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Biomedical subjects

Z Kleinrok

Publications and source records attributed to Z Kleinrok.

At least 91 records · Page 5Linked to original sources
PubMed1996

Intracerebroventricular pertussis toxin enhances sensitivity to chemical convulsants and decreases the protective efficacy of carbamazepine in mice.

The effects of pretreatment with pertussis toxin on pentylenetetrazole-, bicuculline-, aminophylline- and pilocarpine-induced seizures were investigated in mice. In animals treated intracerebroventricularly with pertussis toxin (0.5 microgram animal-1 120 h prior to testing), the CD50 (convulsive dose in 50%) values were considerably decreased in comparison with the CD50 in sham-treated animals. CD50 values of pentylenetetrazole, bicuculline, pilocarpine and aminophylline were calculated to be 39.9, 2.0, 262 and 141 mg kg-1, whereas they were calculated to be 57.7, 2.7, 324 and 230 mg kg-1 in sham-treated animals. The observations suggest that the enhanced sensitivity to a number of chemical convulsants irrespective of their mode of action possibly results from a functional suppression of inhibitory transmission at receptors coupled to pertussis toxin sensitive G proteins, rather than a direct action on G protein linked excitatory neurotransmission. Pertussis toxin significantly decreased the protective action of carbamazepine, increasing its ED50 (effective dose in 50%) from 14.8 to 20.1 mg kg-1 in a maximal electroshock convulsive test. It influenced the ED50 of neither diphenylhydantoin nor diazepam. The diminution of carbamazepine's efficacy might result from a summation effect of adenosine receptor antagonist properties of the drug and a suppression of transmission at adenosine receptors coupled to G proteins sensitive to pertussis toxin. Pertussis toxin pretreatment remained without any significant influence on the total plasma levels of carbamazepine, diphenylhydantoin and diazepam. This may lead to the conclusion that the interaction between pertussis toxin and carbamazepine does not seem to be of a pharmacokinetic nature and occurs probably at neuronal level.

Animals↗
PubMed1996

NG-nitro-L-arginine, a nitric oxide synthase inhibitor, and seizure susceptibility in four seizure models in mice.

Nitric oxide may be involved in seizure phenomena even though data often seem to be contradictory. This prompted us to study the influence of nitric oxide upon electrically and chemically induced seizures. The effects of nitric oxide synthase inhibitor, NG-nitro-L-arginine (NNA), on pentylenetetrazol-, aminooxyacetic acid-, aminophylline-induced seizures or electroconvulsive shock were evaluated. NNA was applied at 1, 10 and 40 mg/ kg 0.5 and 2.0 h before chemical seizures and at 1 and 40 mg/kg 0.5 and 2.0 h prior to electroconvulsions. The nitric oxide synthase inhibitor (up to 40 mg/ kg) did not affect the susceptibility of mice to pentylenetetrazol, amino-oxyacetic acid or electroconvulsions. However, NNA significantly enhanced the convulsive properties of aminophylline when applied at 40 mg/kg, 0.5 h before the test. The CD50 value for aminophylline-induced clonus and tonus/ mortality was decreased from 233 to 191 and from 242 to 212 mg/kg, respectively. However, this pretreatment also led to a significant increase in the plasma levels of theophylline. Our results suggest that differential effects of NNA on chemically-induced convulsions might in some cases be associated with a pharmacokinetic interaction.

Aminooxyacetic Acid↗
PubMed1996

Influence of aminophylline and strychnine on the protective activity of excitatory amino acid antagonists against maximal electroshock-induced convulsions in mice.

Aminophylline reversed the protective action of both, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene-a competitive NMDA antagonist) and valproate (used as a conventional antiepileptic drug for comparative purposes) against maximal electroshock-induced seizures. The respective ED50 values of aminophylline were 55.7 and 98.4 mg/kg i.p. However, aminophylline (up to 100 mg/kg i.p.) did not influence the protective efficacy of 1-(4-aminophenyl)-4-methyl-7,8-methyl- enedioxy-5H-2,3-benzodiazepine (GYKI 52466-a non-NMDA antagonist). Strychnine affected the protection provided by D-CPP-ene, GYKI 52466, and valproate against maximal electroshock-the ED50 values of strychnine for the reversal of the anticonvulsive effects of D-CPP-ene, GYKI 52466 or valproate were 0.082, 0.35 and 0.28 mg/kg s.c., respectively. An involvement of strychnine sensitive glycinergic receptor-mediated events in the mechanism of the anticonvulsive activity of excitatory amino acid antagonists and valproate may be postulated. The ineffectiveness of aminophylline to reduce the anticonvulsive effects of GYKI 52466 may distinguish a new class of antiepileptic drugs offering an advantage over conventional antiepileptics in patients with epilepsy, requiring aminophylline for pulmonary reasons.

