Characterisation of the vascular and inflammatory lesions induced by the PDE4 inhibitor CI-1044 in the dog.
Phosphodiesterase 4 (PDE4) inhibitors are potential therapeutic agents but vascular injury and perivascular inflammation occurs frequently during preclinical toxicology testing of these drugs. The lesions induced by PDE4 inhibitors have been described mainly in rats but there is limited data available for monkeys and no data for dogs. Here we present the toxicological profile of CI-1044, a PDE4 inhibitor, administered orally to dogs. Dogs were treated for 4 days with 5, 10, 20 or 50 mg/kg of CI-1044, and a group of dogs was submitted to a 4-week recovery period after treatment with 20 mg/kg. CI-1044 induced disseminated vascular necrosis and inflammation in various organs/tissues from 20 mg/(kg day). The nasal turbinates and the scrotal skin were the most sensitive tissues but lesions were also observed in the stomach, heart, kidneys and, to a lower extent, in the liver, mesenteric lymph nodes, adrenals and lung. The inflammation was mainly characterized by an infiltration of polynuclear neutrophils, oedema and necrosis. The inflammation observed microscopically correlated with marked increases in serum amyloid A and C-reactive protein. Variations in these acute phase response proteins were detected 24 h after the first dose and were further increased over the course of the treatment. The vascular and inflammatory lesions were reversible over 4 weeks. In conclusion, the lesions induced by the PDE4 inhibitor CI-1044 in dogs differed from the haemodynamically mediated coronary arteritis reported with PDE3 inhibitors.
Hanton
Gilles
G
Department of Toxicology and Comparative Medicine, Pfizer Global Research and Development, ZI Pocé-sur-Cisse, Amboise Cedex, France. gilles.hanton@yahoo.fr
Sobry
Cécile
C
Daguès
Nicolas
N
Provost
Jean-Pierre
JP
Le Net
Jean-Loic
JL
Comby
Pierre
P
Chevalier
Stephan
S
D000210:Acute-Phase Reaction / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000097:blood / Q000633:toxicity*; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D002097:C-Reactive Protein / Q000032:analysis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000633:toxicity*; D005260:Female; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D058988:Phosphodiesterase 4 Inhibitors; D020127:Recovery of Function; D000685:Serum Amyloid A Protein / Q000032:analysis; D018675:Toxicity Tests; D028761:Withholding Treatment
D001381:Azepines; D004791:Enzyme Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D000685:Serum Amyloid A Protein; D009536:Niacinamide; D002097:C-Reactive Protein; C418118:CI 1044