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PubMed2005

Long term phenobarbital administration does not promote the multiplication of hepatocytes replicating after single cyproterone acetate administration.

Cyproterone acetate (CPA) is a synthetic antiandrogenic compound which is widely used in clinic but suspected to be hepatocarcinogenic. CPA is also mitogenic in rat liver. Using genetic labeling of dividing cells, we examined whether hepatocytes dividing in response to acute CPA administration could give rise to preneoplastic foci after administration of a tumor promoter: phenobarbital. CPA was administered orally to rats and dividing hepatocytes were genetically labeled using retroviral vectors carrying the beta-galactosidase gene. After labeling rats were given phenobarbital for 10 months and sacrificed. The presence of beta-galactosidase labeled hepatocytes as well as preneoplastic hepatocytes was assessed by immunohistochemistry. Genetic labeling of hepatocytes was obtained in all animals. At the end of phenobarbital administration, no hepatic tumors were observed. Preneoplastic foci were not increased in treated animals as compared to control rats. Moreover beta-galactosidase positive hepatocytes were never detected in preneoplastic foci. Finally, the size of the beta-galactosidase positive clusters was smaller in treated animals as compared to control rats. We conclude that acute CPA administration is not carcinogenic in rat liver and does not initiate preneoplastic hepatocytes capable to give rise to foci after phenobarbital promotion. Therefore the mitogenic property of CPA is distinct from its putative carcinogenic activity. Finally, analysis of the size of beta-galactosidase positive cells clusters demonstrate that phenobarbital does not induce hepatocyte proliferation in rats.

Androgen Antagonists↗
PubMed2004

No-effect level in the mutagenic activity of the drug cyproterone acetate in rat liver. Part II. Multiple dose treatment.

In order to probe for the existence of a no-effect levels for mutations induced by multiple dose treatment with cyproterone acetate (CPA), female lacI-transgenic Big Blue rats were treated daily for 3 weeks with oral doses of 5.0, 1.0 or 0.2mg/kg CPA b.w., respectively. The dose of 5mg/kg CPA b.w. ineffective as a single dose (see part I) increased the mutation frequency by 2.5-fold. Daily treatment with 1.0 and with 0.2 mg/kg CPA b.w. for 3 weeks, however, was not effective indicating that the 1 mg dose represents a no-effect level for multiple dose treatment. The finding that a total dose of 21 x 5 = 105 mg/kg CPA b.w. caused 50% less DNA adducts, but a mutation frequency three-fold higher (data extrapolated from part I) than observed after daily treatment with 5mg/kg CPA b.w. for 21 days points to a crucial role of cell proliferation in mutagenesis by CPA. Our present results, in combination with previous findings, offer a basis to estimate the risk to develop mutations in human liver following treatment with CPA. Previous studies revealed that CPA-DNA adducts are formed in human hepatocytes at lower levels than in those of female rats [Mutat. Res. 395 (1997) 179; Cancer Res. 56 (1996) 4391]. Moreover, an in vitro-study indicated that human hepatocytes in culture do not respond to the mitogenic effect of CPA, while rat hepatocytes did [Cancer Res. 51 (1991) 1143]. We conclude that the risk of humans to develop mutations under treatment with CPA is substantially lower than in the female rat.

Animals↗
PubMed2004

No-effect level in the mutagenic activity of the drug cyproterone acetate in rat liver. Part I. Single dose treatment.

