Lorazepam In Healthy Volunteers Research Articles

Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study.

Pharmacodynamic effects and safety of single‐dose inhaled loxapine administered via the Staccato® system and intramuscular (IM) lorazepam in combination versus each agent alone were compared in a randomized, double‐blind, crossover study in healthy volunteers. Subjects received: inhaled loxapine 10 mg + IM lorazepam 1 mg; inhaled loxapine 10 mg + IM placebo; IM lorazepam 1 mg + Staccato placebo in random order, each separated by a 3‐day washout. Primary endpoints were maximum effect (minimum value) and area under the curve (AUC) from baseline to 2 h post treatment for respirations/min and pulse oximetry. Least‐squares means (90% confidence interval [CI]) for concomitant treatment versus each agent alone were derived and equivalence (no difference) confirmed if the 90% CI was within 0.8–1.25. Blood pressure (BP), heart rate (HR), sedation (100‐mm visual analog scale), and adverse events (AEs) were recorded. All 18 subjects (mean age, 20.4 years; 61% male) completed the study. There was no difference between inhaled loxapine + IM lorazepam and either agent alone on respiration or pulse oximetery during the 12‐h postdose period, confirmed by 90% CIs for AUC and C min ratios. BP and HR were no different for inhaled loxapine + IM lorazepam and each agent alone over a 12‐h postdose period. Although the central nervous system sedative effects were observed for each treatment in healthy volunteers, the effect was greater following concomitant lorazepam 1 mg IM + inhaled loxapine 10 mg administration. There were no deaths, serious AEs, premature discontinuations due to AEs, or treatment‐related AEs.

The effect of experimentally induced sleep disturbance on the pharmacokinetics of lorazepam in healthy volunteers.

The aim of this study was to evaluate the effect of sleep disturbance on the pharmacokinetics, especially on the absorption, of lorazepam in humans. Eight healthy male volunteers received a single oral dose of lorazepam 1 mg before sleep on two occasions in a cross-over design. In either of the two doses, subjects were intermittently exposed to noise for 1.5 hours after oral lorazepam administration. Plasma lorazepam concentrations were measured by HPLC. The exposure to noise significantly prolonged tmax (control vs. noise: 2.0 vs. 3.0 hours) and significantly decreased AUC of lorazepam in the absorption phase. The reduction was 54% (95% CI, 15 - 75%) and 24% (3 - 40%) for AUC (0 - 1 hours) and AUC (0 - 3 hours), respectively. No significant changes were observed in other pharmacokinetic parameters. The results of this study suggest that the onset of drug action after oral lorazepam administration can be altered by sleep disturbance.

The effects of lorazepam on extrastriatal dopamine D 2/3-receptors—A double-blind randomized placebo-controlled PET study

Lorazepam is a widely used anxiolytic drug of the benzodiazepine class. The clinical actions of benzodiazepines are thought to be mediated via specific allosteric benzodiazepine binding sites and enhancement of GABAergic neurotransmission in the brain. However, the indirect effects of benzodiazepines on other neurotransmitter systems have not been extensively studied. Previous experimental evidence suggests that benzodiazepines inhibit striatal dopamine release by enhancing the GABAergic inhibitory effect on dopamine neurons whereas very little is known about cortical or thalamic γ-amino-butyric (GABA)–dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D 2/3 receptor binding using Positron-Emission Tomography (PET) and the high-affinity D 2/3-receptor ligand [ 11C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D 2/D 3 receptor binding potential was measured with the reference tissue method in several extrastriatal D 2-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D 2/D 3 receptor BP ND in medial temporal and dorsolateral prefrontal cortex (DLPFC) that was also confirmed by a voxel-level analysis. The sedative effect of lorazepam was associated with a decrease in D 2/D 3 receptor BP ND in the DLPFC. In conclusion, lorazepam decreased [ 11C]FLB 457 binding in frontal and temporal cortex, suggesting that cortical GABA–dopamine interaction may be involved in the central actions of lorazepam in healthy volunteers. The correlation between lorazepam-induced sedation and D 2/D 3 receptor binding potential (BP) change further supports this hypothesis.

The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A 2,3 selective agonist, in comparison with lorazepam in healthy volunteers

Benzodiazepines are effective short-term treatments for anxiety disorders, but their use is limited by undesirable side effects related to Central Nervous System impairment and tolerance development. SL65.1498 is a new compound that acts in vitro as a full agonist at the gamma-aminobutyric acid(A) 2 and 3 receptor and as a partial agonist at the 1 and 5 receptor subtypes. It is thought that the compound could be anxiolytic by its activation at the alpha2 and alpha3 receptor subtypes, without causing unfavourable side effects, which are believed to be mediated by the alpha1 and alpha5 subtypes. This study was a double-blind, five-way cross-over study to investigate the effects of three doses of SL65.1498 in comparison with placebo and lorazepam 2 mg in healthy volunteers. The objective was to select a dose level (expected to be therapeutically active), free of any significant deleterious effect. Psychomotor and cognitive effects were measured using a validated battery of measurements, including eye movements, body sway, memory tests, reaction-time assessments, and visual analogue scales. The highest dose of SL65.1498 showed slight effects on saccadic peak velocity and smooth pursuit performance, although to a much lesser extent than lorazepam. In contrast to lorazepam, none of the SL65.1498 doses affected body sway, visual analogue scale alertness, attention, or memory tests. This study showed that the three doses of SL65.1498 were well tolerated and induced no impairments on memory, sedation, psychomotor, and cognitive functions.

