Effects of morin-5'-sulfonic acid sodium salt (NaMSA) on cyclophosphamide-induced changes in oxido-redox state in rat liver and kidney.

Cyclophosphamide (CPX) is an anticancer drug with immunosuppressive properties. Its adverse effects are partly connected to the induction of oxidative stress. Some studies indicate that water-soluble derivative of morin-morin-5'-sulfonic acid sodium salt (NaMSA) exhibits strong antioxidant activity. The aim of present study was to evaluate the effect of NaMSA on CPX-induced changes in oxido-redox state in rat. Experiment was carried out on Wistar rats divided in three experimental groups (N = 12) receiving: 0.9% saline, CPX (15 mg/kg) or CPX (15 mg/kg) + NaMSA (100 mg/kg), respectively, and were given intragastrically for 10 days. Malondialdehyde (MDA) and glutathione (GSH) concentrations and superoxide dismutase (SOD) activity were determined in liver and kidneys. Catalase (CAT) activity was assessed only in liver. Treatment with CPX resulted in significant decrease in MDA level in both tissues, which was completely reversed by NaMSA treatment only in liver. In comparison to the control group significant decrease in SOD activity were observed in both tissues of CPX receiving group. In kidneys this parameter was fully restored by NaMSA administration. CPX evoked significant decrease in GSH concentration in kidneys, which was completely reversed by NaMSA treatment. No significant changes were seen in GSH levels and CAT activity between all groups in liver. Results of our study suggest that CPX may exert significant impact on oxido-redox state in both organs. NaMSA fully reversed the CPX-induced changes, especially MDA level in liver, SOD activity and GSH concentration in kidneys and it may be done by enhancement of activity/concentration of endogenous antioxidants.

The Influence of prolonged beta-blockers treatment on male rabbit's sexual behavior and penile microcirculation.

The aim of the study was to assess the effect of the prolonged intake of three beta-blocking drugs (propranolol, metoprolol and nebivolol) on the sexual behavior and penile microcirculation of rabbits. Drugs were administered p.o. for 9 weeks and every three weeks in each group (n=13) one subgroup (n=7) performed behavioral tests, whereas in the second subgroup (n=6) penile microcirculation was measured with a laser Doppler flowmeter. The copulation studies revealed significant impairment of sexual function only in the propranolol treated group. The measured behavioral parameters suggest that at a given dose propranolol affects more performance rather than arousal aspects of rabbits' sexual behavior. In the course of the whole study no significant difference was observed among groups in penile blood flow. The data indicate that among the beta-blockers given only propranolol interferes with sexual behavior, and that beta-blockers do not appear to have a negative effect on penile microcirculation.

Behavior of silica particles introduced into an isolated rat heart as potential drug carriers.

Silica powders consisting of small spherical particles (50-200 nm) have been obtained by the sol-gel method. A suspension of such particles in the Krebs-Hanseleit solution has been introduced into the coronary circulation of a beating perfused rat heart. The influence of the suspension on the heart muscle and the coronary vessels in the rat body has been histopathologically examined. The particles have not left the lumen of the vessels and have not caused any side effects. These observations suggest the possibility of using such silica particles as a carrier for selected drugs.

Betahistine inhibits food intake in rats.

Betahistine, administered intraperitoneally, decreased, in a dose-dependent manner and in a statistically significant degree, total food intake in different experimental models in rats.

Synthesis and pharmacological properties of new derivatives of 4-methyl-5-oxalo-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one and beta-oxo-5-(4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2 -one)propionic acid.

5-Ethoxalyl 4-methyl-1H-2,3,4,5-tetrahydro 1,5-benzodiazepin-2 -one [I] and 5-ethoxymalonyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepi n-2-one [IV] were subjected to transesterification using alcohols (propanol, butanol, pentanol) giving derivatives II-IV, VII, VIII. The derivatives I and VI were caused to undergo ammonolysis giving 4-methyl-5-oxamoyl-1H-2,3,4,5 tetrahydro 1,5-benzodiazepin-2-one [V] and 5-malonamoyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin++ +-2-one [IX]. The compounds I-IX were tested towards their psychotropic activity. The preparates I, III and V had an anxiolytic action in the four-plate test. The anxiolytic properties of the compound V were confirmed in the test of the black-white box. The antagonism of all investigated compounds for toward reserpine, first of all of the preparations III, IV, V and IX, indicates an antidepressive activity dependent on a stimulation of the adrenergic system.

[The effect of cimetidine and famotidine on esophageal motility]. / Wplyw cymetydyny i famotydyny na motoryke przelyku.

An effect of cimetidine and famotidine on the lower esophagus sphincter pressure and esophageal body motility has been investigated. The studies involved 30 patients with duodenal ulcer. The lower esophagus sphincter pressure, mean force and mean duration of spasms as well as wave transmission velocity in esophageal body, 1-13 cm above the sphincter, have been recorded with Polyphysiograph R-611. The lower esophagus sphincter pressure and esophageal body motility have been recorded 15 minutes prior to and following the administration of 200 mg cimetidine or 20 mg famotidine. It was shown that cimetidine has net changed the lower esophagus sphincter pressure and esophageal body motility parameters. Famotidine increased the lower esophagus sphincter pressure from the initial 2.31 +/- 1.19 kPa to 3.51 +/- 1.61 kPa (p < 0.05) and had no effect on the esophageal body motility parameters. It may be concluded that within H2-receptor antagonists famotidine may be considered a drug of choice in the treatment of gastroesophageal reflux.

Synthesis and pharmacological properties of derivatives of isoxazolo[4,3-d]pyrimidine. III.

Synthesis of new isoxazolo[4,5-d]pyrimidine derivatives is reported. Some of isoxazolo[4,5-d]pyrimidine derivatives were tested for anticonvulsant, anxiolytic and antiserotonine activity. Compounds 14 and 16 proved active against hypothermia induced by reserpine and hyperthermia induced by m-CPP.

