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Biomedical subjects

W Losert

Publications and source records attributed to W Losert.

At least 37 records · Page 2Linked to original sources
PubMed1986

Mespirenone and other 15,16-methylene-17-spirolactones, a new type of steroidal aldosterone antagonists.

The ability of a series of 15,16-methylene-spirolactones in comparison to known antimineralocorticoids to inhibit the renal actions of aldosterone was tested in adrenalectomized, glucocorticoid-treated rats. The standard procedure involved continuous i.v. infusion with an isotonic solution of low sodium content (0.05% NaCl + 5.2% glucose, 3 ml/rat/h) supplemented with d-aldosterone [1 micrograms/(kg X h)] resulting in a long-lasting reduction of renal sodium excretion, increase of renal potassium excretion and hence decrease of the urinary Na/K-ratio. In some experiments sodium input was increased (0.2% NaCl + 4.3% glucose or 0.9% NaCl, respectively). The test drugs either were administered orally 1 h before start of the infusion or were added to the infused solution. With the exception of two steroids which could only be tested at single doses, all compounds were administered at three doses ranging from 2.2 to 40 mg/kg (p.o.) or from 0.83 to 6.7 mg/kg/h (i.v.). Spironolactone or spirorenone (oral administration) and potassium canrenoate (i.v. infusion) served as reference compounds. The antimineralocorticoid activity of the steroids was judged by the increase in the aldosterone-lowered Na/K-ratio in urine which was collected at hourly intervals for 15 or 21 h, respectively. Adrenalectomized, glucocorticoid-treated rats receiving an i.v. infusion without aldosterone were used as controls. To obtain preliminary information on potential antiandrogenic and progestogenic (side-)effects, binding of the test-compounds to androgen receptors (rat prostate cytosol) and progestogen receptors (rabbit uterus cytosol) was measured in vitro using 3H-dihydrotestosterone (DHT) and 3H-progesterone (prog.) as tracer and unlabelled DHT and prog. as references. All steroids tested exhibited antimineralocorticoid activity. For compounds tested at three doses levels the potency relative to the standard used was evaluated using regression analysis based on the Na/K-ratio or the log (Na X 100)/K-ratio. The relative potency of the other compounds was estimated by comparing the biological effect of single doses of test drug and standard drug, respectively, using nonparametric statistical tests.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Progestogens with antimineralocorticoid activity.

The ability of 11 steroids with varying degrees of progestogenic potency to inhibit the renal actions of aldosterone was tested in adrenalectomized, glucocorticoid-treated rats. The rats were continuously infused with an isotonic solution of low sodium content (0.05% NaCl + 5.2% glucose, 3 ml/rat/h) supplemented with d-aldosterone [1 microgram/(kg X h)] resulting in a long-lasting reduction in renal sodium excretion, increase in renal potassium excretion and hence decrease in the urinary Na/K-ratio. The test drugs were administered either subcutaneously or orally 1 h before start of infusion. Their antimineralocorticoid activity was judged by the increase in the aldosterone-lowered Na/K-ratio in urine which was collected at hourly intervals for 15 or 21 h, respectively. Adrenalectomized, glucocorticoid-treated rats receiving an i.v. infusion without aldosterone were used for assessing possible mineralocorticoid effects of the steroids tested. D-Norgestrel, norethisterone acetate, 3-keto-desogestrel (the active metabolite of desogestrel) and cyproterone acetate, respectively, did neither show antimineralocorticoid nor mineralocorticoid activity when injected subcutaneously at a dose of 53.3 mg/kg. In contrast, gestodene (26.7 or 53.3 mg/kg s.c., respectively), progesterone (53.3 mg/kg s.c.), spironolactone (26.7 mg/kg s.c.), spirorenone (13.3 mg/kg s.c.), 1,2-dihydro-spirorenone (13.3 mg/kg s.c.), or 1,2 alpha-methylene-spirorenone (13.3 mg/kg s.c.) exhibited significant anti-mineralocorticoid activity. Canrenone (53.3 mg/kg s.c.) slightly increased the urinary Na/K-ratio. This effect, however, was not significant. Gestodene, like spironolactone or progesterone, was devoid of aldosterone-like mineralocorticoid activity. With the exception of progesterone, the antimineralocorticoid activity of the steroids tested could also be demonstrated after oral administration. Based on the Na/K-ratio or the log (Na X 100)/K-ratio, the potency of each test compound relative to spironolactone was evaluated using regression analysis. The following results (average relative potency, spironolactone = 1.0) were obtained: gestodene: approximately 0.2; canrenone: approximately 0.3-0.35; spirorenone: approximately 7-8; 1,2-dihydro-spirorenone: approximately 8; 1,2 alpha-methylene-spirorenone: approximately 3.5. Progesterone which was evaluated after s.c. injection exhibited an average relative potency of approximately 0.35. Due to these results, gestodene may be regarded as the first progestogen of the nortestosterone series exhibiting a more natural, progesterone-like profile of activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenalectomy↗
PubMed1984

