Experience in the long-term treatment of patients with hirsutism and/or acne with cyproterone acetate-containing preparations: efficacy, metabolic and endocrine effects.

The effects and side effects of long-term treatment with cyproterone acetate (CPA) are described. Hammerstein's reverse sequential regimen (10 days 100 mg CPA, 21 days 50 micrograms ethinylestradiol (EE)) was used in most cases, although postmenopausal and hysterectomized women received 50 mg CPA/day continuously as monotherapy. The degree of androgenization was assessed in 143 of a total group of 188 women treated from 1968 to the present. The results of the treatment were good or very good in about 75% of hirsutism patients and in more than 90% of acne patients. Adverse events were recorded in 23% of cases. Most were mild and transient, and caused discontinuation of the therapy in only 9% of patients. From this population representing all cases treated and analysed retrospectively, a subgroup of patients was selected for a prospective investigation. Thirty-five patients with good response to CPA and longlasting therapy were included into this 2-year follow-up study; of these, 24 had previously received CPA for 5 or more years, 9 for more than 10 years and 2 for more than 15 years. Treatment in these patients consisted of 5 different regimens of various doses of CPA combined with EE and CPA alone in order to evaluate possible effects of concomitant estrogen treatment as well as a possible dose- or time-dependency of potential side effects. Clinicochemical, metabolic and endocrine parameters were determined at the start and end of the study. The hematological and clinicochemical parameters were within the normal ranges. There was a slight decrease of glucose tolerance and a moderate increase of insulin and C peptide after oral glucose loading. The effects of CPA and EE on lipometabolism were slight and apparently dependent on the dose of CPA and the therapeutic regimen. No suppression of adrenal function or of responsiveness to ACTH was seen. Fasting prolactin levels and serum prolactin concentrations after provocation with metoclopramide did not show any gross deviations. Sonography of the breast and liver did not show any abnormalities apart from adenofibrosis or mastopathy in 2 patients. In conclusion, CPA with or without EE was in our hands an effective and safe method of long-term treatment of hirsutism and/or acne in women.

Metabolic effects of anabolic steroids.

After 1935 the best method of discovering and measuring the protein-building action of androgenic steroids in humans proved to be metabolic balance studies. In 1955, when anabolic steroids with less androgens were developed, the nitrogen-balance method was used again to evaluate and compare the nitrogen-sparing effect of the various preparations. The findings of the numerous balance studies that were performed are as follows: The injectable 17 beta-esters, such as nandrolone phenylpropionate, nandrolone decanoate and methenolone oenanthate exert a strong anabolic action for several weeks, amounting to 2-2.50 g nitrogen/day, which corresponds to a daily gain of 12-15 g protein or 60-75 g lean body mass. The orally active 17-alkyl derivatives induce a dose-dependent nitrogen-saving effect of the same order. While the drug is being administered, nitrogen-, calcium- and phosphorus-balance studies in osteoporotic patients show calcium and phosphorus retention in most cases. Anabolic steroids can abolish a negative nitrogen balance brought about by the administration of corticosteroids and anti-androgens. They thus possess anti-catabolic properties. Nitrogen loss after surgical procedures and following accidental traumata can be significantly reduced by pre-operative or post-operative treatment with anabolic agents. Comparison of the metabolic balance method with isotope studies showed a satisfactorily positive correlation. Later calcium metabolism studies in osteoporotic patients were mostly performed with various methods such as in vivo neutron activation analysis and osteodensitometry. They confirm the calcium anabolic effect of certain anabolic steroids.

Comparative effects of monophasic desogestrel plus ethinyloestradiol and triphasic levonorgestrel plus ethinyloestradiol on lipid metabolism.

The effects of the monophasic oral contraceptive preparation desogestrel plus ethinyloestradiol (EE) and triphasic levonorgestrel plus EE on lipid metabolism were compared. Sixteen young healthy female volunteers received monophasic desogestrel plus EE (21 X 150/30), whereas eighteen women received triphasic levonorgestrel plus EE (6 X 50/30 + 5 X 75/40 + 10 X 125/30) for six consecutive cycles. The lipid composition of the various lipoprotein fractions was estimated after separation in a density gradient by ultracentrifugation. In addition, the apolipoproteins A-I and B were assessed. HDL-cholesterol (precipitation method), HDL-2 cholesterol, HDL-2 phospholipids and the ratio apolipoprotein A-I to apolipoprotein B were significantly higher in the monophasic desogestrel group than in the triphasic levonorgestrel group after three and six treatment cycles. HDL-cholesterol (gradient), HDL-phospholipids (gradient), HDL-3 phospholipids and apolipoprotein A-I were only significantly higher after six treatment cycles. No differences between the groups were observed for the other lipid variables studied including triglycerides and VLDL-triglycerides.

Blood level, excretion, and metabolite pattern of [14C]-brotizolam in humans.

