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Nine horses received 20 mg/kg of intravenous (LEV IV ); 30 mg/kg of intragastric, crushed immediate release (LEV CIR ); and 30 mg/kg of intragastric, crushed extended release (LEV CER ) levetiracetam, in a three-way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEV CIR and LEV CER were 50.72 ± 10.60 and 53.58 ± 15.94 μg/ml, respectively. The y-intercept for IV administration was 64.54 ± 24.99 μg/ml. The terminal half-life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEV CIR , LEV CER , and LEV IV , respectively. Volume of distribution at steady-state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg -1  hr -1 . Bioavailability was 96 ± 10, and 98 ± 13% for LEV CIR and LEV CER , respectively. A single dose of Levetiracetam (LEV) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted., (© 2017 John Wiley & Sons Ltd.)

Cholestyramine, a nonabsorbable anion exchange resin, has been reported to bind concomitantly administered drugs and decrease their bioavailability. The objective of the study was to determine the effect of cholestyramine on the plasma concentrations of valproic acid (VPA) following concurrent and staggered (VPA 3 hours before cholestyramine) dosing. Six healthy volunteers participated in an open-label, 3-way crossover study. In each phase fasting subjects received 250 mg of VPA followed by serial blood sampling for VPA plasma concentrations over a 37-hour period. In the concurrent and staggered phase the subjects received 4 g of cholestyramine (CHOL) twice daily 24 hours prior to and following the VPA dose. During the concurrent phase the coadministration of CHOL resulted in a decrease (p < 0.05) in the area under the curve (AUC) for VPA compared to VPA alone (415.2 +/- 113.2 mg*hr/l vs 489.2 +/- 153.0 mg*hr/l, respectively). When the same dose of each drug was administered 3 hours apart, the AUC for VPA (454.8 +/- 123.1 mg*hr/l) was not significantly decreased when compared to VPA alone (489.2 +/- 153.0 mg*hr/l). Also, the bioavailability relative to VPA alone was 86.2% +/- 7.1 for the concurrent phase and 95.3% +/- 13.6 for the staggered phase. Based on the AUC of VPA concurrent administration of CHOL significantly decreases VPA absorption and separating the doses of the 2 drugs by 3 hours may lessen the interaction.

A series of 4- aminobenzamides of some simple primary and secondary amines were prepared and evaluated for anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and pentylenetetrazole ( metrazole ) and in the rotorod assay for neurologic deficit. For those N-alkyl amides tested, 4-amino-N- amylbenzamide (6) was the most potent against maximal electroshock seizures (MES): ED50 = 42.98 mg/kg; however, the N- cyclohexylbenzamide (8) showed the greatest protective index (PI = TD50/ED50), 2.8. The introduction of a second aromatic ring produced more potent compounds, with d,l-4-amino-N-(alpha-methylbenzyl)-benzamide (12) showing the highest level of activity. This compound has an anti-MES ED50 of 18.02 mg/kg in mice when administered intraperitoneally (ip) and a TD50 of 170.78 mg/kg (PI = 9.5) in the same species. These data compare quite favorably with those for phenobarbital and phenytoin in the same assays.

A method for the high-performance liquid chromatographic (HPLC) determination of serum concentrations of d,l-4-amino-N-(alpha-methylbenzyl)-benzamide and its N-acetylated metabolite is described. The compounds are isolated from a 50-microL sample of serum using solid phase extraction. The compounds and internal standard are eluted from the extraction column with acetonitrile. Quantitation is performed via UV detection at 275 nm following isocratic reversed-phase (C18) separation using a ternary solvent system. The assay procedure is useful for the determination of concentrations of parent compound from 0.63 to 87.9 micrograms/mL from 50 microL of serum.

Sodium phenobarbital (PHB) was administered orally as tablets 3 times a day to 6 healthy mature dogs of mixed breeding for 5 days at a dose of 2 mg/kg of body weight. On the 6th day, PHB was administered at 9 AM and venous blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 23, 35, 47, 59, 71, 83, 95, 107, 119, and 131 hours. Additional PHB was not given on day 6. Drug serum concentrations were described by a 1-compartment model with first-order absorption and elimination with fitted correlation coefficients of 0.991 +/- 0.007 (mean +/- SD). The observed PHB half-lives were between 37.3 and 74.6 hours with a mean of 53.0 +/- 15 hours. The calculated volume of distribution (Vd/F) was 743.6 +/- 69.8 ml/kg, and the total body clearance (ClT/F) was 0.173 +/- 0.053 ml/min/ kg. The absorption half-life was 1.27 +/- 0.21 hours. Based on the observed biological half-life after 5 days of dosing, approximately 11 days (8 to 15.5 days) of multiple dosing would be required to achieve steady-state serum concentrations. From average values, predicted maintenance doses of 1.8 mg/kg of body weight 3 times a day or 5.5 mg/kg once daily would be required to achieve average serum concentrations of 20 microg/ml. Due to intersubject variations in ClT/F, these doses would result in subtherapeutic or toxic serum concentrations in 2 of the 6 dogs. Further disposition and dosing regimen studies need to be performed during chronic PHB administration in dogs to evaluate autoinduction and intersubject differences in disposition kinetics.