Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment.

We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi-elimination pathway mediated by CYP3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug-drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta-analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration-time profile for mirabegron in an sRI population (simulated area under the plasma concentration-time curve (AUC) was within 1.5-times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12-times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.

Fatal intoxication with new synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA.

Introduction: Synthetic cannabinoids are currently the largest group of new psychoactive substances. Those that have been subjected to legal control are replaced by newer uncontrolled substances, which causes constant and dynamic changes to the drug market. Some of the most recent synthetic cannabinoids that have appeared on the "legal highs" market are AMB-FUBINACA and EMB-FUBINACA. Case history: A 27-year-old man was found dead on a bed in an apartment. At autopsy, congestion of internal organs, pulmonary oedema and left-sided pleural adhesions were found. The medical examiner concluded that the man died due to acute respiratory failure. The autopsy materials (blood, urine, liver, kidney, stomach, intestine, lung and brain) were collected for further toxicological analyses. Methods: The synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA were isolated from autopsy materials by precipitation with acetonitrile. The quantitative analyses were carried out by LC-MS/MS. Results: AMB-FUBINACA and EMB-FUBINACA were detected and quantified in all post-mortem materials except the blood. The determined concentrations of these compounds in solid tissues were in the range of 0.2-0.9 ng/g and 0.2-3.5 ng/g. The highest concentrations of AMB-FUBINACA and EMB-FUBINACA were revealed in the stomach content (5.8 and 36.2 ng/mL, respectively). Discussion: The presented case demonstrates that even in cases of fatalities, it is possible that the parent substance will not be present in the blood, while being present in other autopsy materials. The determined concentrations of the compounds may indicate oral administration of synthetic cannabinoids. It can also be assumed that AMB-FUBINACA and EMB-FUBINACA probably contributed to death. Conclusion: The presented case shows that synthetic cannabinoids can be undetected in the blood of even seriously or fatally intoxicated people. This situation means that the analysis of only blood samples may not confirm poisoning. The presented case also suggests that AMB-FUBINACA and EMB-FUBINACA use is dangerous to health and may lead to fatal intoxication.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Mirogabalin When Coadministered With Lorazepam, Zolpidem, Tramadol, or Ethanol: Results From Drug-Drug Interaction Studies in Healthy Subjects.

Four randomized, double-blind, placebo-controlled, 4-period drug-drug interaction studies were conducted in healthy subjects to evaluate the pharmacokinetic and pharmacodynamic (PD) interactions between mirogabalin and commonly used central nervous system depressants. Mirogabalin or placebo was administered alone or with single-dose lorazepam, zolpidem, tramadol, ethanol, or interacting drug placebo. Safety was assessed and serial samples for pharmacokinetic parameters were collected for up to 48 hours postdose. PD assessments included body sway (except tramadol), digit symbol substitution test, vertigo symptom scale short form, brief ataxia rating scale, and the Bond and Lader visual analog scale. Coadministration of mirogabalin with any of the 4 drugs did not cause any clinically relevant pharmacokinetic interactions. Peak mirogabalin concentration decreased by 28% (least squares mean ratio, 0.72; 90% confidence interval, [CI] 0.67, 0.76) following tramadol coadministration, and increased by 20% (least squares mean ratio, 1.20; 90%CI, 1.12, 1.28) following ethanol coadministration. Mirogabalin alone had little to no effect on PD parameters, but coadministration of mirogabalin with either lorazepam or ethanol increased the PD effects in body sway and digit symbol substitution test assays. Mirogabalin/lorazepam and mirogabalin/zolpidem increased occurrence of somnolence. Increased incidence of nausea and headache was noted with mirogabalin/tramadol and mirogabalin/ethanol, respectively.

Sedative Plasma Concentrations and Delirium Risk in Critical Illness.

