6 healthy volunteers by daily determination of plasma FSH, LH, estradiol and progesterone. Hormonal profiles during the second treated cycle show that preovulatory gonadotropin surge is blunted and that no significant progesterone secretion occurs. Estradiol production is variable up to the middle of the cycle, and then homogeneously low normal. Menstrual cyclicity is respected and ovarian function is restored during the first cycle after treatment disruption.

Adult↗
PubMed1999

The prognosis of stage A patients treated with the antiandrogen chlormadinone acetate.

To determine the efficacy of the antiandrogen chlormadinone acetate as a treatment option for stage A prostate cancer, a retrospective analysis of 111 patients who received chlormadinone acetate was done. Of 55 stage A1 patients, progression was seen in one patient (1.8%) 8 years after the diagnosis. Six out of 56 stage A2 patients (10.7%) showed disease progression at 1-7 years (mean 68 months) after the diagnosis. Progression rates associated with antiandrogen therapy for stage A1 and stage A2 patients were lower than those without treatment reported in the literature. It could be assumed that antiandrogen treatment with chlormadinone acetate inhibited the progression.

Aged↗