Search PubMed⌕ Search

Biomedical subjects

Z Kleinrok

Publications and source records attributed to Z Kleinrok.

At least 73 records · Page 4Linked to original sources
PubMed1998

Preliminary pharmacokinetic studies of Ukrain in rats.

Ukrain (thiophosphoric acid derivative of Chelidonium majus L. alkaloids) was administered to rats i.p. at a dose of 28 mg/kg (equivalent to 0.1 LD50). A high performance liquid chromatography (HPLC) method for rapid determination of Ukrain in plasma has been described. It was found that Ukrain rapidly penetrated into the plasma of the rats and the elimination of the drug from the plasma was slower. The results obtained were as follows: absorption rate constant ka = 0.0432 [min-1]; elimination rate constant K = 0.0113 [min-1]; drug half-life t1/2 = 61.32 min; actual concentration of Ukrain in the plasma C = 33 e-0.0113t - 39 e-0.0432t [microgram/ml]; and delay in drug absorption T0 = 5.23 min.

Alkaloids↗
PubMed1998

Modification of antinociceptive action of Ukrain by endogenous nitric oxide in the writhing syndrome test in mice.

The effects of L-arginine, the physiological precursor of nitric oxide (NO), and inhibitors of NO-synthase on the antinociceptive action of Ukrain (4.75, 9.5, and 19.0 mg/kg i.p.) were investigated using the writhing syndrome test in mice. It was found that L-arginine (0.1 or 1.0 mg/kg i.p.) significantly decreased or enhanced the antinociceptive effect of Ukrain, depending on the combination administered. In addition, the inhibitors of NO-synthase NG-nitro-L-arginine methyl ester (L-NAME) (1.0 and 10 mg/kg i.p.), 7-nitroindazole (1.0 mg/kg i.p.) and NG-monomethyl-L-arginine acetate (L-NMMA) (1.0 mg/kg i.p.) significantly enhanced Ukrain-induced antinociception. These results suggest that endogenous NO can modify the antinociceptive effect of Ukrain.

Alkaloids↗
PubMed1998

Interaction between Ukrain and Naltrexone in the writhing syndrome test in mice.

The interaction between Ukrain and Naltrexone, a nonselective opioid receptor antagonist, was studied in the 'writhing syndrome' test in mice. Naltrexone (1 mg/kg s.c.) was administered i.p. 30 min before Ukrain (2.375, 4.75, 9.5 and 19 mg/kg). In addition, the antinociceptive properties of Ukrain and Naltrexone in 10-day treatment in mice were studied. The results show that the antinociceptive effect of both single dose and prolonged administration of Ukrain is completely antagonized by Naltrexone.

Alkaloids↗
PubMed1998

[The effect of lithium chloride on the rat behavior after short-term oligemic hypoxia].

The experiments were carried out on male Wistar rats. The influence of brain oligemic hypoxia and lithium chloride (LiCl) on some behavioural parameters was investigated. Reduction of brain blood supply was performed by surgical clamping of both carotid arteries for 60 min in general anaesthesia induced by brietal (Methoxitone sodium, 10 mg/kg i.p.). Control animals had their vessels separated, but not clamped (sham operated). 6 days after surgery animals received LiCl (2.5 mEq/kg i.p.). Behavioral experiments were performed 24 h and 7 days after lithium administration. Experimental groups consisted of 12 animals. It was found that oligemic hypoxia reduced inconsiderably spontaneous locomotor and exploratory activity in rats. Similar influence of LiCl was observed. But LiCl administered to animals after oligemic hypoxia prevented them against locomotor and exploratory impairment. In addition, LiCl strongly enhanced amphetamine-induced hyperactivity and diminished haloperidol-induced catalepsy in hypoxic animals. These effects were not observed in sham operated animals. The above results could be connected with antidepressive action of LiCl and the model of moderate oligemic hypoxia used in present work could be a useful model for investigation of new antidepressive compounds.

Amphetamine↗
PubMed1998

Excitatory amino acids in epilepsy.