BACKGROUND: The relationship between plasma concentration of sedatives and delirium is unknown. OBJECTIVE: We hypothesized that higher plasma concentrations of lorazepam are associated with increased delirium risk, whereas higher plasma concentrations of dexmedetomidine are associated with reduced delirium risk. METHODS: This prospective cohort study was embedded in a double-blind randomized clinical trial, where ventilated patients received infusions of lorazepam and dexmedetomidine. Plasma concentrations of these drugs and delirium assessments were measured at least daily. A multivariable logistic regression model accounting for repeated measures was used to analyze associations between same-day plasma concentrations of lorazepam and dexmedetomidine (exposures) and the likelihood of next-day delirium (outcome), adjusting for same-day mental status (delirium, coma, or normal) and same-day fentanyl doses. RESULTS: This critically ill cohort (n = 103) had a median age of 60 years (IQR: 48-66) with APACHE II score of 28 (interquartile range [IQR] = 24-32), where randomization resulted in assignment to lorazepam (n = 51) or dexmedetomidine (n = 52). After adjusting for same-day fentanyl dose and mental status, higher plasma concentrations of lorazepam were associated with increased probability of next-day delirium (comparing 500 vs 0 ng/mL; odds ratio [OR] = 13.2; 95% CI = 1.4-120.1; P = 0.02). Plasma concentrations of dexmedetomidine were not associated with next-day delirium (comparing 1 vs 0 ng/mL; OR = 1.1; 95% CI = 0.9-1.3; P = 0.45). CONCLUSIONS: In critically ill patients, higher lorazepam plasma concentrations were associated with delirium, whereas dexmedetomidine plasma concentrations were not. This implies that the reduced delirium risk seen in patients sedated with dexmedetomidine may be a result of avoidance of benzodiazepines, rather than a dose-dependent protective effect of dexmedetomidine.

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.

BACKGROUND: Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. METHODS: We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. RESULTS: A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7)0.133*WT0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT0.75. No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. CONCLUSIONS: The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.

Adverse performance effects of acute lorazepam administration in elderly long-term users: pharmacokinetic and clinical predictors.

BACKGROUND: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. METHODS: Cognitively intact elderly individuals (n=37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25-3.00 mg) or placebo on different days, approximately 1 week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. RESULTS: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. CONCLUSIONS: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population.

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.

A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam.

The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.

Acute lorazepam effects on neurocognitive performance.

A double-blind, placebo-controlled, crossover design was employed to determine whether acute lorazepam (2 mg orally) cognitive side effects would emerge in a differential age-dependent fashion in 15 young (mean age=22 years) and 12 older (mean age=64 years) subjects. Acute use of lorazepam is frequently the initial treatment choice for convulsive status epilepticus or repetitive seizure clusters. Cognitive assessment was performed during drug and placebo conditions using a computerized battery of cognitive tests. With the exception of performance on the reasoning composite score, significant drug effects were present on all primary cognitive domain measures. However, the only significant drug-by-age interaction effect was seen for dual-task performance. The relationship between test performance and plasma lorazepam concentrations was generally modest and non-significant, suggesting that individual differences in pharmacokinetics are not a major factor contributing to the emergence of cognitive side effects. Despite robust lorazepam effects on multiple measures of neurocognitive function, differential age effects are largely restricted to dual-task performance. These results indicate that with the exception of dual-task performance, older individuals in the age range of this study do not appear to be at increased risk for the emergence of cognitive side effects following a single 2-mg dose of lorazepam.

ABH gel is not absorbed from the skin of normal volunteers.

