Inflammation, toxicology studies

The usual GLP 30- or 60-day repeat-dose toxicology study with a recovery group offers an opportunity to perform a more systematic investigation of the more subtle pharmacodynamic or toxicologic effects of biopharmaceuticals than those endpoints usually incorporated into such protocols. Some of these demand tissue samples, but many involve noninvasive biomarkers that can be carried forward into early phase human studies. These might include CNS assessments, inflammation and immune activation or suppression, cell proliferation or apoptosis in tissue samples, and end-organ toxicities. 

Three emerging fecal tests are for elastase, calprotectin, and adipsin, but these have yet to be tested widely in toxicology studies. The fecal elastase test has been developed as a noninvasive measurement of exocrine insufficiency, and fecal elastase does not appear to be increased in dogs with intestinal inflammation (Dommguez-Munoz et al. 1995 Stein et al. 1996 Goldberg 2000 Battersby et al. 2005 Schneider et al. 

It is difficult to assess the relationship of HEAR oils and other oils high in docosenoic acid content to the development of focal myocardial degenerative lesions in the monkey. In a recent study, a series of 312 hearts were selected at random from monkeys used in unrelated toxicological studies (Qureshi, 1979). The monkeys, which included squirrel (Saimiri sciureus) cynomolgus Macaca fascicularis), rhesus Macaca mulatta) and assam (Ma-caca assamensis) monkeys were of both sexes. Chronic interstitial myocarditis was found in 34% of the monkeys, approximately evenly distributed in males and females (Table IX). The lesions varied from slight necrosis to myocarditis with focal accumulation of lymphocytes, mononuclear cells, plasma cells, and some eosinophiles. Inflammation of the myocardium was distributed throughout the heart. These lesions, which occur frequently in primates, apparently are not related to bacterial, viral, or parasitic infections, but may be related to, and precipitated by, stress (Qureshi, 1979 Soto et al., 1964). 

Laurencin et al. (1990) conducted extensive local and systemic toxicity studies with P(CPP-SA), which also showed excellent biocompatibility and toxicology. Domb (1992) studied the biocompatibility of P(CPP-IPA), P(CPP IPA-SA), and P(CPP-SA) by subcutaneous and intramuscular implants in rabbits. Inflammation occurred at week one and was more pronounced for the intramuscular implants, but subsided in all cases by week 4 (Domb, 1992). Domb and Nudelman (1995) conducted... 

Gandolfi AJ, White RD, Sipes IG, Pohl LR (1980) Bioactivation and covalent binding of halothane in vitro studies with [3H]- and [14C]halothane. J Pharmacol Exp Ther 214 721-725 Ganey PE, Roth RA (2001) Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents. Toxicology 169 195-208 GL Brody, RB Sweet (1963) Halothane anesthesia as a possible cause of massive hepatic necrosis. Anesthesiology 24 29-37... 

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