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Sleep Initiation and Maintenance Disorders: HELP
Articles from Miscellaneous institutions in San Diego
Based on 21 articles published since 2009

These are the 21 published articles about Sleep Initiation and Maintenance Disorders that originated from Miscellaneous institutions in San Diego during 2009-2019.
+ Citations + Abstracts
1 Clinical Trial Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia. 2010

Al-Shamma, Hussien A / Anderson, Christen / Chuang, Emil / Luthringer, Remy / Grottick, Andrew J / Hauser, Erin / Morgan, Michael / Shanahan, William / Teegarden, Bradley R / Thomsen, William J / Behan, Dominic. ·Arena Pharmaceuticals, Inc., San Diego, California, USA. halshamma@arenapharm.com ·J Pharmacol Exp Ther · Pubmed #19841476.

ABSTRACT: 5-Hydroxytryptamine (5-HT)(2A) receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT(2A) inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.

2 Article The Accuracy, Night-to-Night Variability, and Stability of Frontopolar Sleep Electroencephalography Biomarkers. 2017

Levendowski, Daniel J / Ferini-Strambi, Luigi / Gamaldo, Charlene / Cetel, Mindy / Rosenberg, Robert / Westbrook, Philip R. ·Advanced Brain Monitoring, Carlsbad, California. · Department of Clinical Neurosciences, San Raffaele Scientific Institute, Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Integrative Insomnia and Sleep Health Center, San Diego, California. · Sleep Disorders Center of Prescott Valley, Prescott Valley, Arizona. ·J Clin Sleep Med · Pubmed #28454598.

ABSTRACT: STUDY OBJECTIVES: To assess the validity of sleep architecture and sleep continuity biomarkers obtained from a portable, multichannel forehead electroencephalography (EEG) recorder. METHODS: Forty-seven subjects simultaneously underwent polysomnography (PSG) while wearing a multichannel frontopolar EEG recording device (Sleep Profiler). The PSG recordings independently staged by 5 registered polysomnographic technologists were compared for agreement with the autoscored sleep EEG before and after expert review. To assess the night-to-night variability and first night bias, 2 nights of self-applied, in-home EEG recordings obtained from a clinical cohort of 63 patients were used (41% with a diagnosis of insomnia/depression, 35% with insomnia/obstructive sleep apnea, and 17.5% with all three). The between-night stability of abnormal sleep biomarkers was determined by comparing each night's data to normative reference values. RESULTS: The mean overall interscorer agreements between the 5 technologists were 75.9%, and the mean kappa score was 0.70. After visual review, the mean kappa score between the autostaging and five raters was 0.67, and staging agreed with a majority of scorers in at least 80% of the epochs for all stages except stage N1. Sleep spindles, autonomic activation, and stage N3 exhibited the least between-night variability ( CONCLUSIONS: A strong agreement was observed between the automated sleep staging and human-scored PSG. One night's recording appeared sufficient to characterize abnormal slow wave sleep, sleep spindle activity, and heart rate variability in patients, but a 2-night average improved the assessment of all other sleep biomarkers. COMMENTARY: Two commentaries on this article appear in this issue on pages 771 and 773.

3 Article Efficacy of the Mantram Repetition Program for Insomnia in Veterans With Posttraumatic Stress Disorder: A Naturalistic Study. 2017

Beck, Danielle / Cosco Holt, Lindsay / Burkard, Joseph / Andrews, Taylor / Liu, Lin / Heppner, Pia / Bormann, Jill E. ·Veterans Affairs San Diego Healthcare System, San Diego, California (Ms Beck, Ms Andrews, and Drs Liu, Heppner, and Bormann) · Hahn School of Nursing & Health Sciences/Beyster Institute of Nursing Research, University of San Diego, San Diego, California (Drs Cosco Holt, Burkard, and Bormann) · Department of Family Medicine and Public Health (Dr Liu) and Department of Psychiatry (Dr Heppner), University of California, San Diego · and Veterans Affairs San Diego Center of Excellence for Stress & Mental Health, San Diego, California (Dr Bormann). ·ANS Adv Nurs Sci · Pubmed #27525960.

