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Zonisamide trial

Many thanks to Dr Thilo von Klopmann fromDept. of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover who provided much of the information in this article.

Zonisamide is a new anticonvulsant licensed for man in the US in 2000 and recently studied for its efficacy as an add-on therapy for dogs with refractory epilepsy. It has a half life of about 15 hours in dogs (Matsumoto and others 1983, Thomas 2003). Most is excreted unchanged in urine although some hepatic metabolism occurs.

Zonisamide blocks voltage-dependent sodium and calcium channels and may reduce presynaptic glutamate release (Mac Donald 2002). Furthermore an increase in dopamine and serotonin levels in striatal and hippocampal structures are reported (Kaneko and others 1993, Okada and others 1995).

Zonisamide appears to be safe - few side - effects are reported in dogs, although mild ataxia and sedation may occur when treatment is started and vomiting and loss of appetite have been reported in some dogs (Dewey and others, 2004). An initial dose rate of 5 to 10 mg/kg BID is recommended - aiming for a serum concentration of 10-40 ug/ml. At a dose of 75 mg/kg body weight (four times the recommended dose) slight changes in blood count and an increase of liver weight were observed in one study (Walker and others 1988). Recently, however, in rats, an induction of tolerance has been described (Hamada and others 2001). This may be due to an induction of functional tolerance or an increasing severity of the epileptic process known as kindling phenomenon.

Limited data exist concerning the use of the anticonvulsant zonisamide in canine epilepsy (Dewey and others 2004, Boothe and others 2005, Saito and others 2005). A recent study by von Klopmann and others (2007) evaluated the efficacy of zonisamide as add-on to conventional anticonvulsant therapy in dogs with refractory epilepsy. In this study refractory epilepsy was defined as a lack of sufficient response to phenobarbital and/or potassium bromide treatment despite therapeutic serum levels of one or both of these drugs. Zonisamide was administered as add-on therapy at a dosage of 10mg/kg body weight BID PO (Matsumoto and others 1983, Walker and others 1988, Boothe and others 2005, Saito and others 2005). Serum samples were collected from the dogs in the study at different time points following zonisamide administration and serum concentrations of drug were measured. The reference for zonisamide ranged from 10 to 40 µg/ml (Matsumoto and others 1983, Walker and others 1988).

Mild side-effects were noticed by the owners in six dogs after starting zonisamide therapy such as ataxia and sedation.  Zonisamide is a sulphonamide-based anticonvulsant drug.  Although not yet reported, clinicians should be aware of potential side effects similar to those associated with other sulphonamides.

The frequency and duration of seizures, as well as seizure severity, decreased in most of the dogs in this study following zonisamide administration. The high number dogs responding (at least a 50% reduction in seizures frequency) indicates a beneficial effect of zonisamide in refractory cases. Due to good seizure control in seven dogs a reduction of previous anticonvulsant therapy (phenobarbital, potassium bromide) was possible without subsequent impairment of seizure control. In several animals this led to a reduction in side effects and an improved quality of life. In one dog (a Border collie) dose reduction of conventional anticonvulsants resulted in a reduction of sedation so that breed typical behaviour was displayed again.

In a subgroup of the responder dogs an impairment of seizure control subsequently occurred. This loss of efficacy, after an initial good response, has been described for several drugs and has also been shown for zonisamide in rats (Hamada and others 2001).

The use of zonisamide is limited by its high costs and that it is not available in some countries. In the United States a generic form of active ingredient is available, however, there are no published studies describing the use of this formulation in dogs.

Further studies are warranted to evaluate the development of functional tolerance leading to a kind of “honey-moon effect” in zonisamide add-on therapy and the efficacy of zonisamide as monotherapy.


References

von Klopmann, T., Rambeck B., Tipold A. (2007) A study of zonisamide therapy for refractory idiopathic epilepsy in dogs. JSAP 48

Boothe, D.M., Perkins, J., Dewey, C. (2005) Clinical pharmacokinetics and safety of the anticonvulsant zonisamide in healthy dogs following single and multiple dosing. Proceedings of the 23rd ACVIM forum, Baltimore, USA. p 858

Budsberg, S.C. (2004) Zonisamide therapy for refractory idiopathic epilepsy in dogs. Journal of the AmericanAnimalHospital Association 40, 285-291

Dewey, C.W., Guiliano, R., Boothe, D.M., Berg, J.M., Kortz, G.D., Joseph, R.J., Budsberg, S.C. (2004) Zonisamide therapy for refractory idiopathic epilepsy in dogs. Journal of the AmericanAnimalHospital Association 40, 285-291

Hamada, K., Song, H.K., Ishida, S., Yagi, K., Seino, M. (2001) Contrasting effects of zonisamide and acetazolamide on amygdaloid kindling rats, Epilepsia 42, 1379-1386

Kaneko, S., Okada, M., Hirano, T. (1993) Carbamazepine and zonisamide increase extracellular dopamine and serotonin levels in vivo, and carbamazepine does not antagonize adenosine effect in vitro: mechanisms of blockade of seizure spread. Japanese Journal of Psychiatry and Neurology 47, 371-373

Juergens, U. (1987) Simultaneous determination of zonisamide and nine other anti-epileptic drugs and metabolites in serum. Journal of Chromatography 385, 233-240

Mac Donald, R.L. (2002) Zonisamide. In: Antiepileptic drugs, 5th edn. Eds R.H. Levy, R.H. Mattson, B.S. Meldrum, E. Perucca. Lippincott Williams and Wilkens, Philadelphia. pp 867-898

Matsumoto, K., Miyazaki, H., Fujii, T., Kagemoto, A., Maeda, T., Hashimoto, M. (1983) Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benziosoxazole (AD-810) in rats, dogs and monkeys and of AD-810 in men. Drug Research 33, 961-968

Okada, M., Kaneko, S., Hirano, T. (1995) Effects of zonisamide on dopaminergic system. Epilepsy Research 22, 193-205

Saito, M., Orito, K., Takikawa, S., Kageyama, T., Muto, M. (2005) Pharmacokinetics of zonisamide administered alone and in combination with phenobarbital in dogs. Proceedings of the 23rd ACVIM forum, Baltimore, USA. pp 858-859

Thomas, W.B. (2003) Seizures and narcolepsy. In: A practical guide to canine and feline neurology. Ed C.W. Dewey. Iowa State Press, Ames. ISBN 0-8138-1249-6; pp 193-212

Walker, R.M., DiFonzo, C.J., Barsoum, N.J., Smith, G.S., Macallum, G.E. (1988) Chronic toxicity of the anticonvulsant zonisamide in beagle dogs. Fundamental and applied Toxicology 11, 333-342

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