The anti-androgen and progestagen cyproterone acetate (CPA) is known to cause liver tumors in rats. The drug has been identified recently as a mutagen in the liver of female transgenic lambdalacI (Big Blue) rats at high doses after an expression time of 6 weeks. A dose of 50 mg CPA/kg BW, however, did not increase the mutation frequency (MF) of controls indicating a no-effect level of mutagenicity [Carcinogenesis 19 (1998) 241]. The present study was performed to assess the existence of a no-effect level of mutagenicity. In order to figure out conditions of maximum response, the time course of the MF was determined after administration of a single dose of 100 mg CPA/kg BW to female Big Blue rats. The MF showed a strong initial rise to a maximum 2 weeks after CPA administration accompanied by a corresponding increase of cell proliferation and of DNA adduct levels. Thereafter, the MF decreased within further 2 weeks to one third of the maximum level which was maintained for another 4 weeks. The DNA adduct levels decreased only by 15% during this time period suggesting that mutated hepatocytes were eliminated predominantly. A dose dependence curve determined at a fixation time of 2 weeks revealed a no-effect level of 5 mg CPA/kg BW for mutagenicity. In conclusion, our findings indicate that the length of the observation period may be a critical determinant for the outcome of a mutagenesis study in rat liver. Furthermore, the existence of a no-effect level for the mutagenicity of CPA in rat liver was confirmed. However, it has to be clarified whether the dose of 5 mg CPA/kg BW corresponding to the "transient" type of mutations or the previous dose of 50 mg CPA/kg BW related to a "permanent" type of mutations is more relevant for the assessment of the genotoxic risk.

Animals↗
PubMed1975

Action of cyproterone acetate on the accessory organ of reproduction in prepubertal and sexually mature rats.

The effects of cyproterone acetate on the accessory organs of immature, prepubertal, and sexually mature adult rats were studied. Administration of CA to immature 30-day-old rats for 15 days markedly decreased the silaic acid in the caput and cauda epididymides and decreased the secretory activity of the accessory glands. Treatment of adult rats with CA for 15 days caused an increased incorporation of 3H-uridine into RNA and of 3H-phenylalanine into protein in the caput and cauda epididymides. The percentage of increase in the specific activity of RNA and protein was higher in the cauda epididymidis than in the caput epididymidis.

Age Factors↗
PubMed1993

Effects of a 1-year treatment with a low-dose combined oral contraceptive containing ethinyl estradiol and cyproterone acetate on glucose and insulin metabolism.

OBJECTIVE: To study the effects of the slightly estrogen-dominant monophasic low-dose oral contraceptive (OC) Diane-35 (Schering AG, Berlin, Germany) (35 micrograms ethinyl estradiol [EE2] + 2 mg cyproterone acetate, a 17 alpha-hydroxyprogesterone derivative [17-OHP]) on glucose and insulin metabolism. DESIGN: Seven healthy young women were investigated by using the euglycemic hyperinsulinemic glucose clamp technique (insulin delivery rate = 100 mU/kg per hour for 120 minutes). This test was performed, after an overnight fast, during the last 7 days of a spontaneous cycle and within the last 5 days of pill intake during the sixth and twelfth cycle of a continuous treatment with Diane-35 in each subject. RESULTS: The three indexes measuring the insulin-induced glucose disposal during the clamp (glucose infusion rate, glucose metabolic clearance rate, and glucose infusion rate divided by plasma insulin plateau levels) were not significantly affected by Diane-35. In contrast, the metabolic clearance rate of the exogenous insulin infused during the clamp tended to be slightly increased with Diane-35 (significant after 6 but not after 12 cycles). CONCLUSION: These results suggest that a 1-year treatment with the OC Diane-35, which contains EE2 + a 17-OHP rather than a 19-nortestosterone derivative as the progestogen compound, does not significantly alter peripheral (presumably muscular) insulin sensitivity but slightly increases insulin (presumably hepatic) clearance.

Adult↗
PubMed1995

17 beta-Estradiol: oral or parenteral administration in hyperandrogenic women? Metabolic tolerance in association with cyproterone acetate.

OBJECTIVE: To compare the metabolic effects of two different administration routes of estrogen associated with cyproterone acetate (CPA) in young women. DESIGN: Randomized and prospective study. SETTING: University medical and research center. PATIENTS: Sixty-five premenopausal young women with clinical hyperandrogenism. INTERVENTIONS: A high dose of CPA was administered, associated with either transdermal (group T) or oral (group O) 17 beta-E2. MAIN OUTCOME MEASURES: Glucose tolerance, plasma lipid level, coagulation and fibrinolysis parameters, and angiotensinogen, before and at 6 and 12 months during treatment. RESULTS: At 12 months, fasting blood glucose and basal insulin levels were significantly lower in group O than in group T. The increase in angiotensinogen was greater in group O, however, without modification in arterial blood pressure. No significant difference between the two groups was observed in lipids, coagulation, and fibrinolysis. CONCLUSION: Natural estrogens associated with CPA have no patent deleterious metabolic effect. However, the choice of oral estrogen administration seems to be better among patients with disorders such as hyperandrogenism or obesity with potential hyperinsulinism.