ABSTRACT: Statistics show that more than 80% of Veterans mention posttraumatic stress disorder (PTSD)-related symptoms when seeking treatment. Sleep disturbances and nightmares are among the top 3 presenting problems. Current PTSD trauma-focused therapies generally do not improve sleep disturbances. The mantram repetition program (MRP), a mind-body-spiritual intervention, teaches a portable set of cognitive-spiritual skills for symptom management. The aim of this study was to evaluate the efficacy of the MRP on insomnia in Veterans with PTSD in a naturalistic, clinical setting. Results show that participation in the MRP significantly reduced insomnia, as well as decreased self-reported and clinician-assessed PTSD symptom burden.

4 Article Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder. 2016

Ballard, Elizabeth D / Vande Voort, Jennifer L / Bernert, Rebecca A / Luckenbaugh, David A / Richards, Erica M / Niciu, Mark J / Furey, Maura L / Duncan, Wallace C / Zarate, Carlos A. ·Bldg 10, CRC Room 7-5345, 10 Center Drive, MSC 1282, Bethesda, MD 20892. Elizabeth.Ballard@nih.gov. · Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. · Suicide Prevention Research Laboratory, Stanford Mood Disorders Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA. · Janssen Pharmaceuticals, Neuroscience Research and Development, La Jolla, California, USA. ·J Clin Psychiatry · Pubmed #27337418.

ABSTRACT: OBJECTIVE: Self-reported sleep disturbances may confer elevated risk for suicidal ideation, suicide attempts, and death. However, limited research has evaluated polysomnographically determined sleep disturbance as an acute physiologic risk factor for suicidal thoughts. This study sought to investigate the relationship between nocturnal wakefulness in association with next-day suicidal ideation using overnight polysomnography assessment from data collected between 2006 and 2013. METHODS: Sixty-five participants with DSM-IV-diagnosed major depressive disorder or bipolar depression underwent overnight polysomnography monitoring in a sleep laboratory. The Hamilton Depression Rating Scale (HDRS) was administered the morning after polysomnography recording to assess next-day suicidal ideation, severity of depressive symptoms, and subjective sleep disturbances. RESULTS: Using a generalized linear mixed model, a significant time-by-ideation interaction was found indicating greater nocturnal wakefulness at 4:00 am among participants with suicidal ideation (F4,136 = 3.65, P = .007). Increased time awake during the 4:00 am hour (4:00 to 4:59) was significantly associated with elevated suicidal thoughts the next day (standardized β = 0.31, P = .008). This relationship persisted after controlling for age, gender, diagnosis, and severity of depressive symptoms. CONCLUSIONS: Greater nocturnal wakefulness, particularly in the early morning hours, was significantly associated with next-day suicidal thoughts. Polysomnographically documented sleep disruption at specific times of night may represent an acute risk factor of suicidal ideation that warrants additional research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00024635.

5 Article Sleep and Health Resilience Metrics in a Large Military Cohort. 2016

Seelig, Amber D / Jacobson, Isabel G / Donoho, Carrie J / Trone, Daniel W / Crum-Cianflone, Nancy F / Balkin, Thomas J. ·Naval Health Research Center, San Diego, CA. · Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD. · Naval Medical Center San Diego, San Diego, CA. · Behavioral Biology Branch, Walter Reed Army Institute of Research, Silver Spring, MD. ·Sleep · Pubmed #26951391.

