Biomedical subjects
Publications and source records attributed to J Krupińska.
In the search for pharmacologically active derivatives of xanthone there were obtained amino alcohol derivatives of 2 methylxanthone (I-V). Effects of compounds Ia, IIa, III and IVa on the circulatory system were investigated.
5,5-Diphenylhydantoin derivatives containing amide groups at the position 3 were synthesized as potential antiarrhythmic agents. The most valuable was (X) whose antiarrhythmic activity is stronger than that of phenytoin.
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Sixteen N-substituted urethanes were investigated as potential antiinflammatory agents. Most of them showed no stronger activity than phenylbutazone. The most active in the xylene hyperemia test were N,N'-dicarbethoxy-N,N'-dicyclohexyl-1,3-diaminopropane (XVI) and cyclohexyl piperidine-1-carboxylate (XIII). None of the studied compounds showed analgesic activity.
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Some new compounds containing cyclohexyl substituents, with a structure similar or analogous to that of traditional antiinflammatory drugs, were synthesized and their antiinflammatory activity was investigated. The strongest activity was shown by alpha-(p-cyclohexylphenyl)-gamma-valerolactone W 8.
Several new aminomethyl derivatives of barbituric acid were evaluated pharmacologically. 1-Cyclohexyl-5-piperidylmethyl-5-allylbarbituric acid and 1-cyclohexyl-3-morpholinomethyl-5,5-diallylbarbituric acid displayed antinflammatory activity in the carrageenin-edema and xylene-tests but did not produce analgesia. It has been also found that introduction of aminomethyl groups into the antiinflammatory barbituric derivatives brings about elevation of the resorption of the tested compounds.
Simulataneous oral administration of butylhydroxytoluene (BHT) (50 or 100 mg/kg) with indomethacin (IND) (3, 6 or 20 mg/kg) prevented the damaging effect of IND on the rat gastric mucosa. Butylhydroxyanisole (BHA) and nordihydroguiaretic acid (NDGA) rather potentiated than prevented the noxious action of IND. A reduction of IND toxicity without affecting its anti-inflammatory action seems to be possible to achieve by concomitant administration of IND with BHT.
Three new inhibitors of prostaglandin (PG) synthetase: N-(2-carboxy-4-chlorophenyl)-phenoxyacetamide (ZR 29), N-(2-carobxy-4-chlorophenyl/-bromophenoxyacetamide (ZR-32), N-(2-carboxy-4-chlorophenyl)-4' - nitrophenoxyacetamide (ZR-35), in doses of 30-100-200 mg/kg p.o. inhibited edema in an acute inflammatory model, ZR-32 inhibited formation of granuloma. In the chronic inflammatory model, ZR-32 exerted strongest activity in the second and third weeks. ZR-32 demonstrated strong analgesic activity in the test of stimulation with electric current and in the "hot plate" test, besides antipyretic activity. Both compounds weekly irritated the gastric mucosa. In the tests applied, these compounds had no effect on the CNS. Their acute to toxicity was substantially lower than that of acetylsalicyclic aid and indomethacin.
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Nordihydroguaiaretic acid inhibits prostaglandin (PG) biosynthesis in vitro (ID50=228 muM), with a slope of dose-response curve high (b=209) as compared with indomethacin (ID50=0.1 muM, b=72.1). Butylated hydroxyanisole, in contrast to inactive butylated hydroxytoluene, inhibits PG biosynthesis (ID50=107 muM, b=63). Only norihydroguaiaretic acid (100 mug, s.p.) inhibited the postcarrageenin edema of rat paw. Butylated hydroxyanisole (10 mug, s.p.) given together with a subthreshold (1 mug) dose of indomethacin inhibited the paw edema by 35%, while butylated hydroxytoluene and nordihydroguaiaretic acid produced a similar effect only when given at 10-fold higher doses. The results suggest the possibility of potentiation and prolongation of the anti-inflammatory effect of indomethacin by its simultaneous administration with an antioxidant, butylated hydroxyanisole.
We propose to use in vitro tests for the design of antiinflammatory drugs. These tests are inhibition of prostaglandin synthetase and binding to albumin. The antienzymic potency of a compound is a good indicator of its local antiinflammatory activity. The difference between the antienzymic and the albumin ligand potencies of a compound roughly correlates with its systemic antiinflammatory activity. We found it rewarding to use de novo models for studying structure-activity relationship within our series of prostaglandin synthetase inhibitors. It is supposed that the general chemical character of prostaglandin synthetase inhibitors inclines to a wide application of the additive mathematical model of Free and Wilson for the design of antiinflammatory drugs.
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Esters of N,N-diethylaminoacetic acid and hydroxyamines, obtained from structurally different natural monoterpenes, were pharmacologically examined. It was proved that salts of the obtained compounds had local anesthetic properties in infiltration anesthesia, compounds 9, 6 and 8 having been more potent than lidocaine. Compounds 7-9 slightly increased the arrhythmogenic dose, and compound 12 - the lethal dose of strophanthin. All the examined compounds transiently decreased the arterial blood pressure and displayed a cardiopressive activity.
The aim of this work was to determine the influence of ethanol on the antiarrhythmic activity of verapamil in the model of calcium arrhythmia in rats non-dependent and dependent on ethanol. The results of the experiment show that a combined, single administration of ethanol and verapamil attenuates in a statistically significant manner the antiarrhythmic effect of verapamil. Ethanol administered repeatedly together with verapamil does not diminish the antiarrhythmic activity of verapamil.
The antiarrhythmic action of diltiazem in the model of barium arrhythmia was studied in rats non-dependent and dependent on ethanol. The results of our studies showed that single intragastric administration of ethanol jointly with diltiazem did not significantly attenuate the antiarrhythmic effect of diltiazem. Ethanol administered repeatedly and jointly with diltiazem influenced the antiarrhythmic action of diltiazem in different ways, depending on the used dose of diltiazem. After repeated joint administration of ethanol and diltiazem in a lower dose, attenuation of the antiarrhythmic effect of diltiazem was not observed. Repeated joint administration of ethanol and diltiazem in a higher dose attenuated the antiarrhythmic effect of diltiazem. Those experiments also showed that single administration of diltiazem did not significantly influence the ethanol level in the blood; however, when administered repeatedly, diltiazem reduced the concentration of ethanol in blood.