Administration, Cutaneous↗
PubMed1996

Comparison of spironolactone-oral contraceptive versus cyproterone acetate-estrogen regimens in the treatment of hirsutism.

OBJECTIVE: To compare the efficacy of two antiandrogens, cyproterone acetate (CPA) and spironolactone, in the treatment of hirsutism. DESIGN: Prospective randomized single-blinded study. SETTING: A tertiary hirsutism clinic. PATIENTS: Forty-two premenopausal patients with hirsutism were selected. INTERVENTIONS: Subjects were randomized to receive either 100 mg spironolactone and an oral contraceptive (OC) containing 150 microg desogestrel and 30 microg ethinyl E2 or 50 mg CPA daily on days 1 to 10 of the menstrual cycle, which was administered with 35 microg ethinyl E2 daily on days 1 to 21. MAIN OUTCOME MEASURES: Hirsutism scores were measured according to Ferriman-Gallwey scoring system and side effects were monitored for 9 months of treatment. Blood samples were taken at each visit for assessment of endocrine, biochemical, and hematologic parameters. RESULTS: Hirsutism scores were decreaded significantly in both groups at the end of 9 months. The percent of change in hirsutism scores in CPA and spironolactone group were as follows: 19.23% +/- 14.77% and 24.48% +/- 14.27% at 3 months; 39.01% +/- 19.77% and 37.46% +/- 16.90% at 6 months; and 51.89% +/- 20.87% and 46.39% +/- 16.10% at 9 months, respectively. There was a trend toward a better response with CPA treatment, which did not achieve significance. None of the patients stopped treatment because of side effects. CONCLUSION: The present data suggest that both spironolactone and CPA were similarly effective in treatment of hirsutism.

17-alpha-Hydroxyprogesterone↗
PubMed1999

Prospective randomized study comparing the long-acting gonadotropin-releasing hormone agonist triptorelin, flutamide, and cyproterone acetate, used in combination with an oral contraceptive, in the treatment of hirsutism.

OBJECTIVE: To compare triptorelin, cyproterone acetate (CPA), and flutamide, in combination with an oral contraceptive, in the treatment of hirsutism. DESIGN: Prospective randomized study. SETTING(S): Tertiary care hospital. PATIENT(S): Thirty-nine hirsute women with idiopathic or functional ovarian hyperandrogenism. INTERVENTION(S): Patients were randomly assigned to receive triptorelin (3.75 mg IM every 28 days), CPA (100 mg/d orally on days 1-10 of the menstrual cycle), or flutamide (250 mg orally twice daily). All the patients also received a triphasic oral contraceptive. MAIN OUTCOME MEASURE(S): Before and after 3 and 9 months of treatment, the Ferriman-Gallwey score, hepatic function, and gonadal and adrenal steroid profiles were evaluated. RESULTS: Thirty-three patients completed the 9-month study period. The Ferriman-Gallwey score decreased in all the groups. In the patients treated with CPA or flutamide, a decrease in the hirsutism score was noted as soon as after 3 months of treatment. This decrease was more pronounced after 9 months of treatment, especially in the patients who received flutamide, who had lower hirsutism scores compared with the other treatment groups. None of the patients had abnormal liver function test results. There was a mild increase in serum lipid concentrations, mostly in the group treated with triptorelin. CONCLUSION(S): Triptorelin, CPA, and flutamide are effective drugs for the treatment of hirsutism. Flutamide results in a greater reduction in the hirsutism score, but CPA also offers satisfactory results at a much lower cost. Triptorelin has no advantages over flutamide and CPA, and is the most expensive of the three drugs tested.

Adult↗
PubMedDate not supplied

Chronopharmacokinetic behaviour of cyproterone acetate in rabbits.

