Effects of gabapentin on slow-wave sleep period in critically ill adult patients: A randomized controlled trial.

Sleep deprivation is a prevalent problem in critically ill patients, which leads to delayed recovery and delirium. Slow-wave sleep (SWS) is essential to energy restoration, tissue repair, and immune system strengthening. This study aimed to investigate the effects of gabapentin on SWS in critically ill patients. We performed a prospective open-label randomized controlled study to compare SWS and the clinical outcomes of gabapentin versus a control intervention in critically ill adult patients admitted to the intensive care unit (ICU) within 24 h. The patients' characteristics and sleep-related outcomes were recorded. The sleep-related outcomes, namely, bispectral analysis (BIS), the Richards-Campbell Sleep Questionnaire (RCSQ), and insulin-like growth factor-1 (IGF-1) levels, were evaluated. Furthermore, clinical outcomes and safety were assessed. Sixty patients from 348 cases were eligible for randomization. On day 3 of the study, patients in the gabapentin group had significantly increased SWS (66.79 vs. 0.00 min; p < 0.001), total sleep time (TST) (331.39 vs. 46.16 min; p = 0.001), RCSQ score (55.05 ± 20.18 vs. 32.80 ± 15.31; p < 0.001), and IGF-1 concentrations (84.33 ± 12.40 vs. 44.00 ± 10.20 ng/mL, p < 0.001) compared with the control group. Improvements in clinical outcomes, such as delirium, ICU-free days, and mechanical ventilator-free days, were observed; however, these differences did not reach statistically significant. Gabapentin at bedtime increased SWS, TST, and IGF-1 concentrations in critically ill patients. This regimen might be beneficial to critically ill patients for improving their sleep quality.

Implementing pain, agitation, delirium, and sleep deprivation protocol in critically ill patients: A pilot study on pharmacological interventions.

Critically ill patients frequently experience pain, agitation, delirium, and sleep deprivation, which have been linked to increased mortality and unfavorable clinical outcomes. To address these challenges, the Pain, Agitation, Delirium, and Sleep Deprivation (PADS) protocol was developed, aiming to mitigate mortality and improve clinical outcomes. This study focuses on assessing the protocol's impact using a robust before-and-after study design in the medical and surgical intensive care units (ICUs) at Ramathibodi Hospital. Using an observational approach, this study compares clinical outcomes before and after implementing the PADS protocol in the ICUs. Two patient cohorts were identified: the "before" group, comprising 254 patients with retrospective data collected between May 2018 and September 2019, and the "after" group, consisting of 255 patients for whom prospective data was collected from May to September 2020. Analysis reveals improvements in the after group. Specifically, there was a significant increase in 14-day ICU-free days (9.95 days vs. 10.40 days, p value = 0.014), a decrease in delirium incidence (18.1% vs. 16.1%, p value < 0.001), and a significant reduction in benzodiazepine usage (38.6% vs. 24.6%, p value = 0.001) within the after group. This study emphasizes the protocol's potential to improve patient care and highlights its significance in the ICU context.

Pharmacokinetics and pharmacodynamics studies of a loading dose of cisatracurium in critically ill patients with respiratory failure.

BACKGROUND: Previous studies reported a slow neuromuscular response with the currently recommended dose of cisatracurium in critically ill patients. Pharmacokinetic and pharmacodynamic studies of cisatracurium in critically ill patients are still limited. To our knowledge, this is the first study performed to better understand the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a loading dose of cisatracurium and to identify factors that affect PK and PD changes in critically ill patients. METHODS: A prospective PKs and PDs study was designed. Arterial blood samples of 10 critically ill patients with respiratory failure were collected after administering a loading dose of 0.2 mg/kg of cisatracurium. Plasma cisatracurium and laudanosine concentrations were determined using liquid chromatography-tandem mass spectrometry. The achievement of the desired pharmacodynamic response was evaluated by both 1) clinical assessment and 2) train-of-four monitoring. The PK/PD indices were analyzed for their correlation with patient'characteristics and other factors. RESULTS: The one-compartment model best described the plasma pharmacokinetic parameters of cisatracurium. The volume of distribution at steady state and total clearance were 0.11 ± 0.04 L/kg and 2.74 ± 0.87 ml/minute/kg, respectively. The mean time to train-of-four 0/4 was 6 ± 3.86 minutes. A time to the desired pharmacodynamic response of less than 5 minutes was found in 10% of the patients. A positive correlation was found between cisatracurium concentration and albumin levels and between pharmacokinetics data and patient factors [partial pressure of carbon dioxide and respiratory alkalosis]. CONCLUSION: The currently recommended loading dose of cisatracurium might not lead to the desired pharmacodynamic response in critically ill patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03337373. Registered on 9 November 2017.