ABSTRACT: STUDY OBJECTIVES: Examine the relationship between self-reported sleep parameters and indicators of resilience in a US military population (n = 55,021). METHODS: Longitudinal analyses (2001-2008) were conducted using subjective data collected from Millennium Cohort Study questionnaires and objective data from military records that included demographics, military health, and deployment information. Subjective sleep duration and insomnia symptoms were collected on the study questionnaire. Resilience metrics included lost work days, self-rated health, deployment, frequency and duration of health care utilization, and early discharge from the military. Generalized estimating equations and survival analyses were adjusted for demographic, military, behavioral, and health covariates in all models. RESULTS: The presence of insomnia symptoms was significantly associated with lower self-rated health, more lost work days, lower odds of deployment, higher odds of early discharge from military service early, and more health care utilization. Those self-reporting < 6 h (short sleepers) or > 8 h (long sleepers) of sleep per night had similar findings, except for the deployment outcome in which those with the shortest sleep were more likely to deploy. CONCLUSIONS: Poor sleep is a detriment to service members' health and readiness. Leadership should redouble efforts to emphasize the importance of healthy sleep among military service members, and future research should focus on the efficacy of interventions to promote healthy sleep and resilience in this population. COMMENTARY: A commentary on this article appears in this issue on page 963.

6 Article Polysomnographic Study of Sleep in Survivors of Breast Cancer. 2015

Reinsel, Ruth A / Starr, Tatiana D / O'Sullivan, Barbara / Passik, Steven D / Kavey, Neil B. ·National Sleep Research Institute, New York, NY. · Department of Anesthesiology, Stony Brook Medicine, Stony Brook, NY. · Department of Psychiatry & Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY. · The Rockefeller University Hospital, New York, NY. · Millennium Research Institute, San Diego, CA. · Department of Psychiatry, Columbia University Medical Center, New York, NY. ·J Clin Sleep Med · Pubmed #26194735.

ABSTRACT: STUDY OBJECTIVE: Insomnia is a frequent complaint in breast cancer patients during and after treatment. Breast cancer survivors, 1-10 years posttreatment, underwent in-lab polysomnography (PSG) to objectively define the insomnia in those patients with such a complaint. METHODS: Twenty-six breast cancer survivors (aged 39-80, mean 54.0 months posttreatment) spent 2 nights in the sleep laboratory. Sleep on Night 2 was scored for sleep stages, sleep onset latency, REM sleep onset latency, wake time, apneas and hypopneas, periodic limb movements and arousals. Subjects were allocated into 2 groups by their scores on the Pittsburgh Sleep Quality Index (PSQI): no/ mild sleep disturbance (PSQI score ≤ 9, n = 15) or moderate/ severe sleep disturbance (PSQI ≥ 10, n = 11). RESULTS: Standard PSG/EEG parameters failed to differentiate insomniacs from non-insomniacs. The single variable that distinguished the insomnia group was periodic limb movements in sleep (PLMS). PLMS were significantly correlated (r ≅ 0.7, p < 0.02) with subjective report of insomnia on PSQI and insomnia severity index. Log[Number of PLMS] was higher in the moderate/severe insomnia group (p = 0.008). Five of 11 patients in the moderate/severe insomnia group had a PLMS index ≥ 15, compared to only one of 15 patients in the none/mild insomnia group (p = 0.02). Menopausal symptoms and use of caffeine, hypnotics, and antidepressants were unrelated to insomnia severity or PLMS. CONCLUSIONS: PLMS was the sole PSG variable that separated breast cancer survivors with moderate/severe insomnia from those with no/mild sleep disturbance. Further study of the incidence and significance of PLMS in breast cancer survivors with the complaint of insomnia is merited.

7 Article Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia. 2015

Bonaventure, Pascal / Shelton, Jonathan / Yun, Sujin / Nepomuceno, Diane / Sutton, Steven / Aluisio, Leah / Fraser, Ian / Lord, Brian / Shoblock, James / Welty, Natalie / Chaplan, Sandra R / Aguilar, Zuleima / Halter, Robin / Ndifor, Anthony / Koudriakova, Tatiana / Rizzolio, Michele / Letavic, Michael / Carruthers, Nicholas I / Lovenberg, Timothy / Dugovic, Christine. ·Janssen Research & Development, LLC, San Diego, California Pbonave1@its.jnj.com CDugovic@its.jnj.com. · Janssen Research & Development, LLC, San Diego, California. ·J Pharmacol Exp Ther · Pubmed #26177655.

