Clinical characteristics and treatment with antiepileptic drugs (AEDs) in cats is fundamentally different from dogs and other species. Treatment options are limited, and only limited data are available (Platt 2001). The “International League Against Epilepsy” (ILAE) grades studies for human treatment in four categories of study quality, from class I for well controlled, randomized, double-blind trials with large numbers of cases to class IV for expert opinions and anecdotal case reports. Knowledge on epilepsy treatment in cats can be regarded as lowest grade of evidence (class IV).
Accordingly it is very difficult for a person skilled in the art to choose an appropriate treatment option for cats. In addition, there is a sufficient body of evidence proving that cats react different to most AEDs compared to dogs and other species (Pakozdy et al. 2014). Many AEDs have unfavorable pharmacokinetic properties, low or unproven efficacy or even toxic effects in cats, limiting their potential use as described below in detail.
Oral diazepam has a longer elimination half-life in cats (15-20 h) than in dogs (3-4 h) and cats do not develop functional tolerance to the drug in contrast to other species, including rat, mouse, dog and human. Beside non-fatal adverse events like sedation, polyuria and polydipsia, it has been linked to potentially fatal idiosyncratic hepatotoxicosis, hepatic necrosis and liver failure. Consequently oral diazepam is considered contraindicated in cats (Smith Bailey 2009). This situation is similar to other benzodiazepines, like clorazepate. In terms of efficacy, full benzodiazepine agonists are regarded as very efficacious treatment, but not used due to the possible life-threatening side effects.
Bromide is neither considered sufficiently effective, as seizures are only controlled in about 35% of treated cats, and bromide is associated with severe side effects in cats, especially an idiosyncratic allergic pneumonitis occurring in 35-42% of treated cats. As this adverse event is potentially life-threatening, also bromide is, in contrast to dogs, not a therapeutic option in cats (Boothe et al. 2002).
Phenobarbital is the current treatment of choice, based on its low price, relatively long elimination time, long history of chronic use and acceptable tolerability. However the safety profile and pharmacokinetics are different from dogs and other species. In contrast to dogs, it is not linked to hepatopathy and development of drug tolerance. In cats, sedation, ataxia, polyuria, polydipsia, leukopenia, thrombocytopenia, lymphadenopathies, skin eruptions and coagulopathies have been described as adverse events. In a recent study, sedation was reported in over 40% of all treated cases, and even resulting in two fatal events (one cat was euthanized, as phenobarbital did not control seizures but led to severe sedation, another cat had a fatal accident due to severe sedation) (Pakozdy et al. 2013). In addition, phenobarbital has a strong addictive effect. It is effective in many cases; however there seems to be still a quite high rate of poor responding epileptic cats (ca. 30%).
Approximately half of healthy cats receiving a 20 mg/kg dose of zonisamide experience adverse reactions such as anorexia, diarrhea, vomiting, somnolence and ataxia, and sufficient efficacy has not been convincingly demonstrated.
Levetiracetam was shown in one study to be somewhat effective as add-on therapy in cats with refractory epilepsy under phenobarbital treatment, however in only 10 cats and in a study with methodological weaknesses. Sedation, inappetence and hypersalivation were attributed side-effects. Other drugs were only anecdotally used in cats, and there are no data supporting their routine use in clinical practice (Pakozdy et al. 2014).
Barnes H L et al. (JAVMA 2004, 225(11): 1723-1726) discuss clinical signs, underlying cause, and outcome in 17 cats with seizures.
Fromm G H et al. (Fromm et al. 1985) compared the effect of the experimental antiepileptic gamma-aminobutyric acid (GABA) agonist drug progabide on the trigeminal complex of cats with the effect of established antiepileptic drugs and with the effect of various GABA agonists and antagonists. Their experiments indicated that progabide, but not THIP or muscimol, should have antiepileptic properties. However, the reason for the differential effect of the three GABA agonists remained to be elucidated.
Morimoto K and co-workers (Morimoto K et al. 1993) conducted a comparative study of the anticonvulsant effect of GABA agonists on feline amygdala or hippocampal kindled seizures. They showed that progabide, SKF89976A and gamma-vinyl GABA have potent anticonvulsant effects on partial onset and secondarily generalized limbic seizures. Selective GABAB receptor agonist baclofen, however, did not show anticonvulsant effects on any parameters of kindled seizures.
Quesnel A D et al. (JAVMA 1997, 210(1): 72-77) discuss the clinical management and outcome of cats with seizure disorders in 30 cases.
Schwartz-Porsche D et al. (Feline Epilepsy. In: Inderi R J ed. Problems in Veterinary Medicine. Vol. 1, No. 4, Philadelphia, Pa., Lippincott, 1989: 628-649) gives a review on feline epilepsy.
WO 2013/024023 discloses taste masked pharmaceutical compositions.
In summary, AEDs in cats show an adverse event profile which is significantly different from dogs. Development of drug tolerance, which is common for phenobarbital and benzodiazepines in dogs, humans and rodents, seem to play a minor role in cats. Sedation is a common side effect in all antiepileptic drugs used in the cat, as mentioned above. This can be regarded as relevantly reduced quality of life for the diseased cat, and it also is a disadvantage for the owner-cat interaction.
The objective underlying the present invention is therefore to provide a medication for preventing and/or treating epileptic disorders in feline animals, which overcomes the problems and limitations of the prior art.