Incidence and clinical manifestation of iatrogenic opioid withdrawal syndrome in mechanically ventilated patients.

OBJECTIVE: The incidence of iatrogenic opioid withdrawal syndrome (IOWS) in mechanically ventilated adults has been questioned in settings driven by analgosedation strategies. This study aimed to describe the incidence, risk factors and clinical impact of IOWS in mechanically ventilated adults. METHODS: This prospective, observational study was performed between 1 January and 31 August 2018. IOWS was identified based on the presence of at least three signs or symptoms according to the Diagnostic and Statistical Manual 5th edition (DSM-5) criteria after opioid discontinuation or rate reduction. Incidence of IOWS, patient characteristics, opioid administration, and the impact of IOWS on the duration of mechanical ventilator and length of stay in the intensive care unit (ICU) were collected. RESULTS: Thirteen out of 55 patients (23.6%) manifested withdrawal symptoms. Two patients in the non-withdrawal group also developed hypertensive urgency after opioid discontinuation. Patients who received rapid once-daily weaning, especially rate reduction more than 50 µg as fentanyl equivalent per hour, were associated with IOWS. However, there was no statistically significant difference in ventilator-free days and ICU-free days. CONCLUSIONS: These findings showed that approximately one-fourth of mechanically ventilated patients who received opioid infusion experienced IOWS. Monitoring for IOWS is recommended especially in patients who received rapid weaning rate of opioids. Future studies to develop IOWS assessment tools with the change of hemodynamic parameters should be performed. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov: identifier NCT03374722, date of registration 15 December 2018.

Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus.

BACKGROUND: Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761® , is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits. AIMS: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI. MATERIALS & METHODS: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option. RESULTS: EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals. DISCUSSION: EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD. CONCLUSION: As an expert group, we suggest it is clinically appropriate to incorporate EGb 761® as part of the multidomain intervention for MCI.

Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761®.

BACKGROUND: The Ginkgo biloba special extract, EGb 761® has been widely used in the treatment of neuropsychiatric disorders, including Alzheimer's disease (AD). METHODS: To guide clinical practice in the Asian region, the Asian Clinical Expert Group on Neurocognitive Disorders compiled evidence-based consensus recommendations regarding the use of EGb 761® in neurocognitive disorders with/without cerebrovascular disease. RESULTS: Key randomized trials and robust meta-analyses have demonstrated significant improvement in cognitive function, neuropsychiatric symptoms, activities of daily living (ADL) and quality of life with EGb 761® versus placebo in patients with mild-to-moderate dementia. In those with mild cognitive impairment (MCI), EGb 761® has also demonstrated significant symptomatic improvement versus placebo. World Federation of Societies of Biological Psychiatry guidelines list EGb 761® with the same strength of evidence as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists e.g. memantine (Grade 3 recommendation; Level B evidence). Only EGb 761® had Level B evidence in improving cognition, behaviour, and ADL in both AD and vascular dementia patients. Safety analyses show EGb 761® to have a positive risk-benefit profile. While concerns have been raised regarding a possible increased bleeding risk, several randomized trials and two meta-analyses have not supported this association. CONCLUSIONS: The Expert Group foresee an important role for EGb 761® , used alone or as an add-on therapy, in the treatment of MCI and dementias, particularly when patients do not derive benefit from acetylcholinesterase inhibitors or NMDA antagonists. EGb 761® should be used in alignment with local clinical practice guidelines.

Anticholinergic discontinuation and cognitive functions in patients with schizophrenia: a pharmacist-physician collaboration in the outpatient department.

