Characterization of the inflammatory response to a highly selective PDE4 inhibitor in the rat and the identification of biomarkers that correlate with toxicity

Toxicologic Pathology
Gregory N DietschSuzanne T Kanaly

Abstract

The primary toxicity associated with repeated oral administration of the PDE4 inhibitor IC542 to the rat is an inflammatory response leading to tissue damage primarily in the gastrointestinal tract and mesentery. Although necrotizing vasculitis is frequently seen with other PDE4 inhibitors, blood vessel injury was rare following IC542 administration and was always associated with inflammation in the surrounding tissue. The incidence and severity of the histologic changes in these studies correlated with elevated peripheral blood leukocytes, serum IL-6, haptoglobin, and fibrinogen, and with decreased serum albumin. By monitoring haptoglobin, fibrinogen and serum albumin changes in IC542-treated rats, it was possible to identify rats with early histologic changes that were reversible. Since PDE4 inhibition is generally associated with anti-inflammatory activity, extensive inflammation in multiple tissues was unexpected with IC542. Co-administration of dexamethasone completely blocked IC542-induced clinical and histologic changes in the rat, confirming the toxicity resulted from inflammatory response. In addition, IC542 augmented release of the proinflammatory cytokine IL-6 in LPS-activated whole blood from rats but not monkeys or...Continue Reading

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Citations

Oct 17, 2008·Toxicological Sciences : an Official Journal of the Society of Toxicology·Sevil KorkmazJean-Louis Freslon
May 8, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jacqueline M Tarrant
Apr 6, 2013·BMC Medicine·Neal KumarAlice B Gottlieb
Apr 13, 2007·Expert Opinion on Drug Metabolism & Toxicology·Elizabeth J GribbleSteven D Hughes
Oct 22, 2011·Trends in Molecular Medicine·David J PorteousAkira Sawa
Dec 17, 2015·Journal of the Neurological Sciences·Carina JørgensenChristina Kruuse
Jun 11, 2009·British Journal of Pharmacology·Katharine H Banner, Neil J Press
Feb 13, 2014·Basic & Clinical Pharmacology & Toxicology·Katharine H Abbott-Banner, Clive P Page
Nov 24, 2007·Toxicological Sciences : an Official Journal of the Society of Toxicology·Robert Francis Stachlewitz
Jun 16, 2007·Toxicological Sciences : an Official Journal of the Society of Toxicology·Nicolas DaguèsStephan Chevalier
Apr 30, 2014·Toxicologic Pathology·Igor MikaelianUNKNOWN Vascular Injury Working Group of the Predictive Safety Consortium
Oct 17, 2009·Expert Opinion on Therapeutic Patents·Lluís PagèsMartin D Lehner
May 11, 2012·Central European Journal of Public Health·Konstansa LazarevićDragan Bogdanović

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