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6alpha,9-Difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) in the forms of cream, ointment and fatty ointment was investigated against 5 commercial preparations with beta-methasone-17-valerate, fluocinonide, fluocinolone acetonide, flumetasone pivalate and desoximetasone in 15 simultaneously conducted and multicentre-clinical studies-all on double-blind contralateral studies-involving a total of 1923 patients. The Nerisona preparations proved to be highly effective-particularly in eczematous diseases- and comparable to the above-mentioned commercial preparations. Nerisona ointment was shown to be superior to flumetasone cream. The statistical reliability of such data is discussed.

The acne-inducing effect of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester, Vaspit) 0.75% was compared with that of hydrocortisone acetate 1.0% and diflucortolone valerate 0.1% in a model established by Plewig and Kligman. The steroid and the cream base uniformly used in all preparations were applied to the backs of 20 volunteers over 4 weeks. Dome-shaped red papules developed in the third week of occlusive treatment, and were counted in an area of 16 cm2 at the maximum of their development and graded according to a scale. The degree of papulation under diflucortolone valerate 0.1% was 2.15+/-0.75. No differences were observed between fluocortin butylester 0.75% (0.2+/-0.42), hydrocortisone acetate and the cream base (0.15+/-0.37).

Gynodian-Depot is well suited for treatment of the characteristic symptoms accompanying the menopause in women. The plasma levels of prasterone and 17 beta-estradiol after intramuscular injection of Gynodian-Depot in women were studied using a radioimmunological method. The maximum active ingredient concentrations were found in the plasma of the subjects only a few days after administration. The depot action lasted on an average 14 days (17 beta-estradiol) and 18 days (prasterone) after administration, respectively. Prasterone enanthate is completely hydrolysed into the free steroid and the fatty acid.

The course of infrared thermography including isothermograms on the skin surface was investigated considering blood flow, redness of the skin and permeability of blood vessel, in the following skin reactions: 1. Intracutaneous injection of histamine and histamine liberator compound 48/80 increased the heat radiation. Local application of antihistamine externa which decreased the development of the urticarial histamine reaction, increased the infrared radiation of the skin surface. Combined injection of histamine or histamine liberators with antihistamines in a sufficient dosis (1:1 respectively 4:1) diminished also the heat radiation in addition to the urticarial reaction. 2. The Pyrexal reaction of the skin with early erythema and later papule development shows an equivalent picture in the AGA Thermovision. The pretreatment shows an equivalent picture in the AGA Thermovision. The pretreatment of the skin with corticosteroid ointments shows a corresponding lowering of the erythema, of papule development as well as of heat radiation. The blanching of corticosteroids after occlusive dressing is difficult to recognize by the isotherms of AGA Thermovision. 3. Allergic reactions of the immediate type show, corresponding to the wheal eruption, a marked increased of heat radiation combined with a projection of the enlarged veins on the skin surface. 4. Allergic reactions of the delayed type are combined with a definite elevation of heat radiation of the skin. The area of a positive skin test with allergic eczematous reaction shows a distinct elevation of ann infrared radiation. Although the allergic skin area which was substantiated by a positive skin test was no longer visible, a distinct infrared radiation could be detected. Preventive treatment of the test area of skin patch-testing with corticosteroids inhibits the heat radiation even if the allergic eczematous reaction occurs faintly. The thermographic analysis of the different skin test reactions complied with the morphological aspects of the reaction.

