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Impact of gavage dosing procedure and gastric content on adverse respiratory effects and mortality in rat toxicity studies


, : Impact of gavage dosing procedure and gastric content on adverse respiratory effects and mortality in rat toxicity studies. Journal of Applied Toxicology 31(4): 342-354

Unscheduled mortality preceded by adverse respiratory clinical signs in rats dosed by oral gavage may not only be caused by technical gavage error or systemic toxicity but may also be caused by gastro-esophageal reflux and subsequent aspiration of high concentrations of drug formulation. In a 3 week oral gavage rat toxicity study for an early drug development compound, preterminal deaths (approximately 20% of animals) at high doses (≥1000 mg kg(-1) ) and concentrations (≥60 mg ml(-1) ) were preceded by recurrent dyspnea, rales or excessive salivation, without evidence of accidental intrapulmonary gavage error. Histological evaluation revealed extensive necrosis and inflammatory changes in the upper respiratory tract, especially in the nasal turbinates and/or nasopharynx. The presence of food particles in inflammatory exudates suggested a retrograde aspiration of stomach content with test formulation via the nasopharyngeal duct into the posterior region of the nose. In contrast, no mortality or adverse respiratory effects were observed in rats following 2 week intravenous administration at comparable exposures or oral gavage administration at lower concentrations (≤20 mg ml(-1) ). In a pharmacology study, the compound caused a dose-dependent increase in gastric content (partly due to inhibition of gastric emptying), providing a pharmacological basis for the suspected gavage-mediated gastroesophageal reflux. Reducing the dose volume and dosing fasted animals substantially reduced or eliminated the respiratory effects and mortality at the high test article concentrations, demonstrating that the adverse effects are related to the gavage method.

US$19.90

PMID: 21089156

DOI: 10.1002/jat.1592


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Rabinovich, E.; Egorova, V.; Smirnova, O.; Inge-Vechtomov, S., 1974: Hydrocarbon utilizing mutants of Saccharomyces cerevisiae. VI. lack of sporulation, mating and mitotic recombination in Hyc c and Hyc plus mutants. Genetika 10 (11) 93-99

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Bayanov, M.G.; Sharislamova, K.K., 1965: Survival rate of the plerocercoids of Digramma interrupta in the external environment Data for the Scientific Conference of the Ail-Union Society of Helminthologists, 1965, Part 4. The Ligula, Digramma interrupta, which parasitize the carp in the Transural lakes of Bashkiria reach the sexually mature stages in the intestine of chickens in 44 to 48 hr.; in the common gull 46 to 48 hr.; in the black-necked and Slavonian grebe...

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Bunge, R.P.; Harter, D.H., 1968: Cytopathic effects of visna virus in cultured mammalian nervous tissue. Visna virus in mouse cerebellum cultures produced acute swelling of small cells 18-48 hours after inoculation; these became empty cysts with a condensed nuclear remnant; later, the nuclear and cytoplasmic contents of large neurones condensed; myel...

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