awd-131-138 and Epilepsy

Although benzodiazepines (BZDs) offer a wide spectrum of antiepileptic activity against diverse types of epileptic seizures, their use in the treatment of epilepsy is limited because of adverse effects, loss of efficacy (tolerance), and development of physical and psychological dependence. BZDs act as positive allosteric modulators of the inhibitory neurotransmitter GABA by binding to the BZD recognition site ("BZD receptor") of the GABAA receptor. Traditional BZDs such as diazepam or clonazepam act as full agonists at this site, so that one strategy to resolve the disadvantages of these compounds would be the development of partial agonists with lower intrinsic efficacy at the BZD site of the GABAA receptor. Several BZD site partial or subtype selective compounds, including bretazenil, abecarnil, or alpidem, have been developed as anxioselective anxiolytic drugs, but epilepsy was not a target indication for such compounds. More recently, the imidazolone derivatives imepitoin (ELB138) and ELB139 were shown to act as low-affinity partial agonists at the BZD site of the GABAA receptor, and imepitoin was developed for the treatment of epilepsy. Imepitoin displayed a broad spectrum of anticonvulsant activity in diverse seizure and epilepsy models at tolerable doses, and, as expected from its mechanism of action, lacked tolerance and abuse liability in rodent and primate models. The more favorable pharmacokinetic profile of imepitoin in dogs versus humans led to the decision to develop imepitoin for the treatment of canine epilepsy. Based on randomized controlled trials that demonstrated antiepileptic efficacy and high tolerability and safety in epileptic dogs, the drug was recently approved for this indication in Europe. Hopefully, the favorable profile of imepitoin for the treatment of epilepsy in dogs will reactivate the interest in partial BZD site agonists as new treatments for human epilepsy.

Topics: Animals; Anticonvulsants; Benzodiazepines; Disease Models, Animal; Dogs; Epilepsy; GABA-A Receptor Agonists; Humans; Imidazoles; Receptors, GABA-A

The mainstay of comparative research for epilepsy has been rodent models of induced epilepsy. This rodent basic science is essential, but it does not always translate to similar results in people, likely because induced epilepsy is not always similar enough to naturally occurring epilepsy. A good large animal, intermediate model would be very helpful to potentially bridge this translational gap. Epilepsy is the most common medical neurologic disease of dogs. It has been proposed since the 1970s that dogs with naturally occurring epilepsy could potentially be used as a comparative model for people of the underlying basis and therapy of epilepsy. There have been sporadic studies in the decades since then, with a relative surge in the last 10 years. These canine studies in the areas of genetics, drug therapy, dietary therapy, electroencelphalogram research, and devices for epilepsy show proof of concept that canine epilepsy can be a very good model for comparative research for many, but not all, facets of epilepsy. Results of research in canine epilepsy can and have benefited the improvement of treatment for both people and dogs.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dog Diseases; Dogs; Electroencephalography; Epilepsy; Imidazoles; Species Specificity; Translational Research, Biomedical

Idiopathic head tremor syndrome is a paroxysmal movement disorder of unknown etiology. Spontaneous remission may occur, but owners may request treatment in severely affected dogs with continued episodes. Controlled studies of the disease are not available.. A drug with gamma amino butyric acid-ergic and anxiolytic effects will decrease head tremor episodes.. Twenty-four dogs with severe nonremitting head tremor and presumptive clinical diagnosis of idiopathic head tremor syndrome.. Prospective, blinded, placebo-controlled clinical trial to compare imepitoin with placebo in dogs with frequent episodes of idiopathic head tremor. Evaluation of efficacy used the quotient T2/T1 that represented prolongation of the head tremor-free period compared to a 3-month baseline. A dog was considered a responder if tremors subsided or if the head tremor-free period was 3× longer than the longest period during baseline (T2/T1 ≥ 3). Sample size calculations considered a large effect of imepitoin on T2/T1 (Cohen's d = 0.8).. There were no responders in the placebo group (0/12). In the imepitoin group, the responder rate was 17% (2/12; P = .18) with T2/T1 3.8 and 4.0. Mean T2/T1 was 1.0 ± 1.4 in the imepitoin and 0.4 ± 0.4 in the placebo group (P = .37).. Imepitoin did not result in a significant overall benefit. Future studies should focus on treatment of subgroups with a common pathophysiology and similar comorbidities.

Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Epilepsy; Female; Imidazoles; Male; Prospective Studies; Treatment Outcome; Tremor

Epilepsy in the cat is a serious medical condition. To date there are no licensed treatments for feline epilepsy and no well-controlled clinical studies on the efficacy or safety of antiepileptic drugs in cats. The aim of this study was to collect tolerability data and first exploratory efficacy data of imepitoin in both healthy and epileptic cats.. In two tolerability studies, 30 healthy cats received imepition twice daily in doses of 0, 30, 40 or 80 mg/kg bodyweight for 30 days. No serious adverse events were observed in any of the dose groups. In the imepitoin treated groups, emesis was observed in some animals temporarily and intermittently mainly in the second and third weeks of treatment. In a small, single-arm, open label, uncontrolled clinical trial eight cats suffering from idiopathic epilepsy were treated with imepitoin twice daily at doses of 30 mg/kg bodyweight for 30 days. Four of these cats (50%) achieved seizure freedom for at least 8 weeks under treatment. Adverse events, mostly lethargy, decreased appetite and emesis, were often mild and transient.. In summary, imepitoin was well tolerated in healthy and epileptic cats and showed in a pilot trial indication for efficacy in treating feline epilepsy.

Topics: Animals; Anticonvulsants; Cat Diseases; Cats; Dogs; Epilepsy; Female; Imidazoles; Male; Pilot Projects

Imepitoin was tested as a combination treatment with phenobarbital in an open-label mono-centre cohort study in dogs with drug-resistant epilepsy. Diagnosis of idiopathic epilepsy was based on clinical findings, magnetic resonance imaging and cerebrospinal fluid analysis. Three cohorts were treated. In cohort A, dogs not responding to phenobarbital with or without established add-on treatment of potassium bromide or levetiracetam were treated add-on with imepitoin, starting at 10 mg/kg BID, with titration allowed to 30 mg/kg BID. In cohort B, the only difference to cohort A was that the starting dose of imepitoin was reduced to 5 mg/kg BID. In cohort C, animals not responding to imepitoin at >20 mg/kg BID were treated with phenobarbital add-on starting at 0.5 mg/kg BID.. The add-on treatment resulted in a reduction in monthly seizure frequency (MSF) in all three cohorts. A reduction of ≥50% was obtained in 36-42% of all animals, without significant difference between cohorts. The lower starting dose of 5 mg/kg BID imepitoin was better tolerated, and an up-titration to on average of 15 mg/kg BID was sufficient in cohort A and B. In cohort C, a mean add-on dose of 1.5 mg/kg BID phenobarbital was sufficient to achieve a clinically meaningful effect. Six dogs developed a clinically meaningful increase in MSF of ≥ 50%, mostly in cohort A. Neither imepitoin nor phenobarbital add-on treatment was capable of suppressing cluster seizure activity, making cluster seizure activity an important predictor for drug-resistance.. A combination treatment of imepitoin and phenobarbital is a useful treatment option for a subpopulation of dogs with drug-resistant epilepsy, a low starting dose with 5 mg/kg BID is recommended.

Topics: Animals; Anticonvulsants; Cohort Studies; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Imidazoles; Male; Phenobarbital

Imepitoin has recently been approved in Europe for the management of dogs with idiopathic epilepsy. Currently, there is no evidence-based information available on the efficacy of antiepileptic drugs used as additions to the therapeutic regimen in dogs with idiopathic epilepsy that are not well controlled with imepitoin. The goal of this study was to evaluate the efficacy of phenobarbital or potassium bromide (KBr) as add-on antiepileptic drugs for controlling dogs refractory to a maximum dose of imepitoin (30 mg/kg twice daily). The study was performed as a prospective, randomised, controlled clinical trial. The efficacy of phenobarbital and KBr was evaluated by comparing monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), the presence of cluster seizures during a retrospective 2-month period with a prospective follow-up of 6 months, and the overall responder rate. Twenty-seven dogs were included in the study, 14 dogs in the phenobarbital group and 13 dogs in the KBr group. Both median MSF and MSDF decreased in the phenobarbital group (both P = 0.001) and in the KBr group (P = 0.004 and P = 0.003, respectively). Overall, the number of dogs with cluster seizures decreased (P = 0.0005). The responder rate was 79% vs. 69% in the phenobarbital and KBr groups, respectively. We conclude that phenobarbital or KBr add-on treatment decreases median MSF and MSDF in epileptic dogs refractory to a maximum dose of imepitoin. Combination therapy was generally well tolerated and resulted in an improvement in seizure management in the majority of the dogs.