INTRODUCTION: Cognitive impairment is a core feature and shows the highest impact on functional outcome in patients with schizophrenia. There have been no previous studies investigating the role of the pharmacist in a multidisciplinary team on cognitive outcomes in patients with schizophrenia. PURPOSE: We evaluated the impact of pharmacist intervention on cognitive outcomes in patients with schizophrenia by focusing on anticholinergic discontinuation. PATIENTS AND METHODS: A prospective, open-label, randomized, controlled study was conducted. Patients with schizophrenia were randomly assigned to either the pharmacist intervention or usual care groups. In the pharmacist intervention group, the pharmacist identified drug-related problems (DRPs) and provided a pharmacotherapy suggestion, while there was no intervention in the usual care group. The primary outcome was mean change from baseline of executive function by using Wisconsin Card Sorting Test (WCST) perseverative errors within the pharmacist intervention group at week 12. RESULTS: A total of 30 patients completed the study (13 in the pharmacist intervention group and 17 in the usual care group). WCST perseverative errors at the end of the study within the pharmacist intervention group improved significantly from baseline (P=0.003). DRPs at week 12 were reduced by 85.19% and 9.76% in the pharmacist intervention and usual care groups, respectively. The most common intervention was the discontinuation of anticholinergics in patients without extrapyramidal side effects. CONCLUSION: Added-on pharmacist intervention in a multidisciplinary team could help to improve cognitive functions in patients with schizophrenia by reducing DRPs and optimizing the drug therapy regimen, especially for anticholinergic discontinuation.

In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-ß.

Fibrosis is a pathophysiological state characterized by the excessive formation/deposition of fibrous extracellular matrix. Transforming growth factor-beta (TGF-ß) is a central profibrotic mediator, and targeting TGF-ß is a promising strategy in the development of drugs for the treatment of fibrosis. Therefore, the effect of LY2109761, a small molecule inhibitor against TGF-ß with targets beyond TGF-ß signaling, on fibrogenesis was elucidated in vitro (HepG2 cells and LX-2 cells) and ex vivo (human and rat precision-cut liver slices). Our results displayed an anti-fibrotic effect of LY2109761, as it markedly down-regulated gene and protein expression of collagen type 1, as well as gene expression of the inhibitor of metalloproteinases 1. This effect on fibrosis markers was partially mediated by targeting TGF-ß signaling, seeing that LY2109761 inhibited TGF-ß1 gene expression and SMAD2 protein phosphorylation. Interestingly, particularly at a high concentration, LY2109761 decreased SMAD1 protein phosphorylation and gene expression of the inhibitor of DNA binding 1, which appeared to be TGF-ß-independent effects. In conclusion, LY2109761 exhibited preclinical anti-fibrotic effects via both TGF-ß-dependent and -independent pathways. These results illustrate that small molecule inhibitors directed against TGF-ß could possibly influence numerous signaling pathways and thereby mitigate fibrogenesis.

UGT1A1 polymorphisms associated with prolactin response in risperidone-treated children and adolescents with autism spectrum disorder.

The aim of this study was to investigate the association of drug-metabolizing enzyme and transporter (DMET) polymorphisms with the risperidone-induced prolactin response using an overlapping gene model between serum prolactin level and hyperprolactinemia in autism spectrum disorder (ASD) patients. Eighty-four ASD patients who were receiving risperidone for at least 1 month were recruited and then assigned to either the normal prolactin group or the hyperprolactinemia group based on their serum prolactin level. The genotype profile of 1936 (1931 single nucleotide polymorphisms (SNPs) and 5 copy number variation (CNVs) drug metabolism markers was obtained using the Affymetrix DMET Plus GeneChip microarray platform. Genotypes of SNPs used to test the accuracy of DMET genotype profiling were determined using TaqMan SNP Genotyping Assay kits. Eighty-four patients were selected for the allelic association study after microarray analyses (51 in the normal prolactin group, and 33 in the hyperprolactinemia group). An overlapping allelic association analysis of both analyses discovered five DMET SNPs with a suggestive association (P < 0.05) with risperidone-induced prolactin response. Three UGT1A1 SNPs (UGT1A1*80c.-364C > T, UGT1A1*93 c.-3156G > A, and UGT1A1 c.-2950A > G, showed a suggestive association with the risperidone-induced prolactin response and found to be in complete linkage disequilibrium (D' value of 1). In this DMET microarray platform, we found three UGT1A1 variants with suggestive evidences of association with the risperidone-induced prolactin response both measured by hyperprolactinemia and by prolactin level. However, due to the lack of validation studies confirmation and further exploration are needed in future pharmacogenomic studies.

