PHARMACOLOGY

 DEVELOPMENTAL TOXICITY (TERATOGENICITY STUDY):;

This may be performed in one rodent (preferably rat ) and one non rodent (rabbit) The drug should be administered throughout the period of organogenesis using three dose levels as described above The highest dose should cause minimum maternal toxicity and the lowest one should be proportional to the proposed dose for clinical use in humans or a multiple of it The route of administration should be the same as intended for human therapeutic use 

    The control and the treated groups should consist of at least 20 pregnant rats (or mice ) and 12 rabbits on each dose level All foetuses should to be subjected to gross examination of the foetuses should be examined for skeletal abnormalities and the other half for visceral abnormalities Observation parameters should include signs of intoxication effect on body weight effect on food intake examination of uterus ovaries and uterine contents number of corpora lutea implantation sites resorptions (if any ) and for the foetuses the total number gender body length weight and gross/visceral/skeletal abnormalities 

Developmental Toxicity Study (Perinatal Study ) ::

This study is specially recommended if the drug is to be given to pregnant or nursing mothers for long periods or where there are indications of possible adverse effects on foetal development One rodent species (preferably rat ) is needed Dosing at levels comparable to multiples of human dose should be done by the intended clinical route At least 4 groups (including control ) each consisting of 15 pregnant females are used The drug is administered throughout the last trimester of pregnancy (from day 15 of gestation ) and then the dose that causes low foetal loss is continued throughout lactation and weaning The animals are then sacrificed and examined for various organs 

    One male and one female from each litter of F1 generation (total 15 males and 15 females in each group ) are selected at weaning and treated with vehicle or test compound (at the dose levels described above) throughout their periods of growth to sexual maturity pairing gestation parturition and lactation Mating performance and fertility of F2 generation should thus be evaluated to obtain the F2 generation whose growth parameters should be monitored till weaning The criteria of evaluation should be the same as described earlier 

    Animals are sacrificed at the end of the study and the observation parameters should include body weight food intake general signs of intoxication progress of gestation /parturition periods and gross pathology of the animal for pups the clinical signs sex-wise distribution in dose groups body weight growth parameters gross examination survival and autopsy (if needed) and where necessary histopathology are required to be done