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Biomedical subjects

K Magyar

Publications and source records attributed to K Magyar.

At least 55 records · Page 3Linked to original sources
PubMed1994

Behaviour of (-)-deprenyl and its analogues.

A number of new deprenyl analogues were synthesized during the last decades and structure-activity relationship studies were carried out with the compounds. Among these derivatives U-1424 [N-methyl-N-propargyl-(2-furyl-1-methyl)-ethyl ammonium] and J-508 [N-methyl-N-propargyl-(1-indanyl) ammonium] preserved the selectivity to MAO-B, but the former is slightly less potent inhibitor of the enzyme, while J-508 is more effective than the parent compound. The studies led us to the conclusion that, in the case of a selective and irreversible inhibitor, it is not a proper aim to search for a more potent inhibitor than deprenyl. Nevertheless, the effects of the new derivatives independent of the enzyme inhibitory potency can be beneficial. In this respect p-fluoro-deprenyl (PFD) seems to be promising. In addition to the enzyme inhibitory action, the compounds possess reversible effects e.g. inhibition of uptake and release of the synaptic processes. The fate of the drugs in the body including metabolism is also an important aspect of drug action. PFD is slightly less potent inhibitor of MAO-B in vitro than deprenyl but it maintains a more prolonged concentration in tissues. Its metabolites (p-fluoro-amphetamine and p-fluoro-methamphetamine) are more effective inhibitors of uptake than the parent compound. In respect of the release of transmitter amines, the (+)-isomers of the metabolites are more potent but we did not find significant differences between the uptake inhibitory potencies of the stereoisomers. PFD is more effective to protect the neurodegenerative effects of the noradrenergic neurotoxin DSP-4, compared to deprenyl.

Animals↗
PubMed1994

Relationship between the hydrophobic physicochemical parameters and biological activity of some monoamine oxidase inhibitory drugs.

The MAO-B inhibitory effect of 11 propargylamine derivatives was determined in rat brain and rat liver and the concentration causing 50% inhibition (IC50) was calculated. The hydrophobic (lipophilicity, specific hydrophobic surface area) and hydrophilic (adsorption capacity on slightly acidic and alkaline surfaces, specific hydrophilic surface area on the same surfaces) physicochemical parameters of the MAO inhibitory drugs were determined by various adsorptive and reversed-phase chromatographic techniques. Stepwise regression analysis proved that only the hydrophilic parameters describing the interaction of drugs with alkaline surfaces exert a significant impact on the biological activity. These results make probably the direct interaction between the alkaline hydrophilic substructures of drugs and the secondary carboxyl groups of the target enzyme.

Animals↗
PubMed1992

Influence of pH on the migration properties of oligonucleotides in capillary gel electrophoresis.

The effect of pH on the electrophoretic migration properties of single-stranded oligodeoxyribonucleotides in capillary gel electrophoresis was investigated. Different homooligodeoxyribonucleotides of equal chain length showed significant differences in relative migration when the pH of the gel buffer was varied from pH 6 to 8, parallel with the running buffer. A similar variation in migration order was observed during the electrophoretic equilibration of a pH 8 gel-filled capillary column with a pH 6 running buffer. In the latter instance, the current reached the new level after 20 min of electrophoretic equilibration with the pH 6 running buffer. However, it was observed that the migration order characteristic of the pH 6 gel was achieved only after 4 h of electrophoretic equilibration. To avoid this time-consuming equilibration process, these results suggest that gel-filled capillary columns should be prepared with the same buffer (composition and pH) that will be used as the running buffer during the separations.

Buffers↗
PubMed1992

Lipophilicity determination of some monoamine oxidase inhibitors: the effect of methanol and ammonium chloride.

The lipophilicity (RM value) of seventeen monoamine oxidase inhibitory drugs was determined by reversed-phase thin-layer chromatography, and the effect of salt concentration on the reversed-phase retention was studied by adding ammonium chloride to the eluent. Each drug exhibited regular retention behaviour, its RM value linearly decreasing with increasing concentration of methanol in the eluent. Ammonium chloride decreased the retention: the effect was higher at lower salt concentrations, which indicates that the phenomenon is of saturation character. The influence of ammonium chloride depended on the concentration of methanol (on the dielectric constant of the eluent) suggesting that methanol suppresses the dissociation of ammonium chloride resulting in a modified salting-in effect.

Ammonium Chloride↗
PubMed1992

Relationship between the hydrophobic and hydrophilic molecular parameters of some monoamine oxidase inhibitory drugs, determined by means of adsorptive and reversed-phase thin-layer chromatography.

