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UNC-Chapel Hill ENVR 132 - Characterization of the Inflammatory Response to a Highly Selective PDE4 Inhibitor in the Rat

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Toxicologic Pathology 34 39 51 2006 C by the Society of Toxicologic Pathology Copyright ISSN 0192 6233 print 1533 1601 online DOI 10 1080 01926230500385549 Characterization of the Inflammatory Response to a Highly Selective PDE4 Inhibitor in the Rat and the Identification of Biomarkers that Correlate with Toxicity GREGORY N DIETSCH 1 CHRIS R DIPALMA 1 RUSSELL J EYRE 1 TUAN Q PHAM 1 KAREN M POOLE 1 NOAH B PEFAUR 2 WILLIAM D WELCH 1 ESTHER TRUEBLOOD 1 WILLIAM D KERNS 3 AND SUZANNE T KANALY1 2 1 ICOS Corporation Bothell Washington 98021 USA ICOS Corporation currently at Pacific Northwest National Laboratories Richland Washington 99352 USA 3 Pharma Consulting Harvard Massachusetts 01451 USA 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 humans The effect of IC542 on IL 6 release from rat leukocytes in vitro is consistent with the proinflammatory response observed in vivo and demonstrates species differences to PDE4 inhibition Keywords Biomarkers inflammation interleukin 6 IL 6 phosphodiesterase phosphodiesterase type 4 PDE4 rat toxicity vascular injury INTRODUCTION The elevation of intracellular cAMP levels through the inhibition of phosphodiesterase type 4 PDE4 family of isoenzymes effectively moderates some inflammatory responses by reducing the activity of monocytes and T cells Giembycz et al 1996 Manning et al 1999 Hidi et al 2000 Seldon et al 2005 For example selective PDE4 inhibitors inhibit TNF release in response to LPS both in vitro and in vivo Brideau et al 1999 Manning et al 1999 Gale et al 2002 Alexandre Moreira et al 2005 PDE4 inhibitors have also been shown to either moderate or block inflammation in a number of preclinical disease models including asthma endotoxic shock and arthritis Sekut et al 1995 Bundschuh et al 2001 Alexandre Moreira et al 2005 Moreita et al 2005 and are reported to be efficacious in some human diseases including asthma and chronic obstructive pulmonary disease Giembycz 2001 Lipworth 2005 Although effective in moderating some inflammatory disease processes multiple toxicities have been associated with repeated administration of PDE4 inhibitors Early PDE4 inhibitors failed in clinical trials due to nausea and emesis Dyke and Montana 2002 PDE4 inhibitors have also been reported to cause severe toxicities in some animal species when administered at high doses Larson et al 1996 Losco et al 2004 For example rolipram a prototypic PDE4 inhibitor is reported to produce clinical signs of toxicity that include salivation abdominal distension weight loss and ataxia in rats with repeated dosing Larson et al 1996 Histologic evaluation of rolipram treated rats provided evidence of myocardial degeneration and necrosis arteritis periarteritis of the intramural and extramural coronary arteries necrotizing vasculitis and inflammation of mesentery and interstitial areas of the liver affecting medium sized portal arteries and veins The toxicities reported for rolipram and other early PDE4 inhibitors differ from more recent second generation PDE4 inhibitors Perry et al 1998 These apparent differences may be the result of low potency Sekut et al 1995 and or relatively poor selectivity of the early PDE4 inhibitors leading to the inhibition of other PDE family members such as PDE3 IC542 is a highly selective and potent inhibitor of PDE4 inhibiting all 4 PDE4 isoforms PDE4A PDE4B PDE4C and PDE4D at low nanomolar concentrations IC542 also has 1000 fold selectivity for PDE4 over the other PDE family members PDE1 PDE3 PDE5 PDE7 PDE11 The oral administration of IC542 to rats induced many of the clinical observations described for rolipram at high doses Larson Address correspondence to Gregory N Dietsch ICOS Corporation 22021 20th Avenue SE Bothell WA 98021 425 485 1900 e mail gdietsch icos com Abbreviations ANOVA Analysis of variance BLQ below the lower limit of quantitation cAMP cyclic adenosine monophosphate DMSO dimethylsulfoxide ELISA enzyme linked immunosorbent assay EDTA ethylenediaminetetraacetic acid GALT gut associated lymphoid tissue HPLC high performance liquid chromatography IL 6 interleukin 6 LPS lipopolysaccharide MCP 1 macrophage chemoattractant protein 1 MCP3 macrophage chemoattractant protein 3 PBLs peripheral blood leukocytes PDE phosphodiesterase PDE4 phosphodiesterase type 4 PEG400 polyethylene glycol 400 TNF tumor necrosis factor 39 40 DIETSCH ET AL et al 1996 However many of the important histopathologic changes seen in the tissues from IC542 treated rats are distinctly different from those seen with rolipram Lesions seen with IC542 were characterized by severe inflammation of the mesentery regions of the gastrointestinal tract and thymus In contrast to what has been reported for rolipram and cilomilast vascular injury was rarely seen and when present it was considered secondary to the inflammation in the surrounding tissue To fully characterize toxicities associated with IC542 investigational toxicity studies were conducted with the following objectives 1 fully characterize toxicities associated with IC542 at high doses 2 identify biomarkers that precede the development of histologic lesions 3 determine if the use of an anti inflammatory agent would prevent IC542induced toxicity 4 characterize the inflammatory response in rats for comparison with other species MATERIALS AND


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UNC-Chapel Hill ENVR 132 - Characterization of the Inflammatory Response to a Highly Selective PDE4 Inhibitor in the Rat

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