ABSTRACT: Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone), a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia.

8 Article Assessment of Sleep Disruption and Sleep Quality in Naval Special Warfare Operators. 2015

Harris, Erica / Taylor, Marcus K / Drummond, Sean P A / Larson, Gerald E / Potterat, Eric G. ·Health and Behavioral Sciences Department, Naval Health Research Center, 140 Sylvester Road, San Diego, CA 92106. · Warfighter Performance, Naval Health Research Center, 140 Sylvester Road, San Diego, CA 92106. · Veterans Affairs Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161. · Naval Special Warfare Command, 2000 Trident Way, Building 603M, San Diego, CA 92155. ·Mil Med · Pubmed #26126252.

ABSTRACT: Little is known about sleep in elite military populations who are exposed to higher operational demands, unpredictable training, deployment, and mission cycles. Twenty-nine Naval Special Warfare (NSW) Operators wore an actiwatch for an 8-day/7-night period for objective sleep assessment and completed a nightly sleep log. A total of 170 nights of actigraphically recorded sleep were collected. When comparing objectively versus subjectively recorded sleep parameter data, statistically significant differences were found. Compared with sleep log data, actigraphy data indicate NSW Operators took longer to fall asleep (an average of 25.82 minutes), spent more time awake after sleep onset (an average of 39.55 minutes), and demonstrated poorer sleep efficiency (83.88%) (ps < 0.05). Self-reported sleep quality during the study period was 6.47 (maximum score = 10). No relationships existed between the objectively derived sleep indices and the self-reported measure of sleep quality (rs = -0.29 to 0.09, all ps > 0.05). Strong inter-relationships existed among the subjectively derived sleep indices (e.g., between self-reported sleep quality and sleep efficiency; r = 0.61, p < 0.001). To our knowledge, this is the first study to objectively and subjectively quantify sleep among NSW Operators. These findings suggest sleep maintenance and sleep efficiency are impaired when compared to normative population data.

9 Article Prevalence and Mental Health Correlates of Insomnia in First-Encounter Veterans with and without Military Sexual Trauma. 2015

Jenkins, Melissa M / Colvonen, Peter J / Norman, Sonya B / Afari, Niloofar / Allard, Carolyn B / Drummond, Sean P A. ·Department of Psychiatry, University of California, San Diego, CA. · Research Service, VA San Diego Healthcare System, San Diego, CA. · Psychology Services, VA San Diego Healthcare System, San Diego, CA. · Center of Excellence for Stress and Mental Health (CESAMH), San Diego, CA. · National Center for PTSD, White River Junction, VT. · School of Psychological Sciences, Monash University, Clayton, VIC, Australia. ·Sleep · Pubmed #26085301.

ABSTRACT: STUDY OBJECTIVES: There is limited information about prevalence of insomnia in general populations of veterans of recent wars in Iraq and Afghanistan. No studies have examined insomnia in veterans with military sexual trauma (MST). We assess prevalence of insomnia, identify types of services sought by veterans with insomnia, and examine correlates of insomnia in veterans with and without MST. DESIGN: A cross-sectional study of first-encounter veterans registering to establish care. SETTING: Veteran Affairs San Diego Healthcare System. PARTICIPANTS: Nine hundred seventeen veterans completed questionnaires assessing insomnia, MST, service needs, traumatic brain injury, resilience, and symptoms of depression, posttraumatic stress disorder (PTSD), pain, alcohol misuse, and hypomania. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: 53.1% of veterans without MST and 60.8% of veterans with MST had clinically significant insomnia symptoms, with the MST subsample reporting more severe symptoms, P < 0.05. Insomnia was more prevalent than depression, hypomania, PTSD, and substance misuse. Veterans with insomnia were more likely to seek care for physical health problems and primary care versus mental health concerns, P < 0.001. For the veteran sample without MST, age, combat service, traumatic brain injury, pain, and depression were associated with worse insomnia, P < 0.001. For the MST subsample, employment status, pain, and depression were associated with worse insomnia, P < 0.001. CONCLUSIONS: Study findings indicate a higher rate of insomnia in veterans compared to what has been found in the general population. Insomnia is more prevalent, and more severe, in veterans with military sexual trauma. Routine insomnia assessments and referrals to providers who can provide evidence-based treatment are crucial.

