| Autor: |
Morrissey, Richard E., Horvath, Christopher, Snyder, Eileen A., Patrick, James, MacDonald, James S. |
| Předmět: |
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| Zdroj: |
Toxicological Sciences; Feb2002, Vol. 65 Issue 2, p266-275, 10p, 6 Charts |
| Abstrakt: |
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 × 107 plaque-forming units (pfu)/kg (5.6 × 1010 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 × 109 pfu/kg (1.1 × 1012 particles/kg) was lethal by the iv route and inflammatory to the peritoneal cavity by the ip route. SCH 58500 was rapidly cleared from the systemic circulation in rats (serum t1/2 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 iv 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 iv dosing. A singe high iv dose of SCH 58500 (1.1 × 1012 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 iv dosing in rats. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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