BACKGROUND: Lorazepam (Ativan(®)), diphenhydramine (Benadryl(®)), haloperidol (Haldol(®)) (ABH) topical gel is currently widely used for nausea in hospice because of perceived efficacy and low cost and has been suggested for cancer chemotherapy. However, there are no studies of absorption, a prerequisite for effectiveness. We completed this study to establish whether ABH gel drugs are absorbed, as a prerequisite to effectiveness. INTERVENTION: Ten healthy volunteers, aged 25 to 58 years (mean 37 years), two African Americans and eight Caucasian Americans, applied the standard 1.0 mL dose (2mg of lorazepam, 25mg of diphenhydramine, and 2mg of haloperidol in a pluronic lecithin organogel), rubbed on the volar surface of the wrists by the subject. MEASURES: Blood samples were obtained at 0, 30, 60, 90, 120, 180, and 240 minutes. Plasma concentrations were analyzed by liquid chromatography-tandem mass spectrometry using deuterated internal standards for each drug. OUTCOMES: No lorazepam or haloperidol was detected in any sample from any of the 10 volunteers down to a level of 0.05 ng/mL. Diphenhydramine was found in multiple plasma samples at concentrations >0.05 ng/mL in three patients, with the highest concentration of 0.30 ng/mL in one person at 240 minutes. Overall, five of 10 patients exhibited detectable diphenhydramine in one or more samples, supporting limited absorption. No subject noted any side effects. CONCLUSIONS/LESSONS LEARNED: As commonly used, none of the lorazepam, haloperidol, or diphenhydramine in ABH gel is absorbed in sufficient quantities to be effective in the treatment of nausea and vomiting. Diphenhydramine is erratically absorbed at subtherapeutic levels. The efficacy of ABH gel should be confirmed in randomized trials before its use is recommended.

Bispectral index values, sedation-agitation scores, and plasma Lorazepam concentrations in critically ill surgical patients.

BACKGROUND: Publications on the use of the bispectral index for sedation monitoring in the intensive care unit are increasing. However, few studies have involved correlation of bispectral index with serum drug concentrations. OBJECTIVES: To assess the degree of correlation between bispectral index values, scores on the Sedation-Agitation Scale, and steady-state serum concentrations of lorazepam. METHODS: A prospective open-label study of patients in a surgical intensive care unit who were receiving mechanical ventilation and continuous infusions of lorazepam for more than 24 hours. Bispectral index was measured (BIS-XP, Aspect Medical, Norwood, Massachusetts) to assess patients' sedation. Sensors were applied and values recorded before and after stimulation (endotracheal suctioning). Concomitant plasma samples were obtained to measure lorazepam concentration and scores on the Sedation-Agitation Scale were recorded. RESULTS: Sixteen patients were studied. Correlations between plasma concentrations of lorazepam and measurements of bispectral index for 1, 2, and 3 minutes before endotracheal stimulation were poor (0.21, 0.29, and 0.25, respectively). Correlation of peak values for bispectral index (after stimulation) with plasma concentrations of lorazepam was 0.29. Correlations of scores on the Sedation-Agitation Scale with the aforementioned values for bispectral index were similarly poor. Area under the curve for bispectral index values also correlated poorly with plasma concentration of lorazepam (0.19) and score on the Sedation-Agitation Scale (0.10). CONCLUSIONS: The correlation between bispectral index and score on the Sedation-Agitation Scale was poor. Correlation between bispectral index and plasma concentration of lorazepam was modestly better, but insufficient for clinical utility.

Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers.

PURPOSE: To investigate the plasma-concentration profile of lorazepam when administered by the intranasal and buccal routes to determine their utility for the treatment of prolonged seizures. METHODS: On two occasions separated by at least 7 days washout, 12 healthy adult male volunteers received 2 mg of lorazepam via the intranasal or buccal route. Blood samples were collected at time periods from 0 to 48 h, and pharmacokinetic parameters were determined. RESULTS: Lorazepam was well absorbed from both administration routes; however, there was a more pronounced lag phase with the buccal route and absorption was more rapid from the intranasal route. CONCLUSIONS: Intranasal lorazepam has more favourable pharmacokinetics than buccal lorazepam when considering the need for the rapid blood concentrations required for seizure termination. Further clinical evaluation of this route is required.

Quantification of total and unbound concentrations of lorazepam, oxazepam and temazepam in human plasma by ultrafiltration and LC-MS/MS.

