Acute Toxicity Profile of Maprotiline in the Rat

Abstract

Abstract:The aim of the present study was to examine the toxic effects of single oral administrations of the antidepressant maprotiline at 150 mg/kg or 300 mg/kg using female Sprague-Dawley rats. Body-weight gain was significantly reduced in the group receiving 300 mg/kg on days 1-5 of the study (P<0.01). A significant reduction in food and water intake was observed on days 1 and 2 of the study (P<0.01) in the 300 mg/kg group and on day 1 in the 150 mg/kg group (P<0.05). There was a significant decrease in nocturnal home cage activity over the first five days of the study in the 300 mg/kg group (P<0.01). A significant hypothermic response was observed in both 150 and 300 mg/kg groups at 1, 2 and 4 hr after dosing (P<0.01). that had returned to control values within 8 hr following administration. This study demonstrates that a multi-parameter approach is appropriate for the investigation of high doses of antidepressants in rodents.Acute toxicity testing is of the utmost importance in the preclinical assessment of novel compounds. Traditionally, the acute toxicity of a compound was determined by means of the median lethal dose (LD50) test first described by Trevan (1927). This procedure has since been criticised on ethical grounds and there has been a search for more appropriate tests for acute toxicity in laboratory animals (Zbinden & Flury-Roversi 1981;Tattersall 1982). For instance, the "Fixed Dose" procedure ( Van den Heuvel et al. 1987) and the "Up-and-Down'' test (Bruce 1985(Bruce & 1987 have been developed, validated and have finally attained acceptance by scientific and regulatory authorities such as the Organisation for Economic Cooperation and Development (OECD), see table 1.The Fixed Dose procedure is designed to supply the data needed for classification or labelling purposes and is a three-step procedure (Van den Heuvel et al. 1987). Five rats per sex are given a 50 mg/kg oral dose of the test substance. If survival is less than 90%, a second group of animals is given 5 mglkg. If survival is again less than 900/, the substance is classified as "very toxic"; otherwise it is classified as "toxic". If there is 90% survival after the 50 mg/kg dose but with evident toxicity, the substance is classified as "harmful". If there is no evident toxicity after the 50 mg/kg dose another group of animals is given a 500 mg/kg dose. If there is no evident toxicity and 90% survival following this dose, the substance is classified as "unclassified" or "slightly toxic" (Gad & Chengelis 1998).To determine an acute toxic dose with the Up-and-down procedure female or male rats are used. Rats are dosed one at a time, starting the first animal at the best estimate of the LDS0. If the first animal is alive at the end of 24 hr, the Author for correspondence: Philip Darcy, Department of Pharmacology, National University of Ireland, Galway, Ireland (fax 353 91 525300. e-mail pipdarcy@hotmail.com).next animal is given a higher dose. If the first animal dies, then the next animal receives a lower dose. The dose for the next animal...

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