No abstract

Within six months of the introduction of the new antipsychotic drug clozapine in Finalnd, 17 cases of neutropenia or agranulocytosis were recorded amongst about 3000 patients treated. Agranulocytosis was fatal in eight patients, and in addition, two patients developed thrombocytopenia, and one patient leukaemia. As additional cases might well have been overlooked as banal infections, the risk of developing agranulocytosis during clozapine treatment was at least 0.5%. Impaired elimination of the drug or increased susceptibility of granulocyte precursors to clozapine, possibly due to some inherited characteristic, might explain the high incidence of complications.

The dose-mortality curves for dl-amphetamine after intraperitoneal administration of 10-180 mglkg of it to adult and developing mice in 7 age groups from 3 to 30 days were determined. The dose-mortality curve of adult mice was polyphasic. A 100 % mortality was obtained with 100 mglkg of amphetamine. In developing mice the curves, polyphasic as well, were shifted to the right. At the age of 3 days the mortality caused by 180 mgEkg was only 68 %. With increasing age the animals became more sensitive to the drug, responding partially like the adults from the age of 18 days. The toxicity calculated in relation to the surface area remained unchanged, although the differences between the age groups of developing mice became smaller. In adult mice, pretreatment with 5 mg/kg of amphetamine protected against subsequent toxic doses of the drug, especially in the lower dosage range. Pretreatment given 4 hours before the toxic doses afforded the best protection. It is assumed that the immature CNS of developing mice is partially responsible for the increased tolerance to the drug. The polyphasic shape of the graphs and the protection afforded by the pretreatment reflect the complex lethal actions of amphetamine.

The brain noradrenaline (NA) and dopamine (DA) content of adult and developing mice of 3 age groups (3-5, 13-15 and 32-35 days) was assayed and found to increase with age. In adult mice 4 hrs after the administration of 50 mg/kg of amphetamine the brain NA content was decreased by 65 %. After 100 mg/kg of amphetamine the mice died in 25 min., but the NA and DA levels were only slightly decreased. In all age groups of developing mice, the doses of amphetamine sufficient to be lethal in 30 min. (100-160 mg/kg) caused only a slight decrease or even an increase in brain NA and DA levels. In developing mice surviving 60 min. after amphetamine, the brain amines were massively depleted. In adult mice the brain NA content in 1 hr and 4 hrs after the pretreatment dose of 5 mglkg of amphetamine decreased by 20 %. The dose of 60 mg/kg 4 hrs after the pretreatment caused a massive depletion in brain NA and DA content 1 hr after the latter injection. Even though the mice survived. The lack of correlation between brain catecholamine depletion and amphetamine toxicity reflects the complex lethal mechanisms induced by the drug.

The effect of 150 mg/kg of L‐DOPA methylester on brain catecholamines was studied in adult and developing mice aged 3‐5 days and 13‐15 days. Noradrenaline was moderately increased in the developing brain but dopamine showed a manyfold increase. The increase of dopamine was less pronounced in adult brain. High doses of dl‐amphetamine (50‐160 mg/kg) injected to L‐DOPA pretreated mice further increased the dopamine levels in the developing brain. The adult brain catecholamines were remarkably depleted, provided the observation period was 4 hours after amphetamine. Amphetamine lowered the body temperature in mice aged 13‐15 days; the fall was dose‐dependent and potentiated by pretreatment with L‐DOPA. In adult mice amphetamine caused hyperthermia which was not modified by L‐DOPA. L‐DOPA did not change the mortality rates induced by amphetamine in developing mice, but infant mice pretreated with L‐DOPA showed a lower brain amphetamine concentration after death than the mice given amphetamine only. In adult mice GDOPA enhanced amphetamine toxicity. Special attention is paid to the importance of different turnover rates of catecholamines during development as well as to the complex action of amphetamine on enzymes regulating catecholamine turnover. It is assumed that the hypothermia of developing mice after amphetamine might result from the primary effect of amphetamine on dopaminergic mechanisms.