ABSTRACT
Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Kidney Tubules/drug effects , Naproxen/toxicity , Nephritis, Interstitial/chemically induced , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Blood Urea Nitrogen , Connective Tissue/drug effects , Connective Tissue/pathology , Creatinine/blood , Dose-Response Relationship, Drug , Female , Kidney Tubules/pathology , Macaca fascicularis , Male , Naproxen/pharmacokinetics , Nephritis, Interstitial/pathology , Organ Size/drug effects , Pilot ProjectsABSTRACT
Monochloroacetic acid (MCA) causes front paw rigidity in 10% of mice surviving a single oral toxic dose (320-380 mg/kg). Mice exhibiting front paw rigidity were killed at various times after MCA treatment and their brains were prepared for histological examination. As early as 48 hr post-treatment, RBCs were found outside capillaries in several brain regions, especially the cerebellum. At time points up to 8 weeks after MCA, extracapillary RBCs were seen to be undergoing lysis, and there was loss of cerebellar Purkinje cells. Three hours after oral administration of an LD80 of MCA (380 mg/kg), entry of iv-injected [14C]inulin or [3H]dopamine (1.0 microCi) into all brain regions was significantly increased compared to controls. Increased entry of [14C]inulin into the brains of mice occurred as early as 2 hr after MCA, coinciding with the onset of signs of toxicity, and remained elevated for up to 8 hr following treatment. Further studies revealed that only those mice which were moribund but not those which were unaffected by MCA (380 mg/kg) 4-6 hr after treatment had significantly increased brain levels of [14C]inulin or [3H]dopamine. However, mice which survived an LD80 of MCA and exhibited front paw rigidity 24 hr later also had brain radiotracer concentrations significantly greater than controls. Both the lethal effects of MCA and the physical deficits observed in survivors may be associated with impairment of blood-brain barrier function.
