Subchronic toxicity studies with the leukotriene D4 antagonist RG 12525.

Preclinical safety studies with the leukotriene D4 antagonist RG 12525 were conducted by the oral route in mice, rats, and monkeys. Oral administration of RG 12525 was repeated daily in studies up to 6 months in duration. RG 12525 was shown to have limited high-dose toxicity after repeated oral administration. The effects of RG 12525 were strongly dependent upon the species considered. High doses of RG 12525 caused significant increases in liver weight in mice, rats, and monkeys that were associated with diffuse hepatocellular hypertrophy in mice and rats but not in monkeys. No related clinical chemistry changes were observed in any of the species and hepatic activities of peroxisomal enzymes or cytochrome P450 were increased only slightly. Proliferation of brown adipose tissue (BAT) was observed in rats and mice but not in monkeys. The BAT reaction was more pronounced in the interscapular area but it was also observed in other subcutaneous locations as well as in mediastinal and bone marrow fat. In all locations, the RG 12525-induced BAT had some morphological similarities with cold-adapted BAT. Repeated administration of RG 12525 at high doses to female rats resulted in a lack of progression to the luteal phase of the estrous cycle that was reversible after discontinuation of treatment. Finally, RG 12525 was nephrotoxic in mice with males being more sensitive than females.

Proliferative pituitary lesions in rats treated with salmon or porcine calcitonin.

Calcitonin, the serum calcium-lowering hormone, has been used in the treatment of hypercalcemia of malignancy and postmenopausal osteoporosis in humans for several years without any adverse effects. Recent studies in rats have indicated that calcitonin may be associated with morphologic effects on the pituitary. A large study was performed on 2 strains of rats, Sprague-Dawley (SD) and Fischer-344 (F-344), with 2 types of calcitonin, salmon-derived (sCT) and porcine-derived (pCT) calcitonin to evaluate possible effects on the pituitary. Sixteen groups of 42 male and 42 female SD or F-344 rats were given 0 (vehicle control), 1.25, 5.0, or 80.0 IU/kg/day of sCT or pCT, once daily, subcutaneously, for 1 yr. An increased incidence of adenomas of the adenohypophysis was observed in male SD rats at all dose levels of sCT, female SD rats given 80 IU/kg/day of sCT, male SD rats at the high dose level of pCT, and male F-344 rats at the high dose level of sCT. Also, an increased incidence of total proliferative lesions, due mostly to an increased incidence of focal hyperplasia of the pars distalis, occurred in female F-344 rats given the high dose of sCT. These pituitary proliferations were histologically similar to those that occur spontaneously, and the incidences observed were comparable to those that could occur in rats on 2-yr or lifetime studies, indicating that the injection of calcitonin had decreased the latency period.

A search for cytomegalovirus and herpes viral antigen in brains of schizophrenic patients.

The peroxidase-antiperoxidase method was employed to search for evidence of cytomegalovirus (CMV) or herpes simplex virus (HSV) antigen in the brains of 25 patients with a diagnosis of schizophrenia, 25 nonschizophrenic neuropsychiatric patients, and 16 nonpsychiatric control subjects. Brain specimens from patients with acute CMV and herpes encephalitis served as positive controls. Although early results with low-titer CMV antisera suggested immunoreactivity in specific brain regions of a small number of schizophrenic and control cases, the present studies with high-titer anti-CMV IgG did not give a positive immunoperoxidase reaction in sections from the basal forebrain, hypothalamus, or midbrain. Scattered neurons in the lateral vestibular nucleus and hippocampus showed questionable staining with CMV IgG in one schizophrenic patient and none in control subjects. No schizophrenic or control cases demonstrated an immune reaction to HSV antisera.