Epilepsy has been described as a neurological disorder with a prevalence rate estimated at approximately 0.5% of population. In recent years there have been significant advances in our understanding of the contribution of excitatory glutamatergic transmission to seizures. Glutamate appeared to participate in the initiation, propagation and maintenance of epileptic activity. In epileptic patients, changes in glutamate concentration and receptor function were found. Intracerebral or systemic administration of glutamate receptor agonists has become a popular way to induce seizures in rodents. Glutamate antagonists were shown to be potent anticonvulsants in varying experimental seizure models determined genetically, induced chemically and electrically, or due to kindling. A potential therapeutic role for drugs affecting glutamatergic mechanisms in epilepsy has not yet been defined but is constantly attracting interest. In this review we summarize data from studies performed in humans and animals and focus on iono- and metabotropic excitatory amino acid receptor-mediated events in seizures and epilepsy.

Journal Article↗
PubMed1998

GABA content and GAD activity in colon tumors taken from patients with colon cancer or from xenografted human colon cancer cells growing as s.c. tumors in athymic nu/nu mice.

A significantly high GABA level and GAD activity was found in human colon cancer tissue as compared with normal macroscopically unchanged human colon wall taken from the same patients. Similarly in athymic nu/nu mice transplanted with human colon adenocarcinoma cells established in in vitro culture (line CX-2) the high level of GABA accompanied by high GAD activity was found in subcutaneously growing tumors as compared with the unchanged colon wall and unchanged skin tissue from the same tumor bearing mice. Interestingly, the level of GAD activity in the macroscopically unchanged colon tissue of mice transplanted with tumor cells were increased in comparison with normal colon of healthy control mice. For the skin, only GAD activity was higher in the material coming from tumor bearing mice than in the material from normal control mice, whereas GABA level was even lower in the skin of tumor inoculated mice compared with control group. An increase in GABA level and in GAD activity can perhaps reflect a local immune response to the neoplastic process. The observed direction of GABA metabolism in tumor of the colon indicates a possibility to interfere in this process using the agonists of the GABA-ergic system.

Adenocarcinoma↗
PubMed1997

Impairment of brain kynurenic acid production by glutamate metabotropic receptor agonists.

The role of glutamatergic mechanisms in kynurenic acid (KYNA) production was evaluated in vitro. The selective ionotropic agonists NMDA, kainate and AMPA did not affect KYNA synthesis. Agonists of metabotropic (mGLU) and ionotropic receptors: quisqualate, L-glutamate and L-aspartate as well as agonists of mGLU receptors: (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) diminished KYNA production with different potency. None of the studied mGLU antagonists such as (S)-4-carboxyphenylglycine, alpha-ethylglutamic acid or (RS)-alpha-methylserine-O-phosphate affected the basic or L-glutamate-inhibited synthesis of KYNA. It might be hypothesized that the impairment of KYNA production following the application of mGLU receptor agonists is related to their effects exerted upon the novel subtype of mGLU receptor.

Animals↗
PubMed1997

Isobolographic analysis of interaction between intrathecal morphine and clonidine in the formalin test in rats.

The formalin test, an experimental model of injury-induced central sensitisation, was used. The antinociceptive interaction between intrathecal morphine and clonidine was evaluated based on the inhibition of the phase 1 and 2 of the formalin response, induced by both drugs, given alone or in combinations with fixed dose ratios. Morphine and clonidine, at doses not affecting motor performance, produced dose-dependent inhibition in the formalin test, with similar ID50 values in phase 1 and 2; 0.66 and 0.45 nmol and 4.1 and 3.5 nmol, respectively. Isobolographic analysis revealed a significant synergy. The combination ID50 was found to be significantly lower than the respective theoretical additive ID50 for both fixed dose ratios (1:3 and 1:10) in both phases of the formalin test. The similar total dose fraction of the additive ID50 in phase 1 and 2 indicates the same magnitude of synergy and may suggest that the mechanisms of the spinal clonidine-morphine synergy do not differ significantly between both phases of the formalin test.

