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Biomedical subjects

K Magyar

Publications and source records attributed to K Magyar.

At least 199 records · Page 11Linked to original sources
PubMedDate not supplied

Determination of human serum semicarbazide-sensitive amine oxidase activity: a possible clinical marker of atherosclerosis.

Semicarbazide-sensitive amine oxidase (SSAO) is present in the plasma membrane of several human tissues, e.g. vascular smooth muscle cell adipocytes, and is also found in human serum. Some previous studies on cultured endothelial cells indicate that cytotoxic metabolites (e.g. hydrogen peroxide, formaldehyde, acrolein) formed by serum SSAO may cause endothelial injury and subsequently induce atherosclerosis. To investigate the role of this enzyme in the pathogenesis of macrovascular complications in diabetes, a simple and sensitive radiometric procedure was adapted for human serum measurements. Serum SSAO activity of 35 patients with non-insulin dependent diabetes mellitus (NIDDM) and that of 30 controls was determined using [14C]-benzylamine as substrate. The severity of atherosclerosis was assessed by carotid sonography. Diabetic patients with atherosclerosis exhibited a higher SSAO activity compared to diabetic patients without complications (212.91 +/- 90.54 pmol/mg protein/h versus 133.17 +/- 65.40 pmol/mg protein/h, P <0.04). In diabetic patients without complications, serum SSAO activity was elevated compared to control subjects (133.17 +/- 65.40 pmol/mg protein/h versus 91.79 +/- 31.70 pmol/mg protein/h, P <0.01). These results suggest that determination of human serum SSAO activity might be a useful marker in the prognostic evaluation of diabetic angiopathy and atherosclerosis.

Adult↗
PubMedDate not supplied

Biotransformation of deprenyl enantiomers.

Rats were treated with either (-)- or (+)-deprenyl, and the metabolites extracted from the plasma, liver, kidney and heart homogenates were studied by chiral capillary electrophoresis (CE). Stereoselective dealkylation of both optical isomers with the formation of desmethyldeprenyl (DD), methamphetamine (MA), and amphetamine (A) was found. (-)-MA appears to be the main metabolite of (-)-D, and (+)-A for (+)-D. This suggests that the enantiomers undergo a different dealkylation process.

Animals↗
PubMedDate not supplied

Use of TLC and multivariate mathematical statistical methods to study the interaction of monoamine oxidase inhibitory drugs with amino acids.

The interaction of 17 monoamine oxidase inhibitory drugs (propargylamine derivatives) with amino acids was studied by charge-transfer chromatography. The data set was evaluated by principal component analysis (PCA). To assess the effect of the information loss caused by normalization, PCA was separately carried out on the covariance and on the correlation matrix. The strength and selectivity of interaction was separated by the spectral mapping technique. Calculation proved that the amino group of the drugs interacted with the second carboxyl group of dicarboxylic amino acids, and that the interaction was of electrostatic character. This finding made probable the direct interaction between the drugs and the target enzyme or enzymes. The results of both PCA methods were similar. However, coordinates of the spectral map showed only slight correlation with the corresponding coordinates of the two-dimensional nonlinear maps proving the different information content of the methods.

Amino Acids↗
PubMedDate not supplied

Properties of the melanin binding of p-bromo-methylamphetamine (V-111).

The aim of the present study was to obtain detailed information on the binding properties of p-bromomethylamphetamine (V-111) to melanins under in vitro and in vivo conditions. The results obtained by the methods of both equilibrium and dynamic dialysis revealed that the binding of V-111 to bovine eye melanin was reversible, at least for the part of the binding sites, whereas the dissociation of V-111-melanin adduct was slow. The binding capacity of two different classes of binding sites of bovine eye melanin and dissociation constants of the drug-melanin complexes have been determined. The in vivo melanin binding of V-111-1-14C was studied by the method of whole body autoradiography. Extensive accumulation and retention was observed in the eyes of the pigmented mice while in the albino animal uptake was low in the corresponding tissues. In conclusion, V-111 may most probably be accumulated and retained for long periods in the pigmented cells of intact animals. Our data also imply that melanin in the pigmented cells serves as a depot, which gradually releases p-bromo-methylamphetamine resulting in a prolonged local effect of this compound.