Aminophylline↗
PubMed1996

Influence of a potential anti-asthmatic drug, CR 2039, upon the anticonvulsive activity of conventional antiepileptics against maximal electroshock-induced seizures in mice.

CR 2039 [[4-(1H-tetrazol-5-yl)-N-(4-(1H-tetrazol-5-yl]phenylbenza m ide], in doses of 10, 50, and 100 mg/kg i.p., significantly elevated the threshold for electroconvulsions, increasing the CS50 (current strength 50% in mA) values from 6.3 to 7.2, 7.5, and 7.6 mA, respectively. When combined with carbamazepine, diphenylhydantoin, or valproate, CR 2039 (5 and 10 mg/kg) potentiated the anticonvulsive action of these antiepileptics against maximal electroshock-induced convulsions which was reflected by significant decreases in the respective ED50s (in mg/kg). The protective efficacy of phenobarbital was not affected by the phenylbenzamide derivative. The potentiation of the anticonvulsive activity of three antiepileptics was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (10 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied which speaks against a pharmacokinetic mechanism in the observed results. It is concluded that CR 2039 may prove a safer anti-asthmatic drug for the use in epileptic patients than aminophylline which, either acutely or chronically, considerably impaired the anticonvulsive activity of conventional antiepileptics.

Animals↗
PubMed1996

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice.

Among three calcium channel inhibitors, only nicardipine (10-40 mg/kg) significantly inhibited clonic seizures induced by pentylenetetrazol administered at its CD97 (convulsive dose 97%) of 81 mg/kg, subcutaneously. Nimodipine and flunarizine (both up to 80 mg/kg) did not suppress pentylenetetrazol-induced clonic seizures per se. Co-administration of nicardipine (5 mg/kg) resulted in a significant enhancement of the protective potency of either ethosuximide (50 mg/kg) or valproate (100 mg/kg) against clonic seizures in this test. Similar effects were noted in case of combined treatment of nimodipine (20-40 mg/kg) with these antiepileptics. On the contrary, flunarizine (up to 20 mg/kg) did not modify the anticonvulsive action of these antiepileptic drugs. Moreover, none of the studied calcium channel inhibitors influenced the protective activity of clonazepam (0.01 mg/kg). The antiepileptic drugs, administered alone in above doses, were ineffective against pentylenetetrazol-induced clonic convulsions. In case of ethosuximide and valproate, the motor performance in the chimney test was worsened by co-administration of nimodipine (40 mg/kg). We found no pharmacokinetic interactions (at least in relation to the plasma levels of ethosuximide and valproate) that could explain the observed results. Thus, we conclude that a combination of some calcium channel inhibitors and antiepileptic drugs may provide more efficient protection against experimental seizures which may bear a potential clinical significance.

Animals↗
PubMed1996

Interactions of excitatory amino acid antagonists with conventional antiepileptic drugs.

Excitatory amino acid antagonists possess anticonvulsant properties in many experimental models of epilepsy and were shown to potentiate the protective activity of conventional antiepileptics against maximal electroshock-induced seizures in mice. Combined treatments of valproate with either D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid or dizocilpine (NMDA antagonists), which provided a 50% protection against maximal electroshock, produced no side-effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). Valproate alone at its ED50 against maximal electroshock, induced severe adverse effects. The NMDA antagonists, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid, memantine, procyclidine, and trihexyphenidyl also potentiated the protective activity of conventional antiepileptics but these treatments were associated with considerable side-effects. The non-NMDA receptor antagonists, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline and 1-(amino-phenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine, also enhanced the anticonvulsive action of antiepileptic drugs against maximal electroshock, and these combinations generally resulted in no adverse effects. The potential clinical importance of some combinations of common antiepileptics with excitatory amino acid antagonists is postulated.

Animals↗
PubMed1996

Chronic caffeine and the anticonvulsant potency of antiepileptic drugs against maximal electroshock.

