Preclinical Studies

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Chapter: Essential pharmacology : Aspects Of Pharmacotherapy; Clinical Pharmacology And Drug Development

After synthesizing/identifying a prospective compound/series of compounds, it is tested on animals to expose the whole pharmacological profile. Experiments are generally performed on a rodent (mouse, rat, guinea pig, hamster, rabbit) and then on a larger animal (cat, dog, monkey).


PRECLINICAL STUDIES

 

After synthesizing/identifying a prospective compound/series of compounds, it is tested on animals to expose the whole pharmacological profile. Experiments are generally performed on a rodent (mouse, rat, guinea pig, hamster, rabbit) and then on a larger animal (cat, dog, monkey). As the evaluation progresses unfavourable compounds get rejected at each step, so that only a few out of thousands reach the stage when administration to man is considered.

 

Toxicity tests

 

The aim is to determine safety of the compound in at least 2 animal species, mostly mouse/rat and dog by oral and parenteral routes.

 

Acute toxicity: Single escalating doses are given to small groups of animals that are observed for overt effects and mortality for 1–3 days. The dose which kills 50% animals (LD50) is calculated. Organ toxicity is examined by histopathology on all animals.

 

Subacute toxicity: Repeated doses are given for 2–12 weeks depending on the duration of intended treatment in man. Doses are selected on the basis of ED50 and LD50. Animals are examined for overt effects, food intake, body weight, haematology, etc. and organ toxicity.

 

Chronic toxicity: The drug is given for 6–12 months and effects are studied as in subacute toxicity. This is generally undertaken concurrently with early clinical trials.

Special longterm toxicity: These tests are generally performed only on drugs which cross phase I clinical trials.

 

Reproduction and teratogenicity: Effects on spermatogenesis, ovulation, fertility and developing foetus are studied.

 

Mutagenicity: Ability of the drug to induce genetic damage is assessed in bacteria (Ames test), mammalian cell cultures and in intact rodents.

 

Carcinogenicity: Drug is given for longterm, even the whole life of the animal and they are watched for development of tumours.

 

Standardized procedures under ‘Good Laboratory Practices’ (GLP) have been laid down for the conduct of animal experiments, especially toxicity testing.

 

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