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Biomedical subjects

K Magyar

Publications and source records attributed to K Magyar.

204 records · Page 12Linked to original sources
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Pharmacokinetic aspects of deprenyl effects.

Deprenyl is a selective, irreversible inhibitor of monoamine oxidase type-B (MAO-B). In prolonged treatment (0.05-0.25 mg/kg, sc daily) in spite of the irreversible blocking, selective inhibition pattern of MAO was maintained. 14C-Deprenyl is well absorbed after oral or subcutaneous administration and penetrates rapidly to the central nervous system. When it is given intravenously its highest brain concentration is reached within 30 sec but radioactivity rapidly disappears from the central nervous system. Deprenyl is metabolized to amphetamine and methylamphetamine in rats without producing a remarkable sign of psychostimulant activity. This could partly be due to the distribution properties of deprenyl e.g. low detectable level of radioactivity in the brain after 1-2 min and partly to the fact that from (-) -deprenyl (-) -amphetamines, which have less psychostimulant activity than the (+) -isomere, are formed.

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Binding of (-) deprenyl to serum proteins.

14C-Deprenyl binding to serum proteins has been investigated using equilibrium dialysis and gel chromatography. Experiments in the equilibrium dialysis cells were performed both for binding of deprenyl to the serum proteins and the dissociation of the previously serum bound deprenyl. Comparative investigations were made with substance E, this reference compound showed reversible binding contrary to deprenyl that remained partially irreversibly bound to the serum proteins even in such conditions when substance E became totally released.

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Captopril produces endothelium-dependent relaxation of dog isolated renal arteries. Potential role of bradykinin.

The effects of the angiotensin-converting enzyme inhibitors, captopril, lisinopril and enalapril-maleate (the latter being a prodrug that has to be converted into enalaprilat), and bradykinin were investigated in the presence or absence of indomethacin and bradykinin receptor antagonists in dog renal arterial rings precontracted with either prostaglandin F2 alpha or phenylephrine. At a high precontraction level (10 microM of prostaglandin F2 alpha), captopril did not relax the arteries. However, when the tension was low (0.5 microM), both captopril and lisinopril produced endothelium-dependent relaxations. The maximum relaxations for captopril and lisinopril were 57 +/- 6% and 64 +/- 15%, respectively. Enalapril-maleate failed to relax the renal arteries even when the vascular tone was low. In endothelium-intact arteries precontracted with phenylephrine (0.2 microM), captopril and lisinopril produced a maximum relaxation of 60 +/- 9% and 29 +/- 5%, respectively, in arteries with intact endothelium, whilst responses to enalapril-maleate were inconsistent. Renal artery rings with rubbed endothelium failed to relax in response to bradykinin or captopril. We observed significant variations in both captopril- and lisinopril-induced endothelium-dependent relaxations in one tenth of the preparations. The relaxations to bradykinin and captopril were not affected by indomethacin (3 microM), whereas they were markedly attenuated by NG-nitro-L-arginine (0.1 mM). The bradykinin-antagonist, N alpha-adamantane-acetyl-D-Arg-(Hyp3, Thi5,8, D-Phe7)BK, or the specific bradykinin2 receptor antagonist, HOE140, completely abolished the relaxation responses to captopril and reduced the potency of bradykinin, but failed to affect the acetylcholine-induced responses. The results suggest that the relaxant effect of captopril is mediated by endogenous bradykinin or by activation of bradykinin receptors. The proposed mechanisms by which captopril relaxes the renal arteries are: (1) inhibition of tissue kininase II, which leads to accumulation of endogenous bradykinin; (2) shift in angiotensin I metabolism towards (a) relaxant angiotensin derivative(s); and (3) interaction with bradykinin receptors.

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PubMedDate not supplied

Selective inhibition of the "B form" of monoamine oxidase.

Deprenyl (phenyl-isopropyl-methyl-propinylamine) is a potent inhibitor of monoamine oxidase (MAO) and like the acetylenic type of inhibitors it induces irreversible inhibition of the enzyme. Its levorotatory isomer is a more potent inhibitor than the dextrorotatory one. Deprenyl elevates the concentration of 3H-noradrenaline (3H-NA) in the synaptosomal fraction of rat heart homogenate while pargyline, probably due to its releasing effect, decreases 3H-NA content in the same fraction. Deprenyl is a selective inhibitor of the "B form" of MAO, which preferentially oxidizes beta-phenylethylamine as substrate.

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PubMedDate not supplied

[Effect of selegiline against selective neurotoxins].

The complexity of the pharmacological activity of selegiline cannot be considered only as a result of a simple MAO-B inhibition. The mechanism of its neuroprotective action against the noradrenergic neurotoxin DSP-4 was widely studied (-)-p-fluoro-deprenyl (PFD), the chemical derivative of selegiline, with its possible metabolites were also involved into these studies. The results suggested that the uptake inhibitory effect of selegiline, and mainly that of its metabolite (-)-methylamphetamine (MA), played an essential role in the protection. MA was more potent to inhibit the uptake of noradrenaline and dopamine, than the parent compound. Neither selegiline nor its metabolite inhibited the reuptake of serotonin. In respect of the protection against DSP-4 induced toxicity PFD and its metabolites behaved similarly to selegiline, but their effects were more lasting than that of selegiline. After oral treatment selegiline undergoes an intensive "first pass" metabolism, which leads to an enhanced formation of MA. The better understanding of the fate of selegiline in the body, including its pharmacokinetic behaviour and metabolism, may contribute to a better knowledge of the complex pharmacological activity of the drug. The results could be summarised as follows. a) MAO-B inhibition-which is due to the parent compound-is an irreversible "hit and run" effect, the level of which after an initial phase is independent of the presence of the substance which caused it. b) The uptake inhibition is a reversible process and strictly proportional to the concentration of the substance responsible for the effect. In this respect the uptake inhibitory action of the metabolites exceeds that of the parent compounds. The role of the reversible uptake inhibition in neuroprotection may partly explain the need of the daily administration of selegiline to parkinsonian patients in spite of the irreversible MAO-B inhibitory action of the drug.

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