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.

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.

ACTH 4-9 analogue facilitates the antiimmobility effect of antidepressants and dopamine agonists in swimming rats.

Evidence exists that the 4-10 or 4-9 fragments of adrenocorticotropic hormone (ACTH) produce some behavioral effects in animals and in humans. The present study was designed to investigate whether ACTH 4-9 interferes with the effects of antidepressants: fluoxetine (FLU), fluvoxamine (FOX), selegiline (SEL) or dopamine agonists: piribedil (PRB) or quinpirol (QPR) in forced swimming test and in open field in rats. ACTH 4-9 was given in a single dose (25, 50 or 100 micrograms/kg) or for 7 days (50 micrograms/kg/day), alone or together with antidepressants or dopamine agonists. It was shown that ACTH 4-9 alone did not influence the behavior of rats. However, when given in a single dose, ACTH 4-9 potentiated the antiimmobility effect of all antidepressants and dopamine agonists. ACTH 4-9 given for 7 days, facilitated only the effect of selegiline. The results suggest a functional interaction of ACTH 4-9 with serotonergic and dopaminergic brain mechanisms of drugs action.

Studies on the interaction of antidepressant drugs with adrenocorticotropic hormone or prednisone in rats.

The influence of adrenocorticotropic hormone (ACTH) and prednisone on the effects of amitriptyline (AMI), imipramine (IMI), mianserin (MIA) or nomifensine (NOM) was investigated in forced swimming and in open field tests. ACTH (50 I.U./kg) or prednisone (1 mg/kg) were given in a single dose or for 7 consecutive days alone or together with AMI (10 mg/kg), IMI (10 mg/kg), MIA (10 mg/kg) or NOM (2 mg/kg). It was found that neither ACTH nor prednisone administered alone in a single dose or for 7 days influenced the behavior of rats. ACTH co-administered with AMI or NOM in a single dose or with AMI, IMI or NOM for 7 days potentiated the antiimmobility effect of antidepressant drugs. Prednisone potentiated only antiimmobility effect of NOM in forced swimming test. ACTH as well as prednisone co-administered with NOM (but not with the other drugs), in a single dose as well as for 7 days, increased also locomotor activity in open field. Neither ACTH nor prednisone influenced the effect of MIA in both tests used. It was concluded that the specific synergism exists only between ACTH and tricyclic antidepressants (AMI, IMI). The observed behavioral interaction between ACTH and AMI or IMI does not seem to be mediated by adrenocorticoids (prednisone was without effect). The potentiation of NOM effects by ACTH as well as by prednisone and lack of any interaction with MIA seems to be related with different mechanism of action of those antidepressant drugs.

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.

Competitive NMDA receptor antagonists enhance the antielectroshock activity of various antiepileptics.

CGP 37849 (1 mg/kg i.p.) enhanced the protective action of carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock-induced convulsions in mice. At 0.25 mg/kg CGP 37849 was inactive and at 0.5 mg/kg it potentiated the anticonvulsive activity of phenobarbital. CGP 39551 (5 mg/kg i.p.) reduced the ED50 values of diphenylhydantoin and phenobarbital, being without influence on carbamazepine. In the dose of 1.25 mg/kg, CGP 39551 potentiated the antielectroshock action of diphenylhydantoin and at 2.5 mg/kg that of phenobarbital. Neither NMDA receptor antagonist elevated the total plasma levels of antiepileptic drugs. Consequently, a pharmacokinetic interaction (in terms of total plasma levels at least) seems unlikely to be responsible for the observed potentiation of the antiepileptic drugs' activity. Combinations of CGP 37849 with either carbamazepine or phenobarbital resulted in a motor and memory impairment quantified by the chimney test and passive avoidance task, respectively. Moreover, combined treatment with phenobarbital and CGP 39551 caused a memory deficit. In contrast, diphenylhydantoin combined with either CGP 37849 or 39551 was devoid of adverse effects. It may be concluded that NMDA receptor blockade results in enhanced anticonvulsive action of common antiepileptics against maximal electroshock-induced seizures.

Competitive antagonists of NMDA receptors, CGP 37849 and CGP 39551, enhance the anticonvulsant activity of valproate against electroconvulsions in mice.

