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Based upon animal studies, Serentil^® (mesoridazine besylate), as with other phenothiazines, acts indirectly on reticular formation, whereby neuronal activity into reticular formation is reduced without affecting its intrinsic ability to activate the cerebral cortex. In addition, the phenothiazines exhibit at least part of their activities through depression of hypothalamic centers. Neurochemically, the phenothiazines are thought to exert their effects by a central adrenergic blocking action.

Pharmacological studies in laboratory animals have established that Serentil^® (mesoridazine besylate) has a spectrum of pharmacodynamic actions typical of a major tranquilizer. In common with other tranquilizers it inhibits spontaneous motor activity in mice, prolongs thiopental and hexobarbital sleeping time in mice and produces spindles and block of arousal reaction in the EEG of rabbits. It is effective in blocking spinal reflexes in the cut and antagonizes d-amphetamine excitation and toxicity in grouped mice. It shows a moderate adrenergic blocking activity in vitro and in vivo and antagonizes 5-hydroxytryptamine in vivo. Intravenously administered, it lowers the blood pressure of anesthetized dogs. It has a weak antiacetylcholine effect in vitro.

The most outstanding activity of Serentil^® (mesoridazine besylate) is seen in tests developed to investigate antiemotive activity of drugs. Such tests are those in which the rat reacts to acute or chronic stress by increased defecation (emotogenic defecation) or tests in which "emotional mydriasis" is elicited in the mouse by an electric shock. In both of these tests Serentil^® (mesoridazine besylate) is effective in reducing emotive reactions. Its ED50 in inhibiting emotogenic defecation in the rat is 0.053 mg/kg (subcutaneous administration). Serentil^® (mesoridazine besylate) has a potent antiemetic action. The intravenous ED50 against apomorphine-induced emesis in the dog is 0.64 mg/kg. Serentil^® (mesoridazine besylate), in common with other phenothiazines, demonstrates antiarrhythmic activity in anesthetized dogs.

Metabolic studies in the dog and rabbit with tritium labeled mesoridazine demonstrate that the compound is well absorbed from the gastrointestinal tract. The biological half life of Serentil^® (mesoridazine besylate) in these studies appears to be somewhere between 24 to 48 hours. Although significant urinary excretion was observed following the administration of Serentil^® (mesoridazine besylute), these studies also suggest that biliary excretion is an important excretion route for mesoridazine and/or its metabolites.

Toxicity Studies

Acute LD50 (mg/kg):

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