The toxicity of CI-949, an effective inhibitor of allergic mediator release in pharmacology models, was evaluated in rodents and dogs. Median lethal doses at 24-hr postdose ranged from 343 to 453 mg/kg in mice and 806 to 2058 mg/kg in rats. Delayed toxicity was observed at 300 mg/kg and greater in mice and at 500 mg/kg and greater in rats. Mortality and clinical intolerance occurred in rats at 200 and 400 mg/kg in the subacute studies, and at 100 and 150 mg/kg in the 13-week study. In rats, dose-dependent lymphoid tissue atrophy and depletion or necrosis of lymphocytes in lymphoid tissues were seen in deaths and moribund terminations. Although doses up to 60 mg/kg administrated for 2 weeks to dogs were well tolerated, 60 and 120 mg/kg in the 13-week dog study were poorly tolerated. Cutaneous sores, mucocutaneous purulent discharge, emesis, diarrhea, and weight loss were identified at these lethal doses. Histopathologic changes in dogs included myocardial, vascular and soft tissue inflammation, and gastric ulceration at 60 and 120 mg/kg, and thymic atrophy at 20 mg/kg and greater. Doses of 10 and 50 mg/kg were no-effect doses in 13-week repeated dose studies in dogs and rats, respectively. These results were used to support initial human clinical trials of CI-949.

1991-11-01·Fundamental and applied toxicology : official journal of the Society of Toxicology

Effects of Cl-949, a novel antiallergy compound, on host resistance in mice

Article

作者: Kimber L. White ; Albert E. Munson ; J. Ann Mccay ; Monique M. Fouant ; Michael R. Bleavins ; Ronald A. Martin ; Felix A. de la Iglesia

The effect of CI-949, a novel inhibitor of allergic mediator release, on immune function was assessed with holistic mouse models of immunocompetence. Resistance to the bacterial pathogens Listeria monocytogenes and Streptococcus pneumoniae and the B16F10 melanoma cell line was used to evaluate the potential of CI-949 to affect immune function. CI-949 treatment of female B6C3F1 mice increased pulmonary tumor burden at 100 mg/kg/day in the B16F10 melanoma model, with a no effect level of at least 50 mg/kg/day. A correlation was seen between decreased clearance of the B16F10 cells and increased tumor burden. However, CI-949 produced this effect only at the maximum tolerated dose. No effect of the drug was seen in the S. pneumoniae model. Host resistance to L. monocytogenes was increased after CI-949 administration, with the no adverse effect level in this model being at least equivalent to the top dose of 100 mg/kg/day. Therefore, the immune system does not appear to be adversely affected or to be a specific target for CI-949 even at an overtly toxic dose.

1991-04-01·The Journal of pharmacology and experimental therapeutics

Effects of CI-949, a novel antiallergy agent, on immune function of male Fischer 344 rats.

Article

作者: de la Iglesia, F A ; Bleavins, M R ; White, K L ; McCay, J A ; Fuchs, B A ; Munson, A E ; Stern, M L

CI-949 is an orally effective inhibitor of allergic mediator release as measured with in vitro and animal models. To assess the effects of CI-949 on immune function, male Fischer 344 rats were evaluated for splenic T- and B-lymphocyte populations, antibody-forming cell response to sheep red blood cells (sRBC), concanavalin A- and pokeweed mitogen-induced lymphocyte proliferation, Natural Killer cell activity and reticuloendothelial system clearance of sRBC. CI-949 was administered by gavage to rats at 25, 50 and 100 mg/kg/day for 14 consecutive days. A vehicle control and two positive controls (cyclosporine A and cyclophosphamide) were run concurrently. CI-949 at 100 mg/kg/day decreased body weight gain and was lethal to 5 of 40 rats. The deaths occurred between days 5 and 12 of study. This overtly toxic dose did not alter splenic cellularity or change the percentages of T- and B-lymphocyte subpopulations. Additionally, CI-949 did not inhibit lymphocyte proliferation or hinder clearance of sRBC by the reticuloendothelial system. Antibody-forming cell response after immunization showed a dose-related increase in the number of immunoglobulin M secreting cells. Based on the results of these assays, the immune system does not appear to be adversely affected by CI-949 even at high doses.

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