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Testing for circadian differences in lethality for intravenous ouabain in male mice
A B Forrest1, J C Hawley, M H Malone
1Department of Physiology and Pharmacology, School of Pharmacy, University of the Pacific, Stockton, CA 95211.
Abstract:
Using a randomized, balanced design and double-blind methodology, ouabain octahydrate was administered intravenously to male mice at six clock times. Eight runs were conducted using six constant dosage levels. All the dose-response curves at the clock times of 02:30, 06:30, 10:30, 14:30, 18:30 and 22:30 were parallel and no significant differences were noted between the respective LD50 determinations using nomograph methods. Independent chi-square analysis of all lethality data indicated no significant variation in response between clock times and between runs but a very highly significant difference between doses. Using regression methods, onset time for death was shown to vary inversely with log-dosage, but those periods of possible increased susceptibility could not be correlated with a shortened time to death. These findings are consistent with a random variation in lethality in regard to clock time rather than a true circadian pattern. The pooled (N = 576) intravenous LD50 for ouabain octahydrate was 3.75 mg/kg with 95% confidence limits of 3.60-3.90 mg/kg or, when calculated as anhydrous ouabain, 3.01 (2.89-3.13) mg/kg.
Insights
Ouabain octahydrate lethality in mice did not show a circadian pattern. Lethality varied significantly with dose but not with administration time, suggesting random variation.
Area of Science:
- Pharmacology
- Toxicology
- Chronobiology
Background:
- Circadian rhythms influence physiological processes, potentially affecting drug toxicity.
- Ouabain is a cardiac glycoside with a narrow therapeutic index.
Purpose of the Study:
- To investigate potential circadian variations in the acute toxicity of ouabain octahydrate.
- To determine the lethal dose 50 (LD50) of ouabain octahydrate at different administration times.
Main Methods:
- Randomized, double-blind study in male mice.
- Intravenous administration of ouabain octahydrate at six different clock times.
- Dose-response curves and LD50 determination using nomograph and regression methods.
Main Results:
- Dose-response curves were parallel across all tested clock times.
- No significant differences in LD50 values were found between different administration times.
- Lethality showed a highly significant difference between doses but not between clock times.
Conclusions:
- Findings suggest random variation in ouabain octahydrate lethality rather than a true circadian pattern.
- The pooled intravenous LD50 for ouabain octahydrate was determined.
- Further research may explore other factors influencing ouabain toxicity.