Animal models lead toxicity

Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

Studies in animals have provided abundant support for the plausibility of the neurodevelopmental effects of lead that have been associated with lead exposure in children, and researchers have begun to identify potential mechanisms (i.e., Cory-Slechta 1995a). However, mechanistic connections between behavioral deficits, or changes observed in animals, and those that have been associated with lead exposure in children have not been completely elucidated. Understanding of such connections would be valuable for developing better and more relevant animal models of lead toxicity. 

LPS immunotherapy was the first immunotherapy for cancers assayed in patients in spite of its toxicity. The standardisation of animal models of cancer, the discovery of the LPS composition and of lipid A activity, the discovery of lipid A structure leading to its chemical synthesis, and the synthesis of lipid A derivatives far less toxic than the natural lipids A, restarted research in this field. At the same time, advances in immunology allowed a better understanding of the mechanisms of action of LPS and lipids A in whole organisms. 

The lead optimization process introduces structural variations in the molecule in order to identify the best drug candidate. After a thorough evaluation of its toxicity and pharmacological activity in animal models, the molecule enters the clinical phases, when it is evaluated for tolerability, efficacy, and potential side effects on human subjects. After submittal of all the required documentation and registration to the appropriate authority (e.g. the U.S. Food and Drug Administration), the HIV protease inhibitor is ready for launching on the market. 

Products that may have the potential to stimulate growth or induce proliferation or clonal expansion of cell types, in particular, transformed cells, all processes that may eventually lead to neoplasia should be evaluated with respect to receptor expression in various malignant and normal human cells that are relevant to the patient population under study [27], In such cases normal human cell lines and multiple human cancer cell lines expressing the relevant receptor, as well as primary cells derived from human tumor explants, should be used for in vitro assessment. When in vitro data demonstrate enhanced growth, further studies in relevant in vivo xenograft animal models with receptor expressing tumor cell lines may be needed. In addition incorporation of sensitive indexes of cellular proliferation in long-term repeat-dose toxicity studies may provide useful information. 

The most characteristic toxic effect of benzene in both human and animal models is the depression of the bone marrow, leading ultimately to aplastic anemia (Rozen and Snyder 1985 Snyder and Kocsis 1975 Snyder et al. 1993b). Rozen and Snyder (1985) have noted that abnormalities of humoral and cell-mediated immune responses following benzene exposure of C57BL mice by inhalation are presumably caused by a defect in the lymphoid stem cell precursors of both T- and B-lymphocytes. They also observed that bone marrow cellularity and the number of thymic T-cells increased, presumably as a compensatory response in these cell lines in response to benzene exposure. This compensatory proliferation may play a role in the carcinogenic response of C57BL mice to inhaled benzene. 

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