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Tolerance to alprazolam after intravenous bolus and continuous infusion: Psychomotor and EEG effects
Author(s) -
Kroboth Patricia D,
Smith Randall B,
Erb Randall J
Publication year - 1988
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1988.32
Subject(s) - alprazolam , crossover study , pharmacokinetics , anesthesia , pharmacodynamics , saline , bolus (digestion) , placebo , medicine , pharmacology , anxiety , alternative medicine , pathology , psychiatry
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 μg 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 (k t ) 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 k t in an exponential modification of EC 50 . The resulting tolerance model describes both DSS and SE vs . concentration data from the rapid‐injection and continuous‐infusion treatments. Clinical Pharmacology and Therapeutics (1988) 43, 270–277; doi: 10.1038/clpt.1988.32