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Biomedical subjects

Z Kleinrok

Publications and source records attributed to Z Kleinrok.

At least 55 records · Page 3Linked to original sources
PubMed1998

Mitochondrial toxin 3-nitropropionic acid evokes seizures in mice.

3-Nitropropionic acid, a potent inhibitor of succinate dehydrogenase which thus compromises cellular energy metabolism, evoked convulsions in mice in a dose-dependent manner. CD50 for clonic seizures was 158.5 (144.1-174.3) mg/kg. Tonic seizures were not observed. Broad-spectrum anticonvulsants, namely diazepam, phenobarbital and valproate, prevented the occurrence of 3-nitropropionic acid-induced seizures with ED50 of 4.9 (3.1-7.6), 33.1 (17.9-61.0) and 389.7 (351.2-432.3) mg/kg, respectively. Diphenylhydantoin-like drugs (diphenylhydantoin, and carbamazepine), anti-absence drugs (trimethadione and ethosuximide) and acetazolamide were ineffective. The characteristics of 3-nitropropionic acid-induced seizures resembled those of convulsions evoked by another mitochondrial toxin, aminooxyacetic acid.

Animals↗
PubMed1998

Investigations on the synthesis and properties of N-phenyl derivatives of 1,4-dioxo(1,4,5-trioxo)-1,2,3,4-tetra(1,2,3,4,5,6-hexa) hydropyrido-[3,4-d]pyridazines and allied compounds.

2-(1-Piperidino)- and 2-(4-methyl-1-piperazinyl)-6-methyl-3,4-pyridinedicarboximides (1, 2) react with N-phenylhydrazine yielding N-phenylamino-3,4-pyridinedicarboximides (7, 8). The same reaction with 1,6-dimethyl-2-oxo-1,2-dihydro- and 2-chloro-6-methyl-3,4-pyridinedicarboximides (3, 17) gives the salts of the corresponding N-phenylpyridopyridazines with phenylhydrazine (13, 18), which transform into N-phenylaminoimides (14, 19) during boiling in 80% acetic acid. Compounds 7, 8 and 14 isomerize to the corresponding 2-phenyl-1,4-dioxo(1,4,5-trioxo)-1,2,3,4-tetra(1,2,3,4,5,6-hexa) hydropyrido[3,4-d]pyridazines (9, 10, 15) under the influence of heating in alcoholic solution of C2H5ONa or CH3ONa. Only in the case of imide 19 are 2- and 3-phenyl isomers (20 and 21) formed under these conditions. Some of the obtained compounds were pharmacologically active.

Animals↗
PubMed1998

2-Substituted-3-oxoisothiazolo[5,4-b]pyridines as potential central nervous system and antimycobacterial agents.

The 2-[3-(substituted-amino)-2-hydroxypropyl]-4,6-dimethyl-3-oxo-2,3- dihydroisothiazolo[5,4-b]pyridines 3 were synthesized and pharmacologically evaluated in animal models. The preliminary pharmacological screening study showed that the investigated compounds were toxic and had no significant activity in central nervous system (CNS) tests. Additionally, compounds 3, and several other 2-substituted-4,6- dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridines described here (2), together with those (4) reported in a previous paper, were evaluated in vitro against Mycobacterium tuberculosis H37Rv. For comparison, products of the rearrangement of some isothiazolopyridine 1,1-dioxides (4a,b) with the corresponding pyrido[3,2-e]-1,2-thiazines (5a,b) and different N2-substituted derivatives of the latter (5c-i) were also prepared and investigated in antimycobacterial tests. The most potent antituberculars of the 23 compounds assayed are 2-[3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]-4,6-dimethyl-3-oxo- 2,3- dihydroisothiazolo[5,4-b]pyridine 3d and ethyl (4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridin-2-yl)acet ate 4c (MIC < 12.5 micrograms/ml, 100 and 98% inhibition, respectively).

Analgesics↗
PubMed1998

Felbamate demonstrates low propensity for interaction with methylxanthines and Ca2+ channel modulators against experimental seizures in mice.

