Chronotolerance study of the antiepileptic drug valproic acid in mice

<p>Abstract</p> <p>Background</p> <p>Valproic 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.</p> <p>Methods</p> <p>The 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, <it>i.p.</it>. Such a dose was administered by <it>i.p.</it> 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).</p> <p>Results</p> <p>The 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).</p> <p>Conclusions</p> <p>With 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.</p

Hepatoprotective effect of Opuntia microdasys (Lehm.) Pfeiff flowers against diabetes type II induced in rats

Opuntia sp. has long been used as a folk medicine to treat hepatitis and diabetes in Sicile (Italy). To extract the polyphenols from the flower of Opuntia microdasys Lehm. at post flowring stage and evaluate the antidiabetic activity in vitro and in vivo. The hepatoprotective activity of Opuntia microdasys aqueous flowers extract at post flowering stage (OFP) has been tested for their antidiabetic activity. On fructose-alloxan induced diabete in rat model, evaluating the inhibitory effects of OFP on some carbohydrate metabolizing enzymes, pancreatic α-amylase and intestinal α-glucosidase activities in vitro. The OFP extract showed inhibitory activity against α-glucosidase (IC50 = 0.17 ± 0.012 mg/ml) and α-amylase (IC50 = 2.55 ± 0.41 mg/ml). The inhibitory potential of OFP extract on these enzymes suggests a positive and probable role of this extract in the management and treatment of diabetes mellitus, particularly, for type 2. Oral administration of the OFP at 200 mg/kg to diabetic male rats for 28 days demonstrated a significant protective effect by lowering the levels of glucose (123.21 ± 1.38 mg/dL) and hepatic marker enzymes (AST, ALT, LDH, γ-GT, BT, PAL, TC, LDL-C, HDL-C and TG). OFP attenuated oxidative stress by decreasing the SOD, CAT, GPX activity and the levels of PC and MDA in the liver and restored the histological architecture of the rat liver. OFP has protective effects on the protection of liver, thereby reducing some of the causes of diabetes in experimental animals