A specific and sensitive radioimmunoassay has been developed for a new benzodiazepine, lormetazepam. After intravenous injection, lormetazepam levels in plasma fell in three (alpha, beta, gamma) dispositional phases, two of them (alpha, beta) mainly reflecting different distribution processes. The terminal (gamma) phase correlated well with the rate of renal elimination of glucuronides. Oral doses were completely absorbed with widely varying absorption half-lifes (t1/2s) amounting to an average of 0.67 +/- 0.53 hr. Dose-dependent maximum plasma levels were reached in about 2 hr. Lormetazepam undergoes first-pass metabolism of about 20% of an oral dose. Total clearance was in the range of 200 ml/min. There was a trend toward slower terminal disposition phase in elderly subjects. In younger subjects, the terminal phase t1/2 was about 10 hr. Lormetazepam glucuronide peak plasma levels were reached by about 6 hr. Thereafter, the level fell in one (elimination) phase, with a t1/2 of 12 hr in young subjects and with a significantly (p < 0.05) different t1/2 of about 20 hr in the elderly. Renal clearance was calculated as about 30 to 40 ml and did not show an age-dependent difference. Recovery of lormetazepam glucuronide with urine amounted to 70% to 80% of the dose during 72 hr after intravenous injection in both age groups.

The phototoxic action of ointment and fatty ointment of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester, Vaspit) was examined by means of the epicutaneous test with subsequent UV-irradiation (Kromeyer lamp with Schott filter DG 18) in 20 patients with skin disorders. Photoallergic effects of fluocotrin butylester cream, ointment and fatty ointment were tested in a modified Draize test in which 198 subjects with normal skin participated. The subjects were sensitized in 10 epicutaneous tests conducted at intervals of 24 h and followed by irradiation (1500 W xenon lamp) with 2 MED. Treatment and irradiation were then repeated after a 2-week interval. This proceding permitted additional statements an phototoxicity of the administered preparations. No positive reactions occurred in either of the tests so that phototoxic effects can be excluded and a photoallergic potential is improbable.

The systemic effect of 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) 0.1% as an ointment and fatty ointment was investigated in two studies. The parameters used were the plasma 11-OHCS values and the urinary 17-OHCS and 17-KS values, respectively. Suppression of the plasma cortisol values was observed after topical application of both diflucortolone valerate and betamethasone-17-valerate to healthy subjects under extreme conditions of whole-body occlusion. However, it was still possible to stimulate the adrenal cortex with ACTH. No reduction of the 17-OHCS of 17-KS values in the 24-h urine was observed during open, large-surface treatment of patients with skin diseases.

The systemic corticoid effects of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-regnadien-21-oate (fluocortin butylester, Vaspit) in the form of 0.75% fluocortin butylester cream were tested under conditions which permit maximum absorption of the active principle. Over 8 days 40 g cream daily were applied to the entire body surface of 6 subjects and the trunk, thighs and upper arms covered with polythene foil. The plasma cortisol levels, elimination of free cortisol in the 24-h urine and eosinophilic leucocytes were compared intraindividually with the values before and three days after treatment. In addition 6 further subjects were treated with 0.1% hydrocortisone-17-butyrate cream, a preparation considered to have little systemic action. Fluocortin butylester showed no systemic corticoid effects. Cortisol secretion and eosinophilic leucocytes remained unaffected. In contrast the inhibiting effect of hydrocortisone-17-butyrate was evident in all parameters, especially in the morning plasma cortisol values. Under treatment with hydrocortisone-17-butyrate these dropped from 361 to 11 nmol/l. Under occlusion treatment with fluocortin butyl they remained constant (357 before, 320 nmol/l after treatment). The relevance of the method of examination is discussed.

14C-labelled lisuride hydrogen maleate was administered intravenously (25 micrograms) and orally (200 micrograms) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 +/- 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose. Determination of 14C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a half-life of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant. From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose. The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N'-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds at C2/C3 and C9/C10.

A comparative study (occlusion test according to Marples and Kligman) was conducted in 100 test subjects with several formulations of isoconazole nitrate. The following results were obtained: 1. There are no differences in efficacy between the free base, isoconazole, and the nitrate. 2. Increasing the active substance concentration of isoconazole nitrate above 1% produced a noticeable increase in its effect so that 2% and 4% preparations are appropriate for particular uses. 3. 1% isoconazole nitrate (Travogen cream, Gyno-Travogen cream) is more effective than a commercial cream containing 1% clotrimazole. 4. The addition of a corticosteroid (diflucortolone-21-valerate 0.1%, Travocort cream) does not influence the action of isoconazole nitrate.

