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E Schillinger

Publications and source records attributed to E Schillinger.

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

Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat.

A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro- 6a- carbaprostaglandin-I2 (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-mimetics with a potency equal or even superior to PGI2. The 3-oxa-analogue was found to be stabilized against beta-oxidation, a main metabolic degradation step also for chemically stable PGI2-analogues. The compound is orally available and displays a long duration of 4.5-48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC50 of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED20 being 0.1-0.2 micrograms/kg after injection and less than or equal to 0.05 micrograms/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC50 of 0.037 micrograms/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5-12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects. The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI2) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI2 and Iloprost have already been shown to be therapeutically useful principles.

Administration, Oral↗
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

Effects of high and low preovulatory concentrations of progesterone on ovulation from the isolated perfused rabbit ovary.

Rabbit ovaries were isolated surgically before the ovulatory gonadotrophin stimulation and perfused in vitro. Untreated, control ovaries never ovulated. Ovaries treated in vitro with ovine LH ovulated 10-14 h later and the oocytes had undergone germinal vesicle breakdown (GVB). LH induced increases in progesterone secretion from the treated ovaries. A 3 beta-hydroxysteroid dehydrogenase blocker ('Compound A') effectively reduced progesterone secretion into the perfusate and follicular fluid to very low levels but had no effect on ovulation rate or on oocyte maturation. Excessively high progesterone levels were obtained artificially in perfusates by addition of exogenous steroid; the number of ovaries ovulating was markedly reduced but there was no effect on oocyte maturation. It is concluded that the rise in progesterone that normally occurs immediately after the LH surge is not a prerequisite for ovulation in the rabbit. However, progesterone may have a modifying effect on LH-induced follicle rupture when at a pharmacologically high level.

3-Hydroxysteroid Dehydrogenases↗
PubMed1984

In vitro effects of PGF2 alpha and a metabolically stable derivative on 20 alpha-hydroxysteroid-dehydrogenase activity in corpora lutea isolated from pseudopregnant rat ovaries.

Single intact corpora lutea were isolated from pseudopregnant rat ovaries stimulated with PMSG and HCG. The activity of 20 alpha-hydroxysteroid-dehydrogenase (20 alpha-OH-SDH) was measured at various stages of pseudopregnancy. The influence of PGF2 alpha or a metabolically stable PGF2 alpha-derivative on this enzyme in vitro was assessed. 20 alpha-OH-SDH activity was low from day 6 to 8, started to rise on day 10 and reached a maximum on day 14 after administration of HCG. The enzyme could be stimulated by the PGF2 alpha-derivative on day 10 and 11 but not on day 6, 8, when basal enzyme activity was still very low or on 12 and 14 of pseudopregnancy when the enzyme had already reached maximal levels. PGF2 alpha or its derivative had no effect on enzyme activity in a cytosolic fraction indicating that particulate cell constituents were required for this process. PGE2 as well as cycloheximide (an inhibitor of protein biosynthesis) were without influence on enzyme stimulation. dB-cAMP but not dB-cGMP decreased enzyme activity. Ca2+ -ions were required for the stimulation of 20 alpha-OH-SDH activity. It is concluded that PGF2 alpha or its stable derivative may modulate ovarian steroid metabolism by acute stimulation of luteal 20 alpha-OH-SDH.

20-Hydroxysteroid Dehydrogenases↗
PubMed1984

Binding of prostaglandin F2 alpha and 20 alpha-hydroxysteroid-dehydrogenase activity of immature rat ovaries throughout pseudopregnancy.

PGF2 alpha is involved in the initiation of progesterone decline in the late luteal phase in the pseudopregnant rat. 20 alpha-Hydroxysteroid- dehydrogenase (20 alpha-OH-SDH), an important enzyme in progesterone metabolism, may participate in luteal regression. It was therefore of interest to investigate whether prostaglandin F2 alpha (PGF2 alpha) receptor binding in membrane particles and 20 alpha-OH-SDH activity in a cytosolic fraction in superovulated ovaries of immature rats are related. Scatchard analysis of the radioligand binding data revealed two classes of PGF2 alpha receptors (KD 10(-10) mol/l and 10(-8) mol/l). The number of binding sites varied from day 1 through day 21 of pseudopregnancy. Maximal binding/mg protein was obtained on day 7 with a gradual decrease until day 21 after HCG administration. 20 alpha-OH-SDH activity was low in 1 to 9 days old corpora lutea and increased markedly during days 11 to 13. Maximal enzyme activity was monitored on days 15 to 21 after administration of HCG. The time dependent increase in 20 alpha-OH-SDH activity was partially suppressed by the treatment of the rats with indomethacin, a potent inhibitor of prostaglandin biosynthesis. Since PGF2 alpha-receptor content does not coincide with the increase in enzyme activity (maximal receptor content preceded maximal enzyme activity by about 6 days), PGF2 alpha may not be the only direct factor responsible for the induction of ovarian 20 alpha-OH-SDH, to terminate luteal function.

20-Hydroxysteroid Dehydrogenases↗
PubMed1983

Pharmacological and cardiovascular properties of a hydantoin derivative, BW 245 C, with high affinity and selectivity for PGD2 receptors.

