Diurnal variation in probability of death following self-poisoning in Sri Lanka--evidence for chronotoxicity in humans

Abstract

The absorption, distribution, metabolism and elimination of medicines are partly controlled by transporters and enzymes with diurnal variation in expression. Dose timing may be important for maximizing therapeutic and minimizing adverse effects. However, outcome data for such an effect in humans are sparse, and chronotherapeutics is consequently less practised. We examined a large prospective Sri Lankan cohort of patients with acute poisoning to seek evidence of diurnal variation in the probability of survival. In all, 14 840 patients admitted to hospital after yellow oleander (Cascabela thevetia) seed or pesticide [organophosphorus (OP), carbamate, paraquat, glyphosate] self-poisoning were investigated for variation in survival according to time of ingestion. We found strong evidence that the outcome of oleander poisoning was associated with time of ingestion (P < 0.001). There was weaker evidence for OP insecticides (P = 0.041) and no evidence of diurnal variation in the outcome for carbamate, glyphosate and paraquat pesticides. Compared with ingestion in the late morning, and with confounding by age, sex, time of and delay to hospital presentation and year of admission controlled, case fatality of oleander poisoning was over 50% lower following evening ingestion (risk ratio = 0.40, 95% confidence interval 0.26-0.62). Variation in dose across the day was not responsible. We have shown for the first time that timing of poison ingestion affects survival in humans. This evidence for chronotoxicity suggests chronotherapeutics should be given greater attention in drug development and clinical practice.