The renal action of spirorenone and other 6 beta,7 beta; 15 beta,16 beta-dimethylene-17-spirolactones, a new type of steroidal aldosterone antagonists.

The aldosterone antagonistic activity in vivo and the affinity for mineralocorticoid receptors (MCR) in vitro of 3-(17 beta-hydroxy-6 beta,7 beta; 15 beta,16 beta-dimethylene-3-oxo-1, 4-androstadiene-17 alpha-yl) propionic acid gamma-lactone (spirorenone), a new aldosterone antagonist, and four of its derivatives were studied in comparison with spironolactone in rats. Spirorenone was 8.6 times as potent as spironolactone, but showed a lower affinity for the MCR than the standard. The C1/C2 saturated derivative (compound I) had 7.6 times the antialdosterone potency and 2 times the binding activity of spironolactone. The 17-spiroether derivative of spirorenone (compound II) showed a lower aldosterone antagonistic activity (1.7 the potency of spironolactone) as well as a lower affinity for the MCR (0.5 the affinity of spironolactone). The analogue with a 17 beta-hydroxyl group and a 17 alpha-hydroxypropyl side chain (compound III) possessed a very low binding capacity for MCR (1/10 of that of spironolactone) but still a 1.3 times higher antialdosterone activity than spironolactone. This result is probably due to a transformation of compound III to an active metabolite in vivo. Finally, the derivative with a reversed configuration of the 17-spirolactone ring (compound IV) had no biological activity in vivo and no affinity for the MCR. These results show that spirorenone or one of its active derivatives might lead to a new series of potent aldosterone antagonists.

Adrenalectomy↗
PubMed1983

Comparison of the vasodepressor action of ZK 36 374, a stable prostacyclin derivative, PGI2 and PGE1 with their effect on platelet aggregation and bleeding time in rats.

ZK 36 374, a new, chemically stable prostacyclin derivative, was compared with PGE1 and PGI2 with respect to its action on platelet aggregation in vitro, on bleeding time and on arterial blood pressure in conscious rats. The time of occlusion of a hole in a polyethylene (PE) tube of an AV-shunt between the left carotid artery and the right jugular vein by a microthrombus was considered as an index of bleeding time. All three substances inhibited the ADP-induced aggregation of human and rat platelets. In human PRP, ZK 36 374 was 17 times more active than PGE1 and 2 - 5 times as potent as PGI2. In contrast, in rat PRP, PGI2 was 9.2 and 3.4 times as potent as PGE1 and ZK 36 374, respectively. Similar differences in potency were found in the in vivo experiments where these substances given by an intravenous infusion to conscious rats prolonged bleeding time and depressed mean arterial pressure in a dose-dependent manner. ZK 36 374 was also orally active. At oral doses of 1, 2 and 3 mg/kg this new compound caused a dose-dependent prolongation of bleeding time and a fall in arterial blood pressure. In conclusion, the results show that ZK 36 374 is an intravenously and orally active prostacyclin derivative which may be of therapeutic value for occlusive peripheral vascular diseases.

Alprostadil↗
PubMed1982

Detection and comparative evaluation of aldosterone antagonists in glucocorticoid-treated, adrenalectomized rats.