Animals↗
PubMedDate not supplied

Studies on the biochemical mode of action of EGYT-475, a new antidepressant.

We studied the mode of action of N-benzyl-piperazine-picolinylfumarate (EGYT-475) and of its metabolite N-benzyl-piperazine (EGYT-2760) in CFY rats. It was found that EGYT-475 had no uptake-inhibitory effect but EGYT-2760 inhibited the high-affinity uptake of 3H-noradrenaline, 3H-dopamine and especially that of 3H-serotonin both in vitro and ex vivo. Neither of the two compounds changed the serotonin turnover. Only EGYT-2760 evoked hyperthermia in rats at a high ambient temperature (28 degrees C). This effect was abolished by cyproheptadine but not by amitriptyline. EGYT-2760 antagonized serotonin-induced contractions of the stomach fundus but it was inactive in inhibiting the serotonin-induced platelet aggregation. Our results suggest that EGYT-2760, an active metabolite of EGYT-475, has a central serotoninomimetic action which involves 5-HT uptake-inhibition and 5-HT1 receptor agonistic effect.

Animals↗
PubMedDate not supplied

Endothelium-dependent vasodilator actions of acetylcholine, calcium-ionophore (A23187) and substance P in perfused renal arteries from rabbits.

The role of endothelium on the responses of the perfused rabbit renal artery segments to vasoconstrictor and vasodilator agents was studied. The vasoconstrictor responses of rabbit renal arteries to phenylephrine were enhanced by endothelium destruction. Acetylcholine (ACh), calcium-ionophore (A23187) and substance P (SP), in the presence of indomethacin, induced endothelium-dependent vasodilation of the phenylephrine-constricted renal arteries. Nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, significantly reduced the dilator responses to ACh, A23187 and SP, but did not reduce the responses to sodium nitrite. In conclusion, our results provide evidence for the involvement of lipoxygenase products in the endothelium-dependent vasodilation of rabbit renal arteries to ACh, A23184 and SP.

Acetylcholine↗
PubMedDate not supplied

Critical evaluation of the in vivo selectivity between hypotensive and platelet antiaggregating actions of iloprost and prostacyclin in beagle dogs.

We compared the hypotensive and antiaggregatory effects of PGI2 and iloprost using our computerized aggregometric system. The concentration producing 50% inhibition (IC50) of ADP-induced platelet aggregation in vitro was 0.35 +/- 0.15 nM for PGI2 and 0.56 +/- 0.2 nM for iloprost (n = 5). The in vivo antiaggregatory activity was measured with a modified filtration pressure technique in anaesthetized beagle dogs. PGI2 was equipotent with iloprost in inhibiting platelet aggregation in vivo (ED25 = 0.23 +/- 0.04 nmol/kg; 0.26 +/- 0.05 nmol/kg, respectively). At the same time, PGI2 was twice as potent as iloprost in decreasing the mean arterial blood pressure (ED25 = 0.41 +/- 0.12 nmol/kg; 0.82 +/- 0.17 nmol/kg, respectively). The antiaggregatory and hypotensive effects of iloprost lasted longer in each experiment than those of PGI2; this difference reached the level of significance in the highest bolus dose range. The in vivo selectivity ratios (hypotensive potency/antiaggregatory potency) of iloprost and PGI2 were 0.32 and 0.67, respectively. The results indicate that 1) in anaesthetized beagles iloprost is somewhat more selective than PGI2 in inhibiting platelet aggregation (p less than 0.05); 2) our aggregometric system might be useful for quantitative and rapid determination of the in vivo selectivity of the new PGI2 analogues in anaesthetized beagles.

Anesthesia↗
PubMedDate not supplied

Studies on the melanin affinity of selegiline (deprenyl) and other amphetamine derivatives.

