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Biomedical subjects

A P Roszkowski

Publications and source records attributed to A P Roszkowski.

At least 19 recordsLinked to original sources
PubMed1987

Synthesis and gastric antisecretory properties of allenic 16-phenoxy-omega-tetranor prostaglandin E analogs.

In order to improve the modest oral activity of PGE2 as an inhibitor of gastric acid secretion, analogs were prepared and tested orally in histamine-challenged rats. Insertion of a double bond at C-4, resulting in the 4,5-allene analog of PGE1, gave a small increase in activity. Introduction of the omega-tetranor-16-phenoxy lower sidechain, a modification known to enhance activity in the PGF series, gave an eight-fold increase in activity. The analog having both modifications (enprostil, 2) showed a six hundred-fold increase in oral antisecretory activity over PGE2, which may reflect a potentiation effect. Modification of enprostil at C-1 (various esters) and at C-11 (11-methyl, 11-deoxy) generally resulted in compounds of high activity while modifications at other sites generally resulted in significant reductions in activity.

Animals↗
PubMed1986

Gastric antisecretory and antiulcer properties of enprostil, (+/-)-11 alpha, 15 alpha-dihydroxy-16-phenoxy-17,18,19,20-tetranor-9-oxoprosta- 4,5,13(t)-trienoic acid methyl ester.

Prostaglandins of the E series have been shown, both in animals and humans to produce gastrointestinal antisecretory and antiulcer effects. Enprostil, a modified allenic prostaglandin E was found to be a highly potent inhibitor of gastric HCl secretion in a variety of species. In rats, in which both the pylorus and esophagus were ligated, p.o. ED50 values and 95% CL for inhibiting acid secretion evoked by histamine, pentagastrin and carbachol were 9.9 (6.7-15), 40 (11-145) and 0.83 (0.78-0.89) micrograms/kg, respectively. In inhibiting histamine-evoked acid secretion, enprostil was more potent when administered p.o. than when injected into the duodenum or s.c. When enprostil was injected directly into the pouch of Heidenhein dogs, intense antisecretory activity occurred, ED50 = 0.9 (0.7-1.1) micrograms/kg, whereas, when given p.o. to the main stomach the ED50 was 6.6 (3.2-13.6) micrograms/kg. Administration of cimetidine either p.o. or to the pouch resulted in virtually identical ED50 values, viz., 2.9 and 3.1 mg/kg. Enprostil also inhibited dimaprit- and pentagastrin-induced acid secretion in cats with permanent gastric fistulae. The oral ED50 values for inhibiting acid secretion evoked by these two secretagogues were 2.5 (1.4-4.3) and 0.8 (0.5-1.5) micrograms/kg, respectively. Enprostil was extremely potent in preventing indomethacin plus "cold stress" ulcers in rats. When given orally the ED50 was 0.61 (0.31-1.22) and s.c. it was 22 (9.0-52) micrograms/kg. It was also highly potent in preventing cysteamine-induced duodenal ulcers when given p.o., ED50 = 20 (17-23) micrograms/kg. Thus, enprostil is a highly potent antisecretory and antiulcer agent. It appears to act topically; directly at gastric mucosal sites.

Animals↗
PubMed1983

Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones.

A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.

Animals↗
PubMed1982

A model for evaluation of postural hypotension induced by drugs in conscious restrained normotensive rats.

A rat model was developed for use in evaluating postural hypotensive activity of a compound. Conscious normotensive rats were restrained on a tilt board with special restrainers to avoid blocking limb circulation. Dose response curves were explored to delineate the potential postural hypotensive activity of a compound. In response to a 2-min 90 degree head-up tilt, only a negligible changes in blood pressure was observed in the control state. The conscious rat was therefore able instantaneously to compensate for postural change. This ability, however, was blocked by guanethidine. The compound induced a dose-related hypotension and a further, dose-dependent drop in blood pressure on tilt. Hydralazine, on the other hand, induced only dose-dependent hypotension, but no change in blood pressure response from control tilts. Since these findings appear to be in accord with human clinical data, this rat model may be suitable for use in evaluating potential postural hypotensive activity of compounds.

Anesthetics↗
PubMed1980

Inhibition of histamine-induced gastric secretion by flavone-6-carboxylic acids.

Twenty-five flavone-6-carboxylic acids were synthesized and tested as to their ability to inhibit histamine-induced gastric acid secretion in the rat. 3-Isopropoxy-4'-methoxyflavone-6-carboxylic acid (41) showed consistent oral activity while being devoid of any other noteworthy pharmacological effects. In vitro, this compound was found to be inactive as a histamine H2 antagonist, and its mode of action remains unknown.

Animals↗
PubMed1980

Drug effects on plasma renin activity in the mouse.

To investigate the possible effects of newly synthesized beta-adrenergic blockers on plasma renin activity, an assay was developed using unanesthetized mice and radioimmunoassay. Renin activity was significantly increased by the administration of hydralazine (1 mg/kg, i.p.), furosemide (20 mg/kg, i.v.), and isoproterenol (0.1 mg/kg, s.c.). Unlike isoproterenol, norepinephrine (1 mg/kg, s.c.) and epinephrine (1 mg/kg, s.c.) were active but considerably less effective stimulants. The increase caused by isoproterenol was blocked by clonidine, pindolol, bunolol, atenolol, and l-propranolol, but not d-propranolol. The beta-blockers with intrinsic sympathomimetic activity such as pindolol were found to increase renin activity when given alone, but blocked an increase in renin activity when given prior to isoproterenol. In general, nonselective beta-blocking drugs possessing both beta 1- and beta 2-(vascular) blocking activity were found to be most effective in blocking plasma renin activity on oral administration.

Adrenergic beta-Antagonists↗
PubMed1979

Dibenzotropone- and dibenzosuberonecarboxylic acids with bronchodilator activity.

The syntheses of 44 5H-dibenzo[a,d]cyclohepten-5-one derivatives bearing a carboxyl gropu at the 1, 2, 3, or 10 position and various substituents at the 7, 8, or 9 position are described. Some of the compounds showed significant bronchodilator activity in guinea pigs and protected the animals against a histamine challenge administered either by aerosol or intravenously. The most active compounds were 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one-2-carboxylic acids bearing a methyl or halogen substituent at the 9 position. These compounds were approximately as active as aminophylline by intraperitoneal administration.

Airway Resistance↗
PubMed1978

Synthesis and antiinflammatory activity of 6,11-dihydro-11-oxodibenzo[b,e]thiepinalkanoic acids and related compounds.

Acetic acid derivatives of tricyclic systems, such as 6,11-dihydro-11-oxodibenzo[b,e]thiepin, 4,10-dihydro-4-oxo-thieno[2,3-c][1]benzothiepin, dibenzo[b,f]thiepin, dibenz[b,f]oxepin, etc., were synthesized and assayed for antiinflammatory activity. One of the compounds, 6,11-dihydro-11-oxodibenzo[b,e]thiepin-3-acetic acid (52), was chosen for evaluation in man on the basis of high antiinflammatory activity in both short- and long-term animal assays and a low gastric irritation liability in rats and dogs.

Acetates↗
PubMed1975

A central nervous system depressant-antidepressant.

A new tricyclic agent with an allenyl side chain experimentally shows antidepressant activity similar to amitriptyline and imipramine but also exerts marked CNS depression. Such dual activity should be of clinical interest for treatment of mixed anxiety and depression.

Alkadienes↗