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D Hönack

Publications and source records attributed to D Hönack.

At least 55 records · Page 3Linked to original sources
PubMed1992

Regional alterations in brain amino acids during the estrous cycle of the rat.

Concentrations of 11 amino acids, including the neurotransmitters GABA, glutamate, aspartate, glycine and taurine, were determined in 12 brain regions of female rats during different stages of the estrous cycle. In addition, amino acids and sex hormone levels were determined in plasma. All sample collections were done in the forenoon between 9 and 11 a.m. Most regional amino acid levels measured did not change significantly during estrous cycle, but significant alterations were found for GABA and glutamate in hypothalamus. Both amino acids were slightly decreased in hypothalamus during proestrus, which might reflect an alteration of GABA turnover in response to the high estrogen levels during this stage. A decreased glutamate level during proestrus was also found in thalamus, while both glutamate and GABA did not vary throughout estrous cycle in any of the other examined regions, including substantia nigra, amygdala, striatum, cortex and hippocampus. When diestrus was subdivided according to progesterone levels, high levels of this hormone seemed to be associated with effects on metabolism of certain amino acids, including glycine in substantia nigra, alanine in thalamus and threonine in pons/medulla. However, the few changes in regional amino acid concentrations found during the estrous cycle were so small that the functional significance of these changes cannot be ascertained without further determination of the cellular or subcellular compartments of brain tissue involved.

Amino Acids↗
PubMed1992

Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. I. Biochemical, histopathological and pharmacokinetic studies.

E-2-en-Valproate (E-2-en-VPA; trans-2-en-VPA) and VPA were studied for potential hepatotoxicity in young male Sprague-Dawley rats. Both drugs were administered daily at 750 mg/kg i.p. (divided into three doses a day) for 7 consecutive days. Clinical chemistry parameters were studied before and after the period of treatment. Furthermore, the drug pharmacokinetics and metabolism were analyzed at onset and end of the prolonged administration. Treatment with VPA induced hyperammonemia and other alterations in liver function tests which were not observed after treatment with E-2-en-VPA, although plasma levels of both drugs were comparable. The pharmacokinetics of VPA and E-2-en-VPA in young rats were similar, but analysis of metabolites by gas chromatography-mass spectrometry indicated marked differences in the metabolite profile, e.g., a lack of the suspected hepatotoxic metabolite 4-en-VPA in plasma of rats treated with E-2-en-VPA. Histopathological examination of liver sections showed that VPA and E-2-en-VPA did not induce degenerative liver lesions or significant alterations in hepatic content and distribution of lipids and glycogen at the doses administered. Only one of the VPA treated rats showed fatty infiltration (microvesicular steatosis). The data demonstrate that, although E-2-en-VPA is more potent than VPA as an anticonvulsant in rats, it does not exert more potent hepatotoxic effects and does not alter ammonia metabolism. Thus the data substantiate previous experimental studies that E-2-en-VPA might be a valuable substitute for VPA.

Animals↗
PubMed1992

Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin.

A series of 5 generalized tonic-clonic seizures within 30 min was induced by repeated transauricular electrical stimulation in mice. In this model, the anticonvulsant potency of intravenous valproate was compared with diazepam and phenytoin. All 3 drugs proved capable of rapidly suppressing the seizures after intravenous bolus injection. Potent anticonvulsant activity of diazepam and valproate was already obtained after 30 s, while phenytoin's onset of action was somewhat slower. In contrast to diazepam, valproate and phenytoin suppressed the seizures at non-sedative doses. ED50s for blockade of generalized tonic-clonic seizures throughout the 30-min period of repeated electrical stimulation were 6.6 mg/kg for diazepam, 28 mg/kg for phenytoin and 212 mg/kg for valproate. Determination of valproate in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue. The data indicate that an intravenous formulation of valproate might be a useful alternative to phenytoin as a non-sedative anticonvulsant for diazepam-resistant status epilepticus.

Animals↗
PubMed1991

Tolerance to anticonvulsant effects of the partial benzodiazepine receptor agonist abecarnil in kindled rats involves learning.

