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Biomedical subjects

K Magyar

Publications and source records attributed to K Magyar.

At least 37 records · Page 2Linked to original sources
PubMed1999

Analysis of deprenyl metabolites in the rat brain using HPLC-ES-MS.

Methylamphetamine and amphetamine, the two major metabolites of deprenyl in the rat brain were analyzed using HPLC method combined with electrospray-mass spectrometer. (-)-Deprenyl and (+)-deprenyl were orally administered to rats either in a single dose of 10 mg/kg, or three times a week for three weeks. The metabolites were determined in four different parts of the rat brain, such as in the frontal cortex, corpus striatum, hippocampus, and hypophysis. The ratio of methylamphetamine to amphetamine was also compared after (-)-deprenyl and (+)-deprenyl treatments.

Amphetamine↗
PubMed1999

[Pre- and postsynaptic action of the ATP-dependent K+-channel-(K+ATP)-opener pinacidil in rabbit pulmonary artery].

Low frequency (2 Hz) of electrical depolarisation induced [3H]noradrenaline ([3H]NA) release has been measured from the isolated main pulmonary artery of the rabbit in the presence of uptake blockers (cocaine, 3x10(-5)M and corticosterone, 5x10(-5)M), with parallel measurements of post-junctional contractile responses. The K+ATP-channel opener pinacidil (10(-6)-10(-4)M), slightly potentiated the nerve-evoked release of [3H]NA which failed to show close concentration-dependency. Large concentration of pinacidil (10(-4)M) increased the ratio of [3H]NA release from 0.99 +/- 0.02 to 1.28 +/- 0.05 (P < 0.0005). On the other hand, pinacidil inhibited the nerve-evoked contractions in a concentration-dependent manner. 10(-4)M caused nearly 70% inhibition of contractile response. The pre- and post-junctional effects of pinacidil were studied under the following experimental conditions: 1) exogenously applied 1-NA; 2) excess K+; 3) 'L-type' Ca(2+)-channel activation (BAY K 8644); K(+)-channel inhibition (4-AP); and 5) Na(+)-pump inhibition/reactivation. Pinacidil (10(-4)M) retained its marginal NA-release stimulatory effect in all cases. However, pinacidil inhibited the contraction of smooth muscle, although to a different extent, in all of the experimental conditions used in our study.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Neuroprotective and neuronal rescue effects of selegiline: review.

The effect of selegiline [(-)-deprenyl] cannot be considered as a simple, selective inhibitor of MAO-B. Pretreatment with the drug prevented the effect of specific neurotoxins like MPTP, 6-OH-dopamine, DSP-4 and AF64A. Selegiline pretreatment prevented the depletion of noradrenaline (NA) induced by DSP-4 in the rat hippocampus. This can be due to the uptake inhibitory effect of selegiline and mainly to its metabolite methylamphetamine (MA), which is more potent inhibitor of the re-uptake than the parent compound. SKF-525A pretreatment diminished the protective effect of selegiline against DSP-4, while phenobarbital pretreatment decreased its MAO-B inhibitory potency. Selegiline in low oral doses also prevented the effect of DSP-4 due to its intensive "first pass" metabolism. Selegiline treatment can rescue damaged neurones. It inhibited the apoptosis in M-1 human melanoma cells in a rather low concentration (10(-13)M). The mode of action of the drug regarding the inhibition of apoptosis is not known.

Animals↗
PubMed1999

Metabolic transformation of deprenyl enantiomers in rats.

The optical isomers of deprenyl have different pharmacological activities and potency. Selegiline, an (-)-isomer, is the more potent monoamine oxidase B enzyme inhibitor, and this substance is used in the therapy of Parkinson's disease. The neuroprotective and neuronal rescue effects of deprenyl, as well as the psychostimulant action of its metabolites, methamphetamine and amphetamine are also different for the enantiomers. In this study the biotransformation of deprenyl enantiomers was compared. Stereoselective dealkylation of both optical isomers was found as major metabolic alteration. The difference in the ratio of the formed metabolites suggests the existence of preferred metabolic pathways for the enantiomers.

