[Synthesis of Butyl 6alpha-Fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (Fluocortin Butylester) (author's transl)]. / Synthese von 6alpha-Fluor-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-säure-butylester (Fluocortin-butylester).

Among the metabolites of fluocortolone (1) there was found the alpha-keto acid 4a. This acid, as well as the esters 4b--4k were synthesized and the butyl ester 4c was chosen for local anti-inflammatory therapy.

In vitro studies on enzymatic cleavage of steroid esters in the female organism.

The decreasing water-solubility of steroid esters concomitant with increasing chain lenth of monocarboxylic acids provides a prolonged therapeutic effect of the steroid. Whether a slow release of the steroid from an oily depot in the muscle or a secondary storage of the enter in the body fat ("deep compartment") are responsible for this prolonged action, is open to discussion. The aim of this study was to investigate the steriod ester cleaving enzyme activity of human subcutaneous fatty tissue. The followeing steroid esters were investigated: Testosterone acetate and oenanthate, metenolone acetate and oenanthate, norethisterone acetate and oenanthate, dehydroepiandrosterone acetate and oenanthate, fluocortolone acetate and caproate. In the 10000 X g supernatant phase of the female subcutaneous fatty tissue the rate of enzymatic cleavage of the long-chain oenanthates was considerably greater than that of the corresponding short-chain steroid esters. The nature and position of the ester group in the steroid molecule exhibited a marked effect on the rate of enzymatic cleavage of steroid esters. The cleavage rate of long- and short-chain steroid esters in human myometrium and endometrium resembled that in the fatty tissue. On the other hand, the gastric mucosa, recuts musculature, placenta and vaginal mucosa split the short-chain steroid esters more rapidly than the long-chain esters. The marked differences in the relation of the cleavage rate of long- and short-chain steoid esters in the various tissues allow the assumption that long- and short-chain steroid esters are cleaved by different enzymes.

Metabolism, kinetics and metabolic activity of the beta-cytotropic antidiabetic 4-(5-isobutylpyrimidinyl-2)-sulphamylphenylacetic acid-3-chloro-6-methoxyanilide sodium (glydanile sodium) in man after oral and intravenous administration.

The metabolism and pharmacokinetics of [3H]-labelled 4-(5-isobutylpyrimidinyl-2)-sulphamylphenylacetic acid-3-chloro-6-methoxyanilide sodium ([3H]-glydanile sodium) were investigated in three diabetics and six healthy volunteers after oral and i.v. administration. In the healthy volunteers the level of compound in plasma was correlated to insulin concentration and free fatty acids in plasma or serum, both after oral and i.v. administration of glydanile sodium. After oral administration of 10 mg I13H]-glydanile sodium, maximum [3H] concentration in plasma is found after 2--4 h. The concentration corresponds to 60-90 mug/100 ml when calculated as mug glydanile sodium in plasma. Glydanile is metabolized rapidly. The four metabolites which have been isolated and identified represent more than 95% of total radioactivity in urine. The main metabolite occurring in plasma and urine is the tertiary isobutyl alcohol of glydanile (metabolite I). This metabolite still possesses about 30% of the hypoglycaemic activity of the original compound. The initial half-life of unchanged glydanile after i.v. injection is about 30-40 min. In human plasma more than 99% of the glydanile present is in the protein-bound form. After oral administration, about 20% of radioactivity is eliminated with urine and about 80% with faeces. After i.v. injection, about 70% of radioactivity is eliminated with urine and about 30% with faeces. After oral administration, only about 30% of the compound given was absorbed under these experimental conditions. It may be possible to improve the poor absorption demonstrated in these trials by making the drug available in another, suitable, oral dosage form. Glydanile is eliminated rapidly via urine and faeces after oral and i.v. administration, which means that no accumulation, involving the danger of hypoglycaemic reactions, need be expected. Plasma insulin is increased by a glydanile concentration of 10-20 mug/100 ml plasma.

[Studies on the Pharmacology of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolon valerate) (author's transl)]. / Untersuchungen zur Pharmakologie von 6alpha,9-Difluor-11beta-hydroxy-16-methyl-21-valeryloxy-1,40pregnadien-3,20-dion(Diflucortolonvalerianat)

The topical and systemic anti-inflammatory action of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) was studied in the rat in comparison with fluocortolone, diflucortolone and some other corticoids. In addition the effect of the compounds studied on the following parameters of corticoid activity was examined in the rat: body weight and weights of thymus, spleen and adrenals; blood sugar concentration and liver glycogen content; diuresis and Na+ and K+ elimination with the urine; the binding of diflucortolone and some diflucortolone-21-esters to the cytoplasmic corticoid receptor of the rat's thymus was also determined. In all tests diflucortolone was shown to be a corticoid with very potent topical and systemic action. Diflucortolone valerate showed the same potent anti-inflammatory action on topical application as the unesterified compound. After subcutaneous administration, however, the systemic corticoid action of the valerate was considerably inferior to that of diflucortolone on account of the kinetics of the more lipid soluble ester.

Studies of the kinetics and metabolism of 17 beta-heptanoyl-17 alpha-ethinyl-4-oestren-3-one-7-3H (norethisterone enanthate) in humans following intramuscular injection.

The kinetics and metabolism of 17 beta-heptanoyl-17 alpha-ethinyl-4-oestren-3-one-7-3H (7-3H-norethisterone enanthate, NET-En) after i.m. injection in two female subjects is described. 177.4 mg and 174.5 mg NET-En were injected. Maximum 3H-activity in plasma was reached 8 to 14 days after the injection. In terms of NET-En it amounted to 70-100 mug/100 ml. Maximum NET concentration was reached on the 4th to 8th day and amounted to about 1 mug/100 ml. After 4 weeks NET concentration was still about 0.05 to 0.1 mug/100 ml and even after 6 weeks NET was still detectable in plasma. In 14 days the two subjects excreted about 13% of the administered dose in the urine and about 15% and 21%, respectively, in the faeces. On the basis of a rough calculation, the subjects eliminated about 60% and 55% of the radioactivity with urine and faeces within 42 days.

Studies of biosynthesis of insulin by isolated perfused rat pancreas.

Incorporation studies with 3H-leucine have demonstrated that proinsulin is formed as a precursor of insulin in the perfused pancreas. A dependency of the insulin synthesis on the glucose concentration was revealed, based on a direct stimulation of the proinsulin synthesis. The conversion of proinsulin into insulin was not accelerated by glucose stimulation. The conversion also occurred in the absence of glucose.

Gliflumide, a new oral antidiabetic of high potency and efficacy.

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.