Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit.

The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration may not be feasible.

Pharmacological properties of extracts from the stem bark of Syzygium guineense on the ileum and heart of laboratory rodents.

A methanol extract of Syzygium guineense bark inhibited intrinsic contractions of rabbit isolated ileum. The inhibition, at bath concentrations of 0.5 - 2.0 mg/ml, was dose-related but non-linear. It produced sustained hypotension in anaesthetized rats. A dose of 5 ug lowered systolic, diastolic and mean blood pressure by 16%, 22% and 17%, respectively below the pre-drug levels. Maximum effect was obtained at a dose of 40 ug when the systolic, diastolic and mean blood pressures fell by 23%, 36% and 28%, respectively below the pre-drug levels. The greater fall in blood pressure was in diastolic than systolic blood pressure. The extract caused a weaker but similar effect to isoprenaline on rabbit isolated heart. While the effect on rabbit isolated ileum supports the folkloric use of the plant as an antispasmodic, further work is required to confirm and categorize the observed pharmacological activities.

Pharmacological Properties of Extracts from the Stem Bark of Syzgium guineense on the Ileum and Heart of Laboratory Rodents

A methanol extract of Syzygium guineense bark inhibited intrinsic contractions of rabbit isolated ileum. The inhibition; at bath concentrations of 0.5 - 2.0 mg/ml; was dose-related but non-linear. It produced sustained hypotension in anaesthetized rats. A dose of 5 ug lowered systolic; diastolic and mean blood pressure by 16; 22and 17; respectively below the pre-drug levels. Maximum effect was obtained at a dose of 40 ug when the systolic; diastolic and mean blood pressures fell by 23; 36and 28; respectively below the pre-drug levels. The greater fall in blood pressure was in diastolic than systolic blood pressure. The extract caused a weaker but similar effect to isoprenaline on rabbit isolated heart. While the effect on rabbit isolated ileum supports the folkloric use of the plant as an antispasmodic; further work is required to confirm and categorize the observed pharmacological activities

Interaction between nifedipine and digoxin in rats.

Possible nifedipine-digoxin interaction was investigated in rats by comparing lethal doses of intravenously infused digoxin in control and experimental rats. In the experimental rats, nifedipine was administered intraperitoneally, 30 minutes prior to infusing digoxin at a constant rate of 40mcg per minute. Results indicate that nifedipine administered within the dosage range 0.5-2.0mg per kg rat body weight, lowered the lethal dose of intravenously infused digoxin by 26-38% compared with control rats, thus indicating a synergistic effect between the two drugs. There was very little dose dependence of this effect. It is concluded that concomitant administration of nifedipine and digoxin in humans may lead to drug interactions.