Amphetamine↗
PubMed1998

The neuroprotective and neuronal rescue effects of (-)-deprenyl.

The pharmacological effects of (-)-deprenyl is multi-fold in its nature (dopamine sparing activity, neuroprotective and neuronal rescue effects), which cannot be explained solely by the irreversible MAO-B inhibitory action of the substance. Deprenyl slightly inhibits the re-uptake of noradrenaline and dopamine, but methylamphetamine, the metabolite of the inhibitor, by one order of magnitude is more potent in this respect, than the parent compound. Neither the metabolite nor (-)-deprenyl acts on the uptake of serotonin. The inhibitor has an intensive first pass metabolism after oral treatment. The in vivo pharmacokinetic studies with (-)-deprenyl, using the double labelled radioisotope technique (1.5 mg/kg; orally) in rats revealed that the molar concentration of methylamphetamine can reach the level suitable to induce a significant inhibition of amine uptake. Deprenyl, but especially methylamphetamine pre-treatment can prevent the noradrenaline release induced by the noradrenergic neurotoxin DSP-4. The uptake inhibitory effect of (-)-deprenyl and the metabolites is reversible. After repeated administration of (-)-deprenyl (1.5 mg/kg daily, for 8 days) sustained concentration of its metabolites was detected, compared to that of the acute studies. This can at least partly explain why (-)deprenyl should be administered daily to evoke therapeutic effects in Parkinson's disease. Administration of (-)-deprenyl in a low dose, following the toxic insult, can rescue the damaged neurones. The neuronal rescue effect of the drug was studied on M-1 human melanoma cells in tissue culture. The inhibitor reduced the apoptosis of serum-deprived M-1 cells, but the (+)-isomer failed to exert this effect. The (+/-)-desmethyl-deprenyl almost lacks the property to inhibit apoptosis. For neuroprotection and neuronal rescue an optimal dose of (-)-deprenyl should be administered, because to reach a well balanced concentration of the metabolites in tissues is critical.

Animals↗
PubMed1998

MAO inhibitory side effects of neuroleptics and platelet serotonin content in schizophrenic patients.

In order to study the putative monoamine oxidase (MAO) inhibitory side effect of neuroleptics and simultaneous changes in platelet serotonin content both MAO-B activity and serotonin (5-HT) content in platelets of 30 healthy volunteers and 50 schizophrenic patients treated with neuroleptics were investigated. Our results have shown significantly lower MAO-B activity (15.26 +/- 6.81 S.D. vs. 8.63 +/- 3.82 mmol/hour/10(9) platelets) and higher platelet 5-HT content (906.19 +/- 285.33 vs. 1,727.85 +/- 947.40 ng/10(9) platelets) in the schizophrenic group. Platelet MAO-B activity was considerably lower in paranoid and residual schizophrenics compared with other patients, however, no difference was found in platelet 5-HT content between different subtypes of schizophrenia. Various neuroleptic treatments did not produce different effects either on platelet serotonin content or platelet MAO-B activity.

Antipsychotic Agents↗
PubMed1998

Detection of double-stranded RNA molecules and virus-like particles in different Mucor species.

The presence of double-stranded RNA elements was examined in 123 strains representing 18 Mucor species. These genetic elements were found to be present in 6 strains: 1 M. aligarensis, 1 M. hiemalis, 2 M. corticolus, 1 M. mucedo and 1 M. ramannianus. Electrophoretic separation of the nucleic acids revealed 4 different RNA patterns, with 1 to 5 discrete dsRNA bands. The molecular weights corresponding to these bands were 1.42-4.15 x 10(6) D. Using electronmicroscopy, for the first time the presence of virus like particles in Mucor species has been revealed.

Electrophoresis, Agar Gel↗
PubMed1998

Platelet MAO-B activity and serotonin content in patients with dementia: effect of age, medication, and disease.