The effects of chronic treatment with the beta-carboline, abecarnil, a novel partial and/or subtype-specific agonist at central benzodiazepine receptors, were studied on fully kindled amygdaloid seizures in rats. Two different experimental protocols were used to differentiate between "pharmacologic tolerance', i.e. tolerance as a function of drug exposure, and "contingent tolerance, i.e. tolerance contingent upon the repeated occurrence of the criterion effect, i.e. the anticonvulsant effect. When kindled seizures were repeatedly initiated during chronic treatment of rats with abecarnil (5 mg/kg i.p. three times daily), marked tolerance developed to its anticonvulsant effect, although plasma levels of abecarnil even increased during the 2 weeks of treatment. When the same treatment protocol was used, but seizures were initiated only at the start and end of the treatment period, almost no tolerance to the anticonvulsant effect of abecarnil was measured, indicating an important role of learning processes for the development of tolerance. In contrast to the differences in anticonvulsant tolerance between the two protocols, the motor impairment induced by abecarnil was similarly attenuated during chronic treatment according to both protocols. The data indicate that, because of the response contingency in abecarnil tolerance, development of tolerance to anticonvulsant effects of this compound depends critically on seizure frequency during drug administration, while adverse effects of this compound are reduced independently of seizure frequency.

Animals↗
PubMed1991

Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain.

Gabapentin exerts anticonvulsant effects in different animal models of seizure states and in epileptic patients with different seizure types, but the mechanism of action of these effects is unknown. In the present study, the gamma-aminobutyric acid (GABA) accumulation induced by aminooxyacetic acid (AOAA) was used as a method to study the effects of gabapentin on regional turnover of GABA in the rat brain. Gabapentin was administered at a dose of 23 mg/kg i.p. (the ED95 against tonic electroconvulsions in rats) 1, 2 and 8 h prior to injection of AOAA, 100 mg/kg, i.p. Gabapentin significantly increased the AOAA-induced GABA accumulation in most of the 12 brain regions examined, but the time course of the increases in GABA accumulation differed from region to region. Regions in which the time course of the increase in GABA accumulation was similar to the anticonvulsant time course of gabapentin included substantia nigra, amygdala and thalamus. The data suggest that an effect of gabapentin on GABA synthesis might be involved in its mechanism of anticonvulsant action.

Acetates↗
PubMed1991

The N-methyl-D-aspartate receptor antagonist MK-801 induces increases in dopamine and serotonin metabolism in several brain regions of rats.

MK-801 (dizocilpine maleate), a non-competitive, N-methyl-D-aspartate receptor antagonist which induces a characteristic phencyclidine-like motor syndrome in rodents, was administered to rats after handling habituation to examine the effects of this drug on concentrations of monoamines and their metabolites in 14 brain regions. MK-801 increased dopamine and serotonin metabolism in several regions, the most marked effects being determined in frontal and piriform cortex, nucleus accumbens and striatum. The data indicate that not only effects on dopaminergic transmission but also on serotonergic transmission may be involved in the pharmacological actions of MK-801.

Animals↗
PubMed1991

Regional alterations in brain amino acids after administration of the N-methyl-D-aspartate receptor antagonists MK-801 and CGP 39551 in rats.

The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the novel competitive NMDA receptor antagonist CGP 39551 on levels of 11 amino acids, including several excitatory and inhibitory neurotransmitters, were studied in 12 brain regions of rats. Both drugs were administered at doses which produced comparable behavioural effects (ataxia, hyperactivity). Amino acids were determined in brain tissue by high-performance liquid chromatography after o-phthaldialdehyde precolumn derivatization. MK-801 (0.1 mg/kg, i.p.) moderately increased the concentration of glutamate and GABA in several brain regions. Other amino acids (glutamine, taurine, asparagine, alanine, serine) were only altered in single brain regions, or were not altered at all (aspartate, glycine, threonine, arginine). In contrast to MK-801, CGP 39551 (10 mg/kg, i.p.) increased glutamate levels only in the cerebellum, and produced no significant alterations in levels of GABA. The data demonstrate differences in alterations of amino acid levels in response to competitive and non-competitive NMDA receptor antagonists and support the assumption that competitive NMDA antagonists may be more selective than non-competitive antagonists.

