Chronotolerance study of the antiepileptic drug valproic acid in mice

Abstract

BackgroundValproic acid (VPA) is an antiepileptic drug widely used for the treatment of absence seizures and generalized tonic-clonic seizures. The present work aims to study whether VPA-induced toxicity varies according to the dosing-time in the 24 hour-scale.MethodsThe influence of dosing-time on tolerance to VPA was investigated in 120 male Swiss mice synchronized under a light-dark cycle (12:12). The mean VPA lethal dose was first determined to be 850 ± 0.2 mg/kg, i.p.. Such a dose was administered by i.p. route to a total of 90 mice divided in six circadian stages [1, 5, 9, 13, 17 and 21 Hours After Light Onset (HALO)] (15 mice/circadian time); 30 mice were used as control (5 mice / circadian time).ResultsThe surviving treated mice exhibited a significant circadian variation in rectal temperature and body weight loss (p < 0.001). The least rectal temperature change and body weight loss occurred when VPA was injected at 9 HALO. Drug dosing at 9 HALO resulted in -9 % weight loss whereas drug dosing at 17 HALO was -15 % (Ø = 20.3 HALO ± 1.1 h, p ≤ 0.0001). Lethal toxicity also varied according to circadian dosing-time (χ2 = 42.1, p < 0.0001). The highest (60 %) and the lowest (6.67 %) survival rates were observed at 9 HALO and 17 HALO respectively. Cosinor analyses validated a significant circadian rhythm in survival duration with an acrophase at 8.4 HALO ± 0.75 h (p < 0.001).ConclusionsWith regards to these data the optimal tolerance to VPA occurred when the drug was administered in the second half of the light-rest span of mice which is physiologically analogous to the second half of the night for human patients.

Time of Administration of Acute or Chronic Doses of Imipramine Affects its Antidepressant Action in Rats

“…The pharmacological action of many substances is dependent on the circadian system, and a drug’s dosing time can affect both its therapeutic and toxic effects [12345]. Some drugs work better in the daytime, while other drugs work better at night.…”

Circadian time-dependent hepatic and renal toxicities to valproic acid in mice

“…As in the findings of earlier reports, the peak of rectal temperature in this study occurred almost in the middle of the dark-activity span of mice. This peak location coincides with the highest physical activity in mice, i.e., during the dark span (Ben-Cherif et al 2012).…”

“…The obtained results in our previous study suggest the importance of the circadian time at which a toxic dose of VPA was administered; indeed, a significant circadian rhythm was demonstrated for acute toxicity measured by VPA-induced mortality. The most important finding of that previous study was that the VPA toxicity is maximized when it was administered during nearly the dead center of the animals' activity (time which corresponds to the peak of murine rectal temperature) and minimized when it was administered during the second half of the animals' rest phase (Ben-Cherif et al 2012). This result is very important since VPA is a drug which is always administered during the diurnal phase in humans (activity span).…”

“…Taking into account the circadian injection time, the animals were carefully removed from the cage and were rapidly killed by decapitation; the sacrifices were done 24 h after injection time since a previous study showed that it corresponds to the maximum lethal toxicity (Ben-Cherif et al 2012). All sacrifices were carried out ≈10 min from the various circadian time-points.…”

Chronopharmacology of Anti-Convulsive Therapy

“…A murine study found that the valproate was most toxic when administered 17 hours after light onset. Least toxicity occurred when it was administrated 9 hours after light onset, which corresponds to the second half of the night in humans [85•].…”