Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixty-two patients with uncontrolled partial seizures participated in a 12-week, double-blind, placebo-controlled add-on-trial. Thirty-two patients received loreclezole and 30 a placebo as add-on therapy. Loreclezole was targeted at a plasma level of 1-2 mg/l. In spite of an antiepileptic therapy, usually with 2 or 3 antiepileptic drugs, these patients had at least 4 seizures a month during the baseline period. At the end of the treatment phase with loreclezole and placebo, individual responses varied widely. The median change in the daily seizure frequency was not significantly different in the 2 groups. However, when individual responses are considered, 6 patients in the verum group (19%) experienced a seizure reduction of 50% or more, compared with no patients in the placebo group. During the trial, only mild adverse events were reported in both the loreclezole and the placebo group, nor were any clinically relevant abnormalities seen in the haematological and biochemical analysis. The efficacy and safety of higher loreclezole plasma concentrations were studied in a long-term follow-up trial, the results of which are presented in the following article.
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PMID:A double-blind, placebo-controlled evaluation of the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures. 190 39

Thirteen drug-resistant epilepsy patients received loreclezole as add-on therapy. The trial lasted 6 months. Loreclezole was dosed to reach a target plasma concentration between 1 and 3 mg/l. The seizure frequency in the total group decreased by 23%. A reduction of 50% or more was observed in four patients. These effects are most likely related to loreclezole, as doses and plasma levels of the associated anti-epileptic drugs remained unchanged during the study. Loreclezole was tolerated well and no changes in haematological or biochemical parameters were observed.
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PMID:Efficacy and safety evaluation of loreclezole as add-on treatment in therapy-resistant epilepsy patients. 206 45

A potential antiepileptic drug, loreclezole, was studied in rats of 7, 12, 18, 25 and 90 days old. Metrazol-induced motor phenomena served as a model. Loreclezole did not consistently influence isolated myoclonic jerks or minimal metrazol seizures (predominantly clonic with preserved righting ability). Major metrazol seizures, i.e., generalized tonic-clonic seizures, were suppressed by loreclezole in a dose-dependent manner in all age-groups, except in the 7 day old group where outlined changes did not reach statistical significance. Severity of seizures was significantly diminished at all developmental stages studied. Loreclezole exhibits nearly the same profile of action as phenytoin and carbamazepine in this model.
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PMID:Effects of loreclezole on metrazol-induced phenomena in developing rats. 224 26

Loreclezole is an anticonvulsant and anxiolytic compound which has been reported to potentiate GABA via a novel allosteric site on the beta-subunit of the receptor. We have now studied in rats both the in vivo and in vitro pharmacology of the compound. The dose of loreclezole required to increase by 50% the dose of intravenous pentylenetetrazol eliciting a seizure was comparable to that of barbiturates and chlormethiazole (in mg/kg): diazepam, 1.3; pentobarbitone, 16; chlormethiazole, 22; loreclezole, 25; pentobarbitone, 36. Loreclezole dose-dependently decreased locomotion (dose to decrease locomotion by 50% (in mg/kg): chlormethiazole, 9; pentobarbitone, 16; loreclezole, 25). Loreclezole, chlormethiazole and pentobarbitone all failed to displace [3H]muscimol and [3H]flunitrazepam binding from a rat cortical membrane preparation. All three compounds fully displaced [35S]TBPS binding (IC50 values: loreclezole, 4.34 +/- 0.68 microM; pentobarbitone, 37.39 +/- 3.24 microM; chlormethiazole, 82.10 +/- 8.52 microM). Addition of bicuculline (10 microM) produced a major rightward shift in the loreclezole and pentobarbitone displacement curves, increasing IC50 values for [35S]TBPS binding by 25 times (loreclezole), 6 times (pentobarbitone) and 2.7 times (chlormethiazole), suggesting a greater involvement of GABA in the interaction of loreclezole with the chloride channel than in the case of chlormethiazole. Anticonvulsant activity of the compounds did not appear to relate to [35S]TBPS binding activity. Other binding data suggested that although the evidence of others indicates that loreclezole interacts with a specific allosteric site on the beta-subunit, it nevertheless also alters the binding characteristics of other modulatory sites.
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PMID:A behavioural and neurochemical study in rats of the pharmacology of loreclezole, a novel allosteric modulator of the GABAA receptor. 901 39