Two novel N-methyl-D-aspartic acid (NMDA) competitive antagonists, CGP 37849 (1.25 and 2.5 mg/kg) and CGP 39551 (10 mg/kg), significantly raised the threshold for electroconvulsions in mice. CGP 37849 in doses of 0.125-1.0 mg/kg and CGP 39551 in doses of 0.625-5 mg/kg i.p. considerably potentiated the protective activity of magnesium valproate against maximal electroshock-induced convulsions. The anticonvulsant activity of sodium valproate was potentiated by CGP 37849 (1 mg/kg) to a similar degree, which suggests that magnesium is not involved in the observed interaction. Neither CGP agent influenced the plasma level of valproate, so a pharmacokinetic interaction, in terms of total plasma levels, is not probable. Furthermore, the performance of mice injected with magnesium valproate (91 mg/kg) and CGP 37849 (0.25 mg/kg), which provided 50% protection against maximal electroshock-induced convulsions, in the long-term memory test and chimney test did not differ significantly from that of the control animals. The combination of magnesium valproate and CGP 39551 had a neurotoxic potential comparable to that of valproate alone. The results suggest that a combined treatment of valproate and some competitive NMDA antagonists may be important from a clinical point of view.

Synthesis and pharmacological properties of new derivatives of 1-diphenylacetamide-2-butanol.

Newly synthesized derivatives of 1-diphenylacetamide-2-butanol were investigated pharmacologically for their central properties in mice and rats. The most active were 2 compounds: racemic (RS) and enantiomer S (+) form of N-diphenylacetamide-2-butanol which produced hypothermia in normothermic mice, showed anxiolytic action in the four-plate test and reversed reserpine-induced hypothermia.

Synthesis and pharmacological properties of diphenylimidazolidine acetic and propionic acids derivatives.

Several derivatives of diphenylimidazolidine-2,4-dione and diphenylimidazolidin-4-one acetic and propionic acids have been synthesized. Some of them were screened for their effect on the CNS in mice and rats. All the investigated compounds showed an analgesic activity. The most active one was 1-benzyl-5,5-diphenyl-3-imidazolidine-2,4-dione acetic acid. That compound exerted an inhibitory activity against the CNS, anxiety-relieving, anticonvulsant and antidepressive effects.

Pharmacological studies on the central action of novel benzylidene-imidazothiazolone derivatives.

Pharmacological studies on the central action of novel benzylidene-imidazothiazolone derivatives were carried out on mice and rats. The highest activity showed two compounds: a chloro- and a methoxy- derivative. They produced analgesic, anticonvulsant, anti-anxiety and "antidepressant" effects in mice.

Immobilization stress modifies locomotor response to catecholamine receptor agonists in rats.

The effects of dopaminergic (apomorphine, nomifensine, B-HT 920) and noradrenergic (methoxamine, clonidine, salbutamol) agonists on locomotor activity were investigated in rats submitted to acute (3 h) or repeated (3 h/4 days) immobilization stress. The stress-induced functional changes were monitored by the blood level of corticosterone and the number of lymphocytes as well as the brain utilization of NA and DA. The rats subjected to acute immobilization stress displayed 30 min later an enhanced locomotor activation after apomorphine, nomifensine, or methoxamine and reduced sedative effect of clonidine, salbutamol or B-HT 920. 24 h after the repeated stress only the locomotor responses to apomorphine, nomifensine, B-HT 920 and salbutamol were modified. Spontaneous locomotor activity was not significantly changed under the influence of stressful stimuli. Increased plasma corticosterone level, strong reduction of blood lymphocytes and enhanced NA and DA utilization in the brain of rats after acute stress, together with above mentioned results, suggest that short-lasting stress evokes (30 min later) significant functional changes not only in the blood but also in the brain: enhanced CA neurons activity as well as the increased alpha 1-adrenergic and DA-post-synaptic receptors responsiveness in parallel with reduced alpha 2 - and beta-adrenergic and DA-presynaptic receptors reactivity. On the other hand, 24 h after last session of repeated stress CA brain neurons activity was not changed, however DA and beta-adrenergic responsivity was farther modified. It is postulated that the stress conditions produce in NA and/or DA brain systems a state of readiness to locomotion activating stimuli.

Interaction of antidepressants with antiparkinsonian agents in rats.

The influence of antidepressants: nomifensine, imipramine, amitriptyline and trazodone on the effect of antiparkinsonian agents: trihexyphenidil and L-DOPA + carbidopa mixture (sinemet) in the model of haloperidol catalepsy was investigated in rats. In some experiments deprenyl, a selective MAO-B inhibitor, was used. It was found that antidepressant drugs in doses not influencing haloperidol catalepsy enhanced significantly the anticataleptic effect of trihexyphenidil and L-DOPA + carbidopa. The most effective in the interaction with both antiparkinsonian agents was nomifensine. Imipramine and trazodone potentiated anticataleptic effect of L-DOPA + carbidopa more strongly than those of trihexyphenidil. The most potent anticataleptic effect was observed after combined treatment of rats with deprenyl and L-DOPA + carbidopa.