Adrenergic alpha-Agonists↗
PubMed1997

Influence of 7-nitroindazole on the anticonvulsive action of conventional antiepileptic drugs.

7-Nitroindazole (a selective neuronal nitric oxide (NO) synthase inhibitor) at 25 and 50 mg/kg, 30 min before the test, did not influence the electroconvulsive threshold. However, at 50 mg/kg, it enhanced the anticonvulsive activity of phenobarbital against maximal electroshock and did not affect that of carbamazepine, diphenylhydantoin and valproate. L-Arginine (500 mg/kg) did not modify the protective activity of phenobarbital alone or the 7-nitroindazole-induced enhancement of its anticonvulsive potency against maximal electroshock. 7-Nitroindazole did not alter the plasma levels of antiepileptic drugs, so a pharmacokinetic interaction, in terms of total and free plasma levels, is not probable. 7-Nitroindazole combined with the antiepileptics resulted in motor disturbances, except for the combination with phenobarbital. On the other hand, the combined treatment of 7-nitroindazole with carbamazepine or phenobarbital produced effects superior to those produced by single drugs, as regards long-term memory. Our results indicate that the protective activity of carbamazepine, diphenylhydantoin, or valproate against maximal electroshock may be not dependent upon the central NO level. The enhancement of the anticonvulsive action of phenobarbital by 7-nitroindazole is probably not related to the decrease of NO in the central nervous system.

Animals↗
PubMed1997

N6-2-(4-aminophenyl)ethyl-adenosine enhances the anticonvulsive activity of antiepileptic drugs.

N6-2-(4-Aminophenyl)ethyl-adenosine (APNEA, a non-selective agonist of the adenosine A3 receptors), at the subprotective dose of 1 mg/kg against electroconvulsions, significantly potentiated the anticonvulsive action of phenobarbital, diphenylhydantoin and valproate against maximal electroshock, being ineffective at lower doses. APNEA (0.0039-1 mg/kg) also enhanced the protective activity of carbamazepine. Aminophylline (5 mg/kg) and 8-cyclopentyl-1,3-dimethylxanthine (8-CPX, 5 mg/kg), reversed the APNEA (1 mg/kg)-induced enhancement of the anticonvulsive action of phenobarbital, diphenylhydantoin and valproate, but not that of carbamazepine produced by APNEA at 0.0039 mg/kg. The adenosine agonist did not alter the plasma levels of antiepileptic drugs studied, so a pharmacokinetic interaction is not probable. Finally, APNEA (0.0156 and 1 mg/kg) administered alone or in combination with carbamazepine significantly decreased the body temperature and impaired long-term memory. Our results suggest that APNEA at low doses potentiates the protective activity of carbamazepine most likely through the A subtype of adenosine receptors. At higher doses, APNEA seems to enhance the anticonvulsive effect of other antiepileptics via adenosine A1 receptors.

Adenosine↗
PubMed1997

Influence of isradipine, niguldipine and dantrolene on the anticonvulsive action of conventional antiepileptics in mice.

