The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs.

Twenty-two dogs with idiopathic epilepsy which were pharmacoresistant to phenobarbitone and bromide were treated with levetiracetam as an add-on medication. Records of eight dogs were used retrospectively to determine a safe, efficient levetiracetam dosage. Fourteen dogs were entered into a prospective, open label, non-comparative study. After 2 months of levetiracetam oral treatment (10 mg/kg TID), 8/14 dogs responded significantly to the treatment and seizure frequency was reduced by 50%. In dogs that remained refractory, the dosage was increased to 20 mg/kg TID for 2 months. One further dog responded to levetiracetam treatment. Levetiracetam responders had a significant decrease in seizure frequency of 77% (7.9+/-5.2 to 1.8+/-1.7 seizures/month) and a decrease in seizure days per month of 68% (3.8+/-1.7 to 1.2+/-1.1 seizure days/month). However, 6/9 responders experienced an increase in seizure frequency and seizure days after 4-8 months continuing with the levetiracetam treatment at the last effective dosage. Levetiracetam was well tolerated by all dogs and sedation was the only side-effect reported in just one of the 14 dogs.

[1]  G. Regesta,et al.  Clinical aspects and biological bases of drug-resistant epilepsies , 1999, Epilepsy Research.

[2]  P Ryvlin,et al.  Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy , 2007, Neurology.

[3]  J. Cramer,et al.  New Antiepileptic Drugs: Comparison of Key Clinical Trials , 1999, Epilepsia.

[4]  M. Podell Antiepileptic drug therapy. , 1998, Clinical techniques in small animal practice.

[5]  D. Margineanu,et al.  Levetiracetam has no significant gamma-aminobutyric acid-related effect on paired-pulse interaction in the dentate gyrus of rats. , 2003, European journal of pharmacology.

[6]  W. Löscher,et al.  Lack of effects of prolonged treatment with phenobarbital or phenytoin on the expression of P-glycoprotein in various rat brain regions. , 2002, European journal of pharmacology.

[7]  E. Perucca,et al.  A Multicenter Randomized Controlled Trial on the Clinical Impact of Therapeutic Drug Monitoring in Patients with Newly Diagnosed Epilepsy , 2000, Epilepsia.

[8]  D. Margineanu,et al.  Inhibition of neuronal hypersynchrony in vitro differentiates levetiracetam from classical antiepileptic drugs. , 2000, Pharmacological research.

[9]  T. Alsaadi,et al.  Clinical experience of levetiracetam monotherapy for adults with epilepsy: 1-year follow-up study , 2005, Seizure.

[10]  P. Patsalos Pharmacokinetic profile of levetiracetam: toward ideal characteristics. , 2000, Pharmacology & therapeutics.

[11]  W. Löscher,et al.  Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. , 1998, The Journal of pharmacology and experimental therapeutics.

[12]  Josemir W Sander,et al.  Evidence for sustained efficacy of levetiracetam as add-on epilepsy therapy , 2003, Epilepsy Research.

[13]  J. French,et al.  Fast and Sustained Efficacy of Levetiracetam during Titration and the First 3 Months of Treatment in Refractory Epilepsy , 2005, Epilepsia.

[14]  L. Trepanier,et al.  Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996). , 1998, Journal of the American Veterinary Medical Association.

[15]  A. Pitkänen,et al.  Antiepileptogenesis, neuroprotection, and disease modification in the treatment of epilepsy: focus on levetiracetam. , 2003, Epileptic disorders : international epilepsy journal with videotape.

[16]  Kate Chandler,et al.  Canine epilepsy: what can we learn from human seizure disorders? , 2006, Veterinary journal.

[17]  P. Patsalos,et al.  A microdialysis study of the novel antiepileptic drug levetiracetam: extracellular pharmacokinetics and effect on taurine in rat brain , 2001, British journal of pharmacology.

[18]  S. Budsberg,et al.  Zonisamide therapy for refractory idiopathic epilepsy in dogs. , 2004, Journal of the American Animal Hospital Association.

[19]  Wolfgang Löscher,et al.  The neurobiology of antiepileptic drugs , 2004, Nature Reviews Neuroscience.

[20]  M. Podell,et al.  Bromide therapy in refractory canine idiopathic epilepsy. , 1993, Journal of veterinary internal medicine.

[21]  Cynthia L. Harden Safety Profile of Levetiracetam , 2001, Epilepsia.