Impact of Early Versus Late Intravenous Followed by Oral Nimodipine Treatment on the Occurrence of Delayed Cerebral Ischemia Among Patients With Aneurysm Subarachnoid Hemorrhage.

BACKGROUND: Guidelines for aneurysm subarachnoid hemorrhage (aSAH) management recommend treatment with nimodipine to all patients to reduce delayed cerebral ischemia (DCI) and poor clinical outcome. However, it did not give the most beneficial time to start therapy and route of administration. OBJECTIVES: To compare the DCI occurrence and clinical outcome among aSAH patients who received nimodipine treatment at different times. METHODS: A retrospective cohort study was conducted by collecting data from medical chart reviews between August 30, 2010, and October 31, 2015, at Prasart Neurological Institute, Thailand. Patients were classified into 2 groups by time to receive nimodipine: early group and late group (<96 and >96 hours, respectively). All patients received intravenous (IV) followed by oral nimodipine to complete treatment course. Clinical outcome was graded using the Glasgow Outcome Scale at 21 days. The factors related to DCI were analyzed using multivariate logistic regression. RESULTS: A total of 149 patients were recruited: early (n = 97) and late (n = 52). No difference in baseline characteristics between groups was observed. The occurrence of DCI was not statistically significantly different between groups (early group, 18.60%, vs late group, 20.80%; P = 0.74). The World Federation of Neurosurgical Societies IV to V was associated with DCI occurrence. The proportion of patients with good outcome, poor outcome, or death did not show any difference between groups. CONCLUSIONS AND RELEVANCE: Receiving IV nimodipine 3 to 7 days following oral therapy after bleeding can be the alternative regimen in patients who did not start nimodipine within 96 hours.

Symptomatic orthostatic hypotension in Parkinson's disease patients: Prevalence, associated factors and its impact on balance confidence.

BACKGROUND: Orthostatic hypotension (OH) is a commonly reported sign of the cardiovascular autonomic dysfunctions associated with Parkinson's disease (PD). Patients might suffer from a variety of the clinical symptoms of OH, including dizziness, lightheadedness, or problems with vision and fatigue. OBJECTIVES: To determine the prevalence of, and factors associated with, symptomatic orthostatic hypotension (OH) in Parkinson's disease (PD) and to identify any relationships between the clinical symptoms of OH and balance confidence in this patient population. METHODS: Symptomatic OH was defined as a systolic or diastolic BP fall of ≥20 or ≥10mmHg respectively, within 3min of standing and an Orthostatic Hypotension Questionnaire (OHQ) score of more than zero. Factors related to symptomatic OH were identified from a multivariate logistic regression analysis. Pearson's correlation test was used to reveal any relationships between the clinical symptoms of OH and a patient's confidence in their ability to balance, assessed using the Activities-specific Balance Confidence (ABC) scale. RESULTS: 100 Thai PD patients were consecutively recruited into this study. The prevalence of symptomatic OH was 18%, asymptomatic OH was 4%, while 78% were patients without OH. Factors associated with symptomatic OH were age (OR, 95%CI: 1.06, 1.003-1.115, p=0.038) and hypertension (OR, 95%CI: 6.16, 1.171-32.440, p=0.032). A significant and negative correlation (r=-0.229, p=0.022) between OHQ composite scores and item 3 of the ABC scale (picking up slippers from floor), one of the movements in a vertical orientation, was found. CONCLUSION: Elderly PD patients and with a co-morbidity of essential hypertension should be closely evaluated for the presence of symptomatic OH. In addition, they should be advised to change positions slowly, especially those in a vertical orientation.

Beyond symptomatic effects: potential of donepezil as a neuroprotective agent and disease modifier in Alzheimer's disease.

Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the N-methyl-D-aspartate-receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as a symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. This review explores the potential for disease modifying effects of donepezil. Several neuroprotective mechanisms that are independent of cholinesterase inhibition, are suggested. Donepezil has demonstrated a range of effects, including protecting against amyloid ß, ischaemia and glutamate toxicity; slowing of progression of hippocampal atrophy; and up-regulation of nicotinic acetylcholine receptors. Clinically, early and continuous treatment with donepezil is considered to preserve cognitive function more effectively than delayed treatment. The possible neuroprotective effects of donepezil and the potential for disease pathway modification highlight the importance of early diagnosis and treatment initiation in AD.

Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai Autistic Children and Adolescents.

The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcome in autistic children and adolescents who were treated with risperidone for long periods. Eighty-two autistic subjects diagnosed with DSM-IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI-I, aggressive, overactivity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), overactivity (71.95%), repetitive (70.89%) behaviour and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI-I score. Patients in the non-stable symptom group had DRD2 Taq1A non-wild-type (TT and CT) frequencies higher than the clinically stable group (p = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non-stable clinical outcome (χ2  = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcome. On the other hand, risperidone dose, 9-OH risperidone levels and prolactin levels were significantly higher in the non-stable compared to the stable symptom group (p = 0.013, p = 0.044, p = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body-weight, whereas it was not significantly associated with genetic variations and non-genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long-term treatment. However, Taq1A T - carrier of dopamine 2 receptor gene - is associated with non-stable response in risperidone-treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents.

Impact of pharmaceutical care on pain and agitation in a medical intensive care unit in Thailand.

Background Currently, a lack of pharmaceutical care exists concerning pain and agitation in medical intensive care units (MICU) in Thailand. Pharmaceutical care focusing on analgesics/sedatives would improve clinical outcomes. Objective To investigate the impact of pharmaceutical care of pain and agitation on ICU length of stay (LOS), hospital LOS, ventilator days and mortality. Setting The MICU of a university hospital. Method A before/after study was conducted on mechanically ventilated patients receiving analgesics/sedatives. Medical chart reviews and data collection were conducted in the retrospective group (no pharmacists involved). In the prospective group, pharmacists involved with the critical care team helped select analgesics/sedatives for individual patients. Main outcome measure ICU LOS Results In total, 90 and 66 patients were enrolled in retrospective and prospective groups, respectively. The median duration of ICU LOS was reduced from 10.00 (2.00-72.00) in the retrospective group to 6.50 days (2.00-30.00) in the prospective group (p = 0.002). The median hospital stay was reduced from 30.50 days (2.00-119.00) in the retrospective group to 17.50 days (2.00-110.00) in the prospective group (p < 0.001). Also, the median ventilator days was reduced from 14.00 days (2.00-90.00) to 8.50 days (1.00-45.00), p = 0.008. Mortality was 53.03% in the prospective group and 46.67% in the retrospective group (p = 0.432). Conclusion Pharmacist participation in a critical care team resulted in a significant reduction in the duration of ICU LOS, hospital LOS and ventilator days, but not mortality.

Clinical Recommendations for the Use of Donepezil 23 mg in Moderate-to-Severe Alzheimer's Disease in the Asia-Pacific Region.

BACKGROUND: The 'Asia-Pacific Expert Panel (APEX) for donepezil 23 mg' met in November 2015 to review evidence for the recently approved high dose of donepezil and to provide recommendations to help physicians in Asia make informed clinical decisions about using donepezil 23 mg in patients with moderate-to-severe Alzheimer's disease (AD). SUMMARY: In a global phase III study (study 326) in patients with moderate-to-severe AD, donepezil 23 mg/day demonstrated significantly greater cognitive benefits versus donepezil 10 mg/day, with a between-treatment difference in mean change in the Severe Impairment Battery score of 2.2 points (p < 0.001) in the overall population and 3.1 points (p < 0.001) in patients with advanced AD. A subanalysis of study 326 demonstrated that the benefits and risks associated with donepezil 23 mg/day versus donepezil 10 mg/day in Asian patients with moderate-to-severe AD were comparable to those in the global study population. KEY MESSAGE: Donepezil 23 mg is a valuable treatment for patients with AD, particularly those with advanced disease. The APEX emphasized the importance of patient selection (AD severity, tolerability of lower doses of donepezil, and absence of contraindications), a stepwise titration strategy for dose escalation, and appropriate monitoring and counseling of patients and caregivers in the management of patients with AD.

