Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: A clinical pilot study

Department of Small Animal Medicine and Surgery, University of Veterinary Medicine, and Center for Systems Neuroscience, Hannover, Germany.
The Veterinary Journal (Impact Factor: 1.76). 08/2006; 172(1):86-95. DOI: 10.1016/j.tvjl.2005.04.003
Source: PubMed

ABSTRACT A new antiepileptic and anxiolytic drug, ELB138, was evaluated in a clinical pilot study in dogs with newly diagnosed or chronic idiopathic epilepsy. The purpose was to verify clinically the anticonvulsant effectiveness of this substance, which had already been demonstrated experimentally. Data from 29 dogs treated with ELB138 were compared with results obtained retrospectively from 82 dogs treated with conventional antiepileptic medication. The reduction in seizure frequency using ELB138 in dogs with newly diagnosed idiopathic epilepsy was comparable to the reduction in dogs treated either with phenobarbital or primidone. In dogs with chronic epilepsy and add-on therapy with either ELB138 or potassium bromide, such supplementation reduced the seizure frequency and the duration and severity of seizures. The most obvious difference between ELB138 treatment and conventional medications became clear in the evaluation of side effects, which in those dogs treated with ELB138 were rare, and consisted mostly of transient polyphagia. This pilot study confirmed that ELB138 has a potent anticonvulsant effect in dogs with idiopathic epilepsy. These results will form the basis for a multicentre, blinded study.

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    • "Only for hyperactivity, the frequency was higher for imepitoin than for phenobarbital, however, rated in most cases to be mild. While the duration of these adverse events was not systematically assessed in this study, it is known from a previous study that the behavioural adverse effects following imepitoin were only observed at the beginning of the study but disappeared during the treatment course (Rieck et al., 2006). An increased activity of the dogs under imepitoin treatment compares favourably to somnolence/sedation observed frequently in the phenobarbital group and may be even an indication of normalization. "
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    ABSTRACT: The anticonvulsant activity and safety of imepitoin, a novel antiepileptic drug licensed in the European Union, were evaluated in a multicentre field efficacy study as well as in a safety study under laboratory conditions. Efficacy of imepitoin was compared with phenobarbital in 226 client-owned dogs in a blinded parallel group design. The administration of imepitoin twice daily in incremental doses of 10, 20 or 30 mg/kg demonstrated comparable efficacy to phenobarbital in controlling seizures in dogs. The frequency of adverse events including somnolence/sedation, polydipsia and increased appetite was significantly higher in the phenobarbital group. In phenobarbital-treated dogs, significantly increased levels of alkaline phosphatase, gamma-glutamyl-transferase and other liver enzymes occurred, while no such effect was observed in the imepitoin group. In a safety study under laboratory conditions, healthy beagle dogs were administered 0, 30, 90 or 150 mg/kg imepitoin twice daily for 26 weeks. A complete safety evaluation including histopathology was included in the study. A no-observed-adverse-event level of 90 mg/kg twice daily was determined. These results indicate that imepitoin is a potent and safe antiepileptic drug for dogs.
    Journal of Veterinary Pharmacology and Therapeutics 07/2014; 38(2). DOI:10.1111/jvp.12151 · 1.19 Impact Factor
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    • "While only limited pharmacokinetic data are available preventing an exact analysis, no clinically relevant interaction was visible in dogs which were treated with imepitoin add on to phenobarbital, which is known to be a strong enzyme inducer . Similar imepitoin peak and trough plasma levels were recorded in 19 dogs treated add on to phenobarbital as compared to dogs treated with monotherapy only (Rieck et al., 2006). This lack of interaction with phenobarbital is favorable, as phenobarbital is notorious for drug interaction and even levetiracetam , known to have a very low interaction potential, was cleared more rapidly in dogs treated with phenobarbital as compared to na€ ıve dogs (Moore et al., 2011). "
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    ABSTRACT: Imepitoin is a novel anti-epileptic licensed in the European Union for the treatment of canine idiopathic epilepsy. The aim of this study was to characterize the pharmacokinetics of imepitoin in dogs and to evaluate the interaction with drug metabolizing enzymes. Upon administration of imepitoin tablets at a dose of 30 mg/kg to beagle dogs, high plasma levels were observed within 30 min following oral dosing, with maximal plasma concentrations of 14.9–17.2 μg/mL reached after 2–3 h. In a crossover study, co-administration of imepitoin tablets with food reduced the total AUC by 30%, but it did not result in significant changes in Tmax and Cmax, indicating lack of clinical relevance. No clinically relevant effects of sex and no accumulation or metabolic tolerance were observed upon twice daily dosing. Following single dose administration of 10–100 mg/kg, dose linearity was found. Administering [14C] imepitoin, high enteral absorption of 92% and primary fecal excretion were identified. Plasma protein binding was only 55%. At therapeutic plasma concentrations, imepitoin did not inhibit microsomal cytochrome P450 family liver enzymes in vitro. In rats, no relevant induction of liver enzymes was found. Therefore, protein binding or metabolism-derived drug–drug interactions are unlikely. Based on these data, imepitoin can be dosed twice daily, but the timing of tablet administration in relation to feeding should be kept consistent.
    Journal of Veterinary Pharmacology and Therapeutics 03/2014; 37:421-434. DOI:10.1111/jvp.12117 · 1.19 Impact Factor
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    ABSTRACT: Idiopathic epilepsy (IE) is a common breed-related neurological disorder in contemporary small animal medicine. The number of Border Collies (BCs) with epileptic seizures is increasing while there is a lack of data of IE in this breed. Hypothesis of this study was that IE occurs in BCs and manifests often with severe clinical signs and poor response to medical treatment. IE was diagnosed by recurrent seizures, normal physical, neurological and laboratory examination. MRI and CSF analysis were requested if age at seizure onset was < 6 months or > 5 years of age. Dogs that failed to meet all inclusion criteria were only considered if a first- or second-degree relative was afflicted by IE or if seizures had occurred for at least 2 years without interictal neurological abnormalities. Owners fulfilled a detailed questionnaire. Subsequent phenotypic case classification was performed by evaluation of seizure history and treatment data. Pedigrees were sampled and matched for the appearance of common ancestors. Ninety BCs with a reported seizure history were collected retrospectively and prospectively. Forty-nine of them were diagnosed with IE and were included in the present study. Clinical manifestations were dominated by moderate (33 %) and severe clinical courses (49 %) defined by the occurrence of cluster seizures or status epilepticus, respectively. Pharmacoresistance was apparent in 71 % of 24 dogs treated with ≥ 2 antiepileptic drugs. So far, no predictors for the occurrence of pharmacoresistance were identified in the present study. The epilepsy remission rate was 18 %. Dogs in remission showed a significantly higher median age at onset and a significantly lower initial seizure frequency compared to dogs with active epilepsy (p < 0.05). Survival time was significantly reduced in dogs aged < 2 years at seizure onset and in dogs with severe clinical courses (p < 0.05). Family- and pedigree analyses indicated a strong genetic founder effect in the appearance of epilepsy, resembling autosomal recessive inheritance. Yet, complex inheritance could not be excluded. In conclusion, IE occurs in BCs and is frequently associated with severe clinical signs and pharmacoresistance. While further genetic research is required, the results of this study suggest a substantial hereditary (disease) component.
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