The aim of this study was to determine the interaction potential of the new antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with three Ca2+ channel blockers (nicardipine, nifedipine, and flunarizine), one Ca2+ channel activator (Bay K 8644; 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridi ne carboxylic acid), and two methylxanthines (caffeine and aminophylline (theophylline2 . ethylenediamine)) which are all known to markedly change protective effects of conventional antiepileptic drugs. To do so, the maximal electroshock seizure test in mice (an experimental model predicting drug efficacy in the treatment of human generalized tonic-clonic seizures) was employed to (1) quantify changes in the protective efficacy and potency of felbamate produced by adjunct drugs and (2) assess the ability of aminophylline and caffeine to affect protective efficacy afforded by a submaximal protective dose of felbamate against maximal electroshock-induced seizures. Doses of adjunct drugs were selected based on their effects on the threshold for electroconvulsions and on appropriate literature. Nicardipine (10-30 mg/kg), nifedipine (5-20 mg/kg), flunarizine (2.5-10 mg/kg), Bay K 8644 (2.5-5 mg/kg), and aminophylline (50-75 mg/kg) did not change the protective efficacy and potency of felbamate against maximal electroshock-induced tonic convulsions. Aminophylline in the dose of 100 mg/kg, however, diminished the protective potency of felbamate as evidenced by a statistically significant increase in the protective ED50 value of felbamate (a dose, in mg/kg, predicted to protect 50% of mice against convulsive stimulus) from 79.6 to 118 mg/kg; P < 0.05). Aminophylline and caffeine only at high doses (100 and 161.7 mg/kg, respectively) significantly diminished the protective efficacy of felbamate (110 mg/kg) from 96% to 27% and 40% (P < 0.05), respectively. In conclusion, felbamate shows low interaction potential with Ca2+ channel modulators and methylxanthines. Such low interaction potential clearly differentiates felbamate from conventional antiepileptic drugs where protective effects are readily altered by the compounds tested in the present study.

Aminophylline↗
PubMed1998

Chlormethiazole anticonvulsive efficacy diminished by N-methyl-D-aspartate but not kainate in mice.

The aim of this study was to evaluate the effect of N-methyl-D-aspartate (NMDA) and kainate used at nonconvulsive doses upon protective efficacy of chlormethiazole against maximal electroshock-induced seizures. NMDA (50 mg/kg, i.p.) reduced the anticonvulsant potency of chlormethiazole increasing its ED50 value from 126.9 to 155.0 mg/kg. The effect of NMDA was completely reversed by the competitive NMDA receptor antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) (0.06 mg/kg i.p.). Kainic acid (9 mg/kg i.p.) did not affect the anticonvulsive properties of chlormethiazole. Our results suggest that NMDA but not kainate receptor-mediated events participate in the anticonvulsant action of chlormethiazole.

2-Amino-5-phosphonovalerate↗
PubMed1998

Effect of non-steroidal anti-inflammatory drugs on the anticonvulsive activity of valproate and diphenylhydantoin against maximal electroshock-induced seizures in mice.

Prostaglandins and their inhibitors may affect convulsive phenomena. Thus, the aim of this study was to examine possible interactions between non-steroidal anti-inflammatory drugs and two conventional antiepileptic drugs in terms of their anticonvulsive activity and side-effects. Also, the plasma levels of antiepileptics were measured in order to delineate possible pharmacokinetic interactions. The following non-steroidal anti-inflammatory drugs (NSAIDs) were studied: acetylsalicylic acid, ibuprofen, indomethacin, metamizole, paracetamol and piroxicam. None of these drugs affected the threshold for electroconvulsions. However, all NSAIDs studied enhanced the protective activity of valproate magnesium against maximal electroshock-induced seizures. Only ibuprofen and piroxicam enhanced the anticonvulsive activity of diphenylhydantoin. Ibuprofen decreased the ED50 value of valproate (for the induction of motor impairment) in the rotorod test, whilst piroxicam reduced the ED50 value of valproate in rotorod and chimney tests. Diphenylhydantoin combined with either ibuprofen or piroxicam did not cause any motor impairment in these tests. The total plasma level of valproate and free plasma level of diphenylhydantoin remained unchanged in the presence of all studied NSAIDs. These data demonstrate that NSAIDs could enhance the protective activity of antiepileptics. However, in case of valproate it may be associated with the severe side effects.

Animals↗
PubMed1998

Influence of intracerebroventricular administration of tetanus toxin on experimental seizures and protection afforded by some antiepileptic drugs in mice.

The dose to the intracerebroventricularly administered (i.c.v.) tetanus toxin (Tetx) evoking the death of 50% of experimental mice (LD50) was estimated to be 18.0 (11.5-28.2) times the minimal lethal dose (MLD). MLD is defined as the lowest does of Tetx necessary to kill a 20-g albino mouse within 96 h after intraperitoneal treatment. Tetx (0.25 and 0.5 LD50) increased the convulsive threshold of electric current from 24 to 96 and 120 h, respectively, following i.c.v. administration. Both doses of Tetx diminished convulsant potencies of pentylenetetrazole, bicuculline, aminophylline and pilocarpine 24 h after application. At the same time Tetx (0.5 LD50) increased the protection afforded by carbamazepine, valproate, phenobarbital and diazepam in maximal electroshock (MES) by approximately 36, 11, 21 and 26%, respectively, without affecting total blood plasma levels of antiepileptic drugs. No marked changes in gamma-aminobutyric acid (GABA) concentration and total activity of L-glutamic acid decarboxylase (GAD) assessed in the whole-brain homogenates resulted from Tetx treatment. Our results seem to indicate that low doses (< LD50) of i.c.v. administered Tetx may lead to a relative prevalence of inhibitory over excitatory processes in the central nervous system suggesting a complex action of Tetx at the neuronal level.