This study aimed at determining the effect of drug therapy, age and type of dementia on biological markers. Both platelet monoamine oxidase type B (MAO-B) activity and serotonin content of 57 demented patients and 20 control subjects were determined. Platelet MAO-B activity was measured using [14C]tyramine as substrate. Serotonin content was determined by HPLC-EC method. Increased platelet serotonin content and platelet count was found in patients with dementia compared to controls. A positive correlation was experienced between platelet MAO-B activity, platelet serotonin content and age. Platelet MAO-B activity was higher in the haloperidol treated group, compared with patients treated with anxyolitics. The main original finding of the present study is that platelet serotonin content is increased in demented patients with delusions compared to dementia without complications (p = 0.006). It seems, that platelet MAO-B activity is influenced mainly by drug therapy, while serotonin content rather reflects clinical characteristics in dementia.

Age Factors↗
PubMed1998

Absorption of the new anxiolytic compound deramciclane in rats, dogs and rabbits.

The absorption of deramciclane fumarate ((1R,2S,4R)-(-)-N,N-dimethyl-2-[(1,7,7-trimethyl-2-phenylbicyclo [2,2,1] hept-2-yl) oxy] ethane amine-2-(E)-butenedioate (1:1), CAS 120444-78-8, EGIS-3886), a new anxiolytic compound, was studied in rats, dogs and rabbits by using 3H-camphor- or 14C-phenyl-labelled radioisomers of the substance. The compound was readily absorbed from the intestinal tract after oral administration. The absorption of 14C-deramciclane was also studied from the isolated intestinal loops of rats (duodenal, jejunal, ileal loops) and dogs (duodenal loop). The absorption was faster in rats and rabbits than in dogs (tmax = 1 h or 6 h, respectively). The radioactivity was not absorbed from the isolated stomach of any species studied for 2 h. Meanwhile, the substance was not decomposed by the gastric juice, as it has been proved by TLC and MS analyses. Deramciclane is preferentially excreted via the bile. The intensity of its bile excretion is higher in rats than in dogs. Higher plasma levels of labelled deramciclane were found in female than in male rats.

Animals↗
PubMed1998

Pharmacokinetics of deramciclane in rabbits.

The pharmacokinetics of deramciclane (CAS 120444-78-8, EGIS-3886) was investigated in rabbits after i.v., p.o. and s.c. administration of 3 mg/kg 14C-phenyl-deramciclane. The plasma, concentration-time curves of total radioactivity, the parent compound (deramciclane) and its N-demethylated metabolite (EGIS-7056) were determined. The radioactivity level was measured by liquid scintillation technique while the concentration of the parent compound and its metabolite was determined by gas chromatography-mass spectrometry detection. The p.o. and i.v. studies were carried out on the same group of animals, while a separate group of rabbits was used for studying s.c. absorption. Deramciclane was readily absorbed after p.o. and s.c. treatment (tmax 1.0 to 1.4 h). The terminal elimination half-life (t1/2 beta) of the parent compound fell between 5.8 to 7.1 h, while that of the total radioactivity ranged from 21.6 and 26.0 h. The absolute bioavailability of deramciclane calculated from the AUC0-infinity values was found to be 43 and 60% after p.o. and s.c. treatment. The apparent volume of distribution (Vd) and the whole body clearance (Cl) of deramciclane after i.v. administration were 25.0 +/- 7.1 l/kg and 2.6 +/- 0.5 l/h/kg, respectively. The AUC0-infinity values of the parent compound varied between 4.6 and 7.9% of that of total radioactivity, suggesting that deramciclane was subjected to intensive metabolic conversion. The AUC0-infinity of N-desmethyl-deramciclane was 5.7%, compared to that of the parent compound after i.v. administration.

Animals↗
PubMed1997

Urinary excretion of deprenyl metabolites.

