title: Add-on treatment with verapamil in pharmacoresistant canine epilepsy.
abstract: OBJECTIVE
  Verapamil add-on treatment has been suggested as a novel therapeutic concept for overcoming transporter-mediated pharmacoresistance. Efficacy data have been limited so far to case reports in individual epileptic patients. Therefore, we aimed to thoroughly evaluate the efficacy and tolerability of verapamil add-on treatment.
  
  
  METHODS
  In a prestudy in healthy Beagle dogs the tolerability of verapamil add-on treatment was investigated. The efficacy of verapamil was then evaluated in 11 dogs with phenobarbital-resistant epilepsy.
  
  
  RESULTS
  Verapamil add-on treatment (6.2-7.3 mg/kg) did not affect phenobarbital concentrations in plasma or cerebrospinal fluid. Side effects observed in healthy as well as in epileptic dogs comprised bradycardia and a decrease in blood pressure. Therefore, we had to limit the dosage to 1-1.5 mg/kg in the main study. In phenobarbital nonresponders, verapamil failed to improve seizure control. Verapamil treatment was discontinued prematurely in five animals due to worsening of seizure control or lack of an effect. In the remaining animals, seizure frequency tended to increase during the verapamil add-on phase, reaching a mean of two seizures per month compared to the pre-verapamil phase with phenobarbital monotherapy (mean of 1.4 seizures per month). In view of the detrimental effects in the majority of the dogs, the study had to be discontinued and no further animals were enrolled.
  
  
  CONCLUSIONS
  The failure of the maximum tolerated dosage to improve seizure control in dogs with phenobarbital-resistant epilepsy argues against the suitability of verapamil add-on treatment to overcome pharmacoresistance. Deterioration of seizure control in some individual animals suggests that verapamil might also exert unfavorable effects on seizure thresholds or its spread.
authors.affiliation: Division Neurology, Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Jambroszyk
authors.forename: Andrea
authors.initials: A
authors.lastname: Tipold
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017668:Age of Onset; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000662:veterinary*; D005260:Female; D008297:Male; D010634:Phenobarbital / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D012008:Recurrence; D017211:Treatment Failure; D014700:Verapamil / Q000009:adverse effects / Q000134:cerebrospinal fluid / Q000627:therapeutic use*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D014700:Verapamil; D010634:Phenobarbital