Pharmacokinetics, safety and bioequivalence of intravenous and oral formulations of the antiepileptic drug levetiracetam in healthy Chinese volunteers

The intravenous formulation of levetiracetam (LEV)has been available in clinical practice worldwide for several years,but not in China.In the present study,we aimed to evaluate the bioequivalence of intravenous and oral LEV (tablet), an antiepileptic drug,in healthy Chinese volunteers.Two randomized,single-dose (1500mg),open-label,2-period crossover trials were conducted as follows:study A,15-min infusion;study B,45-min infusion.A total of 22healthy men participated in study A,and 24healthy men and woman were enrolled in study B.In study A,blood samples were collected after termination of each treatment.In study B,samples were collected after oral or after the start of the intravenous administration.Safety and the ratio of intravenous/oral LEV for AUC 0-t and Cmax were evaluated.The 90% confidence intervals of Cmax and AUC0-t ratios for LEV 1500-mg tablets versus 15-min intravenous administration were outside the bioequivalence limits (80.00%-125.00%). For LEV 45-min intravenous administration,bioequivalence versus 1500-mg tablets was within the range for Cmax and AUC 0-t. The most frequently adverse event (AE)was somnolence.A total of eight subjects experienced nine mild AEs in study A, and 19subjects experienced 29mild AEs in study B.Intravenous infusions (15 and 45 min)of 1500-mg LEV were as well tolerated as the oral tablet.Bioequivalence was demonstrated by 45-min infusions.Therefore,direct conversion from oral to intravenous LEV 1500 mg (45-min infusion),or vice versa,was possible.

Acute oral toxicity test and assessment of rhynchophylline in mice

As the main alkaloid constituent of Uncaria species,rhynchophylline has drawn extensive attention in recent years for its antihypertensive and neuroprotective activities.However,toxicity study of the rhynchophylline is still lacking.In the present study,oral acute toxicity of rhynchophylline was conducted in Kunming mice.The mice were orally treated with 520.00,442.00,375.70,319.34 and 271.44 mg/kg of rhynchophylline for 14 d.The general behavior,body weight changes,toxic reaction,and death were recorded,and histopathological analyses were performed.The acute toxicity was evaluated by the assessment of the median lethal dose(LD50).The acute toxicity study showed that no significant difference was found in the body weight of the mice in the control group and those in the drug group.However,the mice treated with rhynchophylline showed obvious abnormal symptoms and mortality.The median lethal dose(LD50)of orally administered rhynchophylline was 308.08 mg/kg.The histopathological results showed that the mice in the high-dose rhynchophylline group displayed toxic effects in the brain,liver,lung,and kidney.The results of the current study indicated that rhynchophylline could not be taken at a high dose.Collectively,our current findings provided a strong basis for further clinical investigation.