Animals↗
PubMed1998

GYKI 52466 [1-(4-aminophenyl)-4-methoxy-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] and the anticonvulsive activity of conventional antiepileptics against pentetrazol in mice.

Excitatory amino acids participate in the generation of seizure activity. Consequently, the effects of GYKI 52466 [1-(4-aminophenyl)-4-methoxy-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride], an antagonist of glutamate-mediated events, on the protective activity of conventional antiepileptic drugs against pentetrazol were studied. GYKI 52466 (up to 10 mg/kg, i.p.) did not affect the clonic phase of pentetrazol (injected s.c. at its CD97 of 90 mg/kg) convulsions. Only the antipentetrazol activity of valproate (100 mg/kg) was enhanced by GYKI 52466 (10 mg/kg)--the percentage of mice protected was significantly increased from 20 to 90%. The anticonvulsive activity of clonazepam (at 0.01), ethosuximide (at 50), and phenobarbital (at 2.5 mg/kg) was not modified by GYKI 52466 (up to 10 mg/kg). The combination of valproate (100 mg/kg) with GYKI 52466 (10 mg/kg) did not affect the performance of mice evaluated in the chimney test. However, this combination resulted in significant memory deficits, measured in the passive avoidance task. In no case did GYKI 52466 (10 mg/kg) affect either total or free plasma levels of antiepileptic drugs (as measured by immunofluorescence), so a pharmacokinetic interaction is not probable. Finally, the interaction of the non-NMDA receptor antagonist with antiepileptic drugs does not seem promising in the pentetrazol test, recognized as a model of human myoclonic epilepsy.

Animals↗
PubMed1998

The influence of L-NG-nitroarginine methyl ester, an inhibitor of nitric oxide synthase, upon the anticonvulsive activity of conventional antiepileptic drugs against maximal electroshock in mice.

NG-Nitro-L-arginine methyl ester (L-NAME, an unspecific nitric oxide synthase inhibitor), applied at 1 and 40 mg/kg, did not influence the electroconvulsive threshold, but impaired the anticonvulsant activity of valproate (at 40 mg/kg) and phenobarbital (at 1 and 40 mg/kg). No effect was observed in the case of carbamazepine and diphenylhydantoin. The effect of L-NAME upon the protective activity of phenobarbital was not reversed by L-arginine (500 mg/kg), a source of endogenous nitric oxide. Moreover, this nitric oxide synthase inhibitor did not alter the plasma levels of antiepileptic drugs studied, so a pharmacokinetic interaction is not probable. L-NAME per se (40 mg/kg) caused a moderate motor impairment but did not affect long-term memory. The combined treatment of L-NAME and antiepileptic drugs (providing a 50% protection against maximal electroshock) resulted in motor disturbances. On the other hand, mice performed the memory task better upon combined treatment of antiepileptic drugs with L-NAME compared to antiepileptic drugs alone. A 4-day administration of L-NAME, similarly to acute injections, decreased the protective action of phenobarbital but not that of diphenylhydantoin. The results indicate that L-NAME is able to reduce the protective activity of some conventional antiepileptics and this effect may be not associated with impaired synthesis of nitric oxide.

Animals↗
PubMed1998

Effect of 5-fluoroindole-2-carboxylic acid (an antagonist of the NMDA receptor-associated glycine site) on the anticonvulsive activity of conventional antiepileptic drugs.

