Animal models dosing conditions

The principle of estimating a therapeutic index prior to clinical trials typically involves determining the no observable adverse effect level (NOAEL) and comparing that to the projected human dose. In providing the estimate, the efficacious dose is typically obtained from in vitro data with human cells or tissues and in vivo preclinical pharmacology studies that involve animal disease models. Not infrequently the species used to estimate the toxic level is different from the species used to estimate an efficacious level. Thus the therapeutic index is not a true ratio as the units (species and/or conditions) are often different. On the other hand, if one were to obtain information relating to toxicity as well as efficacy from studies employing animal models of disease, a direct estimate of therapeutic index could be made provided that appropriate models had been characterized or validated in the relevant species. 

As the basis for decisions about the first dosing in humans, the preclinical safety program needs to mimic the intended clinical regimen. Although these studies are commonly conducted in normal healthy animals, they may also require development and use of an animal model that mimics the health status or condition if it is deemed to possibly sensitize the subject to treatment. For example, we have conducted studies evaluating the safety of recombinant human Factor XIII in an animal model of extracorporeal blood circulation [6] and the safety of recombinant human thrombin in an animal model of hepatic resection [7]. 

It is clear that under in vitro assay conditions, anthocyanins can function as antioxidants. However, in vivo, anthocyanin absorption appears to be low. In animal models, dietary anthocyanins at relatively high doses (1 to 2 mg/kg diet) are protective against oxidative stress induced in a number of models, including ischemia reperfusion, paraquat, CCL4, and t-BHP. In humans, anthocyanins appear to have some vasopro-tective effects, but whether these are the result of antioxidant mechanisms is not clear. It appears that in most of the studies reviewed, the dose of anthocyanins was well above that which might be normally consumed in the diet with natural foods, except for perhaps one study in which 1 cup of blueberries was consumed for 30 days and small increases in plasma antioxidant capacity were observed." ... 

Perhaps the oldest animal model to predict potential antipsychotic drug efficacy is the conditioned avoidance response (CAR) (108, 112, 181, 182). In the conditioned reinforcement model, experimental animals are trained to perform a certain response to avoid a mild shock. Trained avoidance responses may be active (pressing a lever, climbing a pole, or jumping out of a box) or passive (remaining in the darker of two compartments). Classical antipsychotic drugs and benzodiazepines reduce avoidance responding at doses that do... 

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