Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SCH 58500 is a replication-defective recombinant adenoviral vector containing the cloned human wild-type (normal) tumor suppressor gene p53. SCH 58500 is in trials to evaluate potential clinical utility. A series of toxicology studies in rats and mice were conducted via multiple routes of exposure to support these programs. The nonlethal and asymptomatic dose in rats following a 14-day observation period was equal to 7.5 x 10(7) plaque-forming units (pfu)/kg (5.6 x 10(10) particles/kg) by intravenous or intraperitoneal route and was similar by the ip route, following 4 weeks of dosing. The high dose of 1.5 x 10(9) pfu/kg (1.1 x 10(12) particles/kg) was lethal by the i.v. route and inflammatory to the peritoneal cavity by the ip route. SCH 58500 was rapidly cleared from the systemic circulation in rats (serum t(1/2) of 7 to 9 min) following iv administration. Administration by other routes resulted in no (sc) or delayed (ip) serum levels. Since most rats in the i.v. rat study died within 24 h postdose, another study to evaluate potential mechanisms of toxicity in rats was designed in which rats were killed at intervals following a single i.v. dosing. A single high i.v. dose of SCH 58500 (1.1 x 10(12) pfu/kg) was associated with lethargy, soft feces, a ruffled-hair coat, and death within 1 h postdose. Potential mechanisms of toxicity appeared to include a mild coagulopathy and/or vasculopathy, resulting in consumption of platelets and clotting factors, leakage or loss of intravascular fluid, hemoconcentration, electrolyte and/or fluid shifts, a moderate stress and/or inflammatory response, and a mild, direct or indirect toxic effect on liver and/or kidney tissue. These findings suggest a multifocal cause for acute lethality following i.v. dosing in rats.
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PMID:Rodent nonclinical safety evaluation studies of SCH 58500, an adenoviral vector for the p53 gene. 1181 31

Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necro-inflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF- alpha) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes. Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis. Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC) in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with suppression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker's syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache, fullness in the head, dizziness, lethargy, prickling sensation, pruritus and arthralgia.
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PMID:Heavy smoking and liver. 1703 78

Dicyclohexylcarbodiimide (DCC) and Diisopropylcarbodiimide (DIC) are two representative chemicals in the carbodiimide class of chemicals used in industry as stabilizing agents. There is a potential of dermal exposure to these agents in chemical, pharmaceutical and recombinant DNA industries. The National Toxicology Program conducted a number of animal studies to characterize toxicity and carcinogenicity of DIC and DCC. Dermal administration of DCC and DIC in F344/N rats and B6C3F1 mice for 90-days induced skin irritation at the site of application in a dose-dependent manner. Microscopically, dose-dependent increases in epidermal hyperplasia and chronic inflammation were observed. We further evaluated the effects of dermal exposure of DCC and DIC in p53 haploinsufficient and Tg.AC mouse models. Results revealed the skin as the primary target of DCC and DIC exposure as indicated by dose - dependent skin lesions (hyperplasia, inflammation and necrosis). DCC induced squamous cell papillomas in Tg.AC mice but did not induce any neoplastic lesions in p53 haploinsufficient mice. Dermal application of DIC did not induce any neoplastic lesions in Tg.AC mice and p53 haploinsufficient mice. Based on these studies, it was predicted that DIC would be negative and DCC positive for carcinogenic activity in the traditional two-year bioassay. In the subsequent studies, the carcinogenic potential of DIC only in F344 rats and B6C3F1 mice in a traditional 2-year chronic carcinogenicity bioassay was evaluated by the dermal route. Findings revealed the skin as the major target organ of toxicity in both sexes in rats and in male mice. There were no neoplastic lesions observed in rats or mice with the administration of DIC. In rats, there were clinical signs of toxicity in the highest dose-group which included ataxia, excitability, impaired gait, low muscle tone, abnormal breathing, lethargy, and seizures. This was accompanied by non-neoplastic lesions in the brain and lung only at the highest dose level. In conclusion, both DIC and DCC are dermal toxicants. DIC did not have any carcinogenic activity in transgenic mouse models or in the traditional NTP two-year carcinogenicity studies in F344 rats and B6C3F1 mice. DCC was positive in the Tg.AC mouse model and likely to be carcinogenic in the 2-year bioassay as well.
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PMID:Comparative dermal toxicity of dicyclohexylcarbodiimide and diisopropylcarbodiimide in rodents. 2206 Aug 20