10 Article Auricular acupuncture for sleep disturbance in veterans with post-traumatic stress disorder: a feasibility study. 2015

King, Heather C / Spence, Dennis L / Hickey, Anita H / Sargent, Paul / Elesh, Ronald / Connelly, Cynthia D. ·Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134. · US Naval Hospital Okinawa, PSC 482, FPO AP 96362-1600. · University of San Diego, 5998 Alcala Drive, San Diego, CA 92110. ·Mil Med · Pubmed #25939115.

ABSTRACT: The purpose of this study was to examine the feasibility and acceptability of an auricular acupuncture (AA) insomnia regimen among Operation Iraqi Freedom and Operation Enduring Freedom veterans with post-traumatic stress disorder and sleep disturbance. Secondarily, this study examined the effect of an AA insomnia regimen on objective sleep times by wrist actigraphy, subjective sleep times by sleep diary, and sleep quality ratings utilizing the Pittsburg Sleep Quality Index. Veterans (n = 30) were randomized to receive a 3-week AA insomnia regimen. Veterans receiving the AA insomnia regimen reported it as a more acceptable treatment for sleep disturbance than subjects in the control group (AA group median = 5 vs. control group median = 3, p = 0.004). Significant differences between groups were found on the sleep quality and daytime dysfunction components of the Pittsburgh Sleep Quality Index (p = 0.003, p = 0.004). No other significant differences between groups were found for objective and subjective sleep measures. These results suggest that an AA insomnia regimen may improve sleep quality and daytime dysfunction among veterans with post-traumatic stress disorder. Future, large-scale, prospective clinical trials are needed to examine AA effects on sleep.

11 Article Identification of fused bicyclic heterocycles as potent and selective 5-HT(2A) receptor antagonists for the treatment of insomnia. 2012

Xiong, Yifeng / Ullman, Brett / Choi, Jin-Sun Karoline / Cherrier, Martin / Strah-Pleynet, Sonja / Decaire, Marc / Feichtinger, Konrad / Frazer, John M / Yoon, Woo H / Whelan, Kevin / Sanabria, Erin K / Grottick, Andrew J / Al-Shamma, Hussien / Semple, Graeme. ·Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. yxiong@arenapharm.com ·Bioorg Med Chem Lett · Pubmed #22325948.

ABSTRACT: A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.

12 Article Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H₁-antihistamines for insomnia. 2012

Ravula, Satheesh Babu / Yu, Jinghua / Tran, Joe A / Arellano, Melissa / Tucci, Fabio C / Moree, Wilna J / Li, Bin-Feng / Petroski, Robert E / Wen, Jianyun / Malany, Siobhan / Hoare, Samuel R J / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. satheesh.ravula@gmail.com ·Bioorg Med Chem Lett · Pubmed #22153347.

ABSTRACT: The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.

13 Article Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia. 2010

Moree, Wilna J / Li, Bin-Feng / Zamani-Kord, Said / Yu, Jinghua / Coon, Timothy / Huang, Charles / Marinkovic, Dragan / Tucci, Fabio C / Malany, Siobhan / Bradbury, Margaret J / Hernandez, Lisa M / Wen, Jianyun / Wang, Hua / Hoare, Samuel R J / Petroski, Robert E / Jalali, Kayvon / Yang, Chun / Sacaan, Aida / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. wilna.moree@gmail.com ·Bioorg Med Chem Lett · Pubmed #20800486.