A validation of the 7.5% CO2 model of GAD using paroxetine and lorazepam in healthy volunteers

The inhalation of 7.5% carbon dioxide (CO2) in healthy subjects produces an increase in blood pressure and heart rate, and increased feelings of anxiety, fear and tension (Bailey et al. 2005). As this state is similar to that of general anxiety rather than panic, we further validated this by examining the effects of anxiolytic medication. Two separate studies in healthy volunteers are described; study one is a double-blind, placebo-controlled study of a single dose of 2 mg lorazepam and study two describes the effects of 21 days of treatment with paroxetine. Gas challenges were air and 7.5% CO2 inhaled for 20 minutes, delivered on day 0 (before treatment) and day 21 (after treatment) in the paroxetine study. Subjective effects were measured using visual analogue scales and questionnaires. When compared with placebo, lorazepam 2 mg significantly reduced peak CO2-induced subjective fear, feelings of wanting to leave, tension and worry. In the paroxetine study, when compared with day 0, day 21 showed a significantly attenuated peak CO2-induced nervousness and a trend for reduced ratings of anxiety, fear, feel like leaving, tense and worried. In these studies we have shown that this CO2 model of anxiety is sensitive to lorazepam and to a lesser extent paroxetine. This gives support to its utility as an experimental model of general anxiety disorder in healthy volunteers.

Effect of the genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers

Our objective was to investigate the effect of the uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B15 genetic polymorphism on the pharmacokinetics and pharmacodynamics of lorazepam in basal, inhibited, and induced metabolic states in healthy normal volunteers. Twenty-four healthy subjects were enrolled and grouped into UGT2B15*1/*1 or UGT2B15*2/*2 genotype groups. The pharmacokinetic and pharmacodynamic profiles of intravenous lorazepam were characterized before and after inhibition with 600 mg valproate once daily for 4 days and after induction with rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 10 days between. The plasma concentrations of lorazepam and lorazepam glucuronide were analyzed before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours after lorazepam administration by liquid chromatography-tandem mass spectrometry. Visual analog scale assessments and psychomotor coordination tests were administered before and up to 12 hours after drug administration. The UGT2B15*2/*2 group showed 0.58-fold (95% confidence interval, 0.43-0.72; P < .0001) lower systemic clearance during the basal state and 1.37-fold (95% confidence interval, 1.05-1.88; P = .037) higher area under the visual analog scale-time curve during the induced state compared with the UGT2B15*1/*1 group. The mean systemic clearance of lorazepam decreased by 20% in the inhibited state and increased by 140% in the induced state. During the inhibited or induced state, absolute values of clearance were consistently lower in the *2/*2 group, but the percent changes from baseline did not differ significantly by genotype. Our results suggest that the UGT2B15*2 polymorphism is a major determinant of interindividual variability with respect to the pharmacokinetics and pharmacodynamics of lorazepam.

P-2-78 Effect of reboxetine on the pharmacokinetics of lorazepam in healthy volunteers

P-2-78 Effect of reboxetine on the pharmacokinetics of lorazepam in healthy volunteers

A comparison of the psychometric effects of remoxipride with those of haloperidol, thioridazine, and lorazepam in healthy volunteers

AbstractIn this placebo and verum (lorazepam 2 mg) controlled double‐blind crossover study the acute effects of Remoxipride 50 mg and 100 mg; Haloperidol 2·5 mg; and Thioridazine 50 mg were examined in 18 healthy volunteers. CNS function was assessed using a battery of psychometric measures, viz: Critical Flicker Fusion Threshold (CFFT); Choice Reaction Time (CRT); Tracking Accuracy (RMS) and Peripheral Reaction Time (PRT); Sternberg Memory Scanning (SMS); Word Memory (WM) as well as Line Analogue Ratings of subjective sedation (LARS) and the Leeds Sleep Evaluation Questionnaire (LSEQ). Both doses of remoxipride were associated with a reduction of CFFT: 0·9 Hz for 50 mg and 1·3 Hz for 100 mg. The 100 mg dose caused an increase (impairment) in CRT total time of 38 msec. Haloperidol reduced CFFT, while thioridazine and lorazepam impaired performance on the majority of objective measures, as expected for known sedative drugs. Thioridazine led to hypotension in three subjects, and to subjective sedation (LARS), but no treatment affected responses on the LSEQ administered the morning of the day following treatment. These results show that remoxipride has some depressant effects on CNS function, but that these are less prominent than those of sedative neuroleptics such as thioridazine.