We report the effects of two new dihydropyridine derivatives, isradipine (4-(4'-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedic arboxylic acid methylisopropylester) and niguldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid 3-(4,4-diphenyl-1-piperidinyl)-propyl methyl ester hydrochloride), and of dantrolene (1-[(5-[p-nitrophenyl]furfurylidene)-amino]hydantoin sodium, an inhibitor of Ca2+ release from intracellular stores) on the protective efficacy of antiepileptic drugs against maximal electroshock-induced seizures. It was shown that dantrolene (5-20 mg/kg), isradipine (5-10 mg/kg) and niguldipine (up to 2.5 mg/kg) did not influence the electroconvulsive threshold in mice, although a higher dose of niguldipine (5 mg/kg) significantly elevated it. Dantrolene (10-20 mg/kg) and isradipine (1 mg/kg) did not affect the anticonvulsive activity of conventional antiepileptic drugs. In contrast, niguldipine (2.5-5 mg/kg) impaired the protective action of carbamazepine and phenobarbital. No effect of niguldipine (2.5-5 mg/kg) was observed upon the anticonvulsive efficacy of diphenylhydantoin and valproate. BAY k-8644 (methyl-1,4-dihydro-2,6-dimethyl-5-nitro-4- [(2-trifluoromethyl)-phenyl]-pyridine-5-carboxylate, an L-type Ca2+ channel agonist) did not reverse the action of niguldipine alone or the niguldipine-induced impairment of the anticonvulsive action of carbamazepine and phenobarbital. Niguldipine did not influence the free plasma levels of carbamazepine and phenobarbital, so a pharmacokinetic interaction is not probable. The results suggest that in contrast to the anticonvulsive activity of niguldipine against electroconvulsions, this Ca2+ channel inhibitor significantly weakened the protective action of both carbamazepine and phenobarbital. These effects do not seem to result from the blockade of voltage-dependent Ca2+ channels. Isradipine and dantrolene did not have a modulatory action on the threshold for electroconvulsions or on the anticonvulsive activity of antiepileptic drugs. It may be concluded that the use of niguldipine, isradipine, and dantrolene in epileptic patients seems questionable.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1997

Anticonvulsant and adverse effects of MK-801, LY 235959, and GYKI 52466 in combination with Ca2+ channel inhibitors in mice.

This study was designed to investigate the influence of the calcium (Ca2+) channel inhibitors nicardipine, nifedipine, and flunarizine on the protective action of MK-801, LY 235959 [N-methyl-D-aspartate (NMDA) receptor antagonists], and GYKI 52466 (a non-NMDA receptor antagonist) against electroconvulsions in mice. Unlike nicardipine (15 mg/kg) or flunarizine (10 mg/kg) nifedipine (7.5 and 15 mg/kg) potentiated the protective potency of MK-801 (0.05 mg/kg), as reflected by significant elevation of the convulsive threshold (a CS50 value of the current strength in mA producing tonic hind limb extension in 50% of the animals). The protective activity of LY 235959 and GYKI 52466 was reflected by their ED50 values in mg/kg, at which the drugs were expected to protect 50% of mice against maximal electroshock-induced tonic extension of the hind limbs. Nicardipine (3.75 15 mg/kg), nifedipine (0.94-15 mg/kg), and flunarizine (2.5-10 mg/kg) in a dose-dependent manner markedly potentiated the antiseizure efficacy of LY 235959. Flunarizine (5 and 10 mg/kg) was the only Ca2+ channel inhibitor to enhance the protective action of GYKI 52466 against electroconvulsions. Except with MK-801 + flunarizine (motor performance) or GYKI 52466 + flunarizine (long-term memory), combination of NMDA or non-NMDA receptor antagonists with Ca2+ channel inhibitors produced an impairment of motor performance (evaluated in the chimney test) and long-term memory acquisition (measured in the passive avoidance task) as compared with vehicle treatment.

Animals↗
PubMed1997

Effects of dopaminergic agonists and antagonists on the serum prolactin levels in alcoholized rats.

A single dose of ethanol (1 g/kg p.o.) significantly decreased, whereas higher doses of ethanol (2 or 3 g/kg p.o.) significantly increased the serum prolactin (PRL) concentration. Administration of ethanol at a dose of 2 g/kg p.o. for 4 weeks did not affect this parameter but the ethanol withdrawal syndrome caused a significant rise in the serum PRL level. Chronic studies showed that D1-dopaminergic agonist SKF 38390 (2.5 mg/kg) significantly raised serum PRL levels in rats. This effect was reversed by long-lasting treatment of rats with ethanol and ethanol withdrawal. Pimozide (1 mg/kg), D2 antagonist, increased PRL in those rats. On the other hand, D1-antagonist SCH 23390 (0.5 mg/kg) and D2-agonist PPHT (0.5 mg/kg) were without effect in rats administered ethanol for a long period of time. In rats with ethanol withdrawal syndrome, administration of D1-antagonist SCH 23390 (0.5 mg/kg) also did not affect the serum PRL concentrations. However, D1-agonist SKF 38393 (2.5 mg/kg) and D2-antagonist pimozide (1 mg/kg) increased the serum PRL level in rats with ethanol withdrawal syndrome, whereas D2 agonist PPHT (2 mg/kg) decreased PRL level in serum. Thus, the acute effect of ethanol on PRL level appears to be dose-dependent. It seems that chronic ethanol administration and its withdrawal especially affected D1 receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Transformation of some pyrido[2,3-d]pyrimidine derivatives into other di- and triheterocyclic systems.