Topics: Animals; Anticonvulsants; Belgium; Bromides; Dog Diseases; Dogs; Epilepsy; Imidazoles; Phenobarbital; Potassium Compounds; Prospective Studies; Retrospective Studies; Seizures

Since early 2013, imepitoin has been used in most European countries for the management of recurrent single generalised epileptic seizures in dogs with idiopathic epilepsy. It has been reported that imepitoin is as effective as phenobarbital (PB) in controlling seizures in dogs with newly diagnosed idiopathic epilepsy and it has a clinically superior safety profile. As the use of imepitoin gains popularity, its effect on serum thyroid parameters warrants further investigation since long-term PB administration influences thyroid parameters in dogs, which could lead to misinterpretation of laboratory results and incorrect diagnosis of thyroidal illness. A prospective study was conducted to compare the effect of orally administered PB and imepitoin on serum concentrations of total thyroxine (TT4), triiodothyronine, free thyroxine, thyroglobulin autoantibodies, thyroid-stimulating hormone, cholesterol and triglycerides in healthy Beagle dogs. These parameters were determined prior to and at 6, 12 and 18 weeks after antiepileptic drug administration. The starting dose of PB (5 mg/kg PO twice daily; range, 4.4-6.0 mg/kg) was monitored and adjusted to obtain optimal therapeutic serum concentrations (30-35 g/mL). Imepitoin was administered at 30 mg/kg PO twice daily (range, 29.2-35.7 mg/kg). Imepitoin administration did not affect any of the thyroid parameters over an 18-week period. In contrast, serum TT4 concentrations decreased significantly over time in dogs receiving PB (P <0.05). Serum cholesterol concentrations increased significantly over time in dogs in the imepitoin group, but not to the same extent as commonly seen in dogs with primary hypothyroidism.

Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Epilepsy; Female; Imidazoles; Lipid Metabolism; Longitudinal Studies; Male; Phenobarbital; Prospective Studies; Thyroid Gland

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.

Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Epilepsy; Imidazoles; Phenobarbital

Imepitoin is a novel antiepileptic drug for the treatment of canine idiopathic epilepsy. The present study was conducted to demonstrate superior antiepileptic activity of a high dose of 30 mg/kg BID over a low dose of 1 mg/kg BID of imepitoin during 12 weeks of treatment under double blind conditions in a field population of dogs with previously untreated epilepsy. In a consecutive 12 weeks open label follow up (phase 2), all animals received 30 mg/kg BID, to evaluate the persistence of the antiepileptic activity, and to evaluate the effect of a dose step up to 30 mg/kg in the former low-dose animals.. A treatment with 30 mg/kg BID resulted in a significantly greater reduction in monthly seizure frequency relative to baseline data as compared to the 1 mg/kg dose. Both generalized and partial seizures but not cluster seizures were significantly less frequent in the high dose group. The antiepileptic activity was maintained during study phase 2 in the high dose group. An increase to 30 mg/kg BID in the low- dose animals resulted in a significant reduction in generalized and partial seizures, but not cluster seizures. At the end of study phase 2, 32.1 and 46.8 % of dogs of the former high and former low-dose groups respectively, remained free of generalized tonic-clonic seizures. Imepitoin was well tolerated. The frequency of dogs with any adverse drug reactions was higher in the 30 mg/kg BID dose (59 % vs. 41 %, p = 0.041), and the main target organ was the central nervous system (CNS). The occurrence of CNS related adverse reactions was transient and findings were mostly restricted to the first weeks of treatment. No hepatic enzyme increase and no other organ toxicity were observed.. The administration of imepitoin twice daily at a dose of 30 mg/kg results in significant and persistent antiepileptic effects in patients with newly diagnosed epilepsy and generalized tonic-clonic seizures, as observed over a study period of up to 6 months. Imepitoin was well tolerated. Most CNS related adverse drug reactions were transient. Both the antiepileptic activity and the safety profile make the drug suitable for long-term clinical use.

Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Epilepsy; Female; Imidazoles; Male

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 [(14) C] 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.

