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Toxicologic Pathology
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The Toxicity of SCH 351591, a Novel Phosphodiesterase-4 Inhibitor, in Cynomolgus Monkeys

Patricia E. Losco

Schering Plough Research Institute, Lafayette, New Jersey 07848, USA, pat.losco{at}spcorp.com

Ellen W. Evans

Schering Plough Research Institute, Lafayette, New Jersey 07848, USA

Stephen A. Barat

Schering Plough Research Institute, Lafayette, New Jersey 07848, USA

Pamela E. Blackshear

Schering Plough Research Institute, Lafayette, New Jersey 07848, USA

Larisa Reyderman

Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA

Jay S. Fine

Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA

Loretta A. Bober

Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA

John C. Anthes

Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA

Elmer J. Mirro

Schering Plough Research Institute, Lafayette, New Jersey 07848, USA

Francis M. Cuss

Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low- and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.

Key Words: PDE4 inhibitor • asthma therapy • chronic obstructive pulmonary disease • arteriopathy • nonhuman primates • metabolic effects • immunosuppression • T cells.

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Toxicologic Pathology, Vol. 32, No. 3, 295-308 (2004)
DOI: 10.1080/01926230490431493
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J. Zhang, R. D. Snyder, E. H. Herman, A. Knapton, R. Honchel, T. Miller, P. Espandiari, F. M. Goodsaid, I. Y. Rosenblum, J. P. Hanig, et al.
Histopathology of Vascular Injury in Sprague-Dawley Rats Treated with Phosphodiesterase IV Inhibitor SCH 351591 or SCH 534385
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