An animal model of nevirapine-induced skin rash in the female brown Norway rat
Subtitle: discovery, characterization and use to investigate an immune-mediated mechanism.
Published: 2005
Language: eng
Number of pages: 245
Description: Idiosyncratic drug reactions (IDRs) are adverse drug reactions that don't occur in most patients at any dose, cannot be explained based on the pharmacological properties of the drug, and are unpredictable. Severe reactions can be life-threatening and may result in the withdrawal of the implicated drug from the market. Thus, these reactions pose significant problems to pharmaceutical manufacturers, government regulators, clinicians, and patients. The ultimate goal is to be able to treat, predict, and/or prevent these reactions; therefore, an understanding of the mechanism of these reactions is imperative. Currently, we believe the immune system is involved in the etiology of IDRs, but absolute proof is lacking. Mechanistic studies by way of human clinical trials are hampered by the idiosyncratic nature of these reactions. Also, in vitro studies are not very useful without parallel in vivo research. Animal models are more likely to mimic the complex pathogenesis of these reactions; however, the reactions are just as idiosyncratic in animals. Thus, practical animal models are rare. We recently discovered a new animal model of an IDR. Female Brown Norway rats treated with nevirapine (150 mg/kg/day)---a drug used to treat human immunodeficiency virus infection---develop a skin rash with similar characteristics to humans treated with nevirapine suggesting a common mechanism. Importantly, the characteristics of the reaction also implicated the immune system in the pathogenesis of the skin rash. Further studies revealed a role for T cells in the reaction as splenic T cells could adoptively transfer susceptibility to nevirapine-induced rash to naive recipients. T cell infiltrates were also observed in skin sections from nevirapine-treated rats. As for the role of CD4+ versus CD8+ T cells, it appears that CD8+ T cells are not necessary for initiation of the reaction; instead, the evidence implicates CD4+ T cells. For instance, CD4+ T cells adoptively transfer sensitivity to naive recipients (in some cases). A role for CD4+ T cells is also supported by the increased susceptibility of humans with high CD4 counts to nevirapine rash. Understanding the mechanism of nevirapine-induced cutaneous reactions may help guide the development of safer drugs or predict patients at risk.
Notes: Advisor: Uetrecht, Jack

Thesis (Ph.D.)--University of Toronto, 2005.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3083.