Cyproterone acetate (CPA) is an antiandrogenic compound that shows a rhythmic toxicologic behaviour. The purpose of this study was to determine whether CPA pharmacokinetics in the rabbit were influenced by the administration time of day. Previously synchronised rabbits received a single intravenous dose of 4 mg kg(-1) of CPA at two hours after light onset (2 HALO) and 14 hours (14 HALO) after light onset. The drug concentration in plasma samples was determined by high performance liquid chromatography. The mean concentrations in plasma were significantly higher (P<0.05) in 2 HALO than in 14 HALO animals at five, 15 and 30 minutes after dosing. Both plasma concentration profiles were fitted to two-compartment open models. Mean A, Vc and Vss differed significantly between 2 and 14 HALO dosage (P<0.005). Temporal variations in plasma protein binding, drug distribution and in drug elimination may play an important role in explaining these results.

Animals↗
PubMed2002

Effects of finasteride and cyproterone acetate on hematuria associated with benign prostatic hyperplasia: a prospective, randomized, controlled study.

OBJECTIVES: To evaluate the influence of two differently acting antiandrogens, finasteride (FIN) and cyproterone acetate (CPA), on the natural history of hematuria associated with benign prostatic hyperplasia (BPH) in a prospective, randomized, controlled study. METHODS: Forty-two patients with hematuria episodes due to BPH were randomly allocated to three subgroups of 14 patients each and treated daily with either 5 mg FIN or 100 mg CPA or were placed in a watchful waiting arm. Patients were evaluated at 3-month intervals, and 40 patients had at least 1 year of follow-up. RESULTS: Four patients in the FIN group (30%) and three in the CPA group (23%) presented with recurrent hematuria. In both groups, the bleeding episodes were treated conservatively and required no hospitalization. In the control group, 8 patients (57%) presented with recurrent bleeding; in 4, the bleeding was severe and required some form of intervention (catheterization or transurethral prostatectomy). When the frequency and severity of the hematuria episodes were analyzed over time, a statistically significant difference for FIN versus control was present at 9 and 12 months (analysis of variance, P = 0.035 and P = 0.009, respectively). A similar difference was evident for CPA versus control at 9 and 12 months (P = 0.028 and P = 0.008, respectively). No statistically significant difference was present between the FIN and CPA groups. Interestingly, no statistically significant effect in bleeding recurrence for both CPA and FIN over controls was present at 3 and 6 months of follow-up. CONCLUSIONS: Both FIN and CPA seem to exert a comparable control in hematuria recurrence in patients with BPH, thus confirming the rationale behind the use of antiandrogens for such a purpose. Our results support the hypothesis that any antiandrogen, irrespective of the mode of action, would alter the natural history of BPH-associated hematuria. Interestingly, our results indicate that the speed of action of FIN may not be as rapid as previously described.

Aged↗
PubMed1996

Low-dose cyproterone acetate plus mini-dose diethylstilbestrol--a protocol for reversible medical castration.

OBJECTIVES: To determine whether a low dose of cyproterone acetate (CPA) (50 mg twice a day) with minidose diethylstilbesterol (DES) is efficacious in rapidly reducing and maintaining serum testosterone at less than 10% of pretreatment level and whether the effect is reversible upon cessation of therapy. METHODS: Data were collected prospectively on 62 subjects, aged 50 to 90 years (mean 69) with histologically confirmed prostate cancer and normal serum testosterone levels. Treatment was initiated with CPA 50 mg twice a day plus DES 0.11 mg once a day, both administered orally, and continued or 6 months unless discontinued for reasons unrelated to the study. Subsequent management was at the discretion of the investigator/managing physician. Treatment was discontinued with determination of at least one follow-up testosterone level in 28 patients. RESULTS: Mean pretreatment testosterone level was 13.8 nmol/L (range 4.5 to 46.6, median 14.0, 95% confidence interval [CI] 12.0 to 15.0). Testosterone dropped to a mean of 0.6 nmol/L (range 0.1 to 2.2, median 0.5, 95% CI 0.4 to 0.6) by first follow-up (usually 1 month) in all patients (P <0.001) and remained at this level as long as treatment continued. Testosterone normalized in all subjects whose treatment was discontinued. Side effects were minimal. CONCLUSIONS: An oral dosage of CPA of 50 mg twice a day in combination with a mini-dose of DES results in rapid and reversible reduction in serum testosterone to castrate levels. This regimen minimizes morbidity and monetary costs of therapy and allows the implementation of novel treatment approaches such as intermittent or neoadjuvant withdrawal therapy.

