Single Oral Doses Of Lorazepam Research Articles

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.

Recreational Use of Mephedrone (4-Methylmethcathinone, 4-MMC) with Associated Sympathomimetic Toxicity

Cathinone is a pharmacologically active alkaloid that can be extracted from the leaves of the khat plant (Catha edulis). There are synthetic derivatives of cathinone entering the recreational drug market, including mephedrone (4-methylmethcathinone, 4-MMC). There are discrepancies in the legal status of both the khat plant and its extracted alkaloids between the UK and the USA. A 22-year-old man purchased 4 g of mephedrone powder over the Internet from a chemical supplier based in China. He initially ingested 200 mg of the mephedrone orally, with no perceived clinical effects, and thereafter injected the remaining 3.8 g intramuscularly into his thighs. Shortly after the injection, he developed palpitations, "blurred tunnel vision," chest pressure, and sweating and felt generally unwell; he presented to hospital with continuing features of sympathomimetic toxicity. His symptoms settled over the next 4 h after a single dose of oral lorazepam. Qualitative analysis of the urine and serum sample was undertaken using gas chromatography with mass spectrometric (GC/MS) detection, both positive for the presence of 4-methylmethcathinone. Quantitative analysis of the serum sample was undertaken by liquid chromatography with tandem mass spectrometric detection; the estimated mephedrone concentration was 0.15 mg/l. Routine toxicological analysis of the serum and urine specimens using a broad GC/MS toxicology screen did not detect any other drugs or alcohol. This is the first case of isolated 4-MMC toxicity, with confirmatory analytical findings. It is important that clinical toxicologists and emergency physicians work together to ensure a better understanding of the toxicity of novel/emerging drugs such as 4-MMC.

Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study

The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.

Benzodiazépines et hoquet : à propos de trois cas

Hiccup is a sudden contraction of the inspiratory muscles, followed by an abrupt closure of the glottis, thus producing a characteristic sound. In the literature, some drugs have been reported to induce hiccup. We discuss three case reports after administration of benzodiazepine to healthy young subjects during two clinical trials. In the first study (a bioequivalence trial of two forms of lormetazepam, tablets and oral solution), 12 subjects were included in an open controlled crossover study with two periods separated by a washout of 7 days. Two subjects presented with hiccup after administration of lormetazepam (2mg oral solution). The symptom resolved in 10 and 40 minutes, respectively. In one subject, rechallenge with a tablet of lormetazepam was positive. The aim of the second study was to assess the effect of sleep deprivation and lorazepam-induced sedation on saccadic eye movements in 12 healthy subjects. Hiccup occurred in one subject 3h 15 after administration of a single oral dose of lorazepam (2mg) and resolved in 45 minutes. All cases were evaluated according to the French imputation method. These observations are discussed with regard to the drug classes mentioned most frequently in the literature.

Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex

Objectives: The present study explored the effects of lorazepam, a benzodiazepine with agonist action at the GABAA receptor, on human motor cortex excitability as tested using transcranial magnetic stimulation.Methods: We recorded directly the descending volley evoked by single and paired transcranial magnetic stimulation from the spinal cord of a conscious subject with a cervical epidural electrode before and after a single oral dose of lorazepam. We evaluated the effects of lorazepam on the descending volleys evoked by a single magnetic stimulation and paired cortical stimulation using the intracortical inhibition paradigm (subthreshold conditioning stimulus) and the short latency intracortical facilitation paradigm (suprathreshold conditioning stimulus).Results: Using a single magnetic stimulus lorazepam decreased the amplitude of the later I waves in the descending volley; this was accompanied by a decrease in the amplitude of the evoked EMG response. Using the intracortical inhibition paradigm lorazepam increased the amount of corticocortical inhibition, particularly at 4 and 5 ms interstimulus intervals. There was no effect on the amount of facilitation observed in the short latency intracortical facilitation paradigm.Conclusions: The present findings provide direct evidence that lorazepam increases the excitability of inhibitory circuits in the human motor cortex.