The main aim of our study was to assess the melanin affinity of selegiline as well as the pharmacologic and pharmacokinetic aspects of its binding. The in vivo melanin binding of [14C] selegiline was studied by the method of whole body autoradiography. Extensive accumulation was observed in the pigmented mouse eye while in the albino animal uptake was low in the corresponding tissues. Our in vitro investigations demonstrated that the amphetamine derivatives tested can be taken up by melanins. Scatchard analysis of selegiline binding to the dopamine melanin (structurally similar to the neuromelanin) and beef eye melanin showed that more than one class of binding sites may be implicated. The total binding capacity of the beef-eye melanin was higher than that of the dopamine melanin. The selegiline inhibition of the [3H] MPP+ (the neurotoxic metabolite of MPTP) binding to dopamine melanin was also investigated. In the studied concentration range, the binding of [3H] MPP+ was depressed to about 70 per cent of the original maximum value. In conclusion, as a result of its melanin affinity, which is demonstrated in this study, selegiline may most probably accumulate in the pigmented nerve cells. The observed melanin affinity may contribute to the application of this compound for the treatment of Parkinson's disease or may play a role in its protective effect against MPTP neurotoxicity.

Amphetamine↗
PubMedDate not supplied

Effect of MAO inhibitors on the uptake and metabolism of dopamine in rat and human brain.

Complex pharmacological effect of l-deprenyl cannot be explained by its MAO-B inhibitory action only. In contrast to other parent MAO inhibitors (J-512, J-516, LK-63, U-1424) l-, and d-deprenyl inhibit the hypothalamic noradrenaline and striatal dopamine (DA) reuptake without influencing the uptake of serotonin, both in rat and in human brain. Long-term treatment 19 x 0.25 mg/kg or 0.5 mg/kg, sc with l-deprenyl elicits 37 +/- 2.8 and 43 +/- 3.2% inhibition, respectively, of DA reuptake capacity in the rat striatal cell-free homogenate. To compare the potencies of deprenyl isomers on DA and DOPAC levels of rat striatum drugs were given 0.25, 2 and 8 mg/kg ip and their effects measured 4 and 48 h after treatment. DA content was increased only by 8 mg/kg d-deprenyl 4 h after its injection, but DOPAC level was decreased by both isomers. After 48 h, actions of d-deprenyl terminated but the effect of l-deprenyl was still present.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

MAO activity, serotonin metabolism and aggregation of platelets from migraine patients. A preliminary study.

Platelets of migraine patients showed abnormal behavior such as hyperaggregability and reduced monoamine oxidase activity (MAO). We measured the MAO activity, serotonin (5-HT) content and release, adenosine diphosphate (ADP)-induced aggregation, and the prostacyclin (PGI2) antiaggregatory effect using the same sample of platelets from migraine patients to find out if these characteristics are intercorrelated. A significant correlation between MAO activity and sensitivity to PGI2 was found.

Adenosine Diphosphate↗
PubMedDate not supplied

Vasodilator responses in perfused rabbit kidney: the role of endothelium.

The responses to vasodilator agents of renal vasculature were studied in perfused rabbit kidney. Acetylcholine (ACh) and calcium-ionophore (A23187), as endothelium-dependent relaxing agents, and prostacyclin (PGI2), an endothelium-independent vasodilator, induced a rapid and reversible fall in perfusion pressure of the noradrenaline (NA) constricted renal vasculature. The vasodilator responses of the preparations were not lost after perfusing the kidney with hypotonic Krebs-solution or 10 mumol/l mepacrine. Collagenase treatment significantly reduced the vasodilator responses, not only to ACh and A23187, but also to PGI2. Perfusion of the renal vascular bed with dexamethason did not influence the vasodilator responses. Exposure of the renal vasculature to p-bromophenacylbromide (PBPB), which is a known inhibitor of phospholipases, markedly reduced the ACh- and A23187-induced vasodilatation. The responses to PGI2, however, were also moderately depressed in the presence of PBPB. The lipoxygenase-inhibitor nordihydroguaiaretic acid (NDGA), inhibited the responses to ACh and A23187, but did not reduce the responses to PGI2. Some commonly used methods and chemicals, that have been successful in destroying the endothelium of large vessels, were not effective in renal vasculature. We failed to demonstrate that the inhibitory actions of these treatments were specific for the endothelium-dependent responses. Our results provide indirect evidence for the involvement of lipoxygenase products in the vasodilatation responses of the rabbit kidney and for a possible role of endothelium in the reactivity of renal vasculature.

