Lethal Dose Curve: Should its Determination be Made in healthy or in Animal Models of Disease?

ABSTRACT

The lethal dose curve of phenylbutazone was assayed in control animals (A) and in animals in which an experimental arthritis had been produced by injection of Feund's complete adjuvant (B).

Thirty male Wistar rats 3 months old were divided into two groups of 15 rats each: group A consisted of the control group and group B the adjuvant treated group. Arthritis was produced by a single injection of 0.15 Freund's complete adjuvant on the right footpad. The control group was injected with the adjuvant vehicle at the same site. Injections of 200 mg/kg of phenylbutazone once daily for ten days started fifteen days after administration of Freund's adjuvant.

After the first injection of phenylbutazone the LD_6.6 in group A corresponded to LD₅₃ in group B while after the second injection the LD_46.6 for the control group corresponded to LD₁₀₀ in group B. We assume that the therapeutic index would be more representative if lethal dose curves were evaluated in animals suffering from a disease that the drug in question has been designated for.