The absorption capacity, the specific hydrophilic surface area, the lipophilicity and the specific hydrophobic surface area of 17 monoamine oxidase inhibitory drugs were determined by means of adsorptive and reversed-phase thin-layer chromatography for future application of these molecular parameters in quantitative structure-activity relationship studies. Principal component analysis suggests that most of the physicochemical parameters have a different information content, and their application in the elucidation of their mode of action is therefore justified.

Adsorption↗
PubMed1992

Dependence of release of [3H]noradrenaline from rabbit pulmonary artery on internal sodium.

1. [3H]Noradrenaline ([3H]NA) release from the isolated main pulmonary artery of the rabbit has been measured in the presence of uptake blockers (cocaine, 3 x 10(-5) M, and corticosterone, 5 x 10(-5) M) and after blocking the monoamine oxidase enzyme by pargyline (1.2 x 10(-4) M). 2. In normal Krebs solution Mn2+ (2 mM) significantly inhibited both [3H]NA release (approximately 80%; P < 0.001) and the contraction following 2 Hz field stimulation. 3. In Ca(2+)-free, EGTA (1 mM)-containing solution, the Na+ pump was inhibited by removal of K+ from the external medium. In Na+ pump-inhibited arteries, 2 mM Mn2+ (free Mn2+, 1 mM) increased the spontaneous release of [3H]NA according to the time of Na+ loading. TTX (10(-7) M) did not inhibit significantly the Mn(2+)-induced [3H]NA release from Na(+)-loaded preparations (percentage inhibition, approximately 24; P > 0.30). 4. Without Na+ loading (Ca2+ free, EGTA alone), Mn2+ failed to promote 3H release from arteries. 5. With constant Na+ loading (120 min 'K(+)-free' perfusion in Ca(2+)-free, 1 mM EGTA-containing solution), the release of 3H was also directly dependent on free Mn2+ concentration (0.2, 0.6 and 1 mM). 6. The Mn2+ (2 mM; free Mn2+, 1 mM)-induced 3H release from Na(+)-loaded nerves (120 min 'K(+)-free', perfusion) was further enhanced, when external Na+ was simultaneously reduced from 139.2 to 26.2 mM (choline+ or sucrose substitution). 7. Diphenylhydantoin (DPH, 10(-4) M) significantly reduced the Mn(2+)-evoked 3H release (approximately 44%; P < 0.02) when it was present during 'K(+)-free', perfusion. 8. Mn2+ was ineffective in releasing 3H if the Na+ pump was previously reactivated by readmission of K+ to Na(+)-loaded arteries. 9. It is concluded that in Ca(2+)-free solution Mn2+ releases neurotransmitter in a manner which depends on the degree of loading with internal Na+. The results suggest this depends at least partly on a block of Ca2+ efflux.

Animals↗
PubMed1991

Possible regulation of hypothalamus and lung histidine decarboxylase activity by cAMP-dependent protein kinase.

Activity of crude histidine decarboxylases (HisDC) from the hypothalamus and the lungs, was markedly reduced by incubating with ATP.Mg, cAMP and cAMP-dependent protein kinase A, whereas activity of the crude glandular stomach enzyme changed only slightly under equal condition. The omission of one of these components failed to reduce HisDC activity by as much as the complete system. Addition of bovine heart (type II) or rat cerebellum protein kinase A (types I and II) inhibitor to the assay prevented enzyme inactivation; moreover, protein kinase A inhibitors permitted moderate activation under phosphorylating and control conditions. Cytosolic hypothalamus HisDC activity was elevated 2-2.2-fold by incubating the cytosol for 15 min in the presence of MnCl2, a known stimulator of phosphoprotein phosphatase; this was prevented when 20 mM NaF, a common inhibitor of phosphoprotein phosphatase, was added to the cytosol. The apparent Km of ATP.Mg-treated hypothalamus HisDC for histidine was elevated 5-10-fold compared to controls, whereas the Vmax was approximately the same. Under this condition, the Km was calculated as high as 0.5-2.2 mM (depending on phosphorylating conditions), while controls had a Km of 0.1-0.3 mM (depending on the initial phosphorylating states). Addition of rabbit muscle (type I), bovine heart (type II) or rat cerebellum (types I and II) inhibitor of protein kinase A, to the phosphorylating mixture, abolished the difference in Km between control and ATP.Mg-treated HisDC. Moreover, rat cerebellum protein kinase A inhibitors increased Vmax to above the control level; while 20 mM NaF (inhibitor of phosphoprotein phosphatase) decreased Vmax to approximately one half of that of the controls. These data indicate that HisDC activity in the hypothalamus and the lungs, but not in the stomach, is affected in oppositely by protein kinase A and phosphoprotein phosphatases.