Topics: Animals; Anticonvulsants; Area Under Curve; Cross-Over Studies; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Female; Food Deprivation; Half-Life; Imidazoles; Male; Molecular Structure

The aim of this study was to evaluate changes in epileptic seizures (ES) frequency and semiology in antiepileptic-medication (AEM)-naïve dogs with idiopathic epilepsy (DIE) after initiation of imepitoin (IMP) or phenobarbital (PB) monotherapy. In this observational prospective cohort study, inclusion criteria were as follows: diagnosis of idiopathic epilepsy (based on clinical, laboratory and magnetic resonance imaging investigations) in AEM-naïve dogs and presence of a detailed ES-diary. Exclusion criteria were: occurrence of cluster seizures (CS) or status epilepticus (SE) prior to treatment initiation and concurrent disease and/or treatments. Thirty-one DIE commenced IMP at 10-20mg/kg/12h and 30 dogs commenced PB at 2.50-3.30mg/kg/12h. AEM dosage was increased over time (up to IMP 30mg/kg/12h and PB 5.20mg/kg/12h). All dogs experienced generalised-tonic-clonic ES. In the IMP-group, pre-treatment median ES-frequency was 1.50ES/month (range, 1-4ES/month); post-treatment median ES-frequency was 0.95ES/m (range, 1ES/6m-3ES/m); n=21/31 (67.70%) dogs developed CS 1-18 months after initiation of treatment; n=7/31 (22.60%) dogs experienced unacceptable adverse events in the first month of treatment which required switching to an alternative AEM; and n=3/31(9.70%) dogs did not develop CS with a 3year follow-up. In the PB-group, pre-treatment median ES-frequency was 2.46ES/month (range, 1-7ES/month); post-treatment median ES-frequency was 0.36ES/month (range, 0ES/3years-1ES/month); n=11/30 (36.70%) dogs developed CS between 12-25 months after initiation of treatment. Nineteen of 30 (63.30%) dogs did not develop CS with a 3-year follow-up; three of these 19 dogs were ES free. In this study, AEM-naïve DIE receiving imepitoin-monotherapy developed CS significantly more frequently and earlier in the course of the disease, and developed aggression and required earlier discontinuation of monotherapy than AEM-naïve DIE receiving phenobarbital-monotherapy.

Topics: Animals; Anticonvulsants; Cohort Studies; Dog Diseases; Dogs; Epilepsy; Imidazoles; Phenobarbital; Prospective Studies; Seizures; Treatment Outcome

Behavioural changes associated with idiopathic epilepsy (IE) have been identified in dogs, with fear and anxiety-related problems seen in both drug-naïve dogs and dogs treated with anti-epileptic drugs (AEDs). Treating anxiety-related behaviour in dogs with IE may be challenging, as seizures are a contraindication for many conventional anxiolytic drugs. In addition, many dogs with IE are already treated with AEDs to reduce their seizure frequency, which may have negative effects if used in polytherapy. Imepitoin is low-affinity partial agonist at the benzodiazepine (BDZ) site of the GABA. No differences were observed in the five fear/anxiety-related measures between the two time periods (before vs. during treatment) for dog directed fear, stranger directed fear, non-social fear, pain sensitivity and separation related behaviour. A median 45% reduction in seizure frequency/month was observed following imepitoin treatment; however, imepitoin did not appear effective in reducing seizure frequency in a minority of cases. Polyphagia was the most common chronic side effect, and more side effects were reported in polytherapy cases.. Imepitoin does not appear to improve anxiety-related behaviour in dogs with IE treated with this medication for its anti-epileptic effects. Investigating the effects of imepitoin upon the behaviour of dogs with recognised behavioural anxiety-related problems (e.g. specific fears and phobias, separation related behaviours), in both healthy dogs and dogs with epilepsy is required to further explore any potential anxiolytic effects of this medication.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Dog Diseases; Dogs; Epilepsy; Fear; Female; Humans; Imidazoles; Male; Surveys and Questionnaires