Aged↗
PubMed1998

Liarozole--a novel treatment approach for advanced prostate cancer: results of a large randomized trial versus cyproterone acetate. Liarozole Study Group.

OBJECTIVES: To compare the efficacy of oral liarozole, the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors, with that of cyproterone acetate (CPA), an antiandrogen for the treatment of metastatic prostate cancer. Liarozole promotes differentiation of cancer cells by increasing the intratumoral levels of retinoic acid. METHODS: A total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy entered a Phase III international multicenter study (recruitment from February 1992 to August 1994) comparing liarozole (300 mg two times daily) with CPA (100 mg two times daily). RESULTS: Accounting for differences in baseline prognostic factors, the adjusted hazard ratio for survival was 0.74 in favor of liarozole (P = 0.039), indicating a 26% lower risk of death than in patients treated with CPA. Median crude (unadjusted) survival time was the same in the liarozole group as in the CPA group (10.3 months). More patients showed a PSA response (at least 50% reduction in PSA from baseline) when treated with liarozole (20%) than with CPA (4%) (P < 0.001). Prostate-specific antigen (PSA) responders had a median survival benefit of 10 months over nonresponders, irrespective of treatment (hazard ratio 0.43; P = 0.0018). PSA response was apparent within 3 months in approximately 90% of patients who responded. Pain improved more in the liarozole group than in the CPA group (P = 0.03). PSA responders had lower median pain scores than nonresponders (1.7 versus 2.5) and better quality of life (median Functional Living Index-Cancer score 108 versus 98) at end point, ie, treatment discontinuation, as well as throughout the treatment period. Among the most frequently occurring adverse events in the liarozole group were dry skin (51% of patients), pruritus (25%), rash (16%), nail disorders (16%), and hair loss (15%). These adverse events were generally mild to moderate in severity and did not affect the overall quality of life score. There were no detectable effects of either treatment on vital signs such as blood pressure, heart rate, electrocardiogram, and body weight. CONCLUSIONS: Liarozole is superior to CPA in terms of PSA response, PSA progression, and survival, and is capable of maintaining patients' quality of life. The observed adverse events were mild to moderate in nature. These results show that liarozole is a possible treatment option after first-line endocrine therapy has failed.

Aged↗
PubMed2001

Cyproterone acetate induces a cellular tolerance to cadmium in rat liver epithelial cells involving reduced cadmium accumulation.

Several reports indicate that some steroids, in particular sex steroid hormones, can modify cadmium toxicity. We recently reported that cyproterone acetate (CA), a synthetic steroidal antiandrogen that is closely related in structure to progesterone, affects cadmium toxicity in mice. In the present study, we investigated the effect of CA on cadmium toxicity in a rat liver epithelial cell line (TRL 1215) in vitro. Cells were exposed to various concentrations of CA (0,1,10, or 50 microM) for 24 h and subsequently exposed to cadmium (0,50, or 100 microM; as CdCl2) for an additional 24 h. CA pretreatment resulted in a clear decrease in the sensitivity to cadmium. Additional time course study showed CA pretreatment provided protection against cadmium toxicity but only when given for 6 or more hours prior to cadmium exposure. Cellular cadmium accumulation was markedly reduced (60% decrease) in cells pretreated for 6 or more hours with CA. In the presence of protein synthesis inhibitors the protective effect of CA toward cadmium toxicity was abolished. However, in the presence of the GSH synthesis inhibitor, L-buthionine (S,R)-sulfoximide (BSO), the protective effect of CA toward cadmium toxicity remained. CA alone increased metallothionein (MT) levels 2.4-fold, while cadmium (50 microM) alone resulted in a 8.9-fold increase over control. However, cadmium-induced MT synthesis was markedly decreased by CA pretreatment probably because of reduced cadmium accumulation. Analysis of various metal transporters by bDNA signal amplification assay revealed that the ZnT-1 transporter gene, which encodes for a membrane protein associated with zinc efflux, was expressed three-fold more in CA treated cells than control. These data show that CA pretreatment provides protection against cadmium toxicity in vitro and indicate that this protection is due to a decreased accumulation of cadmium rather than through activation of MT synthesis. This decrease of cellular cadmium accumulation appears to be related to events that require protein synthesis and may be due to activation of the genes associated with zinc efflux.

