Summary. Beagle bitches were treated with equine anti-LH serum (ALHS)

The azole antifungal drug posaconazole caused phospholipidosis in neurons of the central nervous system, dorsal root ganglia of the spinal cord, and myenteric plexus in chronic toxicity studies in dogs. The time of onset, light and electron microscopic features, neurologic and electrophysiologic effects on the central and peripheral nervous systems, and potential for regression were investigated in a series of studies with a duration of up to one year. Nuclei of the medulla oblongata were the prominently affected areas of the brain. Neurons contained cytoplasmic vacuoles with concentrically whorled plasma membrane-like material (i.e., multilamellar bodies) morphologically identical to that commonly caused in other tissues by cationic amphiphilic drugs. Some axons in the brain and spinal cord were swollen and contained granular eosinophilic, electron-dense lysosomes. There were no features suggesting degeneration or necrosis of neurons or any associated elements of nervous tissue. The earliest and most consistent onset was in neurons of dorsal root ganglia. The observed neural phospholipidosis did not result in any alteration in the amplitude or latency of the auditory, visual, or somatosensory evoked potentials. The histopathologic changes did not progress or regress within the three-month postdose period. The results indicate that phospholipidosis can be induced in central and peripheral neurons of dogs by administration of posaconazole, but this change is not associated with functional effects in the systems evaluated.

No 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.

No abstract

The carcinogenic potential of chlorpromazine hydrochloride, a psychotropic agent, was assessed in the p53 heterozygous mouse assay. In a 4-week dose range finding study in p53 wild-type mice, doses of 20,40, 60, and 80 mg/kg were poorly tolerated because of mortality secondary to the severe sedative and hypotensive effects of chlorpromazine. Based on 40% mortality at a dose of 20 mg/kg in the dose-range finding study, a high dose of 10 mg/kg was chosen for the 26-week carcinogenicity study in p53 heterozygous mice. Doses of 2.5, 5, and 10 mg/kg chlorpromazine hydrochloride were well tolerated in the 26-week study. The administration of chlorpromazine hydrochloride at dose levels up to and including 10 mg/kg to p53 heterozygous and wild-type mice did not result in a dose-related increase in tumor incidence or in the type of tumors seen in comparison to controls. Findings related to the administration of chlorpromazine in the 26-week study were limited to minimal uterine and ovarian atrophy in p53 wild-type mice dosed with 10 mg/kg chlorpromazine hydrochloride. However, p53 heterozygous mice administered 400 mg/kg p-cresidine, a genotoxic carcinogen commonly used as a positive control for this model, developed urinary bladder tumors. Administration of p-cresidine also resulted in a regenerative anemia, splenic and hepatic hemosiderosis, renal findings, and ovarian and uterine atrophy. This study demonstrated that chlorpromazine hydrochloride, at the doses tolerated, was not carcinogenic in the p53 heterozygous mouse assay.

Flutamide, a potent nonsteroidal antiandrogen, was administered orally to male beagle dogs for 2, 3, or 4 years at doses of 10, 20, or 40 mg/kg/day. At each study interval, the results of clinical pathology examinations, organ weight determinations, necropsy, and histopathologic examinations generally were similar and included atrophy of the prostate gland, testicular interstitial cell hyperplasia, and seminiferous tubular atrophy and degeneration. After 3 years of drug exposure, there were 3 dogs with testicular interstitial cell adenomas and a few dogs with 1 or more enlarged mammary gland nipples. Based upon the pharmacologic activity of flutamide, these findings were expected and considered the consequence of long-term blocking of testosterone receptors and an exaggerated compensatory response to increased secretion of luteinizing hormone. The findings of this study were consistent with other examples of dysregulated hormone stimulation of target tissues noted during the nonclinical safety assessment of flutamide. In consideration of the clinical indication of flutamide for advanced prostatic carcinoma and based upon reports of minimal flutamide-related adverse clinical responses, the findings of this study pose no concern for human risk assessment.

Flutamide, a potent nonsteroidal antiandrogen, was administered orally to male beagle dogs for 2,3, or 4 years at doses of 10,20, or 40 mg/kg/day. At each study interval, the results of clinical pathology examinations, organ weight determinations, necropsy, and histopathologic examinations generally were similar and included atrophy of the prostate gland, testicular interstitial cell hyperplasia, and seminiferous tubular atrophy and degeneration. After 3 years of drug exposure, there were 3 dogs with testicular interstitial cell adenomas and a few dogs with 1 or more enlarged mammary gland nipples. Based upon the pharmacologic activity of flutamide, these findings were expected and considered the consequence of long-term blocking of testosterone receptors and an exaggerated compensatory response to increased secretion of luteinizing hormone. The findings of this study were consistent with other examples of dysregulated hormone stimulation of target tissues noted during the nonclinical safety assessment of flutamide. In consideration of the clinical indication of flutamide for advanced prostatic carcinoma and based upon reports of minimal flutamide-related adverse clinical responses, the findings of this study pose no concern for human risk assessment.