The purpose of this study was to evaluate the long-term (12 months) efficacy and tolerability of imepitoin as first-choice treatment in 56 dogs suffering from idiopathic epilepsy and identify possible factors affecting the outcome. Primary treatment success (PTS) was defined as the achievement of a seizure-free interval three times longer than the pretreatment interictal interval (at least three months). Secondary treatment success (STS) was achieved by a decrease in seizure frequency ≥50 per cent compared with the pretreatment frequency. In the long-term follow-up, PTS was recorded in 14 (25 per cent) dogs and responder-dogs (PTS+STS) were 30 (54 per cent) showing significant reduction in the monthly average number of seizures (P<0.001). Median seizure frequency per month was 1.69 pretreatment and 0.3 at 12-month follow-up. Dogs with cluster seizures were significantly reduced (P=0.02). PTS at three and six months was associated with PTS (P=0.006 and <0.001, respectively) and with the status of responder dogs (P=0.002) at 12-month follow-up. Dogs aged >36 months at the start of imepitoin treatment had a positive association to become responder dogs (P<0.001) and achieve PTS (P=0.004). 16 dogs (29 per cent) discontinued imepitoin due to its inefficacy. The receiver operator curve highlighted ≥19 mg/kg twice a day as the most effective minimal dosage. Mild and transient side effects were observed in 16 dogs (29 per cent).

Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Epilepsy; Female; Follow-Up Studies; Imidazoles; Male; Seizures; Treatment Outcome

Phenobarbital or potassium bromide (KBr) add-on treatment decreases the average monthly seizure frequency in dogs with idiopathic epilepsy resistant to a maximum dose of imepitoin. The importance of continued administration of imepitoin in these dogs is currently unknown. The goal of this study was to assess whether imepitoin withdrawal would destabilize epileptic seizure control. In this prospective clinical trial epileptic seizure control was evaluated by comparing the monthly seizure frequency of 13 dogs with well-controlled idiopathic epilepsy receiving a combination of imepitoin and phenobarbital (n=4), imepitoin and KBr (n=7), and imepitoin, phenobarbital and KBr (n=2) during a period of 3-6 months (pre-withdrawal period), with a follow-up period of 9-12 months after withdrawal of imepitoin (post-withdrawal period). Adverse effects were also recorded before and after withdrawal of imepitoin. Imepitoin was tapered off over 3 months as follows: 20mg/kg twice daily for 1 month, then 10mg/kg twice daily for 1 month, then once daily for 1 month. Withdrawal of imepitoin did not increase monthly seizure frequency (P=0.9). Moreover, all owners reported improvement in the adverse effects experienced by their dog after withdrawal of imepitoin. Imepitoin withdrawal in epileptic dogs that were well-controlled with imepitoin and phenobarbital and/or KBr did not worsen epileptic seizure control, and possibly decreased antiepileptic treatment-related adverse effects. However, a worsening of seizure frequency could occur in individual cases.

Topics: Animals; Anticonvulsants; Bromides; Dog Diseases; Dogs; Drug Therapy, Combination; Epilepsy; Female; Imidazoles; Male; Phenobarbital; Potassium Compounds; Seizures; Treatment Outcome

The macroscopic appearance of cutaneous adverse drug reactions can be similar to a plethora of skin diseases and in particular may resemble autoimmune and immune-mediated disorders. The reaction can occur after single or multiple administrations, with the latter varying in durations of up to years of treatment. These reactions are mostly self-limiting with cessation of the offending drug.. To report a cutaneous adverse drug reaction associated with chronic administration of imepitoin.. A 4-year-old, Jack Russell terrier dog was presented with progressive skin lesions of 1-week duration. The dog had a 6 month history of idiopathic epilepsy treated with imepitoin for the previous 5 months. Imepitoin is an anti-epileptic drug that acts as a low-affinity partial agonist of the benzodiazepine site at the GABAA receptor. The dosage of imepitoin was increased from 20 mg/kg twice daily to 30 mg/kg twice daily, 3 days before the onset of skin lesions, due to uncontrolled seizures. [Correction added on 15 February 2016 after first online publication: In the preceding sentence, the dosage of imepitoin was previously incorrect and has been amended in this current version.] Dermatological examination revealed erythema and exfoliation at the mucocutaneous junctions of the lips, lip folds, philtrum, ears, axillae and the ventral abdomen. Small erosions and depigmentation were visible on the oral mucosa, lip folds and philtrum. Histopathology was supportive of a lupoid drug reaction. Complete resolution of skin lesions was seen after discontinuation of imepitoin and low dose of prednisolone during a period of 4 weeks. No recrudescence of skin lesions was observed during a 6 month follow-up period.. Imepitoin may result in cutaneous adverse drug reactions in dogs.