Androgen Antagonists↗
PubMed1985

The effect of cyproterone and gonadotrophins on the adrenal gland of juvenile and adult rats. A morphological and morphometrical study.

Up to now the question whether antiandrogens and gonadotrophins cause a reaction of the adrenal cortex has not been settled. 32 juvenile and 32 adult male albino rats were divided into 4 groups with 8 animals each. One group of juvenile and of adult rats were treated with cyproterone (Cp) as an anti-androgen, Primogonyl (Pg) served as an LH equivalent and Pergonal (Per) as a FSH-LH dose. One group of juvenile and adult rats served as controls. The animals were killed on the 28th day of the experiment. Microphotographic black-and-white pictures from the histologic adrenal cortex specimens were taken with a magnification of 800. The morphometric and histologic evaluation of the adrenal cortex was carried out separately for the zona glomerulosa (z.g.), the zona fasciculata (z.f.) and the zona reticularis (z.r.). No measurable changes can be found in the z.g. under experimental conditions. Both the juvenile and the adult rats exhibit a distinct atrophy of the z.f. and the z.r. after the administration of Cp and gonadotrophins. The severest regressive transformations can be observed in the adult rats after Cp was given. The atrophy of z.f. and z.r. is obviously due to the inhibition of corticotropic regulation in the hypothalamic-hypophysic axis. This is astonishing in so far as this regulation is usually responsible for the production of glucocorticoid and only to a lesser degree for the production of sex hormone. A glucocorticoid-like effect of Cp is assumed. Similar changes are also caused by the administration of gonadotrophins.

Adrenal Cortex↗
PubMed2002

Hormone replacement therapy with estradiol valerate and cyproterone acetate: effects on endothelium-dependent vasodilatation and arterial wall compliance.

OBJECTIVE: to evaluate changes in vasomotor endothelium function and elastic properties of the brachial artery in postmenopausal women beginning hormone replacement therapy (HRT) with Climen(R), a 28-day sequential therapy combining estradiol valerate (E2V) 2 mg/day D1-D21 with cyproterone acetate (CPA) 1 mg/day D12-D22, followed by a 7-day treatment-free interval. METHODS: Thirty-one women with natural or surgical menopause were included in an open multicenter study. Before treatment, at the end of the estrogen-only phase of cycle 1, and after the combined phase in cycles 1 and 3, endothelium-dependent vasodilatation (EDVD%) in the brachial artery was measured by the post-ischemia increase of the inner diameter, and pulse wave velocity (PWV) was measured in the same artery by simultaneous continuous wave Doppler and photo-plethysmography. RESULTS: compared to pre-treatment values, the median increase in EDVD was 14.3% after cycle 1 (P=0.0001) and 27.9% after cycle 3 (P=0.0001). CPA did not alter the effect of E2V on EDVD in cycle 1. Median arterial systolic pressure was unchanged, but median diastolic pressure fell from 70 to 67.5 mmHg (P=0.04) after cycle 3. Median PWV was reduced by 0.76 m/s after cycle 3 (relative reduction -9.3%) (P=0.035). There was a significant correlation between PWV and EDVD changes from pre-treatment values at the end of the 3rd cycle. CONCLUSION: treatment of postmenopausal women with E2V/CPA led to an immediate and significant improvement in endothelium-dependent vasodilatation. The estrogen-related vasomotor effect was not suppressed by the progestogen CPA. The WV changes are consistent with slower improvement of arterial compliance in some women. The non-invasive measurement of EDVD and PWV is a convenient method for the evaluation of both mechanical and functional effects of combination HRT on the arterial wall.