5-Fluoroindole-2-carboxylic acid, an antagonist of the glycine site within the NMDA receptor complex, administered intraperitoneally in doses of 150 and 200 mg/kg, 120 min before electroconvulsions, significantly raised the convulsive threshold from 6.8 to 7.9 and 8.3 mA, respectively. At lower doses, it did not influence the threshold. However, lethality was observed 24h after administration of the threshold-elevating doses of this glycine site antagonist. 5-Fluoroindole-2-carboxylic acid (100 mg/kg), applied together with carbamazepine, valproate or phenobarbital, significantly reduced their ED50 values against maximal electroshock - from 13.9 to 7.5 mg/kg, from 291 to 242 mg/kg, and from 18.6 to 11.1 mg/kg, respectively. At the dose of 50 mg/kg, it also potentiated the protective activity of carbamazepine. However, 5-fluoroindole-2-carboxylic acid, up to 100 mg/kg, did not affect the anti-convulsive activity of diphenylhydantoin. When applied at doses equal to their ED50 values against maximal electroshock-induced convulsions, carbamazepine (13.9 mg/kg), phenobarbital (18.6 mg/kg) and valproate (291 mg/kg) did not affect the motor performance of mice in the chimney test. 5-Fluoroindole-2-carboxylic acid (100 mg/kg produced a significant motor impairment, at 50 mg/kg it did not affect the motor performance. The combined treatment of 5-fluoroindole-2-carboxylic acid (100 mg/kg) with carbamazepine, phenobarbital or valproate, providing a 50% protection against maximal electroshock, resulted in motor impairment. Only the combination of 5-fluoroindole-2-carboxylic acid (50 mg/kg) with carbamazepine (8.6 mg/kg) did not significantly influence this parameter. Almost all of the antiepileptic drugs studied, when administered at doses equal to their ED50 values against maximal electroshock, did not influence retention in the passive avoidance task, which is a measure of long-term memory. Only valproate (291 mg/kg) worsened long-term memory. The combined treatment of 5-fluoroindole-2-carboxylic acid (100 mg/kg) with carbamazepine or phenobarbital, providing a 50% protection against maximal electroshock, did not affect the retention. The combination of 5-fluoroindole-2-carboxylic acid (100 mg/kg) with valproate (242 mg/kg) caused a significant impairment of long-term memory and mortality of 50% of animals 24h following the administration. The results suggest that the blockade of the strychnine-insensitive glycine site may lead to an enhancement of the protective activity of some conventional antiepileptic drugs, which is associated with pronounced side-effects and lethality in some cases.

Animals↗
PubMed1998

Rimcazole, a sigma receptor ligand, and the anticonvulsive action of conventional antiepileptic drugs.

Rimcazole (a selective sigma receptor antagonist) at 5 and 10 mg/kg, 30 min before the test, lowered the electroconvulsive threshold, being ineffective at 2.5 mg/kg. Rimcazole (2.5 and 5 mg/kg) enhanced the protective activity of phenobarbital and valproate, but not that of carbamazepine and diphenylhydantoin against maximal electroshock. The effect of rimcazole upon the electroconvulsive threshold was reversed by haloperidol (0.5 mg/kg), but the rimcazole-induced potentiation of the anticonvulsive action of antiepileptics was not. Moreover, rimcazole (2.5 mg/kg) did not alter the total or free plasma levels of valproate or phenobarbital, so a pharmacokinetic interaction is not probable. The combined treatment of rimcazole with antiepileptic drugs, providing a 50% protection against maximal electroshock, did not affect motor performance in mice, although it resulted in significant long-term memory deficits. Our data indicate that rimcazole, in spite of lowering the seizure threshold, may enhance the protective activity of some antiepileptic drugs.

Animals↗
PubMed1998

An isobolographic analysis of drug interaction between intrathecal clonidine and baclofen in the formalin test in rats.

The inhibition of both phases of the formalin response by intrathecal (IT) clonidine and baclofen, given alone or in combination at a fixed dose ratio, was studied. Both drugs, at doses not affecting motor performance, produced a dose-dependent inhibition of phase 2 of the formalin test. The potency of baclofen and clonidine, defined by their ID50's for phase 2 of the formalin test, was 0.56 and 3.4 nmol, respectively. The combination ID50 of baclofen and clonidine, with the equieffective dose ratio of 1:6, was found to be statistically lower than the theoretical additive ID50. These data suggest that co-administration of alpha2-adrenoceptor or GABA(B) receptor agonists may prove therapeutically useful in treating chronic pain.

Adrenergic alpha-Agonists↗
PubMed1998

A potential anti-asthmatic drug, CR 2039, enhances the anticonvulsive activity of some antiepileptic drugs against pentetrazol in mice.

CR 2039 (4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl]phenylbenzam ide), in doses of 10, 20, and 100 mg/kg i.p., did not modify the seizure pattern observed after subcutaneous pentetrazol, administered at its CD97 of 90 mg/kg for the clonic phase. However, when combined with antiepileptic drugs, this phenylbenzamide derivative (20 mg/kg) converted the subprotective doses of ethosuximide (100 mg/kg) or valproate (100 mg/kg) against the clonic phase into anticonvulsive ones. The protection observed was comparable to that noted after doubling the doses of these antiepileptics. Also, a combination of valproate (100 mg/kg) with CR 2039 (10 mg/kg) resulted in a clear-cut protection against clonic seizures induced by pentetrazol. The protective efficacy of clonazepam was not affected by the phenylbenzamide derivative up to 40 mg/kg. The potentiation of the anticonvulsive activity of ethosuximide or valproate was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (20 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied, which speaks against a pharmacokinetic mechanism in the observed results. In conclusion, CR 2039 seems devoid of a hazardous influence of the anti-asthmatic drug, aminophylline, on the anticonvulsive effects of conventional antiepileptics.

