Evolution of the CANDA at Roche.

Computer-assisted NDAs (CANDAs) have evolved from an instrument that provides information to regulators to also providing information to internal researchers. They are still not as useful internally during the NDA process as they will be in the future. The portion of CANDA that allows summary, display, and query of the raw data is the most complicated part of the CANDA. Roche's current CANDA system, as well as the challenges in using, documenting, and validating such a system, is described, stressing the features that make it usable in-house. Roche's vision of the future is outlined, covering the strategies, targets, and expected savings.

Evaluation of methods of administering tyramine to raise systolic blood pressure.

To compare the relative merits of two different administration regimens, tyramine was administered intravenously in ascending doses to 12 healthy subjects to raise systolic blood pressure slightly more than 30 mm Hg. Six subjects received tyramine by bolus injection and six other subjects received tyramine by infusion. The bolus dose of tyramine needed was 4.34 +/- 1.51 mg (X +/- SD) and the infusion rate needed was 1.11 +/- 0.33 mg/min. Four blood pressure response patterns to continuous tyramine infusion were observed. Because different units were measured for the quantity of tyramine administered, the between-subject variance estimate to within-subject variance estimate ratios were calculated. The two techniques had equivalent consistency. With the bolus method, in contrast to the infusion procedure, the dose-response relationship was obvious in most subjects. Therefore the bolus method was judged to be more useful than the infusion method.

Effect of oral cibenzoline on steady-state digoxin concentrations in healthy volunteers.

The effect of oral cibenzoline on steady-state digoxin concentrations was studied in 12 healthy subjects ranging from 41 to 55 years of age. Each subject received an oral dose of 0.25 mg or 0.375 mg digoxin once daily for 27 days. On days 14 to 21, 160 mg of oral cibenzoline were administered concomitantly every 12 hours for a total of 15 doses. Plasma digoxin concentration-time profiles obtained before, during, and after cibenzoline coadministration were compared to determine the effect of oral cibenzoline on steady-state digoxin concentrations. The maximum plasma concentration, time of maximum concentration, area under the curve during a dosing interval and steady-state trough plasma concentration for digoxin, during and after concomitant doses of cibenzoline were similar to those before administration, indicating that cibenzoline did not affect the pharmacokinetics of digoxin. In addition, plasma cibenzoline concentration-time profiles after the first and last dose of cibenzoline were similar to those observed in previous studies in which multiple doses of cibenzoline alone were administered. The results of this study indicate that there is no pharmacokinetic interaction between digoxin and cibenzoline when the two drugs are coadministered to healthy subjects in multiple doses.

Trimoprostil plasma concentration-gastric acid inhibition relationships in duodenal ulcer patients.

The effect of single 0.25 mg, 0.75 mg, 1.5 mg, and 3.0-mg oral doses of trimoprostil and placebo on the inhibition of meal-stimulated gastric acid secretion was investigated in duodenal ulcer patients. Drug and placebo were administered in a double-blind, randomized, crossover study under fasting conditions. A bactopeptone meal was administered 30 minutes after dosing. Gastric acid output was measured by intragastric titation (pH 5.5) and trimoprostil plasma concentrations were measured by a specific gas chromatography-negative chemical ionization-mass spectrometric method. Meal-stimulated gastric acid secretion was significantly reduced when compared to placebo for one hour after 0.25 mg, 1.5 hours after 0.75 mg, and for 2.5-3.0 hours after both 1.5 mg and 3.0 mg doses. The maximal inhibition of gastric acid ranged from 65% reduction after 0.75 mg to 74% after 1.5 mg to 82% after 3.0-mg doses. Trimoprostil was rapidly absorbed and eliminated; terminal elimination half-life ranged from 21 to 45 minutes. Both maximum concentration and area under the plasma concentration-time curve increased proportionately with an increase in the dose. The concentration-effect data at a given dose were simultaneously fit to a pharmacokinetic/pharmacologic effect model. An IC50 (plasma concentration needed to elicit a 50% inhibition effect) value of 0.2 ng/mL was observed at doses of 0.75 mg to 3.0 mg. Overall, trimoprostil was effective in inhibiting acid output in a dose-related manner in duodenal ulcer patients.

Trimoprostil plasma concentration--gastric acid inhibition relationships: potentiation by food.