It was stated that three analogous ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylates (7-9) react with hydrazine hydrate giving derivatives of the new heterocyclic system pyrido[2,3,4-ef]pyridazino[3,4-e]-1,2,4-triazepine (10-12), pyrido[3,4-d]pyridazine (16-18) and pentaazaphenalene (13-15). The latters were formed in low yields. The results of the preliminary pharmacological study of 2 of these compounds are reported.

Analgesics↗
PubMed1996

Ca2+ channel blockade and the antielectroshock activity of NMDA receptor antagonists, CGP 40116 and CGP 43487, in mice.

Nicardipine, nifedipine and flunarizine showed anticonvulsive activity (reflected by significant elevations of the seizure threshold for tonic hindlimb extension) in doses of 20, 20 and 15 mg/kg, respectively. In combination studies, CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] or its methyl ester derivative (CGP 43487) was administered in a constant dose of 0.25 and 3.5 mg/kg, respectively. At these doses both competitive NMDA receptor antagonists were able to elevate significantly the convulsive threshold. Nicardipine, nifedipine, and flunarizine were administered at maximal doses (or lower) not affecting the convulsive threshold (15, 15 and 10 mg/kg, respectively). The protective activity of CGP 40116 and CGP 43487 was dose dependently potentiated by all three Ca2+ channel inhibitors. The combined treatment caused motor impairments (evaluated in the chimney test) and long-term memory deficits (measured in the passive avoidance task) similar to these produced by CGP 40116 or CGP 43487 alone. Our results indicate that nicardipine, nifedipine and flunarizine significantly potentiate the protective activity, but not the adverse effects, of CGP 40116 and CGP 43487 in mice.

2-Amino-5-phosphonovalerate↗
PubMed1996

NG-nitro-L-arginine differentially affects glutamate- or kainate-induced seizures.

The effects of nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (NNA) on seizures induced by excitatory amino acids, bicuculline, pentylenetetrazol and pilocarpine were studied in mice. NNA (10 and 40 mg kg-1, i.p.) enhanced the susceptibility to intracerebroventricular (i.c.v.) kainate (KA) which was reflected by a decrease in its convulsant dose 50% (CD50) from 0.66 nmol to 0.38 and 0.29 nmol/mouse, respectively. Also, NNA (40 mg kg-1) increased the KA-induced mortality. Conversely, NNA (40 mg kg-1) produced an anticonvulsant effect against i.c.v. glutamate whose CD50 value was significantly elevated from 0.49 mumol to 0.84 mumol/mouse. The convulsive activity of i.c.v. N-methyl-D-aspartic acid (NDMA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) was not affected by the pretreatment with NNA (40 mg kg-1). NNA (5-40 mg kg-1) also potentiated the convulsive action of systematic KA and KA-induced mortality but (up to 40 mg kg-1) remained without effect on seizures produced by bicuculline, N-methyl-D, L-aspartic acid (NMDLA), pentylenetetrazol, and pilocarpine. Only bicuculline-produced lethality was significantly enhanced. It may be concluded that the manipulation of the NO level affects differently seizures arising from a diffuse stimulation of glutamate receptors and seizures resulting from an activation of an individual subtype of these receptors. It is noteworthy that in the majority of convulsive tests used in this study, NNA exerted no modulatory effect.

Animals↗