Carboxylic esters derivatives of 2-thioxo-1H-2,3,4,5-tetrahydropyrido-[2,3-e]-1,3,4-triazepin-5-ones and 2-thioxo-1H-2,3,4,5-tetrahydro-1,3,4-benzotriazepin-5-ones.

2-Thioxo-1H-2,3,4,5-tetrahydropyrido[2,3-e]-1,3,4-triazep in -5-ones [I] and 2-thioxo-1H-2,3,4,-5-tetrahydro-1,3,4-benzotriazepin-5-ones [V] furnish with methyl, ethyl and phenyl chloroformates two series of the corresponding 3-methoxy-, ethoxy- and phenoxycarbonyl triazepines. In the pharmacological screening, compounds [I], [V] and [II] showed an antianxiety activity in the four plate test, compounds [II] and [III] inhibited the 5-HTP- induced head twitches, and compound [VI] showed an analgesic activity in the "writing" test. The replacement of the benzene ring by the pyridine one in triazepines is accompanied by the enhancement of anxiolytic activity as well as toxicity.

Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part II.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-20 were synthesized and evaluated for their pharmacological activity. Compounds 11-14, 17-19 showed antiaggressive effect, compounds 5, 8, 9, 11, 12 and 19 displayed antiserotonin activity while compound 14 exerted antireserpine action.

Acylated derivatives of 1,5-benzodiazepines. Part II.

Acylated derivatives of 4-methyl-1H-tetrahydro-1,5-benzodiazepin-2-one (1) and of 2-methyl-4-phenyl-1H-tetrahydro-1,5-benzodiazepino-2-carboxylic acid ethyl ester (10) were synthesized and preliminarily tested on their central activity. Acylation was carried out with alpha, beta-unsaturated acid chlorides, dicarboxylic acid monoester monochlorides, and dicarboxylic acid dichlorides. Compounds 2, 3, 11 and 12 had analgesic, compounds 4, 11 and 12--anticonvulsant, and compounds 3 and 11--antiaggressive properties.

Synthesis and properties of 4-substituted-1-piperazinyl-propyl derivatives of 1-phenyl-7-methylpyrimido-[4,5-d]pyrimidin-4-one.

In reactions of 1-phenyl-7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimido[ 4,5-d]pyrimidin e (1) with 1-(3-chloropropyl)-4-methyl(phenyl, 3-chlorophenyl, 2-pyrimidynyl, 2-thiazolyl)piperazines (5), mixtures of isomeric N- and S-substituted derivatives of compound 1 (3 and 4) were obtained. Isomers were separated by fractional crystallization. The structure of novel compounds 3 and 4 was confirmed by elemental and spectral analyses. In pharmacological screening compounds 3b and 4b displayed rather strong analgesic action, inhibited amphetamine hyperactivity and abolished apomorphine stereotypy. Compounds 3e,3d and 4e attenuated m-chlorophenylpiperazine-induced hypothermia.

Synthesis and pharmacological properties of derivatives of alpha-amino-beta-(p-chlorobenzoyl)-propionic acid and alpha-amino-gamma-(p-chlorophenyl)-tetrahydrofuran-2-one.

Several new alpha-aminoderivatives of gamma-(p-chlorophenyl)-tetrahydrofuran-2-one were synthesized. alpha-Aminoderivatives of beta-(p-chlorobenzoyl)-propionic acid 2-13 were used as the substrates. After the reduction with NaBH4 at 10-12 degrees C and cyclization the compounds were converted into the appropriate derivatives of tetrahydrofuran-2-one 16-26. In pharmacological tests compounds 9 and 26 abolished the aggressiveness in isolated mice while compound 8 showed antiinflammatory activity.

Synthesis and preliminary pharmacological investigation of the central action of derivatives of 3-aminomethyl-5-(p-chlorophenyl)-tetrahydrofuran-2-one and 2-aminomethyl-4-(p-chlorophenyl)-4-hydroxybutyric acid.

Using 3-cyano-5-(p-chlorophenyl)-tetrahydrofuran-2-one 4, 3-aminomethyl derivatives of 5-(p-chlorophenyl)-tetrahydrofuran-2-one were synthesized. The starting material under alkaline hydrolysis yielded 5-(p-chlorophenyl)-tetrahydrofuran-2-one-3-carboxylic acid 5, which was transformed, via an acid chloride, into amide 6. From acid 5 by aminomethylation compounds 7-12 were obtained. Some of them (7, 8, 12) in reactions of ammono-, amino-, and hydrazinolysis yielded corresponding derivatives of 2-aminomethyl-4-(p-chlorophenyl)-4-hydroxybutyric acid 13-20. In pharmacological tests compounds 10 displayed analgesic activity while compounds 2 and 3 revealed anxiolytic properties.

Acyl derivatives of 1,5-benzodiazepines. III. Acyl derivatives of ethyl ester of 4-methyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acid.

Two series of derivatives of ethyl ester of 4-methyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acid (1) have been synthesized. The acetyl derivative (2) of ester 1 in preliminary pharmacological screening showed analgesic activity in the "writhing" test and the benzoyl derivative (5) exhibited antianxiety properties in the four plate test, while N,N-disubstituted aminoacetyl derivatives of 1 showed analgesic and anticonvulsant activity (10).

Synthesis and preliminary pharmacological studies on dihydropyrido-1,3,4-triazepinone derivatives.

New 4,5-dihydropyrido-[2,3-e]-1,3,4-triazepin-5-one derivatives (2-9) were synthesized. The preliminary pharmacological tests revealed antinociceptive action of compounds 4-7 and 9 and antianxiety action of compound 4.