Targets human subjects

Attempts to find the cause(s) of depression have adopted two main approaches. One is to look for the neurobiological basis of depression in human subjects and animal models of this condition. The second is to investigate the pharmacology of established antidepressant agents to see whether they consistently augment some, and ideally the same, neurobiological targets in the brain. 

As Fig. 7.58 indicates, our task was to explain the ordering of the eight probe molecules in the human in vivo target, but subjecting the eight probe molecules to each of the 50 PAMPA lipid models. For each PAMPA model, the regression correlation coefficient, r2, was used to assess the appropriateness of the model. 

The targeting of the lipid absorption and metabolism pathways has yielded several promising venues for the treatment of dyslipidemia and insulin resistance. Small molecule inhibitors of MTP have conferred significant reductions in total and LDL cholesterol, as well as plasma TG, in human subjects. While some mechanism-related side effects due to increased hepatic and intraintestinal TG... 

In the absence of target organ toxicity with which to set the high dose at the maximally tolerated dose, the high dose can be set at the dose that produces an area under the curve (AUC). This is 25-fold higher than that obtained in human subjects. 

In drug discovery, specific enzymes or receptors are first targeted for drug action. The earliest experiments use chemistry to synthesize drugs experimental animals to test the biochemical, behavioral, and toxic actions of the drugs and human subjects, both normal volunteers and patients, to test the safety and efficacy of the drugs... 

What could be done to better assess immunomodulatory effects in NHP that will be predictive of the outcome in humans One important consideration comes back to the relevance of the animal species. Not only should the binding affinity and functionality at the target be considered, but the relative potency as well can be a critical factor. Understanding the dose-concentration-response relationships for receptor occupancy, receptor modulation and functionality, and target expression and distribution in comparison to normal human subjects and in disease state can help us to better assess risk to patients. 

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