Animals↗
PubMed1998

Ukrain (NSC-631570) in experimental and clinical studies: a review.

The need to find a safe and highly effective cure for neoplastic disease remains a major challenge for modern pharmacology. This paper reviews the available literature on Ukrain (NSC631570), a novel semisynthetic drug obtained from Chelidonium majus L. alkaloids. Ukrain has been demonstrated to possess antineoplastic and immunomodulatory properties. Inhibition of the growth of cancer cell lines in vitro, tumor mass reductions in vivo, and partial and complete remissions in oncological patients, occur as a result of Ukrain application. The drug may interfere directly with the metabolism of cancer cells and it also improves the functioning of the host immune system. Diminished synthesis of DNA, RNA and proteins, the inhibition of cellular oxygen consumption, and the induction of programmed cell death in malignant cells have been described following Ukrain administration. The drug can also modify the immunological response via an increase in the number of total T-cells and a normalization of the T-helper/T-suppressor lymphocyte ratio. Ukrain therapy produces neither toxic consequences nor allergic reactions towards the drug. Several case reports and clinical trial data indicate that Ukrain may ameliorate effectively the progress of neoplastic disease and/or induce a total cure.

Adjuvants, Immunologic↗
PubMed1998

Six-week treatment with Ukrain in rabbits. Part I: Morphological parameters.

This study was performed to evaluate the effect of 6-week treatment with Ukrain in doses of 0.3, 1.5 and 3.0 mg/kg i.v. on the morphological and biochemical parameters of peripheral blood and morphology of body organs in rabbits. Ukrain application did not change the body organs and total body weight. The drug did not affect biochemical parameters of peripheral blood, except for a minor reduction in the total plasma level and increases in serum uric acid and urea indicating enhanced catabolism of proteins. The peripheral erythrocyte and leukocyte counts were not altered, whereas the percentages of lymphocytes, monocytes, and eozynophils were increased after higher doses of Ukrain. An increase in rod neutrophils and a decrease in the percentage of segmented neutrophils were also noted. These observations indicate a lack of organ toxicity following long-term treatment with Ukrain.

Alkaloids↗
PubMed1998

Six-week treatment with Ukrain in rabbits. Part II: Serum levels of gonadal hormones.

The effect of 6-week treatment with Ukrain at doses of 0.3, 1.5, and 3.0 mg/kg i.v. on the serum levels of steroid hormones, i.e., estradiol, testosterone, and progesterone, was studied in rabbits of both sexes. It is demonstrated that Ukrain treatment exerts minor changes in serum hormone levels. The level of estradiol was increased in the serum of male rabbits following Ukrain treatment only at the dose of 1.5 mg/kg i.v. Similarly, the estradiol serum level was increased after Ukrain given at 1.5 mg/kg i.v. in female rabbits. In male rabbits Ukrain application at 0.3 mg/kg i.v. increased the serum testosterone level. Serum testosterone levels were not altered following Ukrain administration up to 3.0 mg/kg i.v. in female rabbits. Ukrain raised the serum progesterone levels in male rabbits at the doses of 0.3 and 3.0 mg/kg i.v. in females, only the highest dose of Ukrain produced a significant increase of serum progesterone.

Alkaloids↗
PubMed1998

Six-week treatment with Ukrain in rabbits. Part III: Serum levels of thyroid hormones.

The influence of 6-week treatment with Ukrain at doses of 0.3, 1.5 and 3.0 mg/kg i.v. on serum levels of thyroid hormones, i.e., thyroxine and triiodothyronine, was studied in rabbits of both sexes. Ukrain affected the serum levels of both hormones in males. An increase in the thyroxine level was found after Ukrain used at a dose of 1.5 and 3.0 mg/kg i.v., whereas increased triiodothyronine was noted when Ukrain was given at all studied doses. In females the thyroxine level was not altered by Ukrain administration, whereas the triiodothyronine concentration was increased following Ukrain at 0.3, 1.5 and 3.0 mg/kg i.v. it is probable the altered thyroid hormone levels as a result of Ukrain application may contribute to the drug's potent immunomodulatory action.

Adjuvants, Immunologic↗