BACKGROUND: A fast and sensitive assay for quantifying total and unbound concentrations of lorazepam (Lzp), oxazepam (Ozp) and temazepam (Tzp) in human plasma was needed for a plasma protein binding study. RESULTS: Plasma samples were precipitated with acetonitrile for determination of total concentrations or subjected to ultrafiltration for determination of unbound concentrations. An LC-MS/MS assay was developed with an Allure® PFP propyl column and a mobile phase of 35% acetonitrile/0.1% formic acid over 4.5 min and ESI+-MS/MS detection. Matrix effects were negligible in plasma and approximately 70% in ultrafiltrate but were accounted for by the internal standards Lzp-d4, Ozp-d5 and Tzp-d5. The assay was validated for total concentrations of 10-100 ng/ml Lzp, 200-2000 ng/ml Ozp and 100-1000 ng/ml Tzp, and for unbound concentrations of 1-10 ng/ml Lzp, 20-200 ng/ml Ozp and 10-100 ng/ml Tzp. Precision was <14% CV and accuracy was 96-110% throughout the calibration range. The mean precision of triplicate analysis of 60 study samples was <4% CV for total and <8% CV for unbound concentrations. CONCLUSION: A fast and sensitive assay was developed and validated. It has been applied successfully to a protein binding study.

Quantitation of benzodiazepines in blood and urine using gas chromatography-mass spectrometry (GC-MS).

The benzodiazepine assay utilizes gas chromatography-mass spectrometry (GC-MS) for the analysis of diazepam, nordiazepam, oxazepam, temazepam, lorazepam, alpha-hydroxyalprazolam, and alpha-hydroxytriazolam in blood and urine. A separate assay is employed for the analysis of alprazolam. Prior to solid phase extraction, urine specimens are subjected to enzyme hydrolysis. The specimens are fortified with deuterated internal standard and a five-point calibration curve is constructed. Specimens are extracted by mixed-mode solid phase extraction. The benzodiazepine extracts are derivatized with N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSFTA) producing tert-butyldimethyl silyl derivatives; the alprazolam extracts are reconstituted in methanol without derivatization. The final extracts are then analyzed using selected ion monitoring GC-MS.

Simultaneous determination and quantification of 12 benzodiazepines in serum or whole blood using UPLC/MS/MS.

The benzodiazepines are a large, commonly prescribed family of psychoactive drugs. We describe a method permitting the simultaneous detection and quantification of 12 benzodiazepines in serum using ultra-performance liquid chromatography (UPLC) coupled with tandem mass spectrometry (MS/MS). Analytes included alprazolam, temazepam, oxazepam, nordiazepam, clonazepam, lorazepam, diazepam, chlordiazepoxide, midazolam, flunitrazepam, 7-aminoclonazepam, and 7-aminoflunitrazepam. Sample pretreatment is simple consisting of protein precipitation using cold acetonitrile (ACN) mixed with the deuterated internal standards. Samples were capped and vortexed for 5 min to ensure maximum precipitation. Following a 5-min centrifugation period, 400 microL of the supernatant was transferred to a clean tube and evaporated down under nitrogen. Samples were reconstituted in 200 microL of a deionized water:ACN (80:20) mixture and transferred to appropriate vials for analysis. Chromatographic run time was 7.5 min, and the 12 analytes were quantified using multiple reaction monitoring (MRM) and 6-point calibration curves constructed for each analyte at concentrations covering a clinically significant range.

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 gamma-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 [(11)C]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 [(11)C]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.

High performance liquid chromatographic analysis of rabeprazole in human plasma and its pharmacokinetic application.

A simple and sensitive HPLC method for the analysis of rabeprazole in plasma is described using UV detection in the presence of lorazepam as the internal standard. Rabeprazole and lorazepam were extracted with ethyl ether and quantitated using a reverse-phase C(18) column. The method was specific as there were no interfering peaks in the human plasma eluting at the retention times of rabeprazole and lorazepam. The method was fully validated in human plasma for the concentration range of 20.0-1000.0 ng/ml. The correlation coefficients were greater than 0.999. Extraction recoveries were 72.3% for the drug and 79.1% for the internal standard. The method was simple, reliable, and accurate for the quantitation of rabeprazole in human plasma. The same plasma samples, which were collected in healthy male volunteers administered a 20 mg tablet of Pariet, were analyzed by HPLC and LC/MS/MS. As a result of that, there was no significant difference between pharmacokinetic parameters. The suitability of HPLC method for pharmacokinetic studies was verified by determining the relevant pharmacokinetic parameters.

