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Jane C.F. Chang Paul Ciaccio Patricia Schroeder Lindsay Wright Russell Westwood Anna-Lena Berg 《Journal of toxicologic pathology》2014,27(1):31-42
AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine
(5-HT1B) receptor, was explored as a potential treatment for depression. To
support clinical trials, repeat dose toxicity studies in rats and dogs were conducted.
Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month
study, there were minimal neuronal vacuolation in the brain, a marked increase in liver
enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD),
and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month
study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86
days. Extensive pathologic changes were seen in all animals in retina epithelium
(inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber
degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic
and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung,
kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues.
Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and
pathology study showed that the concentration of AZD3783 in the brain was approximately 4
times higher than in the plasma after 4 weeks of dosing, however, they were similar in all
regions examined, and did not correlate with areas with pathologic findings. Our findings
with AZD3783 in dogs have not been reported previously with other CNS compounds that
effect through serotonergic pharmacology. 相似文献
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Schultze AE Sullivan JM 《Veterinary clinical pathology / American Society for Veterinary Clinical Pathology》2007,36(2):123-136
BACKGROUND: Veterinary clinical and anatomic pathologists play a critical role in assessing the safety of new molecules. The process for evaluation of candidate molecules in drug discovery may vary markedly, depending on the unique characteristics of the compound class. OBJECTIVES: The goal of this report is to describe the evaluation process for assessing the potential toxicity of 2 anticoagulant compounds that were representative of molecules tested in early screening studies in Fisher rats, and to use these studies as an example of the strategic approach used by veterinary pathologists in pharmaceutical safety assessment. METHODS: Groups of 3 rats were given vehicle alone or one of several doses of compound A or B by oral gavage daily for 4 consecutive days. Survival; clinical signs; body and organ weight measurements; hematologic, coagulation, and clinical biochemical testing; and gross and histologic findings at necropsy were assessed. Transmission electron microscopy was used to characterize unique findings in the liver of rats treated with compound B. RESULTS: Both compounds caused dose-dependent prolongation of the prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin clotting time (TCT). Hepatobiliary and intestinal toxicity were identified by alterations in serum chemistry data, and by histopathologic findings. Electron microscopy and tissue inorganic phosphorus analysis revealed phospholipidosis in rats treated with compound B. CONCLUSIONS: Pharmacologically mediated or "on target" effects for these molecules were characterized by dose-progressive prolongation of the PT, APTT, and TCT. Nonpharmacologically mediated or "off-target" toxicity consisted of hepatoxicity and enterotoxicity. These liabilities required that scientists alter the original molecular scaffold to reach the desired therapeutic target and minimize toxicity. 相似文献
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