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1.
Psychopharmacology (Berl) ; 239(7): 2143-2154, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35296912

ABSTRACT

RATIONALE: Novel compound with potent antagonistic activity against orexin receptors may be new treatment option for patients with insomnia. OBJECTIVE: The aim was to investigate the efficacy and safety of single oral doses of the dual orexin receptor antagonist TS-142 in patients with insomnia. METHODS: This multicenter, double-blind, crossover randomized clinical trial included non-elderly patients with insomnia. Patients were randomized to receive single doses of placebo and TS-142 at doses of 5, 10, and 30 mg in one of four different sequences, with a 7-day washout period between treatments. Primary efficacy endpoints were latency to persistent sleep (LPS) and wake time after sleep onset (WASO) measured by polysomnography. RESULTS: Twenty-four patients were included (mean age 50.3 ± 10.5 years; mean duration of insomnia 5.71 ± 8.68 years). Least-squares mean differences (95% confidence interval) from placebo in LPS with 5, 10, and 30 mg TS-142 were - 42.38 (- 60.13, - 24.63), - 42.10 (- 60.02, - 24.17), and - 44.68 (- 62.41, - 26.95) minutes, respectively (all p < 0.001). Least-squares mean differences (95% confidence interval) from placebo in WASO with 5, 10, and 30 mg TS-142 were - 27.52 (- 46.90, - 8.14), - 35.44 (- 55.02, - 15.87), and - 54.69 (- 74.16, - 35.23) minutes, respectively (all p < 0.01). Self-reported aspects of sleep initiation and sleep quality, determined using the Leeds Sleep Evaluation Questionnaire (LSEQ), were also improved with TS-142 administration versus placebo. TS-142 was well tolerated; all adverse events were mild or moderate and none were serious. CONCLUSION: Single-dose TS-142 was well tolerated and had clinically relevant effects on objective and subjective sleep parameters in patients with insomnia. CLINICAL TRIAL REGISTRATION: JapicCTI173570 (www. CLINICALTRIALS: jp); NCT04573725 (www. CLINICALTRIALS: gov).


Subject(s)
Orexin Receptor Antagonists , Sleep Initiation and Maintenance Disorders , Adult , Double-Blind Method , Humans , Lipopolysaccharides/pharmacology , Middle Aged , Orexin Receptor Antagonists/adverse effects , Sleep , Sleep Initiation and Maintenance Disorders/drug therapy , Treatment Outcome
2.
Psychopharmacology (Berl) ; 239(3): 841-850, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35106620

ABSTRACT

RATIONALE: The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance. OBJECTIVE: To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance. METHODS: In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks-road-tracking, car-following, and harsh-braking-using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone. RESULTS: The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71-5.79) and 4.07 cm (90% CI: 2.02-6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94-6.69) and 24.6 ms (90% CI: 12.7-36.4), respectively. CONCLUSIONS: The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance.


Subject(s)
Automobile Driving , Psychomotor Performance , Azabicyclo Compounds/pharmacology , Cross-Over Studies , Double-Blind Method , Healthy Volunteers , Humans , Hypnotics and Sedatives/pharmacology , Male , Piperazines , Reproducibility of Results
3.
Psychopharmacology (Berl) ; 238(3): 775-786, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33236169

ABSTRACT

RATIONALE: Although driving simulators (DS) are receiving increasing attention due to concern over traffic accidents under the influences of drugs, few DS are recognized for their reliability and validity. Therefore, the development of an evaluation system using DS for driving performance is urgently needed. OBJECTIVES: To investigate whether the standard deviation of lateral position (SDLP) increases with blood alcohol concentration (BAC) using a DS with reliability and calculate the SDLP threshold from the difference between BAC levels of 0 and 0.05%. METHODS: Twenty healthy Japanese men performed the DS tasks up to 60 min in Study 1 and DS tasks twice at 1-week intervals in Study 2. Twenty-six healthy men conducted the same DS tasks under BAC level (0, 0.025, 0.05, and 0.09%) in double-blind, randomized, crossover trial in Study 3. The primary outcome was SDLP in a road-tracking test. The test-retest reliability of DS data was assessed, and the estimated difference in SDLP between BAC levels of 0 and 0.05% was calculated using a linear regression model. RESULTS: The cumulative SDLP values at 5-min intervals were stable, and the intraclass correlation coefficient for its values was 0.93. SDLP increased with BAC in a concentration-dependent manner. The predicted ΔSDLP value for the difference between BAC levels of 0 and 0.05% was 9.23 cm. No participants dropped out because of simulator sickness. CONCLUSIONS: The new DS used in these studies has reliability, validity, and tolerability and is considered suitable for evaluating the influence of drugs on driving performance.