Development and evaluation of lorazepam microemulsions for parenteral delivery.

The objective of this investigation was to develop lorazepam (LZM) microemulsions as an alternative to the conventional cosolvent based formulation. Solubility of LZM in various oils and Tween 80 was determined. The ternary diagram was plotted to identify area of microemulsion existence and a suitable composition was identified to achieve desired LZM concentration. The LZM microemulsions were evaluated for compatibility with parenteral fluids, globule size, in vitro hemolysis and stability of LZM. Capmul MCM demonstrated highest solubilizing potential for LZM and was used as an oily phase. LZM microemulsions were compatible with parenteral dilution fluids and exhibited mean globule size less than 200 nm. The in vitro hemolysis studies indicated that microemulsions were well tolerated by erythrocytes. The LZM microemulsions containing amino acids exhibited good physical and chemical stability when subjected to refrigeration for 6 months.

The apolipoprotein E epsilon4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge.

RATIONALE: The APOE epsilon4 allele, an established genetic risk factor for late-onset Alzheimer's disease, has been linked to an increased risk for dementia especially in older individuals with HIV-1 infection. This allele has also been associated with increased memory impairment following oral lorazepam challenge in healthy elderly. Lorazepam and other benzodiazepines are widely prescribed in individuals with HIV-1 infection who are at increased risk for cognitive impairment. OBJECTIVE: The aim of this study was to examine if the epsilon4 allele influences lorazepam-induced memory deficits in this population. MATERIALS AND METHODS: Forty-one non-demented, HIV-1 seropositive adults (15 epsilon4 carriers, mean age = 43.47 +/- 8.25; 26 epsilon4 non-carriers, mean age = 46.77 +/- 8.56) participated in a double-blind, placebo-controlled crossover design, receiving single acute oral doses of lorazepam 0.5, 1.0 mg, or placebo over three sessions, each 1 week apart. Standardized neuropsychological assessments, including measures of immediate and delayed verbal recall, were conducted at baseline and at 1, 2.5, and 5 h post-drug administration in each condition. RESULTS: Acute lorazepam administration produced dose- and time-dependent impairments in measures of verbal recall. However, the e4 allele did not modulate these adverse effects. An APOE epsilon4 group by time interaction was also found such that the APOE-epsilon4-positive subjects had significantly better immediate and delayed verbal recall than the negative subjects at baseline assessment, but the groups did not significantly differ at any subsequent time point. CONCLUSION: Future studies should clarify the role of epsilon4 in the modulation of drug-induced cognitive toxicity and baseline performance and their relationship to progressive decline, especially in older individuals with HIV-1 infection, a group at increased risk for dementia.

Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects.

Pharmacokinetic and pharmacodynamic profiles of lorazepam and valproate were analyzed according to uridine 5'-diphosphate-glucuronosyltransferase (UGT)2B7 genotype in 14 healthy subjects with UGT2B15*2/*2 genotype. Systemic clearance of lorazepam (2 mg intravenously) and area under the concentration-time curve (AUC) of valproate (600 mg once daily for 4 days) were analyzed as pharmacokinetic parameters, and area under the effect-time curve (AUEC) of psychomotor coordination tests (Vienna) was used for pharmacodynamic parameter. No significant differences were found in systemic clearances of lorazepam by UGT2B7 genotype. AUCs of valproate showed an increasing tendency as the number of UGT2B7*2 alleles increased, but the difference was insignificant. Psychometric results were significant among the UGT2B7 genotype group (AUEC_tracking 261.5+/-298.9 in *1/*1, and 3,396.8+/-947 in *2/*2, P=0.047) when the two drugs were coadministered. Our study suggests that the UGT2B7 genotype probably affects lorazepam-valproate pharmacodynamic interaction, especially in subjects who have homovariant genotypes of UGT2B7 and UGT2B15, although the effects on the pharmacokinetics are less significant.