Ann Marie Ciraulo

Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials.

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4–24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration‐time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose‐adjusted Cmax for both tablet formulations and for the dose‐adjusted AUCs for the buprenorphine‐naloxone tablets. For both formulations, the maximal buprenorphine‐induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Functional magnetic resonance imaging of alprazolam-induced changes in humans with familial alcoholism

This study sought to identify whether subjects with a family history (FH + ) of alcoholism had changes in regional cerebral blood volume (rCBV) after an alprazolam challenge which distinguished them from subjects without a family history (FH -) of alcoholism using functional MRI (fMRI). Twelve FH + and eight FH - subjects were challenged with 1 mg of alprazolam or placebo in a double-blind crossover design. FMRI scans were obtained at baseline, 1 and 2 h after the challenge using the dynamic susceptibility contrast method with gadolinium. Mood scales, the Tufts Addiction Research Center Inventory-Morphine Benzedrine Group Scale and the drug liking scale, were administered every 30 min to assess drug effects. Global analysis of CBV showed a treatment by time decrease on alprazolam relative to placebo, but no effect by family history. The FH + group showed rCBV decreases at 1 h in the left caudate and left inferior prefrontal region, while the FH - group showed rCBV decreases at 2 h in the right inferior prefrontal region and anterior cingulate in response to alprazolam relative to placebo. FH + subjects reported more mood enhancement with alprazolam. This fMRI technique detected global and regional CBV changes induced by alprazolam. The location and rate of alprazolam-induced rCBV changes differed between FH + and FH - subjects. These changes may be related to the increased mood enhancement found in subjects genetically predisposed to alcoholism.

Alterations in Pharmacodynamics of Anxiolytics in Abstinent Alcoholic Men: Subjective Responses, Abuse Liability, and Electroencephalographic Effects of Alprazolam, Diazepam, and Buspirone

Subjective responses, including those associated with abuse liability and changes in frontal electroencephalographic activity, were assessed in abstinent alcoholic men and control subjects after administration of alprazolam, diazepam, buspirone, and placebo. Plasma concentrations of alprazolam, diazepam, and desmethyldiazepam also were determined. Abuse liability scales were elevated for alcoholic participants above control levels after alprazolam and diazepam. Areas under the concentration—time curve differed only for desmethyldiazepam, which was lower for the alcoholic participants. Compared with control subjects, alcoholic participants had greater declines in the absolute power of the alpha band after diazepam challenge. Alcoholic participants, unlike control subjects, had areas under the effect—time curve for alpha and theta bands that were lower after administration of alprazolam or diazepam than they were after receiving placebo. These results suggest that alprazolam and diazepam are more likely to be abused by alcoholic men than by nonalcoholic men and that alcoholic men have enhanced sensitivity to the effects of benzodiazepines on alpha and theta activity.

Decreased EEG Sensitivity to Alprazolam in Subjects with a Parental History of Alcoholism

Altered benzodiazepine sensitivity in subjects with a history of parental alcoholism (PHP) compared to control subjects (NC) has been reported for regional brain blood volume, eye movement tasks, and subjective effects. This study tests the hypothesis that PHP subjects are less sensitive to benzodiazepine effects on EEG activity than are NC subjects. Frontal EEG activity was recorded in PHP and NC subjects after administration of the benzodiazepine, alprazolam (1 mg), or placebo. PHP subjects had decreased sensitivity to the EEG effects of alprazolam compared to NC subjects. Significant differences were detected for change in percent relative beta activity and alpha and theta band power. Pharmacokinetic parameters did not differ significantly between groups. These results suggest that PHP subjects are less sensitive to the effects of alprazolam on central electrophysiological activity than are NC subjects.