Subject(s)
Alcohol Drinking/psychology , Attention/drug effects , Automobile Driving/psychology , Driving Under the Influence/psychology , Psychomotor Performance/drug effects , Adult , Alcohol Drinking/blood , Aldehyde Dehydrogenase, Mitochondrial/blood , Aldehyde Dehydrogenase, Mitochondrial/genetics , Blood Alcohol Content , Computer Simulation , Cross-Over Studies , Double-Blind Method , Female , Genotype , Humans , Male , Models, Psychological , Reproducibility of Results
4.
Endocrinology ; 154(10): 3807-16, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23913447

ABSTRACT

Contributions from estrogen receptor (ER) subtypes (ERα and ERß) to postpartum anxiogenic and depressive responses remain unresolved in rats. Using the elevated-plus maze (EPM) and forced swim (FS) tests, we confirmed that primiparous rats exhibited anxiogenic and depressive responses 3 weeks postpartum, improved 5 weeks postpartum (EPM), and recovered at 5 (FS) or 10 weeks postpartum (EPM) compared with diestrus nulliparous females. Immunohistochemistry suggested that these behavioral changes were temporally associated with decreased ERα but not ERß expression in the medial amygdala (MEA). Additionally, ERα expression in the medial preoptic area (MPOA) significantly increased 10 weeks postpartum. Brain-derived neurotrophic factor (BDNF) expression was significantly elevated in the MEA 3 weeks postpartum. BDNF receptor tropomyosin-related kinase expression was significantly elevated in the MEA at 3 and 10 weeks but not at 5 weeks postpartum. The phosphorylation of ERK (pERK)-2 in the MEA, MPOA, and hippocampal CA1 region was significantly elevated 3 and 5 weeks postpartum. The effects of single daily sc injections of the ERα-selective agonist, propyl pyrazoletriol (PPT); ERß-selective agonist, diarylpropionitrile; 17ß-estradiol (E2); and vehicle for 6 days in primiparous rats were assessed. PPT and E2 significantly produced anxiolytic and antidepressant actions in the EPM and FS tests but PPT to a lesser degree than E2 in the EPM test. Diarylpropionitrile affected the EPM test but was not significantly different from vehicle. BDNF expression was significantly increased 3 weeks postpartum by all treatments in the MPOA but not the CA1 and MEA. E2 and PPT treatment significantly increased tropomyosin-related kinase and pERK1/2 expression in the MEA and MPOA and increased pERK1/2 expression in the CA1. The onset of anxiety- and depression-like behaviors in postpartum rats may be partly caused by a complex estrogen-mediated mechanism; nevertheless, changes in the ERα-related system, likely in the MEA, are predominantly involved.


Subject(s)
Amygdala/drug effects , Anxiety/drug therapy , Depression, Postpartum/drug therapy , Estrogen Receptor alpha/agonists , Estrogens/therapeutic use , Neurons/drug effects , Up-Regulation/drug effects , Amygdala/metabolism , Animals , Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Anxiety/etiology , Behavior, Animal/drug effects , Brain-Derived Neurotrophic Factor/metabolism , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/metabolism , Estradiol/therapeutic use , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/agonists , Estrogen Receptor beta/metabolism , Estrogens/metabolism , Female , MAP Kinase Signaling System/drug effects , Neurons/metabolism , Phenols , Preoptic Area/drug effects , Preoptic Area/metabolism , Pyrazoles/therapeutic use , Rats , Rats, Long-Evans , Receptor, trkB/metabolism
5.
Prog Neuropsychopharmacol Biol Psychiatry ; 34(1): 159-65, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-19883713

ABSTRACT

Glucocorticoids are known to cause psychiatric disorders including depression. Prednisolone (PSL) is one of the most widely used synthetic glucocorticoids to treat various medical diseases; however, little is known about PSL-induced behavioral changes and its molecular basis in the brain. Growing evidence has implicated that hippocampal remodeling or damage play a role in the pathogenic effect of glucocorticoids. In this study, mice were administered PSL (50 or 100mg/kg) or vehicle for 6 or 7 days and subjected to a series of behavioral tests, i.e., open field, elevated plus maze, prepulse inhibition, forced swim, and tail suspension tests. Hippocampal tissues were subject to microarray analysis using the GeneChip Mouse Genome 430 2.0 Array (Affymetrix) containing 45,101 probes of transcripts. Increased anxiety- and depression-like behaviors assessed with open field, elevated plus maze, and tail suspension tests were observed. Microarray analysis detected 108 transcripts with a fold change of >2.0 or <0.5 in which many cell-death-related genes were found. The microarray data was validated by quantitative reverse transcriptase-polymerase chain reaction analysis. Our results demonstrated that PSL causes anxiety- and depression-like behaviors, and suggest that altered gene expressions related to hippocampal remodeling or damage are involved in the effect of PSL on such behaviors.


Subject(s)
Anxiety , Apoptosis/genetics , Depression , Gene Expression Regulation/drug effects , Hippocampus/metabolism , Prednisolone , Acoustic Stimulation/methods , Animals , Anxiety/chemically induced , Anxiety/metabolism , Anxiety/pathology , Apoptosis/drug effects , Depression/chemically induced , Depression/metabolism , Depression/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Gene Expression Profiling/methods , Hindlimb Suspension/methods , Hippocampus/drug effects , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Neural Inhibition/drug effects , Oligonucleotide Array Sequence Analysis/methods , Prednisolone/pharmacology , Reflex, Startle/drug effects , Signal Transduction/drug effects , Signal Transduction/genetics , Swimming/psychology
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