2-Amino-5-phosphonovalerate↗
PubMed1991

Kindling from stimulation of a highly sensitive locus in the posterior part of the piriform cortex. Comparison with amygdala kindling and effects of antiepileptic drugs.

The piriform cortex, especially its deep anterior part, has been recently suggested to be a crucial epileptogenic site in the rat brain. We investigated the susceptibility of different parts of the piriform cortex to the development of electrical kindling as compared to that of the basolateral amygdala. A locus in the deep cell layer (layer III) of the rostral portion of the posterior piriform cortex (PPC) is described, which is considerably more sensitive to electrical stimulation than adjacent areas of the PPC, including the deep prepiriform cortex or the amygdala. The sensitive locus in the PPC can be readily kindled, and focal seizure thresholds in fully kindled rats are 60-90% lower than respective thresholds in rats kindled from other loci. Treatment of fully kindled rats with antiepileptic drugs diazepam, carbamazepine, phenobarbital, and valproate showed that anticonvulsant effects of these drugs in animals kindled from stimulation of the PPC were comparable to respective effects in animals kindled from stimulation of the basolateral amygdala, although the locus in the PPC tended to be more resistant. The data support the idea that the piriform area may contain the most sensitive neuronal tissue responsible for the generation of seizures during kindling. It remains to be determined if the described locus in the PPC is critical to the kindling process when kindling is induced from other structures within the olfactory-limbic system.

Amygdala↗
PubMed1991

Kindling does not induce persistent changes in fluorographic labeling patterns of benzodiazepine binding proteins in various rat brain regions.

The GABAA receptor has been implicated in the mechanisms underlying the phenomenon of kindling. Photoaffinity labeling with 3H-flunitrazepam followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis allows the fluorographic visualization of GABAA receptor proteins with benzodiazepine binding sites which presumably correspond to different alpha-subtypes. This method offers an opportunity to investigate whether up- or down-regulation of single benzodiazepine binding proteins occurs. In the present study, labeling patterns of benzodiazepine binding proteins were determined in 12 brains regions of amygdala-kindled rats (2 weeks after the last fully kindled seizure) and sham-operated controls. For most brain regions, labeling patterns were separately determined for the ipsi- and contralateral side. A comparison of the labeling patterns thus obtained revealed no persistent changes between kindled animals and controls in any of the brain regions, including amygdala, substantia nigra and hippocampus. Thus, we conclude that kindling does not induce fluorographically detectable changes in the expression patterns of the benzodiazepine binding proteins. The results confirm the existence of regional heterogeneity of benzodiazepine binding proteins and extend the findings to brain regions which had previously not been investigated.

Affinity Labels↗
PubMed1991

Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs.

The anticonvulsant potency of the trans isomer of 2-en-valproate (trans-2-en-VPA) was determined in standardized models for different seizure types in rodents and dogs. In mice and rats, adverse effects were quantified by the rotarod and chimney tests. Clinically established antiepileptic drugs (valproate, ethosuximide, phenobarbital, carbamazepine, phenytoin, diazepam) were used for comparison. Based on time course studies, drug potencies were determined and compared at the individual time of peak anticonvulsant effect. Potency comparisons were based on administered dosages and, in the case of trans-2-en-VPA and valproate, also on plasma levels determined after administration of anticonvulsant doses. The data show that trans-2-en-VPA exerts anticonvulsant effects against different seizure types, i.e., myoclonic, clonic, and tonic seizures in rodents and (myo)clonic seizures in dogs. In most seizure models, trans-2-en-VPA was more potent than valproate, when both compounds were compared at their individual times of peak effect. Time course and pharmacokinetic studies showed that duration of action and pharmacokinetic characteristics of trans-2-en-VPA and valproate are similar. In the rotarod and chimney tests in mice and rats, trans-2-en-VPA was more potent than valproate. However, because of the higher anticonvulsant potency of trans-2-en-VPA, protective indices calculated from rodent models were similar to those of valproate. Similarly, in dogs trans-2-en-VPA exerted anticonvulsant effects at doses below those which induced sedation and ataxia. In view of the previously reported advantages of trans-2-en-VPA compared to valproate with respect to teratogenic and hepatotoxic effects, the present data substantiate that trans-2-en-VPA might be a valuable alternative to valproate in antiepileptic therapy.