Lack of interaction between amisulpride and lorazepam on psychomotor performance and memory in healthy volunteers

The potential pharmacodynamic interaction between amisulpride (a benzamide-type antipsychotic) and lorazepam was evaluated in a randomized, double-blind, cross-over, placebo-controlled study involving 18 healthy caucasian male volunteers, aged 18–35 years. They received single doses of amisulpride 50 mg and 200 mg. The interaction of the drug with a single oral dose of lorazepam 2 mg was assessed on six 1-day treatment periods separated by wash-out periods of 1 week. Pharmacodynamic criteria were: critical flicker fusion frequency, multiple choice reaction time, tapping, body sway, arithmetic calculation, Buschke's test for short and long term memory and self-ratings by ARCI scale. Prolactin as assayed for each treatment period. Statistical analysis was performed using a 3-way ANOVA. For psychometric tests and body sway, analyses were evaluated on changes from baseline. For memory test, analyses were done on raw data. Amisulpride alone, at single oral dose of 50 mg and 200 mg, was devoid of any clinically relevant impairment psychometric tests, short term and long term memory and mood. A single oral dose of lorazepam 2 mg induced marked impairment in psychometric performances, which all, except CFF test, were severely affected. Disturbances were also recorded in memory tests, and in subjective sensation (ARCI). The peak effects were 2–4 h after administration, but the majority of results were also affected up to 8 h. Prolactin levels were increased after either dose of amisulpride, but not after placebo or lorazepam. The co-administration of amisulpride plus lorazepam induced a prolactin elevation equivalent to that of amisulpride alone. In conclusion, the co-administration of amisulpride, at both doses of 50 mg and 200 mg, did not potentiate nor antagonize the detrimental effect of lorazepam 2 mg on pharmacodynamic parameters. © 1998 John Wiley & Sons, Ltd.

Lack of interaction between amisulpride and lorazepam on psychomotor performance and memory in healthy volunteers

The potential pharmacodynamic interaction between amisulpride (a benzamide-type antipsychotic) and lorazepam was evaluated in a randomized, double-blind, cross-over, placebo-controlled study involving 18 healthy caucasian male volunteers, aged 18–35 years. They received single doses of amisulpride 50 mg and 200 mg. The interaction of the drug with a single oral dose of lorazepam 2 mg was assessed on six 1-day treatment periods separated by wash-out periods of 1 week. Pharmacodynamic criteria were: critical flicker fusion frequency, multiple choice reaction time, tapping, body sway, arithmetic calculation, Buschke's test for short and long term memory and self-ratings by ARCI scale. Prolactin as assayed for each treatment period. Statistical analysis was performed using a 3-way ANOVA. For psychometric tests and body sway, analyses were evaluated on changes from baseline. For memory test, analyses were done on raw data. Amisulpride alone, at single oral dose of 50 mg and 200 mg, was devoid of any clinically relevant impairment psychometric tests, short term and long term memory and mood. A single oral dose of lorazepam 2 mg induced marked impairment in psychometric performances, which all, except CFF test, were severely affected. Disturbances were also recorded in memory tests, and in subjective sensation (ARCI). The peak effects were 2–4 h after administration, but the majority of results were also affected up to 8 h. Prolactin levels were increased after either dose of amisulpride, but not after placebo or lorazepam. The co-administration of amisulpride plus lorazepam induced a prolactin elevation equivalent to that of amisulpride alone. In conclusion, the co-administration of amisulpride, at both doses of 50 mg and 200 mg, did not potentiate nor antagonize the detrimental effect of lorazepam 2 mg on pharmacodynamic parameters. © 1998 John Wiley & Sons, Ltd.

Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers

Potential interactions between the imidazopyridine anxiolytic alpidem and the full benzodiazepine agonist lorazepam were assessed in a randomized, double-blind, four-way cross-over, placebo-controlled study in 16 healthy young male volunteers. Each volunteer received alpidem, 50 mg, or a placebo twice daily for 8 days with a 1- week wash-out interval. The interaction between alpidem, at the steady state, and a single oral dose of lorazepam 2 mg or a placebo was assessed after concomitant administration on days 7 or 9 of each treatment period. Psycho motor performance and cognitive function were evaluated before and 2, 4, 6 and 8 h post-dose, using objective tests [critical flicker fusion threshold (CFF), choice reaction time (CRT), digit-symbol substitution (DSST), body sway and short-term memory (Sternberg memory scanning)] and self-ratings [line analogue rating scales: (LARS)]. Long-term memory (delayed free recall and recognition of pictures) was assessed before the dose and 2 and 4 h post-dose. Pharmacodynamic interactions were evaluated by applying repeated measures ANOVA to a 2 x 2 factorial interaction model. Alpidem, 50 mg twice daily at the steady state, was free of any clinically relevant detrimental effects on skilled performance, information processing or memory. In contrast, a single 2 mg dose of lorazepam induced marked impairment of psychomotor performance and cognitive function (significant reductions in CFF and DSST and increases in CRT and body sway), as well as subjective sedation from 2 to 8 h post-dose, depending on the test used. In addition, lorazepam induced anterograde amnesia, characterized by a decrease in delayed free recall and recognition, and a deficit in short-term memory. Finally, alpidem 50 mg did not potentiate the detrimental effects of lorazepam 2 mg. On the contrary, alpidem significantly antagonized the lorazepam-induced CRT increase and anterograde amnesia, and produced similar trends on most of the other cognitive parameters; thus, the results obtained with the combination of alpidem and lorazepam consistently indicated less impairment than those measured after lorazepam alone. These results are consistent with the suggested partial agonsist properties of alpidem at the benzodiazepine receptor and indicate that such properties can be assessed in humans based on antagonism of the effects of a full agonist.

