Animal model lethality

Figure 5.9. Dose-response profile in a population. (A) Relationship between responding patients, expressed as percentage of individuals, and plasma drug concentrations. With increasing drug concentration, the proportion of patients who derive therapeutic benefit, without concentration-limited side effect peaks, and then declines. (B) A schematic representation of dose-response curves. Typical therapeutic and lethal responses at indicated doses are evaluated in animal models to estimate therapeutic index, TI. ED50, effective dose needed to produce a therapeutic response in 50% of animals, exhibiting therapeutic response LD50, effective dose needed to produce lethal effects in 50% of animals.

In animal models, dimercaprol prevents and reverses arsenic-induced inhibition of sulfhydryl-containing enzymes and, if given soon after exposure, may protect against the lethal effects of inorganic and organic arsenicals. Human data indicate that it can increase the rate of excretion of arsenic and lead and may offer therapeutic benefit in the treatment of acute intoxication by arsenic, lead, and mercury. 

TFPI, when administered to rabbits, has been shown to have an antithrombotic effect when thromboplastin was used as a thrombogenic challenge (I 10). TFPI was also shown to be an effective inhibitor when thrombosis was induced in rabbit jugular veins by endothelial destruction and restricted blood flow. The antithrombotic and antiprotease actions of TFPI have been tested in several other animal models. Warn-Cramer et al. investigated the effect of immunodepletion of TFPI in factor Vila and Xa induced coagulation in rabbits (III). These rabbits were observed to be sensitized to the procoagulant effects of factor Vila, but not factor Xa in the absence of factor Vila. Two studies have indicated that TFPI administration reduces the lethal effects of . coli administration in a septic shock model in baboons (I 12). These studies also indicated that TFPI may have an anti-inflammatory effect, as an attenuation of the IL-6 response was also observed. Administration of TFPI has been observed to prevent... 

Whether or not Hb accentuates lethal effects of endotoxin is also not resolved. When inoculation with living E. coli or endotoxin has been used to induce sepsis in mice, some Hb preparations have been found to demonstrate deleterious effects. " In contrast, other studies using better characterized, modified Hb solutions have failed to confirm these findings, both in mice and in other animal models. ... 

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