Quantitative structure-pharmacokinetic relationships (QSPR) of beta blockers derived using neural networks.

This study demonstrates the application of neural networks to predict the pharmacokinetic properties of beta-adrenoreceptor antagonists in humans. A congeneric series of 10 beta-blockers, whose critical pharmacokinetic parameters are well established, was selected for the study. An appropriate neural network system was constructed and tested for its ability to predict the pharmacokinetic parameters from the octanol/water partition coefficient (shake flask method), the pKa, or the fraction bound to plasma proteins. Neural networks successfully trained and the predicted pharmacokinetic values agreed well with the experimental values (average difference = 8%). The neural network-predicted values showed better agreement with the experimental values than those predicted by multiple regression techniques (average difference = 47%). Because the neural networks had a large number of connections, two tests were conducted to determine if the networks were memorizing rather than generalizing. The "leave-one-out" method verified the generalization of the networks by demonstrating that any of the compounds could be deleted from the training set and its value correctly predicted by the new network (average error = 19%). The second test involved the prediction of pharmacokinetic properties of compounds never seen by the network, and reasonable results were obtained for three out of four compounds tested. The results indicate neural networks can be a powerful tool in exploration of quantitative structure-pharmacokinetic relationships.

Nonparametric pharmacokinetic calculations: one-compartment open model.

A nonparametric method suitable for estimation of parameters in nonlinear problems was developed for one-compartment pharmacokinetic data. The method was tested by running 500 simulations with various types of error and comparing the results with a standard nonlinear regression computation. The nonparametric method was superior to nonlinear regression techniques if the assumptions for the error structure of the regression were not true.

Sensitive high-pressure liquid chromatographic determination of disopyramide and mono-N-dealkyldisopyramide.

A high-pressure liquid chromatographic procedure for the accurate determination of disopyramide and its chief metabolite in plasma is presented. The method is suitable for monitoring patients receiving disopyramide therapy. A reversed-phase cyanopropylsilane column is utilized with a mobile phase of 50% acetonitrile and 50% 0.01 M sodium acetate buffer at pH 4.0. Absorption was monitored at 254 nm with a detection limit of 0.2 microgram/ml of plasma. The reproducibility and precision of the procedure were demonstrated on samples containing 0.50-12 microgram/ml of plasma.

Effect of an antacid on gastrointestinal absorption of theophylline.

The effect of a magnesium-aluminum hydroxide antacid (Maalox) on the oral absorption of aminophylline tablets was studied. Twelve healthy adults were administered 200 mg of aminophylline alone or with 30 ml of antacid in a complete crossover study. Blood samples were drawn at 0.33, 0.67, 1, 2, 4, 8, 12, and 24 hours following theophylline (as aminophylline) administration. Theophylline plasma levels were measured by high-performance liquid chromatography. The plasma theophylline concentrations of the group receiving theophylline only were significantly greater than those of the group receiving theophylline plus antacid at the 0.67- and 1-hour sample times only (p less than 0.05). The extent of theophylline absorption and the eliminated rate constant were not significantly affected by the antacid. Antacid significantly decreased theophylline's absorption rate constant (p less than 0.05), indicating a slower absorption of theophylline with antacid. Concurrent administration of the antacid Maalox should not significantly change theophylline's clinical effect.

Sensitive high-pressure liquid chromatographic determination of propranolol in plasma.

A high-pressure liquid chromatographic method is presented for the determination of propranolol in human plasma. A reversed-phase cyanopropylsilane column was utilized with a liquid phase consisting of 70% acetonitrile and 30% 0.02 M acetate buffer, pH 7.0. A spectrofluorometric detector with an excitation wavelength of 276 nm and an emission filter with a 340-nm cutoff provided a detectable peak for 0.8 ng of propranolol/injection with this system. The reproducibility and precision of the method are shown from the analyses of samples containing 10--150 ng/ml of plasma.

Quantitative determination of theophylline in pharmaceutical dosage forms by differential spectrophotometry.

Theophylline was determined with good precision in tablets and capsules by differential spectrophotometry. Xanthines such as caffeine and theobromine did not interfere providing the total xanthine concentration was kept below 100 mug/ml. At a higher total xanthine concentration, nonlinearity occurred, presumably due to complex formation. This interference could be minimized by proper selection of the analytical wavelength.

High-speed liquid chromatographic determination of procaine in pharmaceuticals.

The operating conditions for a quantitative method of determining procaine in pharmaceutical preparations by high-speed liquid chromatography are described. The presence of decomposition products and the possible interference of other ingredients usually present in pharmaceutical preparations were found to have no effect. The method, because of its simplicity, is highly suited for routine analysis of pharmaceutical preparations containing procaine.

GLC analysis of lidocaine in blood using an alkaline flame-ionization detector.

A method was developed for the quantitative GLC determination of lidocaine and its major metabolite monoethylglycinexylidide. By using the specificity of the alkaline flame-ionization detector, this simple analytical procedure is extremely sensitive, rapid, and easily performed.

Synthesis of potential adrenergic blocking agents: 2-substituted aminomethylnaphthol(2,3-b)-1,4-dioxans.

Eleven 2-substituted aminomethylnaphtho(2,3-b)-1,4-dioxans were synthesized. The nucleophilic displacement of 2-tosyloxymethylnaphtho(2,3-b)-1,4-dioxan by appropriate amines was carried out using dimethyl sulfoxide as the solvent. Preliminary pharmacological evaluation revealed a potentiation of norepinephrine at low doses and a noncompetitive antagonism at high doses in the rat vas deferens and a dose-related hypotensive action of short duration in the anesthetized rat.