In order to establish relations appropriate to therapy between pathogenesis and pathoplastics of psychic disturbances, the psychiatrist requires a general medical education overlapping on many marginal fields. Topically and prospectively, psychiatry is faced with, for example, the following tasks: development of new conceptions of genetics, interdisciplinary research of early cerebral damage, of the systemic factor of psychosis and the psychosocial releasing factor, cutting of the dwelling time at a hospital, community-supported treatment and after-care. Availability of specialised establishments for oligophrenia and socially endangered persons. Construction of socially integrated care systems. Institutional and personal equality with other special fields.

Gliflumide is an optically active sulfonylaminopyrimidine. In rats, the drug exhibited a long-lasting hypoglycemic effect following oral as well as intravenous administration. This effect resembled the action of glibenclamide, but was brought about by doses 5-10 times lower. In healthy volunteers, oral administration (0.0125 mg/kg) or intravenous injection (0.01mg/kg) of gliflumide resulted in a 30-40 per cent decrease of blood glucose characterized by slow onset and long duration. The stimulation of insulin secretion was studied after intravenous injection of gliflumide (0.01 mg/kg) and compared to the action of glibenclamide (0.01 mg/kg) and tolbutamide (10 mg/kg). Although the effect of these doses, measured by the area above the initial level, was similar, a different time course of action was found. Gliflumide and glibenclamide, compared with tolbutamide, produced a delayed and prolonged response. These characteristics were more pronounced with gliflumide. Maximal serum insulin levels were found after 3, 23, and 90 minutes for tolbutamide, glibenclamide, and gliflumide, respectively. In maturity-onset diabetics requiring glibenclamide or glibenclamide + biguanide, gliflumide was shown to have about the same efficacy as glibenclamide, the corresponding doses being 1.5-5 (generally 3) times lower.

A circadian rhythm of plasma activity (PRA) was demonstrated for both Japanese and North American women, the latter mostly Caucasians of mixed ethnic origin. The results were based on blood samples withdrawn at 4-hour intervals during a 24-hour span (in March 1978) from 20 subjects from Fukuoka (average age 20.4 +/- 0.1 years) and 16 subjects from Minneapolis (average age 20.2 +/- 0.4 years). The rhythms in the two populations showed similarities in some characteristics and differences in others. The timing of high values, i.e., of acrophases, objectively assessed by curve-fitting (and of corresponding 95 per cent confidence limits) was at 07(36) (05(00), 10(16) and 06(32) (03(00), 10(00) for Japan and USA, respectively. As objective measures of the extent of predictable rhythmic change mean amplitudes, in nanograms per milliliter per hour (ng/ml/hour), were similar (0.31 and 0.32); a statistically significant difference (P less than 0.05) was found in mean amplitudes expressed as percentage of the rhythm-adjusted average. Mean rhythm-adjusted average values (mesors) were lower in women from Japan than in those from the United States: (1.64 +/- 0.14 and 2.39 +/- 0.23 ng/ml/hour, respectively; P less than 0.01). A statistically significant difference in dietary salt, indicated by differences between the Japanese and North American women in the urinary excretion of sodium and chloride (P less than 0.05), almost certainly contributed to these results.

The anticoagulant effect of a new potent heparin was compared with commercial heparin after a single i.v. application in human subjects. Determinations of thrombin time, whole-blood clotting time, activated partial thromboplastin time and plasma heparin levels using factor Xa inactivation assay were performed 5, 10, 15, 30 and 60 min after application. The new potent heparin was 1.5 to 2.0 times more effective than commercial heparin per mg dry weight depending upon the coagulation tests used and the length of observation period. In addition, determinations of biochemical and haematological parameters, 24 h after heparin application indicated no signs of any adverse effect.