(+)-Deprenyl metabolites in rat's urine, such as nordeprenyl. methamphetamine amphetamine and p-hydroxy. methamphetamine were identified by HPLC-MS. After oral administration of 10 mg of pure (-)- and (+)-deprenyl to human volunteers, their urine was analyzed by gas chromatography. The concentration of methamphetamine was found to be overwhelming in the case of the (-)-isomer, while amphetamine and methamphetamine were excreted in equal amounts when (+)-deprenyl was administered. The metabolic processes of deprenyl resulted in metabolites possessing different lipophilicity, as it has been shown by planar displacement chromatography.

Animals↗
PubMed1997

Pre-junctional stimulatory and post-junctional inhibitory effects of pinacidil in the isolated main pulmonary artery of the rabbit under different experimental conditions.

Low frequency (2Hz) nerve-stimulation induced [3H]noradrenaline ([3H]NA) release has been measured from the isolated main pulmonary artery of the rabbit in the presence of uptake blockers (cocaine, 3 x 10(-5)M; corticosterone, 5 x 10(-5), with parallel measurements of post-junctional contractile responses. The K+ ATP-channel opener pinacidil (10(-6)-10(-4)M), slightly potentiated the nerve-evoked release of [3H]NA which failed to show close concentration-dependency. Large concentration of pinacidil (10(-4)M) increased the ratio of [3H]NA release from 0.99 +/- 0.02 to 1.29 +/- 0.05; P < 0.0005). On the other hand, pinacidil inhibited the nerve-evoked contractions in a concentration-dependent manner. 10(-4)M caused nearly 70% inhibition of contractile response. The pre- and post-junctional effects of pinacidil were studied under the following experimental conditions: (1) exogenously applied I-NA; (2) excess K+; (3) 'L-type' Ca(2+)-channel activation (BAY K 8644); (4) K(+)-channel inhibition (4-AP); and (5) Na(+)-pump inhibition/reactivation. Pinacidil (10(-4)M) retained its marginal NA-release stimulatory effect in all cases. However, pinacidil inhibited the contraction of smooth muscle, although to a different extent, in all of the experimental conditions used in our study.

Animals↗
PubMed1997

Hip-Arg-Phe-, Hip-Phe-Arg- and Hip-His-Leu-cleaving dipeptidyl carboxypeptidases in human adrenal tumors.

Hip-Arg-Phe-, Hip-Phe-Arg- and Hip-His-Leu-cleaving dipeptidyl carboxypeptidase activities were measured in the supernatant (S2) and pellet (P2) fractions obtained by ultracentrifugation of human adrenal tumor preparations. Negligible enzyme activity was found in cortical tumor whereas highly significant activities were present in the P2 fractions of the two pheochromocytoma specimens. The hydrolysis rates, expressed in terms of the percent of added substrate were 58-66%/60 min for Hip-Phe-Arg, 55-58%/60 min for Hip-Arg-Phe and 19-30%/60 min for Hip-His-Leu. The angiotensin-converting enzyme inhibitor, captopril, differentially inhibited the enzyme splitting Hip-His-Leu versus the one cleaving Hip-Arg-Phe; Hip-Phe-Arg is probably the substrate of both. It is concluded that the Hip-Arg-Phe-cleaving enzyme in adrenomedullary tumor is probably identical to the purportedly novel dipeptidyl carboxypeptidase that we detected earlier in rabbit ear artery wall, which converts (Met5)-enkephalin-Arg6,Phe7 to (Met5)-enkephalin.

Adrenal Gland Neoplasms↗
PubMed1996

The pharmacology of B-type selective monoamine oxidase inhibitors; milestones in (-)-deprenyl research.