Animals↗
PubMed1991

In vivo antiaggregatory action of platelet-activating factor in beagle dogs: role for prostacyclin.

The effects of platelet-activating factor (PAF) on in vivo platelet aggregation were studied in anaesthetized beagle dogs by using the extracorporeal filter-loop technique. Intraarterial administration of PAF caused an immediate increase in filter pressure, indicating enhanced in vivo platelet aggregation. Intravenous administration of PAF (3-100 ng kg-1) resulted in a transient dose-dependent inhibition of spontaneous platelet aggregation on the filter with concomitant elevation in plasma 6-keto-PGF1 alpha levels. These changes were significantly attenuated by pretreatment of the animals either with BN 52021 (4 mg kg-1), a specific PAF receptor antagonist or with acetylsalicylic acid (25 mg kg-1). Intraarterial infusion of exogenous prostacyclin at concentrations similar to those observed following intravenous PAF administration, resulted in a transient inhibition of the spontaneous platelet aggregation. These data provide evidence for prostacyclin release in response to PAF, and suggest that prostacyclin may mediate the in vivo anti-aggregatory action of PAF in anaesthetized dogs.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Comparison of serotonin agonistic and antagonistic activities of a new antidepressant agent Trelibet (EGYT-475) and its metabolite EGYT-2760 on isolated rat fundus.

The effects of Trelibet (EGYT-475, N-benzyl-piperazine-picolinyl-fumarate) and its active metabolite (EGYT-2760, N-benzyl-piperazine) on the serotoninergic responses of rat stomach fundus were investigated and compared with those of MCPP (m-chlorophenyl-piperazine) which is the common metabolite of the arylpiperazine antidepressants Trazodone and Etoperidone. The contraction inhibitory potencies of the agents were determined on the equipotent contractions (EC50) to serotonin (5-HT) and prostaglandin F2 alpha (PGF2 alpha). Isotonic contractile responses to 5-HT were not affected by EGYT-475, however, both EGYT-2760 and MCPP produced concentration related and reversible inhibition of the serotoninergic responses. The IC50 values for EGYT-2760 and MCPP were 40.5 +/- 7.5 mumol/l and 125 +/- 35 nmol/l, respectively. The inhibition was selective for the serotoninergic responses, as the equipotent responses to PGF2 alpha were not affected. EGYT-2760 and MCPP displayed not only 5-HT antagonistic, but also partial agonistic activities on the rat fundus preparation. Maximum contractile response of the fundus preparation to MCPP was approximately 25%, to EGYT-2760 was 10% of the maximum response to 5-HT.

Animals↗
PubMed1991

Prevention and treatment of atrophic rhinitis in pigs with Getroxel, chlorquinaldol and oxytetracycline.

The sensitivity of ten Bordetella bronchiseptica and ten Pasteurella multocida strains, each isolated from cases of atrophic rhinitis (AR), was examined in tube dilution test. Getroxel, chlorquinaldol and oxytetracycline and the former two ones combined with trimethoprim inhibited the growth of both species in vitro. The minimum inhibitory and the minimum bactericidal concentration was less than 0.5 microgram/ml. When efficacy was tested in SPF in the group fed a combination of Getroxel, chlorquinaldol and oxytetracycline (60 mg, 240 mg and 360 mg/kg of feed, respectively), P. multocida disappeared from the nasal cavity by the end of a 30-day treatment. B. bronchiseptica was reisolated in low numbers from 2 out of 9 piglets. The daily body mass gain was by 7.9% higher and the feed conversion rate was by 19% better than in the control group. After slaughter, only mild signs of AR were seen in 3 out of 9 piglets treated with the above-mentioned drug combination, while in the control group severe lesions were observed in 8 out of 9 pigs. In treated commercial herds P. multocida disappeared from the nasal cavity of the piglets by the end of the treatment (42nd day of life), but the B. bronchiseptica strains could not be completely eliminated. Due to the treatment, mortality between 2 and 6 weeks of age decreased by 0.8-7.6%. Daily body mass gain was, on the average, 16.4% higher, the amount of feed needed for 1 kg body mass gain was by 15.3% lower and the duration of fattening was by 30.8 days shorter than in the control groups.

Animals↗
PubMed1990

Uptake, metabolism, and release of [3H]-histamine by glial cells in primary cultures of chicken cerebral hemispheres.