A single, oral, 1.5-mg dose of trimoprostil was taken before a standard meal and a matching placebo was taken after a standard meal by 10 subjects (group A). A second group of 10 subjects took placebo before a meal and trimoprostil after the meal (group B), while a third group took placebo both before and after the standard meal (group C). Food-stimulated gastric acid production was measured by intragastric titration for 6.5 hr after dosing. Trimoprostil taken after the meal had a greater effect on gastric acid secretion than when taken before the meal: Duration of effect was 5 to 5.5 hr in group B and 2 to 2.5 hr in group A. Blood samples were drawn and assayed for trimoprostil by gas chromatography-mass spectrometry. Mean trimoprostil plasma concentration and mean inhibition of gastric acid secretion data were fit to two models by the Hill equation. The mean plasma concentration associated with 50% inhibition of gastric acid secretion was 1.25 ng/ml. Trimoprostil plasma concentrations between 3 and 4 ng/ml were associated with 70% to 80% gastric acid inhibition. Overall, there appears to be a pharmacokinetic-pharmacologic correlation between trimoprostil plasma concentrations and inhibition of gastric acid secretion. Trimoprostil (1.5 mg) in the presence of food appears to have a therapeutic advantage, in that it decreases acid secretion longer than when taken without food and suffers no loss of bioavailability.

Toxic effects of lasalocid in horses.

Lasalocid was given to horses in a series of sequentially increasing single oral doses ranging between 5 and 30 mg/kg of body weight, with an appropriate washout period between treatments. One of the 5 horses died after a dosage of 15 mg/kg, 1 of 3 horses died after 21 mg/kg, 1 of 3 horses died after 22 mg/kg, and 1 of 2 horses died after 26 mg/kg. The LD50 of lasalocid for horses was estimated to be 21.5 mg/kg. Monensin was given to horses in a similar manner at dosages of 1, 2, and 3 mg/kg of body weight. One of the 2 horses died after a dosage of 2 mg/kg and 1 horse died after a dosage of 3 mg/kg. The clinical signs of toxicosis observed in horses given either drug were progressive and included depression, ataxia, paresis, and paralysis with partial anorexia. Intermittent profuse sweating was observed before death in horses given monensin.

Effects of lasalocid (.0125%) in combination with roxarsone on lesion reduction and oocyst suppression in chickens infected with Eimeria tenella field isolates.

Lasalocid (.0125%) alone and combined with roxarsone (.005%) was evaluated for its effect on lesion reduction and oocyst suppression in thirty-five controlled replicated battery experiments, using in excess of 6200 broiler chickens. The chickens were inoculated with field isolates containing predominantly Eimeria tenella species. Lasalocid (.0125%) used alone exhibited a high degree of anticoccidial activity. Lasalocid (.0125%) fed in combination with roxarsone (.005%) showed, in addition to high anticoccidial activity, a further reduction in gross lesion (P less than .01) and oocyst production (P less than .05) over lassalocid used alone.

Compatibility and anticoccidial activity of lasalocid in combination with roxarsone and antibiotics against Eimeria mixed infection in chicks.

Lasalocid at the concentration of .0075% (68 g/ton) with and without roxarsone 45.4 g/ton was fed in combination with the growth promotants bacitracin methylene disalicylate 200 g/ton, bambermycins 2 g/ton, lincomycin 4 g/ton, nosiheptide 2.5 g/ton, zinc bacitracin 200 g/ton g/ton, and virginiamycin 20 g/ton exhibited a high degree of anticoccidial activity against mixed Eimeria infection in chickens in 9 day challenged battery trials. In these short term challenge trials chicks fed lasalocid, and the lasalocid growth promotant combinations, performed significantly better (P < .05) for growth and anticoccidial efficacy than those fed the growth promotants alone, and the infected, unmedicated controls. In almost all instances, the lasalocid-roxarsone-antibiotic combinations allowed for numerical increases in gains, improvement in feed conversion, and numerical decreases in lesions (in some cases, statistically significant (P < .05) over chicks fed lasalocid alone and/or the lasalocid antibiotic combination. The growth promotants did not interfere with the anticoccidial activity of lasalocid. The growth promotants fed alone exhibited no anticoccidial activity. However, when roxarsone was combined with the antibiotics, the combination resulted in numerically improved performance, reduced mortality, and in most instances, statistically significant decreases in lesions (P .05) over the infected, unmedicated control.