(-)-deprenyl cannot be considered as a simple, selective inhibitor of MAO-B. It increases the dopaminergic tone in the central nervous system by a complex mechanism. The MAO-B inhibition could result in a potentiation of the effect and the reduction of the dose of L-dopa, including the restoration of the sensitivity to L-dopa treatment, when the response to the drug has already been diminished or lost. Pre-treatment with (-)-deprenyl prevent the effect of neurotoxins like MPTP, 6-hydroxydopamine, DSP-4, AF64A by inhibiting the conversion of the pretoxin to toxin, or by inhibiting the neuronal reuptake mechanisms, or the combination of the two processes. However, other effects of the inhibitor cannot be ruled out. (-)-deprenyl, but not its (+)-enantiomer, proved to be a potent inhibitor of programmed cell death (apoptosis) of PC12 cells and that of human melanoma cells, in a concentration which does not induce MAO-B inhibition. The activity of MAO-B increases with age and the age related changes led to an overproduction of neurotoxic agents. The inhibition of the enzyme activity can play a preventive role against neurodegenerative brain disorders. The most widely used MAO-B inhibitor in the therapy is (-)-deprenyl and it lacks the "cheese reaction". The complex mechanism for the lack of the former effect is not fully known.

Age Factors↗
PubMed1996

Platelet rich plasma serotonin content in patients suffering from different psychiatric disorders.

Platelet rich plasma serotonin contents were examined using HPLC-EC method in patients suffering from different anxiety states and compared to age matched healthy controls. We have found significant increase of PRP serotonin level in the group of schizophrenic patients and in patients suffering from dementia compared to controls. PRP serotonin content was significantly lower in heavy drinkers but in patients suffering from panic disorder did not differ significantly from the controls.

Alcoholism↗
PubMed1995

The distribution of orally administered (-)-deprenyl-propynyl-14C and (-)-deprenyl-phenyl-3H in rat brain.

Using alternatively labelled (-)-deprenyl (3H label in the ring and 14C in the propargyl group) the distribution of the compound was studied in 15 brain regions and the plasma of rats over a period of 96 h, after oral administration of 1.5 mg/kg of (-)-deprenyl. The compound is rapidly absorbed (within 15-30 min) from the gastrointestinal tract, as indicated by its high plasma level. It penetrates to the central nervous system, where it reaches a peak level within 45-60 min. During the first 2 h in the plasma the 14C label, whilst in cerebral tissues during the whole period of the experiment the 3H tracer dominates. The difference in the ratio of 3H to 14C radioactivity (compared to the 0 time relation) develops as early as in the first 15 min, which indicates the operation of a rapid "first pass" biotransformation of the compound. Our data represent the tissue molar concentration -time curves of (-)-deprenyl calculated from both the 3H and 14C radiolabels. A ratio of 1 of the concentrations of the two tracers would indicate that the molecule remained unchanged. The changes in the ratio, therefore, suggest the formation of considerable quantities of metabolites (methylamphetamine and amphetamine) and their presence in the brain. The difference between the area under the curves (AUC0-t for 3H and AUC0-t for 14C) represents the amount of metabolites expected to be formed during the experiment. The concentration of the metabolites should be taken into account while evaluating the pharmacological effect of (-)-deprenyl. We proved earlier that a dose of 1.5 mg/kg of (-)-deprenyl completely blocks MAO-B activity in the central nervous system. The fast metabolism of the inhibitor indicates that a minor part of the orally administered (-)-deprenyl is sufficient to produce a high level of selective MAO-B inhibition in the brain.

Administration, Oral↗
PubMed1995

Gas chromatographic procedure for simultaneous determination of selegiline metabolites, amphetamine, methamphetamine and demethyl-deprenyl in pig plasma.

A sensitive assay for the simultaneous quantitative determination of amphetamine, methamphetamine and demethyl-deprenyl in pig plasma is described. NP-Gas chromatography is used to determine the extracted plasma concentrations of the three target compounds as their N-penta-fluoro-benzoyl derivatives. Quantitation is performed using 1-phenyl-2-pentylamine as internal standard. The derivatives are separated on a phenyl-methylsilicone capillary column. Quantitation limit for each target compound was 1.2 ng ml-1. Levels of amphetamine, methamphetamine and demethyl-deprenyl have been determined in plasma of pigs treated with Selegiline in different formulations and doses.

Amphetamine↗