[22]  V. Shkryl,et al.  Selective Blockade of N‐Type Calcium Channels by Levetiracetam , 2002, Epilepsia.

[23]  L. Garosi,et al.  Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy , 2006, Veterinary Record.

[24]  T. Serikawa,et al.  Separation of Antiepileptogenic and Antiseizure Effects of Levetiracetam in the Spontaneously Epileptic Rat (SER) , 2005, Epilepsia.

[25]  W. Löscher,et al.  Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. , 1985, Journal of veterinary pharmacology and therapeutics.

[26]  H. Klitgaard Levetiracetam: The Preclinical Profile of a New Class of Antiepileptic Drugs? , 2001, Epilepsia.

[27]  Brian D. Hale,et al.  Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  W. Löscher,et al.  Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. , 1993, European journal of pharmacology.

[29]  M. Strolin Benedetti,et al.  Comparative pharmacokinetics and metabolism of levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog , 2004, Xenobiotica; the fate of foreign compounds in biological systems.

[30]  C. Marescaux,et al.  Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy , 1995, Epilepsy Research.

[31]  C. Hovinga Levetiracetam: A Novel Antiepileptic Drug , 2001, Pharmacotherapy.

[32]  B. Lynch,et al.  Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines. , 2003, European journal of pharmacology.

[33]  M Sculpher,et al.  Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. , 2005, Health technology assessment.

[34]  L. Gram,et al.  Epilepsy and seizure classification in 63 dogs: a reappraisal of veterinary epilepsy terminology. , 1999, Journal of veterinary internal medicine.

[35]  E McColl,et al.  Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients. , 2001, Health technology assessment.

[36]  B Malgrange,et al.  The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents , 2002, British journal of pharmacology.

[37]  Ettore Beghi,et al.  Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines , 2004, The Lancet Neurology.

[38]  W. Löscher,et al.  Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy , 2002, Epilepsia.

[39]  R. Malik,et al.  Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent. , 2005, Australian veterinary journal.

[40]  Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society , 2004 .

[41]  M. Gillard,et al.  Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain. , 2003, European journal of pharmacology.

[42]  Josemir W Sander,et al.  Long-term continuation of levetiracetam in patients with refractory epilepsy , 2001, Neurology.

[43]  Shili Lin,et al.  Clinical presentations of naturally occurring canine seizures: similarities to human seizures , 2002, Epilepsy & Behavior.

[44]  M. Whittington,et al.  Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat , 1999, Epilepsy Research.

[45]  S. Dedeurwaerdere,et al.  The Acute and Chronic Effect of Vagus Nerve Stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) , 2005, Epilepsia.

[46]  A. Verrotti,et al.  Efficacy and safety of levetiracetam: An add-on trial in children with refractory epilepsy , 2005, Seizure.

[47]  Curtis Wells Dewey Anticonvulsant therapy in dogs and cats. , 2006, The Veterinary clinics of North America. Small animal practice.

[48]  K. Nocka,et al.  The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[49]  G. Bernardi,et al.  Levetiracetam does not modulate neuronal voltage-gated Na + and T-type Ca 2+ currents , 2001, Seizure.

[50]  T. Tomson,et al.  Therapeutic Drug Monitoring of the Newer Antiepileptic Drugs , 2003, Therapeutic drug monitoring.

[51]  M. Gillard,et al.  Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. , 2006, European journal of pharmacology.

[52]  E. H. Reynolds,et al.  WHY DOES EPILEPSY BECOME INTRACTABLE? Prevention of Chronic Epilepsy , 1983, The Lancet.

[53]  J. Leach,et al.  Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. , 1997, European journal of pharmacology.

[54]  J. French,et al.  Levetiracetam safety profiles and tolerability in epilepsy patients , 2004, Expert opinion on drug safety.

[55]  Dieter Schmidt,et al.  Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs , 2006, Epilepsia.

[56]  J. Gobert,et al.  Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. , 1998, European journal of pharmacology.

[57]  D. Margineanu,et al.  Levetiracetam inhibits the high-voltage-activated Ca2+ current in pyramidal neurones of rat hippocampal slices , 2001, Neuroscience Letters.

[58]  W T Blume,et al.  Proposal for a New Classification of Outcome with Respect to Epileptic Seizures Following Epilepsy Surgery , 2001, Epilepsia.

[59]  M. Bialer,et al.  Pharmacokinetics of Levetiracetam and Its Enantiomer (R)‐α‐ethyl‐2‐oxo‐pyrrolidine acetamide in Dogs , 2001, Epilepsia.