Lack of interaction between a new antihistamine, mizolastine, and lorazepam on psychomotor performance and memory in healthy volunteers.

1. The possible interaction between a new H1 antihistamine, mizolastine, and lorazepam was assessed in a randomised, double-blind, cross-over, placebo-controlled study involving 16 healthy young male volunteers who received mizolastine 10 mg or placebo once daily for 8 days with a 1 week wash-out interval. The interaction of mizolastine, at steady-state, with a single oral dose of lorazepam or placebo was assessed on days 6 or 8 of each treatment period. 2. Psychomotor performance and cognitive function were evaluated using objective tests (critical flicker fusion threshold, choice reaction time, tapping, arithmetic calculation, body sway) and self-ratings (visual analogue scale, ARCI) before and at 2, 4, 6 and 8 h after dosing. Short-term memory (Sternberg memory scanning immediate free recall of a word list) and long-term memory (delayed free recall and recognition of words and pictures) were assessed before and at 3 h after dosing. Pharmacodynamic interactions were evaluated by repeated measures ANOVA in a 2 x 2 factorial interaction model. 3. Mizolastine, 10 mg once daily, at steady-state, was devoid of sedation and detrimental effect on skilled performance and memory. 4. In contrast, a single 2 mg dose of lorazepam produced marked impairment of psychomotor performance, cognitive functions (significant reduction in flicker fusion threshold, tapping and arithmetic calculation and increase in reaction times and body sway) and subjective sedation from 2 to 8 h after dosing. In addition, lorazepam induced an anterograde amnesia, characterised by a decrease in delayed free recall and recognition, and a deficit in short term memory.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines I: Lorazepam

This investigation compares the time course changes in the central nervous system (CNS) impairment effects on psychomotor and cognitive skills and relates these changes to the plasma lorazepam concentrations in a pharmacokinetic-pharmacodynamic (PK-PD) model. Six male subjects received a single oral dose of lorazepam or placebo. The CNS effects were measured by using computerized continuous tracking (TRKN), body sway with eyes open (SWAY OPEN), and digit symbol substitution (DSS) tests. Plasma lorazepam concentrations were best characterized by a two-compartment model with first-order absorption. Plotting the plasma lorazepam concentration and measured effect across time revealed a counterclockwise hysteresis loop. Fitting the time course of the effects in an integrated PK-PD model required an effect compartment with the equilibrium rate constant between it and the plasma compartment. The magnitude of the temporal lag was quantified by the half-time of equilibration between concentration in the hypothetical effect compartment and the plasma lorazepam level (t1/2keo). The CNS effect measured by TRKN was characterized by a mean estimate of maximum predicted effect (Emax) of 418 with a t1/2keo of 0.43 hr, an estimate of effect site drug level to produce 50% of Emax (EC50) of 35.8 ng/ml and a power parameter (gamma) of 6.29. Corresponding parameter mean estimates for SWAY OPEN and DSS as measures of drug CNS effect were quite similar.

Sedative Effects and Impaired Learning and Recall After Single Oral Doses of Lorazepam

Seven healthy subjects received oral placebo, 1.5 mg lorazepam, or 3.0 mg lorazepam in a single-dose, three-way crossover study. Plasma lorazepam concentrations and subjects' self-rated sedative effects were evaluated at multiple points during 24 hours after each dose. Information acquisition and recall was studied by use of a 16-item word list at 3 and 24 hours after dosing. Lorazepam plasma concentrations were proportional to dose. Self-rated sedation was maximal 2 to 3 hours after lorazepam dosing, persisted for 8 hours, and was dose dependent in intensity; no significant sedation occurred with placebo. At 3 hours after placebo dosing, subjects learned a mean 96% of words presented during six trials; this was reduced to 79% and 62% after lorazepam, 1.5 and 3.0 mg, respectively (F = 6.2; P < 0.02). Twenty-four hours after placebo, subjects recalled 92% of words presented the previous day, then improved to 99% after six relearning trials. After 1.5 and 3.0 mg lorazepam, however, only 52% and 44% of words were initially recalled from the previous day. Thus single oral doses of lorazepam within the therapeutic range produce dose-dependent sedation and impairment of information acquisition and recall. Clinical Pharmacology and Therapeutics (1986) 39, 526–530; doi:10.1038/clpt.1986.90