Anticonvulsant and proconvulsant properties of viloxazine hydrochloride: Pharmacological and pharmacokinetic studies in rodents and the epileptic baboon

Abstract

Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED50 for abolition of tonic extension was 9 mg/kg-1 after 30-min pretreatment (mouse) rising to 30 mg/kg-1 after 60 min (mouse and rat). Comparable ED50 values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED50 for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5 -- 1 microgram/ml-1. In the baboon, significant protection against photomyoclonic responses is observed 1 -- 2h after viloxazine (2.6 mg/kg-1 IV), during which period the plasma concentration was again 0.5-1 microgram/ml-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed.

Comparison of the (Pro)convulsive Properties of Fluvoxamine and Clovoxamine with Eight Other Antidepressants in an Animal Model

“…These results indicate that imipramine has proconvulsive properties. Viloxazine was found to be anticonvulsive in a number of test models in mice up to a dose of 100 mg/kg orally [Greenwood, 1975], but later studies in apes showed viloxazine, given intravenously, to be proconvulsive after toxic doses [Meldrum et al, 1982],…”

“…A variety of animal models have been developed to determine the (pro)convulsive potency of drugs by determining their effects on: -thalamic discharges in rats and cats [Ito et al, 1977]; -photically evoked afterdischarges in hooded rats [Big ler. 1977]; -seizure activity in photosensitive baboons (Trimble et al, 1977;Meldrum et al" 1982]; -afterdischarges induced by electric stimulation of the rabbit amygdala [Ossows/ca and Wolfarth, 1980;Sayers, 1979] or the rat amygdala [Kamei et al, 1975]; -spontaneous EEG in locally anesthetized cats immo bilized with gallamine [Koella et al, 1979] or nonanesthetized, noncurarized rabbits [Tartara et al, 1982]; -hippocampal afterdischarges in rabbits [Tartara et al, 1982], Contradictory results have been reported by various authors using the same methods. After amygdala stimula tion in the rabbit, Ossowska and Wolfarth [1980] found that imipramine at 10 mg/kg inhibited both the length of the afterdischarge and the behavioral seizure.…”

A disfunção do lobo frontal em crianças e adolescentes com epilepsia de lobo temporal e sua possível correlação com a ocorrência de transtornos psiquiátricos

“…Os ratos GEPR-9 apresentam um déficit de transmissão NE mais pronunciado, e, portanto exibem crises mais graves do que os ratos GEPR-3 (31) . Aumentos da transmissão da NE e/ou da 5HT podem prevenir a ocorrência de crises; por outro lado, a sua redução tem um efeito oposto, aumentando as crises epilépti-cas (32) . O uso de inibidores da recaptação da serotonina (ISRS) e dos inibidores da mono-amino-oxidase (IMAOs) exercem um efeito anticonvulsivante nestes camundongos geneticamente predispostos à epilepsia (31) e nos macacos babuínos (31)(32) , assim como em outros animais não-geneticamente predispostos: em gatos (33) , coelhos (34) e macacos Rhesus (35) .…”

Depressão em crianças e adolescentes com epilepsia

“…Aumentos da transmissão da NE e/ou da 5-HT podem prevenir a ocorrência de crises; por outro lado, a sua redução tem um efeito oposto, aumentando as crises epilépticas (Meldrum et al, 1982).…”

“…O uso de inibidores da recaptação da serotonina (ISRS) e dos inibidores da monoaminoxidase (IMAOs) exercem um efeito anticonvulsivante nestes camundongos geneticamente predispostos à epilepsia (Lehmann, 1967) e nos macacos babuínos (Lehmann, 1967;Meldrum et al, 1982), assim como em outros animais não-geneticamente predispostos: em gatos (Polc et al, 1979), coelhos (Piette et al, 1963) e macacos Rhesus (Yanagita et al, 1980). Evidências adicionais podem ser encontradas nos estudos sobre o efeito das DAE na 5-HT e na NE.…”