Animals↗
PubMed1991

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models.

Although seizure models using systemic administration of the chemoconvulsant pentylenetetrazol (PTZ) for induction of generalized clonic seizures in rodents are widely employed to identify potential anticonvulsants, the important role of diverse technical, biological and pharmacological factors in interpretation of results obtained with these models is often not recognized. The aim of this study was to delineate factors other than sex, age, diet, climate, and circadian rhythms, which are generally known. For this purpose, experiments with 8 clinically established antiepileptic drugs were undertaken in the following PTZ models: (1) the threshold for different types of PTZ seizures, i.e., initial myoclonic twitch, generalized clonus with loss of righting reflexes, and tonic backward extension of forelimbs (forelimb tonus), in mice; (2) the traditional PTZ seizure test with s.c. injection of the CD97 for generalized clonic seizures in mice; and (3) the s.c. PTZ seizure test in rats. In rats, in addition to evaluating drug effects on generalized clonic seizures, a ranking system was used to determine drug effects on other seizure types. When drugs were dissolved in vehicles which themselves did not exert effects on seizure susceptibility, the most important factors which influenced drug potencies were: (1) bishaped dose-response curves, i.e., a decline in anticonvulsant dose-response at high doses of some drugs, leading to misinterpretations of drug efficacy if only a single high drug dosage is tested; (2) effects of route of PTZ administration (i.v. infusion vs. s.c. injection) on estimation of anticonvulsant potency; (3) species differences in drug metabolism; (4) differences in drug potencies calculated on the basis of administered doses compared to potency calculations based on 'active' drug concentrations in plasma; (5) qualitative and quantitative species differences in drug actions; (6) endpoints used for PTZ tests; (7) misleading predictions from PTZ seizure models. Analysis of anticonvulsant drug actions indicated that myoclonic or clonic seizures induced by i.v. or s.c. PTZ might be suitable for predicting efficacy against myoclonic petit mal seizures in humans, but certainly not to predict efficacy against absence seizures. Tonic seizures induced by PTZ were blocked by drugs, such as ethosuximide, which exert no effect on tonic seizures in humans. In order to reduce the variability among estimates of anticonvulsant activity in PTZ seizure models, the various factors delineated in this study should be rigidly controlled in experimental situations involving assay of anticonvulsant agents.

Animals↗
PubMed1991

Anticonvulsant and behavioral effects of two novel competitive N-methyl-D-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine.

The orally active competitive N-methyl-D-aspartate (NMDA) receptor antagonists CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) and its ethyl ester CGP 39551 were evaluated in amygdala-kindled rats, a model for complex partial and secondarily generalized seizures. Anticonvulsant and behavioral effects of these novel compounds were compared with those of the noncompetitive NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e] and the antiepileptic drug carbamazepine, one of the major drugs for treatment of partial and generalized seizures in humans. For comparative evaluation, the compounds were injected i.p. at the following doses: 1 to 10 mg/kg (CGP 37849 or CGP 39551), 0.05 to 0.3 mg/kg (MK-801) and 20 to 40 mg/kg (carbamazepine), respectively. In contrast to carbamazepine, CGP 37849, CGP 39551 and MK-801 exerted only weak anticonvulsant effects in fully kindled rats and did not increase the focal seizure threshold. The weak anticonvulsant effects of the NMDA receptor antagonists in kindled rats were associated with profound untoward behavioral effects. The behavioral syndrome induced by the NMDA receptor antagonists in kindled rats was characterized by marked ataxia, hyperactivity and, in case of CGP 37849 and MK-801, stereotypies, such as head weaving. The low or absent effectiveness of the novel NMDA receptor antagonists against kindled seizures suggests that these compounds will not be clinically useful antiepileptics against partial and secondarily generalized seizures. Furthermore, in view of the recent clinical findings on psychotomimetic effects of MK-801 in epileptic patients, the similarities in the excitatory effects produced by CGP 39551, CGP 37849 and MK-801 in kindled rats may indicate that competitive NMDA receptor antagonists may also produce psychotomimetic effects in humans.

