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Biomedical subjects

J Lengyel

Publications and source records attributed to J Lengyel.

At least 19 recordsLinked to original sources
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

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

Control of early neurogenesis of the Drosophila brain by the head gap genes tll, otd, ems, and btd.

The progenitors of the Drosophila central nervous system (CNS), called neuroblasts, segregate from the neurectoderm of the early embryo in a stereotyped pattern. The neuroblasts that give rise to the brain segregate from the procephalic neurectoderm and form three neuromeres, called protocerebrum, deuterocerebrum, and tritocerebrum. The expression of the proneural genes of the achaete-scute complex (AS-C) is required for neurectodermal cells to acquire the competency to form neuroblasts. We show here that the expression of the proneural gene lethal of scute (l'sc) is required for the development of the majority of the procephalic neuroblasts. l'sc expression in the procephalic neurectoderm is controlled by the head gap genes tailless (tll), orthodenticle (otd), buttonhead (btd), and empty spiracles (ems), which are expressed in partially overlapping domains of the head neurectoderm. Loss of function of a given head gap gene results in the absence of l'sc expression in its domain, followed by the absence of neuroblasts that would normally segregate from this domain. Loss of tll function results in the absence of all protocerebral neuroblasts, otd functions in a domain that includes a large part of the protocerebrum and a smaller part of the adjacent deuterocerebrum. Both ems and btd are required in partially overlapping subsets of neuroblasts of the deuterocerebrum and tritocerebrum.

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↗
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↗
PubMed1990

Determination of N-(3-nitro-4-quinoline)morpholino-4-carboxamidine in plasma high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method was developed for the determination of the radiosensitizing agent N-(3-nitro-4-quinoline)morpholino-4-carboxamidine (EGIS-4136) in plasma using an internal standard. HPLC separation was achieved on a LiChrosorb C18 column using acetonitrile-sodium acetate buffer (pH 7.2) (40:60) as the mobile phase and UV detection at 330 nm. The plasma samples were prepared for measurement by protein precipitation with methanol and centrifugation. The assay was validated with respect to linearity, sensitivity, accuracy, precision, stability and recovery in plasma. The limit of detection for EGIS-4136 in plasma was 0.05 microgram/ml. A straight line was obtained on plotting the peak-area ratio of EGIS-4136 to the internal standard against concentration in plasma in the range 0.1-20 microgram/ml. The method was applied to study the pharmacokinetics of EGIS-4136 in six male rats after a single oral dose of 50 mg/kg, and allowed the compound to be monitored in the concentration range 5-10 micrograms/ml occurring in rats 24 h post-administration.

Administration, Oral↗
PubMed1989

[Not Available].

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History of Pharmacy↗
PubMed1989

[Not Available].

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History of Pharmacy↗
PubMed1989

[Not Available].

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History of Pharmacy↗
PubMed1988

[Not Available].

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History of Pharmacy↗
PubMed1984

[Not Available].

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History of Pharmacy↗
PubMed1975

hnRNA size and processing as related to different DNA content in two dipterans: Drosophila and Aedes.

The size of hnRNA transcripts and the fraction of hnRNA that is converted to mRNA in cell lines of Drosophila melanogaster and Aedes albopictus are compared. Both insects belong to the order Diptera, but Aedes has a 5-6 fold larger genome than does Drosophila. The Aedes line produces significantly (2-2.5 fold) larger hnRNA than does the Drosophila line, even though the two cell lines grow under similar conditions and produce mRNA of the same size and sequence complexity. These data suggest that within a given taxonomic order, the size of hnRNA increases with increasing genome size. The fraction of hnRNA converted to mRNA [cytoplasmic poly(A)+ RNA] has been measured for the two cell types by comparing initial rates of labeling of hnRNA with initial rates of appearance of labeled mRNA in the cytoplasm. While 20of the Drosophila hnRNA is converted to mRNA, only 3.3% of the Aedes hn %RNA is converted to mrRNA. The poly(A) content of the hnRNA from the two species is also different; Drosophila hnRNA has approximately three times as much poly(A) as does Aedes hnRNA. The data show-at least for these two species-that the average amount of hnRNA transcribed relative to the amount of mRNA formed increases as genome size increases. The data are consistent with the interpretation that more DNA is transcribed into hnRNA in Aedes, the organism with the larger genome, than in Drosophila.

Adenine Nucleotides↗