M Bliss

Isolation of monoclonal antibodies to phencyclidine from ascites fluid by preparative isoelectric focusing in the Rotofor

A monoclonal antibody to phencyclidine was developed, produced in mouse ascites fluid, and purified. The purification used only preparative-scale isoelectric focusing in the Rotofor and dialysis. In 4 h, 25% (4 mg) of the antibody from 10 ml of ascites fluid was purified to homogeneity while 63% of the total antibody was recovered.

Steady-state interaction between amiodarone and phenytoin in normal subjects☆

Amiodarone has been reported to increase phenytoin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction at steady-state. Pharmacokinetic parameters for phenytoin were determined after 14 days of oral phenytoin, 2 to 4 mg/kg/day, before and after oral amiodarone, 200 mg daily for 6 weeks in 7 healthy male subjects. During amiodarone therapy, area under the serum concentration time curve for phenytoin was increased from 208 +/- 82.8 (mean +/- standard deviation) to 292 +/- 108 mg.hr/liter (p = 0.015). Both the maximum and 24-hour phenytoin concentrations were increased from 10.75 +/- 3.75 and 6.67 +/- 3.51 micrograms/ml to 14.26 +/- 3.97 (p = 0.016) and 10.27 +/- 4.67 micrograms/ml (p = 0.012), respectively, during concomitant amiodarone treatment. Amiodarone caused a decrease in the oral clearance of phenytoin from 1.29 +/- 0.30 to 0.93 +/- 0.25 liters/hr (p = 0.002). These results were due to a reduction in phenytoin metabolism by amiodarone as evidenced by a decrease in the urinary excretion of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, 149 +/- 39.7 to 99.3 +/- 40.0 mg (p = 0.041) and no change in the unbound fraction of the total phenytoin concentration expressed as a percentage, 10.3 +/- 2.7 versus 10.7 +/- 2.1% (p = 0.28) during coadministration of amiodarone. The alterations in phenytoin pharmacokinetics suggest that steady-state doses of phenytoin of 2 to 4 mg/kg/day should be reduced at least 25% when amiodarone is concurrently administered. All dosage reductions should be guided by clinical and therapeutic drug monitoring.

Digoxin-diltiazem interaction: a pharmacokinetic evaluation.

SummaryThe pharmacokinetics of digoxin were studied before and after a 2 week course of diltiazem, 30 mg four times daily, in 7 healthy volunteers. Each subject received an IV dose of digoxin before starting diltiazem and again on day 15 of the study. Diltiazem was continued until all sera and urine were collected. During the control and diltiazem phases, respectively, the terminal elimination rate constants were 0.0231±0.007 h−1 and 0.0254±0.007 h−1, the volumes of distribution were 10.5±3.95 l/kg and 10.2±3.26 l/kg, and the total body clearances were 3.72±0.78 ml·min−1·kg−1 and 4.09±0.94 ml·min−1·kg−1. None of these pharmacokinetic parameters of digoxin were significantly different before or during diltiazem administration. Overall, there does not appear to be an interaction between digoxin and diltiazem.

Disposition kinetics of cefamandole during continuous ambulatory peritoneal dialysis.

Cefamandole disposition kinetics were examined in six male subjects with renal impairment who were undergoing continuous ambulatory peritoneal dialysis. Creatinine clearance values ranged from less than 1 to 11 ml/min. Cefamandole was given as a 1-g intravenous dose infused over 30 min. Cefamandole concentrations were determined in serum, urine, and dialysis fluid by a high-performance liquid chromatographic method. The following average parameter values were obtained (range): half-life, 6.1 h (4.6 to 9.7); systemic clearance, 21.9 ml/min (8.4 to 35.5); renal clearance, 11.5 ml/min (0.03 to 22.3); dialysis clearance, 0.92 ml/min (0.7 to 1.3); nonrenal clearance, 12.2 ml/min (2.9 to 27.0); volume of distribution, 0.18 liter/kg (0.09 to 0.25); steady-state volume of distribution, 0.17 liter/kg (0.09 to 0.24). Approximately 5% of the dose was dialyzed (range, 2.8 to 8.3), indicating that there is no need to supplement a dosing regimen of cefamandole due to loss by dialysis. There was a positive correlation between creatinine clearance and the terminal elimination rate constant of cefamandole (r2 = 0.41) and cefamandole renal clearance (r2 = 0.83).