An improved method for the evaluation of aldosterone antagonists in adrenalectomized, glucocorticoid-treated rats is described. The method involved assessing the pharmacological effects of spironolactone and potassium canrenoate and comparing them with the action of prorenone and potassium prorenoate, respectively. Adrenalectomized rats were pretreated with fluocortolone caproate (10 mg/kg s.c.), a long-acting glucocorticoid, immediately after surgery. Fluocortolone (1.25 mg/kg s.c.), a short acting preparation, was administered 4 days after this treatment. On the 5th day after adrenalectomy, the actual diuresis experiment was performed. The rats received a continuous i.v. infusion of aldosterone [1 microgram/(kg x h)] for 10, 15 or 20 h. Spirnolactone or prorenone (6.7, 13.4 or 26.8 mg/kg of each steroid) were administered in single oral doses 1 h before or 4 h after the start of the i.v. infusion. Potassium canrenoate and potassium prorenoate (1.9, 3.8, or 6.7 mg/(kg x h) of each compound) were infused intravenously over 10 or 15 h. Urine was collected in 1 h fractions and the anti-aldosterone activity was assessed by the ability of the compounds to reverse the aldosterone effect on the Na/K ratio. The anti-aldosterone activity of the steroids studies was clearly detectable with the method described. Prorenone was as potent as spironolactone and potassium prorenoate was on the average 3.9 times as potent as potassium canrenoate. The method appears suitable for the characterization of the time course and duration of anti-aldosterone activity and for the calculation of relative potencies in comparison to standard compounds.

Adrenalectomy↗
PubMed1979

Blood glucose lowering sulfonamides with asymmetric carbon atoms. 3. Related N-substituted carbamoylbenzoic acids.

Both enantiomers of 4-N-[1-(5-Fluoro-2-methoxyphenyl)ethyl]carbamoylmethylbenzoic acid display hypoglycemic activity. The more potent (S) enantiomer is approximately equipotent with the acylaminoethylbenzoic acids of the type HB 699 (Figure 1; Table I). Observations are given that suggest that these benzoic acids act at the same receptor as the hypoglycemic sulfonylureas and sulfonylaminopyrimidines and further that this receptor includes important binding sites.

Animals↗
PubMed1977

Improved method for comparative evaluation of aldosterone antagonists in healthy man.

A method of assessing the qualitative and quantitative activity of competitive aldosterone antagonists in healthy man is described. It requires intravenous infusion of aldosterone (0.5 mg/6 h), iv and oral water loading for six hours and fractionated collection of urine over eight hours. Aldosterone antagonists were administered orally 1.5 h before the start of the infusion (spironolactone 50, 200 or 800 mg) or added to the infused solution (potassium cnarenoate 300, 600 or 1000-1200 mg). The effect was assessed by changes in urinary sodium and potassium excretion and in urinary Na+/K+ ratio. The plasma levels and urinary excretion of canrenone, canrenoate and canrenoate ester glucuronide, respectively, were determined after administration of spironolactone and potassium canrenoate. Between 4-8 h (spironolactone) or 2-8 h (potassium canrenoate) after commencement of the infusion there was linear dose-dependent reversal of the mineralocorticoid-induced sodium retention and/or decrease in the Na+/K+ ratio. The plasma levels and urinary excretion of the metabolites measured were also dose-dependent. The method appears suitable for comparison of the potency of aldosterone antagonists and for defining the time course of drug action within the observation period employed.

Adult↗
PubMed1977

A tissue-selective prostaglandin E2 analog with potent antifertility effects.

N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 is a prostaglandin analog which is markedly more tissue selective than PGE2. This compound is 10-30 times more potent than PGE2 in animal models which are considered relevant to antifertility effects in humans. In pharmacological tests which are believed to be predictive for side effects in humans, the compound has potency either equal to or less than that of PGE2.

Abortifacient Agents↗
PubMed1976

[Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation (author's transl)].

The time course of 1-butylbiguanide concentration in plasma and the urinary and fecal elimination of the substance were measured in six female elimination of the substance were measured in six female diabetic patients after oral administration of 100 mg of 14C-1-butylibiguanide hydrochloride as Sindiatil. The mean maximum plasma concentration was 37 mug/100 ml and was reached after about 2 1/2 h. At least semi-maximum plasma concentrations (greater than or equal 18 mug/100 ml) were maintained between the 1st and 8th h after administration. Within 24 h 64% of the administered dose were eliminated (36% via the kidneys, 28% with the faeces). After 3 days a total of 80% had been eliminated, one-half each in urine and faeces, respectively. The average time taken for 50% of maximum renal elimination, and thus of the absorbed quantity, to be excreted was 7.2 h.

Aged↗
PubMed1975

Application of regression analysis to the hypoglycemic activities of a series of substituted benzenesulfonamidopyrimidines.