The purpose of this study was to assess the concentration-anti-convulsant effect relationships of a number of anti-convulsant drugs in the direct cortical stimulation model, to obtain more insight in the properties and predictive value of this model. The time course of the effect of lamotrigine, loreclezole, flunarizine, CGP40116 and CGP39551 was determined after iv. administration in conjunction with their pharmacokinetics. Convulsive activity was induced by stimulation of the motor cortex with a ramp-shaped pulse train. This technique allows consecutive measurements of the treshold for localized (TLS) and for generalized (TGS) seizure activity. Increase in threshold was used as measure of the anti-convulsant effect. After administration of lamotrigine, pronounced elevation of the TGS, with little change in the TLS, was observed. Flunarizine caused a similar effect, but much less intense. Loreclezole strongly elevated the TGS and to a lesser extent the TLS, also. The concentration-anti-convulsant effect relationship of the three compounds could be fitted by an exponential model. The NMDA antagonists, CGP40116 and CGP39551, induced minor changes in the TLS and a slight increase in the TGS. The onset of this effect was marked by a delay relative to blood concentrations. The biophase equilibration kinetics was estimated and a linear model was applied to describe the concentration-effect relationship of both NMDA antagonists. The present results show that the cortical stimulation model is a suitable technique for integrated pharmacokinetic-pharmacodynamic modelling and for assessing anti-convulsant efficacy. The results show that the model is rather insensitive to calcium channel blockers and NMDA antagonists.
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PMID:Pharmacokinetic-pharmacodynamic correlation of lamotrigine, flunarizine, loreclezole, CGP40116 and CGP39551 in the cortical stimulation model. 1077 Dec 57

Loreclezole (5 mg/kg) exerted a significant protective action in amygdala-kindled rats, reducing both seizure and afterdischarge durations. The combinations of loreclezole (2.5 mg/kg) with valproate, clonazepam, or carbamazepine (applied at their subprotective doses) also exhibited antiseizure effect in this test. However, only two first combinations occurred to be of pharmacodynamic nature. Among several chemoconvulsants, bicuculline, N-methyl-D-aspartic acid and BAY k-8644 (the opener of L-type calcium channels) reversed the protective activity of loreclezole alone and its combination with valproate. On the other hand, bicuculline, aminophylline and BAY k-8644 inhibited the anticonvulsive action of loreclezole combined with clonazepam. The results support the hypothesis that the protective activity of loreclezole and its combinations with other antiepileptics may involve potentiation of GABAergic neurotransmission and blockade of L-type of calcium channels.
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PMID:Effect of some convulsants on the protective activity of loreclezole and its combinations with valproate or clonazepam in amygdala-kindled rats. 1470 68

Loreclezole (5 mg/kg) exerted a significant protective action against amygdala-kindled rats, reducing both seizure and afterdischarge (AD) durations. Subsequently, the effect of combinations of loreclezole (at non-effective doses) with some conventional antiepileptics (at their subtherapeutic doses) was evaluated. The co-administration of loreclezole (2.5 mg/kg) with phenobarbital (15 mg/kg) or diphenylhydantoin (2.5 mg/kg) did not influence any seizure correlates. However, the combined treatment of loreclezole (2.5 mg/kg) with valproate (50 mg/kg) significantly reduced the afterdischarge duration. Its combination with carbamazepine (15 mg/kg) reduced the seizure severity (SSv) and both seizure and afterdischarge durations. Also, the concomitant treatment of loreclezole (2.5 mg/kg) with clonazepam (0.05 mg/kg) resulted in a significant decrease of seizure and afterdischarge durations. Loreclezole did not affect the free plasma concentrations of valproate or clonazepam, so a pharmacokinetic interaction is not probable. Although, loreclezole significantly increased the free plasma concentration of carbamazepine. The results point to the potential therapeutic effects of combinations of loreclezole with valproate or clonazepam.
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PMID:Interaction of loreclezole with conventional antiepileptic drugs in amygdala-kindled rats. 1505 85