Tolerance to alprazolam after intravenous bolus and continuous infusion: psychomotor and EEG effects.

A study was undertaken to compare the time course of changes in psychomotor performance and spectral edge (SE) of the EEG and to relate these changes to alprazolam concentrations in a pharmacokinetic/pharmacodynamic tolerance model. Digit symbol substitution (DSS) tests were administered and EEG data were obtained for SE calculation in a four-way crossover study in four normal men. Each treatment consisted of a 2-minute bolus injection followed by an 8-hour infusion. Treatment A, placebo, consisted of a 50% propylene glycol injection followed by a saline infusion. Active drug treatments were: B, 0.5 mg alprazolam plus saline infusion; C, 2.0 mg alprazolam plus saline; and D, 1.0 mg plus 72 micrograms alprazolam/hr for a total dose of 1.576 mg in 8 hours. For both DSS and SE data, three distinct effect-concentration curves result from the three alprazolam treatments, with successive shifts to the right as dose increases. A tolerance rate constant (kt) of 0.15 hr-1 was calculated from the DSS vs. time data during the 8 hour alprazolam infusion. The Hill equation was altered by using kt in an exponential modification of EC50. The resulting tolerance model describes both DSS and SE vs. concentration data from the rapid-injection and continuous-infusion treatments.

Digital plethysmography for assessing erythrityl tetranitrate bioavailability.

The bioavailability or oral, sublingual, and chewable tablets or erythrityl tetranitrate (ETN) was evaluated in 15 normal men. In a randomized, complete crossover investigation with nitroglycerin and placebo controls, drug-induced changes in the diastolic amplitude response intensity were measured with a digital plethysmogram. Values for area under the response intensity curve (AUC), maximum response intensity (Imax), and time lapse from dosing to peak response (tmax) were obtained by computer processing and converted to intensity values and AUC segments for specific time intervals. Sublingual nitroglycerin induced a response (p less than 0.05) from placebo within the first hour. Although somewhat slower in reaching peak intensity, all forms of ETN induced significant responses over placebo (p less than 0.05) for 2 hr, with oral (swallowed) ETN different 6 hr. Our results indicate that all the ETN dosage forms were bioavailable, with the longest duration of effect by the oral form.

The pharmacokinetic-pharmacodynamic (Digit Symbol Substitution Test) relationship of flumazenil in a midazolam steady-state model in healthy volunteers.

To characterize the plasma concentration-effect relationship of flumazenil in the presence of a predefined midazolam level, a double-blind, placebo-controlled, randomized two-way crossover study was conducted in nine healthy male subjects. After reaching a criterion level of midazolam-induced depression of the Digit Symbol Substitution Test (DSST), volunteers received a dose of flumazenil (1.0 mg) or placebo over 1 minute, with the infusion of midazolam continued. Blood samples were collected, simultaneously with the DSST assessment, at predetermined intervals and were assayed for flumazenil and/or midazolam plasma concentrations. Pharmacokinetic-pharmacodynamic modeling techniques were used to estimate the equilibration rate constant (keo) between plasma concentration and effect for flumazenil; a sigmoidal maximum-effect model was used to relate the DSST score to the flumazenil plasma concentration. Flumazenil exhibited a rapid onset (the half-life of equilibration between drug concentration in the blood and drug effect was 3.3 minutes) and short duration of action (the flumazenil plasma concentration causing half-maximal effect was 7.4 ng/ml, which was reached about 1 hour after dosing). The results of this study also show the competitive nature of flumazenil as a midazolam antagonist.

Serum prolactin level increase in normal subjects following administration of perphenazine oral dosage forms: possible application to bioavailability testing.

Two pilot studies were performed to determine if oral phenothiazine products could generate a significant increase in serum levels of the hormone prolactin. The two studies employed three and four healthy normal male subjects, respectively. In the first study the subjects received a screening dose, a placebo, one 8-mg perphenazine tablet, and two 8-mg perphenazine tablets. In the second study, the subjects were dosed with two 10-mg amitriptyline tablets, one 10-mg amitriptyline tablet with one combination tablet containing 10 mg of amitriptyline and 4 mg of perphenazine, and two combination tablets, each containing 10 mg of amitriptyline and 4 mg of perphenazine. In both cases the drug treatments produced a significant rise in the serum prolactin levels versus a placebo or control. This increase was defined as a prolactin response. The possible utility of this response in bioavailability testing is discussed.

Predictive conversion of in vitro drug dissolution data into in vivo drug response versus time profiles exemplified for plasma levels of warfarin.

A mathematical approach to computing the in vivo drug response profiles (such as plasma level, pharmacological response, and urinary recovery versus time curves) corresponding to observed in vitro dissolution of drug dosage form versus time profiles is described. The method is exemplified for warfarin tablets,for which observed in vivo plasma level profiles are compared to corresponding predicted profiles computed from in vitro dissolution data. The potential of the method is demonstrated; approaches to its improvement, as well as its limitations, are discussed.

Introduction to backpropagation neural network computation.

Neurocomputing is computer modeling based, in part, upon simulation of the structure and function of the brain. Neural networks excel in pattern recognition, that is, the ability to recognize a set of previously learned data. Although their use is rapidly growing in engineering, they are new to the pharmaceutical community. This article introduces neurocomputing using the backpropagation network (BPN).

Pharmacodynamics and biophasic drug levels of methionine enkephalin.

Methionine enkephalin (Met-E) is a naturally occurring pentapeptide. It appears to mediate pain perception by blocking CNS pathways. Using rabbits, a log dose relationship was obtained between Met-E-induced dilation of the pupil (mydriasis) and constant intravenous infusion dose rates (14, 20, 28, 37, 56, 73, and 129 micrograms/min/kg). Steady-state dilation is reached within 9 min. Dose-effect curves (DEC) were fitted by a linear regression analysis of the log dose versus percentage dilation plots. Fitted DEC were used to determine temporal profiles for the relative biophasic drug level.