Following a single oral dose of 14C-labeled brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3, 2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine. We 941, Lendormin) the plasma level concentration and the total excretion of the radioactivity as well as the plasma level of the unchanged substance was measured in 4 healthy subjects. [14C]-Brotizolam was rapidly absorbed. The elimination half-life of the radioactivity from the plasma was 9.5 h, that of the unchanged [14C]-brotizolam 4.4 h. Using a two-compartment open model, the stimulation of giving 0.5 mg of the drug once daily showed no accumulation of brotizolam and its metabolites. Within the 4-day study 64.9% of the given radioactivity was eliminated renally. The total excretion was 86.5% of the dose. Extraction and thin layer chromatographic fractionation of the renally excreted radioactivity indicated two major metabolites one of which predominated. The metabolites were completely conjugated. Unchanged [14C]-brotizolam was excreted in minor amounts below 2-3% of the dose.

Pharmacokinetics of transdermally delivered clonidine.

We detail a series of pharmacokinetic investigations to determine the dose linearity, the effect of site of application, the duration of steady-state plasma concentrations, and the effect of chronic application when clonidine is administered transdermally. Dose linearity was assessed in six subjects with normotension after application of increasing sizes of transdermal clonidine systems (3.5, 7.0, and 10.5 cm2 size) to the upper outer arm. Of the six subjects studied, five had linear relationships between clonidine plasma concentrations at steady state and system size of greater than 0.975; in the sixth subject the correlation was greater than 0.90. The mean steady-state plasma concentrations with 3.5, 7.0, and 10.5 cm2 systems were 0.39, 0.84, and 1.12 ng/ml, respectively. The influence of site and duration of application on the absorption of transdermal clonidine was studied in eight subjects with normotension by use of the 3.5 cm2 system. The mean steady-state plasma concentration over the time interval from 3 to 7 days after application to the arm or to the chest did not significantly differ. When a system was left on the chest or arm for a total of 11 days (4 days beyond the recommended time to change systems), the plasma concentrations of seven of eight subjects with application to the arm and of six of eight subjects with application to the chest remained constant through day 11. The influence of consecutive applications of 3.5 cm2 transdermal clonidine systems on steady-state plasma clonidine concentrations was also studied in eight subjects with normotension over an 11-day period.(ABSTRACT TRUNCATED AT 250 WORDS)

[Biochemical studies with oxitropium bromide. 2. Pharmacokinetics and metabolism in humans]. / Biochemische Untersuchungen mit Oxitropiumbromid. 2. Pharmakokinetik und Metabolismus im Menschen.

The present paper reports on the human pharmacokinetics of (8r)-6 beta, 7 beta-epoxy-8-ethyl-3 alpha-/(-)-tropoyloxy/-1 alpha H, 5 alpha H-tropanium bromide (oxitropium bromide, Ba 253 BR, Ventilat) after intravenous and oral administration as well as following inhalation. The 14C-labelled substance was used. The concentrations of radioactivity measured in the plasma after i.v. administration show a biphasic course, a rapid alpha phase and a terminal phase (t 1/2 = 1.5 h). Once the alpha phase has passed the radioactivity concentrations measured after i.v. administration of 1 mg are comparable with those after 20 mg administered orally. The concentration course after inhalation corresponds essentially to the course after oral administration of lower doses. The cumulative renal excretion of the radioactivity is 68-78% for i.v. administration, 13% for oral administration, and 10% for inhalation. 7% (i.v.), 77% (p.o.) and 88% (inhalation) is excreted in the faeces. Oxitropium bromide is rapidly hydrolysed after oral administration. As little as 4 h later only 2-3% of intact active ingredient is found, whereas there is 85% of the hydrolysed product in the urine. A similar distribution pattern is observed in urine samples taken later. Some other metabolites are also recorded in minimal quantities. After i.v. administration, too, the hydrolysed product is excreted as the main component.

Effect of cyproterone acetate on pituitary-adrenocortical function in man.

Recent literature (1973-1976) suggests suppression of pituitary-adrenal function in patients (eg with pubertas praecox) who are treated with cyproterone acetate in high doses for prolonged periods. Therefore we investigated in our metabolic ward the effects of administration of 200 mg cyproterone acetate per day during 20 days to 4 healthy male volunteers. Baseline plasma cortisol and ACTH levels, repeated diurnal plasma cortisol and ACTH profiles and the results of tetracosactide (Synacthen) stimulation tests and single-dose metyrapone (Metopiron) tests proved to be comparable before, during and after treatment. Moreover, a slight gradual increase in urinary cortisol excretion during the observation period indicated that cyproterone acetate in the given dose during 20 days certainly does not reduce the pituitary-adrenal function of 4 healthy male volunteers. Long-term administration (during 1 to 7 years) of the combination of cyproterone acetate and ethinyloestradiol did not suppress serum levels of cortisol, prolactin, thyroxine and TSH in 18 female patients with hirsutism and/or acne.

A double blind crossover tolerance study of AR-L 115 BS in health volunteers.

In a double blind crossover study in 20 healthy volunteers, aged between 19 and 32 years, 2-[(2-methoxy-4-methyl-sulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) 100 mg q.i.d. for 1 week was compared with placebo. No drug effect was found on blood pressure (lying and standing, systolic and diastolic), heart rate, full blood count, blood chemistry (including liver functions), urinalysis; no side-effects were reported.