The anticonvulsant activities of intraperitoneally (IP) given carbamazepine (CBZ) or diphenylhydantoin (DPH), expressed as their respective ED50 values in mg/kg, were assessed after caffeine (CAFF) treatment against maximal electroshock-induced seizures in mice. CAFF was administered IP either in a single dose or every 12 h for 3 (subchronic CAFF) and 14 days (chronic CAFF). Moreover, the protective activity of the antiepileptics was determined in mice which, following chronic CAFF, received a challenge dose of CAFF after either 24 or 72 h since CAFF withdrawal. A significant reduction of the protective efficacy of CBZ was observed after chronic CAFF treatment (in a dose of 11.55 mg/kg), while a single dose and a 3-day treatment did not alter the action of CBZ. In case of CAFF (23.1 mg/kg), a significant elevation of CBZ's ED50 value was noted after 3- and 14-day treatments with CAFF. In contrast, chronic CAFF (23.1-46.2 mg/kg) decreased the anticonvulsive activity of DPH to the same extent as did acute CAFF. Moreover the ED50 values for both, CBZ and DPH, evaluated 24 h after a 14-day treatment with CAFF (in doses of 23.1 and 46.2 mg/kg, respectively), were significantly elevated compared to respective control groups. A strong impairment of the anticon-vulsant action of CBZ and DPH was observed when a challenge dose of CAFF was injected following either 24 or 72 h injection-free time. Pharmacokinetic interactions do not seem to explain the obtained results in terms of total plasma levels of the antiepileptics after chronic treatment with CAFF. Our results may suggest that epileptic patients should avoid CAFF-containing beverages and medicines.

Animals↗
PubMed1996

Anticonvulsant activity of phenobarbital and valproate against maximal electroshock in mice during chronic treatment with caffeine and caffeine discontinuation.

We evaluated the protective activity (expressed as ED50 values in mg/kg of phenobarbital (PB, 120 min before testing) and valproate (30 min) alone or combined with caffeine in male mice with seizures induced by maximal electroshock (MES). Both antiepileptic drugs (AEDs) were administered by intraperitoneal (i.p.) injection in a single dose to mice receiving intraperitoneal caffeine either in a single dose 30 min before the test or as pretreatment every 12 h for 3 and 14 days. In addition, we determined the ED50 values of the AEDs 24 and 72 h after 14-day treatment with caffeine. Finally, we studied the influence of a challenge dose of caffeine, injected in mice 24 and 72 h after 14 days of treatment with caffeine, on the protective activity of PB or VPA. Caffeine in a single dose of 23.1 mg/kg reduced the anticonvulsant effect of PB. Its protective activity was further impaired after 3 and 14 days of caffeine treatment. The ED50 for VPA was significantly increased both by the single dose of caffeine and by chronic treatment. The anticonvulsant activity of PB and VPA measured 24 and 72 h after 14-day treatment with caffeine did not differ from control values, but a challenge dose of caffeine injected 24 or 72 h after daily injections for 14 days resulted in a significant reduction in the protective activity of both AEDs. Measurement of the total plasma levels of caffeine, VPA, and PB did not suggest pharmacokinetic interactions as an explanation for our results. Our results indicate that chronic caffeine exposure may progressively reduce the antiepileptic potency of VPA and PB.

Animals↗
PubMed1996

Competitive NMDA-receptor antagonists, LY 235959 and LY 233053, enhance the protective efficacy of various antiepileptic drugs against maximal electroshock-induced seizures in mice.

PURPOSE: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 l(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-qu inoline-3-carboxylic acid; < or = 0.5 mg/kg] or LY 233053 cis-(+/-)-4-[(2H-tetrazol-5-yl) methyl]piperidine-2-carboxylic acid; < or = 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. METHODS: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, reiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance ask (long-term memory). Plasma levels of antiepileptic rugs were measured by immunofluorescence. RESULTS: Both LY 235959 and LY 233053 ( < or = 0.5 and 5 mg/kg, respectively) did not influence the electroconvulsive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydantoin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. CONCLUSIONS: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.

Animals↗
PubMed1996

[Biological role of carbon monoxide in nervous system function].

Carbon monoxide (CO), like nitric oxide (NO), is a vasodilatating substance. CO acts also as a putative neural retrograde messenger in the nervous system where it has been implicated in the regulation of large number of physiological and pathological processes, including long-term potentiation and depression, learning and memory, pain processing, vasodilatation and myorelaxation, inhibition of platelet aggregation and hormone releasing.

Carbon Monoxide↗
PubMed1996

Effect of six-month treatment with Ukrain on early osteoporosis induced by ovariectomy in rats. Part I: Preliminary studies of bone parameters.

Ukrain, thiophosphoric acid alkaloid derivatives from Chelidonium majus L. was administered intraperitoneally in a dose of 28 mg/kg (equivalent to 0.1 LD50) every other day for six months to female rats with ovariectomy-induced early osteoporosis. Administration of Ukrain was started on the second day after the surgical operation. At the end of the long-term treatment with Ukrain each rat was tested for the strength of both humeri and some parameters of rat femur were measured. The body weight of ovariectomized rats was also examined. The present results show that the decrease in the mechanical strength of the humeral bones and some changes in the femur caused by ovariectomy were prevented by the six-month treatment with Ukrain. However, in both ovariectomized groups and in ovariectomized rats pretreated with Ukrain an increase of body weight was observed.

Alkaloids↗
PubMed1996

Effect of six-month treatment with Ukrain on early osteoporosis induced by ovariectomy in rats. Part II: Preliminary studies of peripheral blood parameters.