Animals↗
PubMedDate not supplied

Pharmacokinetic aspects of the mode of action of EGYT-475, a new antidepressant agent.

EGYT-475 (N-benzyl-piperazine-picolinyl fumarate; Trelibet) metabolism was compared in rats, dogs and man. In the rat 7 urinary metabolites of EGYT-475 were found, and 4 were identified as: N-picolinyl-piperazine (EGYT-1354) (30%), picolinic acid (28.5%), hippuric acid (53%) and N-benzylpiperazine (EGYPT-2760) (3.7%). The results show that debenzylation is the main route of EGYT-475 metabolism in the rat. By this route EGYT-2760, the active EGYT-475 metabolite, is further metabolized. In the dog the main metabolic pathway is hydrolysis, and because of that the formed EGYT-2760 is not metabolized further and its urinary content exceeds 50%. In man, similarly as in the rat, debenzylation is the preferred route of EGYT-475 metabolism. These results explain much higher toxicity of EGYT-475 in dogs than in rats and man.

Animals↗
PubMedDate not supplied

In vitro metabolic study of EGYT-3615 using rat liver microsomes.

In vitro metabolism of EGYT-3615, a prospective new antidepressant was studied by using rat liver microsomes. The metabolite (M) found in earlier in vivo studies was unanimously found to be the product of a microsomal enzymatic process. The Michaelis-Menten constant of the reaction was calculated.

Animals↗
PubMedDate not supplied

The metabolism of EGYT-475, a new antidepressant agent, in rats.

The metabolites of EGYT-475 excreted by the kidney were studied in rats using radioactive analogues of the compound tested. 40% of the total radioactivity was found in rat urine which was collected over 48 h, pooled, centrifuged, membrane-filtered, and from which the metabolites were separated by combined chromatographic procedures or extracted after acidic hydrolysis. Gas chromatographic and GC/MS studies showed that 31.1% of the radioactivity found in urine proved to be picolinyl-piperazine, 3.7% was N-benzyl-piperazine and 28.5% of it was picolinic acid. Hippuric acid accounted for 53.2% of the radioactivity of the acid hydrolyzed urine.

Animals↗
PubMedDate not supplied

Species differences in the in vitro metabolism of EGYT-475, a new antidepressant agent.

The metabolism of N-benzyl-piperazine-picolinyl fumarate (EGYT-475), a new antidepressant agent, was studied in rat and dog liver homogenate and microsomes. The metabolites were separated by HPLC technique. Quantitative analysis was performed using radioactive labelled form of EGYT-475. The metabolic pathways of EGYT-475 in both species involve hydrolysis in the piperazine-picolinyl part and oxidation of the benzyl group to benzoic acid. The rate of these transformations differs in the two species. The possibility of the formation of polar conjugates was also studied.

Animals↗
PubMedDate not supplied

Studies on serum binding of some drugs.

Binding of three potential antidepressive compounds, EGYT-3615, EGYT-475 (trelibet) and EGYT-2760 to human serum was investigated by equilibrium dialysis method using radiolabelled drugs. All three compounds bound to serum proteins and the binding was sensitive to pH and salt concentration. The binding of trelibet and EGYT-3615 was not saturable at a wide range of drug concentration. The results show that EGYT-3615 has both specific and non-specific, while trelibet has only non-specific binding sites on serum proteins.

Antidepressive Agents↗
PubMedDate not supplied

Inhibition by deprenyl of dopamine uptake in rat striatum: a possible correlation between dopamine uptake and acetylcholine release inhibition.

Optical isomers of deprenyl inhibit the resting and ouabain induced release of acetylcholine (ACh) in isolated striatal slices of the rat and this effect correlates with the capability of deprenyl to inhibit the uptake of 3H-dopamine in striatal homogenate in a concentration of 10(-4)--10(-4) M. The release of ACh is significantly increased in striatal slices taken from rats pretreated with a single dose of 250 micrograms of 6-hydroxydopamine. 5 mg/kg of deprenyl given 30 min prior to 6-hydroxydopamine treatment prevented completely the chemical destruction of the dopaminergic neurons. In contrast to deprenyl, clorgyline potentiated the effect of 6-hydroxydopamine.

Acetylcholine↗