Labelled histamine was taken up into cultured glial cells of chick embryonic brain by a system with high affinity for histamine and diffusion. The active uptake, occurring at low concentrations of the amine, was Na+ dependent and gave an apparent Km of 0.24 microM and a Vmax of 0.31 pmol x mg protein-1 x min-1. The uptake was completely blocked by desmethylimipramine (Ki = 2.5 microM) and partially by the histamine agonists and histamine-N-methyltransferase blockers 4-methylhistamine and 2-methylhistamine (I30 values obtained were 2 microM and 5 microM). Other psychoactive drugs were either ineffective (imipramine) or they showed moderate inhibitory effects (amitriptyline and cocaine). Ouabain (100 microM) inhibited uptake by approximately 50%. Diffusion occurred at high concentrations of the amine, was insensitive to extracellular Na+, and was proportional to histamine concentration up to 1 mM. [3H]-Histamine, taken up into the cells, was metabolized and/or released. The spontaneous efflux of the radioactivity measured after 10 min of exposure to [3H]-histamine (when most of it was still unmetabolized), was moderately Ca++ dependent, accelerated by both reduced concentrations of extracellular Na+ and enhanced concentrations of K+ and inhibited by desmethylimipramine. After prolonged (60 min) incubation, histamine metabolites detected in the cells presented 78% of the chromatogram radioactivity and consisted of N tau-methylhistamine and N tau-methylimidazole acetic acid. These results indicate that at low nM concentrations, histamine is taken up and metabolized by (and released from) glial cells by an Na(+)-dependent system, and the intracellular metabolism seems to serve an increased uptake of the amine.

Animals↗
PubMed1990

Contribution of glial cells to histamine inactivation.

DL-alpha-aminoadipic acid (DL-alpha AA), a selective gliotoxic agent produced significant reductions in histamine-N-methyl-transferase (HNMT) and monoamine oxidase-B (MAO-B) activities and an enhancement in histamine (HA) level in the hypothalamus of rats 2 and 4 h after single intracerebroventricular (i.c.v.) or subcutaneous (s.c.) injections of the compound. Histidine decarboxylase (HD) and monoamine oxidase-A (MAO-A) were unaffected after these treatments. Following a single i.c.v. injection of DL-alpha AA of 200 micrograms/rat, or a single s.c. injection of 5 mg/rat, marked diminutions in the astrocytic marker glutamine synthetase (GS) activity occurred suggesting marked glial damage in the hypothalamus. In total, these studies indicate an important role for glial cells in HA metabolism (inactivation).

2-Aminoadipic Acid↗
PubMed1990

Depolarization promotes caffeine induced [3H]-noradrenaline release in calcium-free solution from peripheral sympathetic nerves.

The transmitter releasing action of caffeine was studied in the absence of extracellular Ca2+ from the peripheral sympathetic nerves of the rabbit main pulmonary artery. Caffeine (10 mM) increased the release of [3H]-noradrenaline moderately, but not significantly in Ca2(+)-free (+1 mM EGTA) Krebs solution. When peripheral nerve endings/varicosities were depolarized by elevating extracellular K+ to 47.2 mM and 70.8 mM in Ca2(+)-free solution, the transmitter releasing effect of 10 mM caffeine became significant. Ca2+ removal itself transiently increased the [3H]-noradrenaline outflow. In the individual experiments the amount of the caffeine evoked transmitter release at 47.2 mM and 70.8 mM K(+)-depolarization was inversely correlated to the release evoked by Ca2(+)-removal. Our results suggest that caffeine-sensitive calcium stores are present in peripheral nerve terminals of rabbit pulmonary artery, and part of the caffeine sensitive calcium stores may discharge during Ca2(+)-removal from the extracellular solution.

Animals↗
PubMed1990

Platelet aggregation of migraineurs during and between attacks.

Platelet aggregation induced by ADP, collagen and platelet-activating factor was studied in common (migraine without aura) and classical migraine (migraine with aura) patients during and between attacks. The EC50* values for ADP and platelet-activating factor were significantly higher, whilst that for collagen was significantly lower in classical migraine patients during headache-free intervals compared to healthy volunteers. The EC50 values obtained for common migraine sufferers during symptom-free periods were similar to those of controls. During attacks, the EC50 value for ADP, but not for collagen and platelet-activating factor, was significantly higher than that of the controls. In healthy subjects a positive correlation was found between ADP and collagen-induced aggregation. In contrast, there was a U-shaped correlation matrix in classical migraine patients. The present observations show that platelet aggregation is altered in migraine patients and this raises the possibility that platelet-activating factor may be involved in the pathogenesis of migraine.

Adenosine Diphosphate↗