2-Amino-5-phosphonovalerate↗
PubMed1991

The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencyclidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1 and serotonin1A receptors.

The novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) was found to produce a phencyclidine (PCP)-like behavioral syndrome (ataxia, locomotion, stereotypies) in amygdala-kindled rats, whereas the amphetamine-like behavioral alterations of the syndrome (locomotion, stereotypies) were only infrequently seen in nonkindled rats. In dose-response experiments in kindled and nonkindled rats, behavioral effects were scored using a ranked intensity scale, and the behaviors and behavioural scores determined after CGP 37849 were compared with those determined after i.p. administration of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801). In kindled rats, 20 mg/kg of CGP 37849 produced about the same scores for hyperlocomotion and head weaving as 0.1 mg/kg of MK-801. Kindled rats exhibited higher behavioral scores than nonkindled rats, especially in the case of CGP 37849. The behavioral effects produced by CGP 37849 in kindled rats were almost indistinguishable from the PCP-like behavioral effects induced by MK-801, indicating that CGP 37849 indeed produces a PCP-like pattern of behavior in kindled rats. Hyperlocomotion and head weaving induced by CGP 37849 in kindled rats could be attenuated or totally prevented by pretreatment with ipsapirone, a partial agonist/antagonist at postsynaptic 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype. Furthermore, these behavioural effects were attenuated or blocked by the dopamine antagonist haloperidol and the alpha-1 adrenoceptor antagonist, prazosin. The data demonstrate that kindling induces a hypersensitivity to PCP-like behavioral effects of competitive and noncompetitive NMDA receptor antagonists, which could relate to the recent finding of increased function of NMDA receptors following kindling.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1990

High doses of memantine (1-amino-3,5-dimethyladamantane) induce seizures in kindled but not in non-kindled rats.

Memantine (1-amino-3,5-dimethyladamantane) has previously been shown to attenuate or block chemically or electrically induced seizures in rodents at doses of 5-20 mg/kg i.p., suggesting that the drug might have potential utility in the treatment of seizures. In the present study, the effects of memantine were examined in amygdala-kindled and non-kindled rats. In fully kindled rats, i.e. a model of focal seizures with secondary generalization, memantine exerted no effects on seizure parameters at 5 mg/kg i.p., but reduced seizure severity and duration at 10 mg/kg. The threshold for induction of afterdischarges recorded from the amygdala was not altered after administration of 10 mg/kg. At 20 mg/kg, memantine induced spontaneous motor seizures in amygdala-kindled rats. No motor seizures were observed in non-kindled rats, but in both kindled and non-kindled animals memantine, 20 mg/kg, induced spikes in the electroencephalogram. Additional dose-dependent behavioural alterations observed after memantine included hyperactivity, ataxia and stereotypies, which may relate to the dopaminomimetic properties of the drug. The results demonstrate that kindled rats are more sensitive to central nervous system stimulating effects of memantine than non-kindled rats, which could relate to an impairment of inhibitory processes and/or alterations in synaptic transmission mediated by excitatory amino acids in the kindled brain.

Amantadine↗
PubMed1990

Phenytoin potently increases the threshold for focal seizures in amygdala-kindled rats.

Previous studies on the effects of phenytoin in the kindling model have yielded equivocal results, in that some groups reported anticonvulsant effects, while others found the drug to be only weakly active, inactive or even proconvulsant. Although part of these discrepancies might relate to factors such as the time of testing, route of administration, doses and administration vehicles, variable results were also obtained by studies in which these factors were comparable. For further investigation of the reasons of the reported discrepancies in the effectiveness of phenytoin in kindled rats, the influence of current intensity on the effects of phenytoin were examined in this model. In fully amygdala-kindled rats, phenytoin was only weakly active against seizures evoked by a fixed suprathreshold current of 500 microA. However, when the current was decreased to 250 microA, phenytoin exerted potent anticonvulsant effects. Determination of the threshold for focal afterdischarges showed that phenytoin, 12.5-75 mg/kg dose-dependently increased the threshold up to about 600% over controls at 75 mg/kg. Average levels in plasma, determined at this dose were about 30 micrograms/ml. In contrast to the potent effect on the seizure threshold, the severity or duration of seizures, evoked in phenytoin-pretreated rats by increasing the current, was not reduced. These data indicate that the primary effect of phenytoin in kindled rats in an increase in focal seizure threshold, while the ability of phenytoin to reduce the spread of seizures appears to be small. The present data might explain the discrepancy in reports on phenytoin in kindled rats, because most studies which found the drug to be ineffective used current intensities far exceeding the seizure threshold.