Topics: Animals; Anti-Inflammatory Agents; Dog Diseases; Dogs; Drug Eruptions; Epilepsy; Imidazoles; Male; Prednisolone

Idiopathic epilepsy (IE) is a common chronic neurological disease of the dog. Previous studies of anti-epileptic drug (AED) treatment have indicated that acceptable AED adverse effects are as important to owners as reductions in seizure frequency. AEDs in both dogs and human beings are frequently associated with the adverse-effect ataxia. The aim of this study was to compare ataxia levels in dogs with IE treated chronically with phenobarbitone or imepitoin, the two currently available first-line AED treatments. The gait of 6 imepitoin-treated dogs, 8 phenobarbitone-treated dogs and 10 age-matched healthy control dogs were compared. Fifty strides from a walking gait were analysed for each dog, quantifying ataxia via the variability in six established gait parameters. Three variables differed significantly between groups: lateral distance between (i) pelvic paw placements, (ii) thoracic paw placements and (iii) stance time, which were significantly more variable in the phenobarbitone-treated dogs than imepitoin-treated or control dogs. These results indicate that dogs treated with phenobarbitone experience ataxia compared with controls and imepitoin-treated dogs. Conversely, there was no difference between imepitoin-treated dogs and controls. These results along with further research are needed to quantify AEDs adverse effects, to help vets and owners make more informed drug-choices.

Topics: Animals; Anticonvulsants; Ataxia; Case-Control Studies; Dog Diseases; Dogs; Epilepsy; Gait; Imidazoles; Phenobarbital; Treatment Outcome

Topics: Animals; Anticonvulsants; Behavior, Animal; Dog Diseases; Dogs; Epilepsy; Imidazoles; Treatment Outcome

Topics: Adverse Drug Reaction Reporting Systems; Animals; Dog Diseases; Dogs; Drug Labeling; Epilepsy; Imidazoles; Seizures; Tablets; United Kingdom

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.

Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Drug Therapy, Combination; Epilepsy; Female; Imidazoles; Male; Pilot Projects; Recurrence; Seizures; Severity of Illness Index; Treatment Outcome

Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, loss of efficacy (tolerance), development of dependence, and the potential for drug abuse limit the clinical use of benzodiazepines (BZDs) for long-term treatment of epilepsy or anxiety. BZD ligands that are in current use act as full allosteric modulators of gamma-aminobutyric acid (GABA)-gated chloride channels and, on long-term administration, trigger a functional uncoupling between the GABAA and BZD recognition sites. Partial allosteric modulators, which have a low intrinsic activity at the BZD recognition site of the GABAA receptor, might eventually overcome the limitations of full agonists such as diazepam (DZP).. In the present study, the new low-affinity partial BZD-receptor agonist ELB 138 [former name AWD 131-138; 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one] was evaluated in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures.. ELB 138 was shown to increase potently the pentylenetetrazole (PTZ) seizure threshold in dogs. Prolonged oral administration with twice-daily dosing of ELB 138 with either 5 or 40 mg/kg over a 5-week period was not associated with loss of anticonvulsant efficacy in the PTZ dog model. To study whether physical dependence developed during long-term treatment, the BZD antagonist flumazenil was injected after 5 weeks of treatment with ELB 138. Compared with prolonged treatment with DZP, only relatively mild abstinence symptoms were precipitated in dogs treated with ELB 138, particularly at the lower dosage (5 mg/kg, b.i.d.). In a prospective trial in dogs with newly diagnosed epilepsy, ELB 138 markedly reduced seizure frequency and severity without significant difference to standard treatments (phenobarbital or primidone) but was much better tolerated than the standard drugs. In dogs with chronic epilepsy, most dogs exhibited a reduction in seizure frequency and severity during add-on treatment with ELB 138.. The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures.

Topics: Animals; Anticonvulsants; Bromides; Chronic Disease; Disease Models, Animal; Dog Diseases; Dogs; Drug Therapy, Combination; Epilepsy; Flumazenil; GABA Agonists; GABA-A Receptor Agonists; Imidazoles; Pentylenetetrazole; Phenobarbital; Potassium Compounds; Primidone; Receptors, GABA-A; Seizures; Substance Withdrawal Syndrome; Treatment Outcome