Administration, Oral↗
PubMed2003

Permeation of cyproterone acetate through pig skin from different vehicles with phospholipids.

The permeation of cyproterone acetate (CPA) from Derma Membrane Structure (DMS) creams and liposomal formulations was investigated. Standard diffusion experiments with dermatomed porcine skin were performed. The cumulative CPA amount permeated of the DMS creams was between 2.9 and 6.8 microg/cm(2) within 48 h. By addition of a phospholipid concentrate, the CPA permeation could be 2.6-fold further increased compared to the control DMS. A working temperature of 60 degrees C resulted in a change of the preparation and a higher permeation which could be confirmed by additional differential scanning calorimetry studies. In case of the liposomal formulations, the CPA permeation was strongly dependent on the lipid content. The higher the lipid content, the higher was the CPA permeation. Extruding procedures for decreasing the particle size of the liposomes resulted in a two-fold increase in CPA permeation compared to the unextruded liposomes. It is possible to control the CPA permeation by combining various formulations containing different phospholipids with saturated and unsaturated fatty acids.

Animals↗
PubMed2003

Simultaneous spectrophotometric determination of cyproterone acetate and estradiol valerate in pharmaceutical preparations by ratio spectra derivative and chemometric methods.

Ratio spectra derivative spectrophotometry and two chemometric methods (classical least squares, CLS and inverse least squares, ILS, were proposed for the simultaneous quantitative analysis of a binary mixture consists of cyproterone acetate (CA) and estradiol valerate (EV) in the commercial pharmaceutical preparations. In the ratio spectra derivative method, linear regression equations for both drugs were obtained by measuring the analytical signals at the wavelenghts corresponding to either maximums and minimums in the first derivative spectra of the ratio spectra. In the chemometric techniques, the concentration matrix was prepared by using the synthetic mixtures containing these drugs. The absorbance matrix corresponding to the concentration matrix was obtained by measuring the absorbances at 14 wavelengths in the range 220-290 nm for the zero-order spectra. Two chemometric calibrations were constructed by using the absorbance matrix and concentration matrix for the prediction of the unknown concentrations of CA and EV in their mixture. The numerical values were calculated by using 'MAPLE V' software. The accuracy and the precision of the methods have been determined and they have been validated by analyzing synthetic mixtures containing these two drugs. The proposed methods were successfully applied to a pharmaceutical formulation, sugar-coated tablet, and the results were compared with each other.

Algorithms↗
PubMed2003

Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation.

OBJECTIVE: To review the incidence of venous thromboembolism (VTE) in association with combined cyproterone acetate and ethinylestradiol (CPA/EE) use, compared to the incidence of VTE in association with conventional oral contraceptive (OC) use, in women aged 14 to 49 years. METHODS: A review consistent with the guidelines of "best evidence synthesis" was conducted on 6 peer-reviewed, controlled epidemiological studies reporting both outcome numerators and exposure denominators. Relative risks as the estimate of the association between CPA/EE and the clinical outcome of VTE were set aside in favour of absolute incidence rates, rate differences, or attributable risks. RESULTS: The range of absolute incidence rates of VTE among CPA/EE users varied from 1.2 to 9.9 per 10 000 women-years (WYs). All other marketed conventional OCs were the reference. In 6 studies conducted in 3 European countries, CPA/EE exhibited an attributable risk in women not higher than 0.04% when compared to approved conventional OCs. Except for 1 study exhibiting a small statistically significant benefit, there was no difference between the incidence rates of VTE among CPA/EE users and those among conventional OC users. VTE as an adverse event for CPA/EE was either rare or very rare, according to the criteria set by the World Health Organization/ Council for International Organizations of Medical Sciences. No deaths were reported in the studies reviewed. CONCLUSIONS: The evidence in the worldwide literature does not demonstrate an excess of health-threatening harm for CPA/EE. A best-evidence synthesis, using sound epidemiological methods, showed clearly that the risks of VTE among CPA/EE users do not exceed the risks of VTE among conventional OC users.

Adolescent↗