Mexazolam

Mexazolam is a benzodiazepine. As a rule, benzodiazepines act as central nervous system depressants capable of producing all levels of depression, from mild sedation to hypnosis and coma, depending on the dose.

The exact sites and mode of action have not been fully elucidated, but it appears to be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), by the stimulation of specific receptors. Both GABA and chloride may enhance the binding to those receptors.

Sedative effects it was shown in mice, rats and monkeys that mexazolam causes a higher inhibition on conflict behaviour, violence, aggressivness and excitation than diazepam. Studies in cats and rabbits suggest that those sedative effects may result from the drug action upon the limbic system, including amygdala and hypothalamus.

Anticonvulsant effects it was shown in mice, rats and monkeys that mexazolam causes a higher inhibitory effect on bemegride- and pentetrazol-induced convulsions than diazepam.

Myorelaxant effects mexazolam inhibited the decerebrate stiffness and depressed the activity of gamma-motor neurones in cats.

Effects on motor function: Studies in mice, rats and dogs on the influence of mexazolam upon motor function (for example, inhibition of the spontaneous motor function, myorelaxant effect, inhibition of righting reflex and ataxic effect) showed that the effect is limited.

Following oral administration of mexazolam, the unchanged drug is not detected in blood. Only some active metabolites CND (chlornordiazepam) and COX (chloroxazepam) are found. It is suggested that mexazolam may be hydroxylated in the liver and conjugated through metabolic pathways, one of benzodiazepine-type (active metabolites) and the other of benzophenone-type (inactive metabolites).

The CND is the main plasmatic metabolite of mexazolam. With a single dose of mexazolam, CND maximum serum concentration is attained after 1-2 hours. The distribution apparent volume is 150 L. The used pharmacokinetic model is of bicompartimental type. Following repeated administration, the half-lives of CND and COX is large (130-200 h).

CND and COX protein binding is >90%.

Less than 10% of the mexazolam dose administered orally is eliminated as metabolites in urine, given that most of the drug is excreted through the bile. The COX represents >50% of the total amount of excreted metabolites, and is essentially found as conjugate.

Studies held in several animal species, including mice, rats, rabbits, dogs and monkeys indicated a broad safety profile and a very low toxicity. In fact, the LD₅₀ for oral use was 4.687 mg/kg in the rat, 8.100 mg/kg in the Wistar-Imamichi rat and 1400 mg/kg in the Fischer rat.

In subacute toxicity studies in rats (10, 30, 125, 250, 500 and 1500 mg/kg, orally, 5 weeks) mortality was observed only in the group receiving 1500 mg/kg. Hypertrophy of hepatocytes occurred with similar doses or higher than 250 mg/kg, but disappeared after drug discontinuation. Mexazolam administered orally along 26 weeks to rats that received daily doses of 2, 10, 50 or 125 mg/kg have shown that the weight of liver, kidneys and adrenal glands increased in females of the group receiving the highest dose. Moreover, the histological exam has not shown significant changes. Changes in copulation or fertility of male rats were not detected (2, 10 or 20 mg/kg during 9 weeks); either lethal or teratogenic effects in the foetuses of female rats were not detected (2, 10 or 20 mg/kg, from the 14th day before copulation up to the 7^th day of gestation). The administration of mexazolam during the period of organogenesis (rat – 2, 10 or 20 mg/kg/day during 11 days; rabbit – 0.04, 0.2, 1 or 5 mg/kg/day during 13 days) hasn’t caused death or teratogenic effects in rat embryos and foetuses. The administration of mexazolam during the perinatal period and lactation (rats- 2, 10 or 20 mg/kg/day during 4 weeks from the 17^th day of gestation) hasn’t caused changes during the labour, lactation or in the sucklings (external abnormalities, post-natal time differentiation and reproduction capacity). Mexazolam didn’t exhibit mutagenic potential in vitro, in the test of reversion and Rec-assay. The antigenicity of mexazolam was investigated in guinea pigs and rabbits, and no evidence of antigenicity was shown.