Efficacy and safety of mirtazapine in fibromyalgia syndrome patients: a randomized placebo-controlled pilot study.

BACKGROUND: Data from an open-label trial suggest that mirtazapine might prove useful in treatment of fibromyalgia syndrome (FMS). OBJECTIVE: To obtain preliminary efficacy data of mirtazapine for estimation of sample size requirements for a Phase 2 clinical trial in FMS. METHODS: This 13-week randomized controlled trial compared the effects of mirtazapine 15 mg/day, mirtazapine 30 mg/day, and placebo in 40 patients with FMS. The primary outcomes were change in Pain Visual Analog Scale (PVAS) and proportion of pain responders (≥30% PVAS reduction). Secondary outcomes included scores from the Jenkins Sleep Scale (JSS), Patient Global Impression of Change (PGIC), Fibromyalgia Impact Questionnaire (FIQ), Hamilton Depression Rating Scale (HAM-D), Patient Global Assessment, and self-reported adverse events. RESULTS: Significant within-group PVAS reductions from baseline were observed in all 3 groups, with the greatest improvement in the mirtazapine 30-mg group (p < 0.005); between-group difference was not significant. The proportion of pain responders did not meet significance criteria (66.67% for mirtazapine 30 mg, 50% for mirtazapine 15 mg, 41.67% for placebo). Significant within-group improvement in JSS scores was seen for mirtazapine 30 mg (p < 0.01) and mirtazapine 15 mg (p < 0.05). Between-group comparison achieved significance for JSS item 3, waking several times per night (p < 0.05). On the PGIC, 72.73% felt better with both mirtazapine dosages compared with 50% for placebo. Within-group FIQ responses indicated improvement in only mirtazapine-treated groups, whereas within-group improvement for HAM-D and Patient Global Assessment was observed in all groups. Based on our findings, the sample size requirement (80% power, 5% type I error) should be 83 per group to detect PVAS change difference between mirtazapine 30 mg and placebo. Common mirtazapine-related adverse events were increased appetite and weight gain. CONCLUSIONS: Patients with FMS taking mirtazapine exhibited within-group significant improvement in most of the measured outcomes. Between-group analysis was predictably compromised by the small sample size. Mirtazapine was well tolerated. Further study with a larger sample size is likely to be useful.

The glucuronidation of R- and S-lorazepam: human liver microsomal kinetics, UDP-glucuronosyltransferase enzyme selectivity, and inhibition by drugs.

The widely used hypnosedative-anxiolytic agent R,S-lorazepam is cleared predominantly by conjugation with glucuronic acid in humans, but the enantioselective glucuronidation of lorazepam has received little attention. The present study characterized the kinetics of the separate R and S enantiomers of lorazepam by human liver microsomes (HLMs) and by a panel of recombinant human UDP-glucuronosyltransferase (UGT) enzymes. Respective mean K(m) and V(max) values for R- and S-lorazepam glucuronidation by HLM were 29 ± 8.9 and 36 ± 10 µM, and 7.4 ± 1.9 and 10 ± 3.8 pmol/min ⋅ mg. Microsomal intrinsic clearances were not significantly different, suggesting the in vivo clearances of R- and S-lorazepam are likely to be similar. Both R- and S-lorazepam were glucuronidated by UGT2B4, 2B7, and 2B15, whereas R-lorazepam was additionally metabolized by the extrahepatic enzymes UGT1A7 and 1A10. Based on in vitro clearances and consideration of available in vivo and in vitro data, UGT2B15 is likely to play an important role in the glucuronidation of R- and S-lorazepam. However, the possible contribution of other enzymes and the low activities observed in vitro indicate that the lorazepam enantiomers are of limited use as substrate probes for UGT2B15. To identify potential drug-drug interactions, codeine, fluconazole, ketamine, ketoconazole, methadone, morphine, valproic acid, and zidovudine were screened as inhibitors of R- and S-lorazepam glucuronidation by HLM. In vitro-in vivo extrapolation suggested that, of these drugs, only ketoconazole had the potential to inhibit lorazepam clearance to a clinically significant extent.