Initial experiments demonstrated that the hydantoin prostaglandin derivative, BW 245 C, has potent anti-aggregatory activity on human platelets which may result from its structural similarity with one of the natural prostaglandins. The aim of the present study was to extend this preliminary pharmacological characterization and to determine which, if any, prostaglandin receptor-type is responsible for mediating the biological activity of BW 245 C. A marked species variation was observed in the anti-aggregatory potency of BW 245 C such that in the human (0.36 X PGE1) it was about one hundred times more effective than in the rat (0.003 X PGE1). The relative potencies of PGI2 (ca. 10 X PGE1) and PGE1 were, however, similar in both species. An intravenous bolus injection of 250 micrograms/kg BW 245 C lowered systolic (-23%) and diastolic (-34%) blood pressure in spontaneously hypertensive rats. In radioligand binding studies it showed a high affinity and selectivity for PGD2 platelet receptors, binding to PGI2 or PGE2 receptors was not detectable. Therefore it is concluded that the platelet and cardiovascular actions of BW 245 C are mediated by PGD2 receptors and this accounts for the observed species variation which is a characteristic of this prostaglandin.

Animals↗
PubMed1983

Pharmacokinetics and biotransformation of methane sulphonanilides with anti-inflammatory activity in the rat and monkey--comparison with piroxicam.

The biotransformation of N-(6-phenoxyindan-5-yl)methansulphonamide (PMS) and of its 2',4'-difluoro derivative (DF-PMS) were studied in vitro using rat-liver homogenate followed by h.p.l.c. separation and mass-spectrometric identification of metabolites. Both sulphonamides were rapidly oxidized at positions 1 and 3. The pharmacokinetics of DF-PMS and of piroxicam were examined in the rat and monkey (Macaca fascicularis). Considerable concentrations were achieved in the plasma only by the 1-oxo metabolite of DF-PMS but not by the unchanged drug, indicating that the administered compound was a pro-drug of the active principle. 1-Oxo DF-PMS exhibited shorter half-lives, larger volumes of distribution and higher total clearance rates than piroxicam in the animal model studied.

Animals↗
PubMed1982

Non-steroidal anti-inflammatories--XII. Mode of action of anti-inflammatory methane sulfonanilides.

The influence of anti-inflammatory methane sulfonanilides on the arachidonic acid metabolism in ram seminal vesicle homogenate depends on the pK3 of the individual substance: more acidic compounds suppress, less acidic compounds stimulate PG synthesis and enhance the PGH2/PGG2 ratio. As oxygen radicals are liberated during the conversion of PGG2 to PGH2 it is suggested that the less acidic methane sulfonanilides are scavengers of the (pro-inflammatory) oxygen radicals.

Animals↗
PubMed1979

Receptor binding in various tissues of PGE2, PGF2 alpha and sulprostone, a novel PGE2-derivative.

Sulprostone is a tissue-specific PGE2-derivative with high abortifacient activity in various species including man. The dissociation constant KD of the receptor binding of this compound was compared with PGE2 and PGF2 alpha in various tissue preparations of different species. A structure-binding relationship was developed from competition curves after a logit/log transformation. It is demonstrated that the relative affinities of Sulprostone, PGE2 and PGF2 alpha remain essentially constant in all the tissues investigated. It is concluded that the tissue-specificity of Sulprostone cannot be ascribed to structural differences of the receptor molecule.

Animals↗
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↗
PubMed1977

Changes in insulin receptor concentration in rat fat cells following treatment with the gestagens clomegestone acetate and cyproterone acetate.

Specific insulin receptors were measured in isolated fat cells of rats after treatment with clomegestone acetate. Under conditions when peripheral insulin insensitivity was observed, the number of insulin receptors was simultaneously reduced. A similar though smaller decrease in insulin receptor concentration was seen in rats after treatment with cyproterone acetate, a compound which did not cause insulin resistance. It is concluded that the gestagenic compounds tested decrease insulin receptor concentration. Only drastic reduction of the number of binding sites results in significant perturbations of carbohydrate metabolism.

Adipose Tissue↗
PubMed1976

Hormone receptors.

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Adrenal Cortex↗
PubMed1976

[Comparative studies on oral glucose tolerance and serum lipids under the influence of a new oral contraceptive (SH B 209 AB: 2 mg cyproterone acetate + 0.05 mg ethinyl estradiol), the combination D-norgestrel/ethinyl estradiol and in a control group (author's transl)].

24 healthy women given the combination of cyproterone acetate (2 mg) + ethynyl estradiol (0.05 mg) [SH B 209 AB] and D-norgestrel (0.25 mg) + ethinyl estradiol (0.05 mg) [Neogynon] were compared with a control group in oral glucose tolerance tests. The volunteers were divided into three groups. Two received alternately both preparations with each treatment cycle preceded by one cycle without medication. The third group served as an independent control. On the 25th day of each cycle blood was withdrawn before and 15, 30, 45, 60, 90 and 120 min after the carbohydrate load. Blood glucose and insulin and free fatty acids in serum were determined. Fasting values of triglycerides and cholesterol in serum were determined. The following results were obtained: 1. The mean fasting levels of blood glucose, serum insulin and free fatty acids were unchanged. 2. The total area under the blood glucose curve over the initial value was not altered 2 h after treatment with SH B 209 AB or Neogynon. The total area under the insulin and free fatty acids curves were also unchanged after the oral glucose load. 3. There was no change in serum cholesterol. 4. Serum triglycerides were significantly increased after SH B 209 AB. 5. The implications of the structural differences between both gestagens are discussed.

Blood Glucose↗