Studies on Wistar rats have demonstrated that six months after ovariectomy no changes were observed in peripheral blood morphology other than a decreased leukocyte count. A similar effect was noted in the sham-operated group. The present results show that Ukrain treatment started on the second postoperative day and continued every other day for six months significantly increased leukocyte count in comparison with the untreated ovariectomized and sham-operated groups. The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also estimated in this study. In none of the groups studied was any change of ALT activity noted. The activity of AST was significantly increased in the sham-operated and untreated ovariectomized rats. After six-month treatment with Ukrain, the activity of this enzyme was significantly decreased in the serum of untreated ovariectomized rats. In rats pretreated with Ukrain some of the studied parameters of peripheral blood were similar to those of the control group.

Alanine Transaminase↗
PubMed1996

Effect of six-month treatment with Ukrain on early osteoporosis induced by ovariectomy in rats. Part III. Preliminary studies of some hormone levels.

The effect of six-month treatment with Ukrain on the level of some hormones was investigated in ovariectomized rats. The serum levels of prolactin, adrenocorticotropic hormone (ACTH), corticosterone, aldosterone and progesterone were measured by radioimmunoassay (RIA). Six months after ovariectomy, a decrease in prolactin and progesterone levels was observed. No changes were noted in the levels of ACTH, corticosterone and aldosterone in the serum of the ovariectomized animals. On the other hand, six-month treatment with Ukrain increased the levels of prolactin and progesterone and decreased the levels of corticosterone and aldosterone in the ovariectomized rats. The progesterone level in the treated group was four times higher than in the ovariectomized group. The six-month treatment with Ukrain had no effect on the level of ACTH of the serum of the ovariectomized rats. The present results show that prolonged treatment with Ukrain significantly affects hormone secretion after ovariectomy.

Adrenocorticotropic Hormone↗
PubMed1996

Antinociceptive effect of ten day administration of Ukrain in mice and interaction of the treatment with morphine.

The present study shows that Ukrain, administered i.c. in doses of 9.5 and 19 mg/kg once daily for 10 days in mice, produced evident antinociceptive action in the writhing syndrome and hot-plate tests. Moreover, we found that as a result of 10-day treatment with Ukrain the antinociceptive action of morphine (0.1 mg/kg s.c. administered after the last dose of Ukrain) was significantly decreased. These results and the observed interaction between Ukrain and morphine seem to be contra-indications to their combined usage.

Alkaloids↗
PubMed1996

Interaction between Ukrain and morphine in their ten-day treatment in mice in the writhing syndrome test.

The antinociceptive properties of Ukrain and of morphine in their 10 day treatment in mice were studied by the writhing syndrome test. It was found that the antinociceptive action of Ukrain after 10 days of treatment was similar to that of morphine (0.1 mg/kg s.c.) in the same period. Results indicate that the combined treatment with Ukrain and morphine for 10 days completely reduced their antinociceptive action.

Alkaloids↗
PubMed1996

Influence of bilateral clamping of carotid arteries on the seizures susceptibility and central action of AOAA in mice.

In the experiments carried out on Albino-Swiss mice it was found, that bilateral clamping of carotid arteries (BCCA) for 30 min produce the increase of GABA content in hippocampus, striatum and frontal cortex and decrease of the seizures susceptibility to bicuculline, investigated 7 days after surgery. Moreover, BCCA modulates the action of aminooxyacetic acid (AOAA): potentiates anticonvulsive effect of low doses of AOAA (33 mg/kg) and inhibits the convulsive action of high doses. Also the potentiation of the anticonvulsive effect of diazepam, phenobarbital and valproic acid (VPA) was observed in BCCA and AOAA (CD97, 150 mg/kg) treated animals. Observed effects suggests that enhanced GABA-ergic activity and decrease of excitatory amino acid (EAA) system could be involved in these processes.

Aminooxyacetic Acid↗
PubMed1996

NG-nitro-L-arginine sensitizes mice to 4-aminopyridine-induced seizures.

We investigated the influence of NG-nitro-L-arginine (NNA), the inhibitor of nitric oxide synthese, on seizures induced by 4-aminopyridine (4-AP), the K+ channel antagonist, in mice NNA (5, 10 and 40 mg/kg, i.p.) significantly reduced the respectives CD50 of 4-AP from 9.0 to 7.6, 7.5 and 6.8 for clonic seizures, and from 9.2 to 7.7, 7.5 and 6.9 for tonic seizures and death. Lower doses of NNA (1.0 and 2.5 mg/kg) had no effect on 4-AP-induced convulsions and lethality. Our results indicate that 4-AP-induced seizures may be, at least in part, dependent on nitric oxide level.

4-Aminopyridine↗