awd-131-138 and Seizures

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

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

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

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

Recently, the imidazolinone derivative imepitoin has been approved for treatment of canine epilepsy. Imepitoin acts as a low-affinity partial agonist at the benzodiazepine (BZD) site of the GABAA receptor and is the first compound with such mechanism that has been developed as an antiepileptic drug (AED). This mechanism offers several advantages compared to full agonists, including less severe adverse effects and a lack of tolerance and dependence liability, which has been demonstrated in rodents, dogs, and nonhuman primates. In clinical trials in epileptic dogs, imepitoin was shown to be an effective and safe AED. Recently, seizures in dogs have been proposed as a translational platform for human therapeutic trials on new epilepsy treatments. In the present study, we compared the anticonvulsant efficacy of imepitoin, phenobarbital and the high-affinity partial BZD agonist abecarnil in the timed i.v. pentylenetetrazole (PTZ) seizure threshold test in dogs and, for comparison, in mice. Furthermore, adverse effects of treatments were compared in both species. All drugs dose-dependently increased the PTZ threshold in both species, but anticonvulsant efficacy was higher in dogs than mice. At the doses selected for this study, imepitoin was slightly less potent than phenobarbital in increasing seizure threshold, but markedly more tolerable in both species. Effective doses of imepitoin in the PTZ seizure model were in the same range as those suppressing spontaneous recurrent seizures in epileptic dogs. The study demonstrates that low-affinity partial agonists at the benzodiazepine site of the GABAA receptor, such as imepitoin, offer advantages as a new category of AEDs.

Topics: Animals; Anticonvulsants; Carbolines; Dogs; Dose-Response Relationship, Drug; Drug Partial Agonism; Female; GABA-A Receptor Agonists; Imidazoles; Male; Mice; Pentylenetetrazole; Phenobarbital; Seizures

New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure-activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABAA mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.

Topics: Administration, Oral; Animals; Anti-Anxiety Agents; Anticonvulsants; Binding Sites; Brain; GABA Antagonists; GABA-A Receptor Agonists; Imidazoles; Male; Mice; Models, Molecular; Morpholines; Pentylenetetrazole; Piperidines; Pyrroles; Quantitative Structure-Activity Relationship; Radioligand Assay; Rats; Rats, Wistar; Rotarod Performance Test; Seizures

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