SEQUENTIAL SCREENING: ITS ADAPTATION TO THE SEARCH FOR SUBSTANCES AFFECTING ACTIVITY OF KNOWN PHARMACOLOGICAL AGENTS

¹ Experimental Therapeutics Research, Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

A description of the development and use of a sequential screening procedure for the detection of substances affecting activity of known pharmacological agents has been presented. For illustrative purpose, the procedure has been adapted to the screening of substances which will increase the blood concentrations of tetracycline following their concomitant oral administration with the antibiotic. The resultant criteria for acceptance or rejection of the tested substances are based upon the 4-hour serum concentration of a standard (tritiated tetracycline plus citric acid) and those of tritiated tetracycine plus the test substances. The antibiotic (50 mg/kg) and citric acid, or test substances, at 140 mg/kg, are administered orally to overnight fasted Wistar rats. At these doses, the average (± standard error) tetracycline serum concentrations for the control (tetracycline alone) and standard groups are 5.09 (±0.41), and 8.56 (±0.42) µg/ml. Eighty-two per cent of the test substances are disposed of after the first stage (two animals per stage). For the remaining, a second or third stage is necessary. Control charts are maintained to, a) ascertain that, in each experiment, the responses of the control and standard groups are within tolerable limits, and, b) detect any general trend, over several consecutive experiments, of the control and standard groups.