Amygdala↗
PubMed1990

The effect of interstimulation interval on the assessment of anticonvulsant drug potency in fully kindled rats.

Multiple stimulation regimes with interstimulation intervals of 0.25-2 h were investigated in fully kindled rats as methods of testing the time course and potency of anticonvulsant drugs after a single administration. Protocols with conventional interstimulation intervals of 1-3 days were used for comparison. Prior to the drug experiments, the different stimulation regimes were examined in drug-naive, kindled rats in order to determine the extent of postseizure inhibition occurring with such protocols. All stimulations were carried out with a suprathreshold current of 500 microA. Using protocols with 3-9 stimulations within 8 h, seizure severity was relatively stable, but motor seizure duration was reduced in most experiments. Both decreases and increases were observed with respect to afterdischarge duration (ADD). The increases in ADD were primarily due to the appearance of 'secondary' afterdischarges with small amplitude, which were associated with immobility, intermittent facial clonus and head nodding. After a series of stimulations at short intervals, reduced seizure severity was observed after this series for at least 1 week, so that an interval of at least 2 weeks had to be interposed between multistimulation experiments in the same group of rats. When the effects of carbamazepine, 15 mg/kg, were determined with 4 different stimulation regimes, it was found that the anticonvulsant potency of the drug was higher in experiments with short interstimulation intervals compared to conventional protocols with interstimulation intervals of 1-3 days, indicating synergistic effects between the drug and postictal inhibition. Indication for such synergism was also found when the animals were only stimulated once daily during the drug experiments. With higher doses of carbamazepine or phenobarbital, 30 mg/kg, the difference between the stimulation protocols was less marked. Furthermore, the time course of anticonvulsant action determined with different stimulation regimes was similar. The data indicate that multistimulation regimes can be used in kindled rats to determine the time course following single administration of anticonvulsant drugs, but such protocols may lead to an overestimation of anticonvulsant potency.

Animals↗
PubMed1990

Pharmacokinetics, anticonvulsant efficacy and adverse effects of the beta-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs.

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a novel beta-carboline with high affinity for central benzodiazepine (BZ) receptors, has been shown recently to be a potent anxiolytic and anticonvulsant in animal models whereas lacking ataxia-producing effects, a profile typical for a partial agonist at BZ receptors. In the present study abecarnil was tested in dogs after acute and chronic administration. Pharmacokinetic studies showed that abecarnil was eliminated rapidly after i.v. or p.o. administration, but elimination was delayed substantially after s.c. injection. After i.v. injection, the drug penetrated rapidly into the cerebrospinal fluid, but maximum concentrations reached in cerebrospinal fluid were only 6 to 8% of those in plasma. Anticonvulsant potency of abecarnil in dogs was studied by means of seizures induced by i.v. infusion of pentylenetetrazol. After i.v. administration of single doses, abecarnil was about half as potent as diazepam, dose-dependently increasing the pentylenetetrazol threshold by doses of 0.1-1 mg/kg. In contrast to diazepam, most dogs injected with abecarnil at anticonvulsant doses showed no ataxia. During chronic s.c. administration of abecarnil for 6 weeks, the anticonvulsant efficacy of the drug increased markedly during the first week(s) of treatment, possibly indicating drug accumulation in the brain. During the subsequent weeks of treatment, there was a slight reduction in anticonvulsant potency. No withdrawal symptoms were observed after cessation of the 6-week administration period. Furthermore, injection of the BZ antagonist Ro 15-1788 (flumazenil), 1 mg/kg i.v., after 5 weeks of treatment did not precipitate withdrawal symptoms except slight tremor in two of seven dogs studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