Quantitative structure-activity relationship studies have been performed on two types of sulfonamides with hypoglycemic activity. In the case of the 2-benzenesulfonamidopyrimidines, substituted in the 5 position of the pyrimidine ring a correlation between hydrophobic forces, expressed as Rm values, and the binding to serum albumin as well as to the heights of the equipotent dose has been found. In the series of 2-benzenesulfonamidopyrimidines additionally substituted in the 4 position of the benzene ring, however, a correlation between electronic parameters, expressed as the chemical shift of the anilide NH-(type IIA) and benzylamide NH-(type IIb) protons and the biological response was observed. This correlation indicated a charge-controlled second fixation of these molecules to the receptor. This is supported by the observation of stereospecificity of the blood-glucose lowering effect and also by the importance of a constant distance between the nitrogen in the side chain and the nitrogen atom in the sulfonamido group. The correlation between the logarithm of the biological response and the electric effects of the substituents is linear as long as one homologous series is considered. If the anilide and benzylamide derivatives are combined, a linear correlation can only be obtained if a dummy parameter is included which may account for differences in conformation within these two series of compounds.

Animals↗
PubMed1975

[Influence of indole-3-alkanecarboxylic acids on glucose utilization in rats].

The influence of various indole-3-alkane-carboxylic acids (indole-3-propionic acid, indole-3-butyric acid and derivatives of this substance) on some parameters of carbohydrate, fat and insulin metabolism were studied in normal and experimentally induced diabetic rats. Earlier it had been shown, by Schillinger and Loge (1973) using rat liver slices for in vitro studies and adrenalectomized rates for in vivo experiments that indole-3-butyric acid and its analogues investigated suppress gluconeogenesis from pyruvate and that these substances have a hypoglycaemic effect when administered orally at doses of 50-250 mg/kg. Indole-3-propionic acid, indole-3-butyric acid, 1-methyl-indole-3-butyric acid, 2-methyl-indole-3-butyric acid and 1-carboxy-6-fluor-1,2,3,4-tetrahydrocarbazol, administered orally at doses up to 1000 mg/kg, had either only a slight or no hypoglycaemic effect at all in intact and streptozotocin-diabetic rats. The suppression of gluconeogenesis observed in vitro thus only has an appreciable effect on blood glucose in vivo when the capacity of the liver to synthetize glucose is reduced. In normal rats indole-3-propionic acid and indole-3-butyric acid led to a deterioration of glucose tolerance following i.v. glucose loading and to a reduction of 14C-U-glucose oxidation. An increase in the concentration of serum free fatty acids (FFA) measured after treatment with indole-3-butyric acid and its 1- and 2-methylated derivatives was not--in accordance with a theory of an interference of the glucose and fatty acid utilization published in literature--considered to be the primary cause since the reduced formation of 14CO2 from radioactive glucose is not normalized when the increased FFA content is reduced by an inhibitor of lipolysis (5-methyl-isoxazol-3-carboxylic acid)...

Animals↗
PubMed1975

[Biology of prostaglandins with reference to therapeutic aspects].

Prostaglandins are highly potent derivatives of unsaturated fatty acids with multiple biological activities. They are synthesized and metabolized in almost all tissues studied so far. The E- und F-type prostaglandins may be regarded as local modulators of hormonal effects on cell function and--in some cases (kidney, uterus-corpus luteum)--as regional or tissue hormones. Thus they seem to be involved in the regulation of neurotransmission, kidney function, triglyceride metabolism in adipose tissue and progesterone biosynthesis. Apart from their influence on renal blood flow prostaglandins of the A-type possibly have an additional function as circulatory hormones regulating blood pressure. Second messenger-systems (cAMP, Ca++-cGMP) which mediate the effects of most non-steroidal hormones are also involved in the action of prostaglandins, at least of the E-and F-types. Disturbances in prostaglandin metabolism (increased or decreased biosynthesis) are discussed to play a role in the pathogenesis of inflammation, pain, fever, hypertension, bronchial asthma and gastric or duodenal ulcer formation. Drugs with antiinflammatory, analgesic and antipyretic activity have been shown to be potent inhibitors of prostaglandin formation. The correlation of a local prostaglandin deficit or the therapeutic use of single effects of prostaglandins by administration of exogenous compounds (natural prostaglandins or modified derivatives) has so long been less satisfactory because of their large number of biological actions which lead to undesired side effects. Extensive experience have been obtained in the successful induction of therapeutic abortion. This effect is based on the stimulatory action of E- and F-type prostaglandins on the smooth muscles of the pregnant uterus which is resistent to the influence of other stimuli, e. g. oxytocin. Here the incidence of side effects could be reduced by local administration of low doses of prostaglandins into the uterine cavity. A general improvement of the therapeutic usefulness of prostaglandins will however only be achieved, if modified derivatives with more specific actions on the desired "target" tissues are available.

Animals↗