ABSTRACT: Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.

14 Article Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia. 2010

Xiong, Yifeng / Ullman, Brett / Choi, Jin-Sun Karoline / Cherrier, Martin / Strah-Pleynet, Sonja / Decaire, Marc / Dosa, Peter I / Feichtinger, Konrad / Teegarden, Bradley R / Frazer, John M / Yoon, Woo H / Shan, Yun / Whelan, Kevin / Hauser, Erin K / Grottick, Andrew J / Semple, Graeme / Al-Shamma, Hussien. ·Arena Pharmaceuticals, San Diego, California 92121, USA. yxiong@arenapharm.com ·J Med Chem · Pubmed #20684606.

ABSTRACT: Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.

15 Article The discovery and structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles as selective, CNS penetrating H1-antihistamines for insomnia. 2010

Lavrador-Erb, Karine / Ravula, Satheesh Babu / Yu, Jinghua / Zamani-Kord, Said / Moree, Wilna J / Petroski, Robert E / Wen, Jianyun / Malany, Siobhan / Hoare, Samuel R J / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. ·Bioorg Med Chem Lett · Pubmed #20347297.

ABSTRACT: A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.

16 Article Selectivity profiling of novel indene H(1)-antihistamines for the treatment of insomnia. 2010

Li, Bin-Feng / Moree, Wilna J / Yu, Jinghua / Coon, Timothy / Zamani-Kord, Said / Malany, Siobhan / Jalali, Kayvon / Wen, Jianyun / Wang, Hua / Yang, Chun / Hoare, Samuel R J / Petroski, Robert E / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, San Diego, CA 92130, USA. ·Bioorg Med Chem Lett · Pubmed #20227880.

ABSTRACT: A series of indene analogs of the H(1)-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H(1)-antihistamines with desirable selectivity over CYP enzymes, the M(1) muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.

17 Article Novel benzothiophene H1-antihistamines for the treatment of insomnia. 2010

Moree, Wilna J / Jovic, Florence / Coon, Timothy / Yu, Jinghua / Li, Bin-Feng / Tucci, Fabio C / Marinkovic, Dragan / Gross, Raymond S / Malany, Siobhan / Bradbury, Margaret J / Hernandez, Lisa M / O'Brien, Zhihong / Wen, Jianyun / Wang, Hua / Hoare, Samuel R J / Petroski, Robert E / Sacaan, Aida / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. wilna.moree@gmail.com ·Bioorg Med Chem Lett · Pubmed #20188547.

ABSTRACT: SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.

18 Article Discovery of 1-[3-(4-bromo-2-methyl-2h-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (nelotanserin) and related 5-hydroxytryptamine2A inverse agonists for the treatment of insomnia. 2010

Teegarden, Bradley R / Li, Hongmei / Jayakumar, Honnappa / Strah-Pleynet, Sonja / Dosa, Peter I / Selaya, Susan D / Kato, Naomi / Elwell, Katie H / Davidson, Jarrod / Cheng, Karen / Saldana, Hazel / Frazer, John M / Whelan, Kevin / Foster, Jonathan / Espitia, Stephan / Webb, Robert R / Beeley, Nigel R A / Thomsen, William / Morairty, Stephen R / Kilduff, Thomas S / Al-Shamma, Hussien A. ·Arena Pharmaceuticals, Inc, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. bradteegarden@ymail.com ·J Med Chem · Pubmed #20143782.

ABSTRACT: Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.

19 Article Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia. 2009

Moree, Wilna J / Li, Bin-Feng / Jovic, Florence / Coon, Timothy / Yu, Jinghua / Gross, Raymond S / Tucci, Fabio / Marinkovic, Dragan / Zamani-Kord, Said / Malany, Siobhan / Bradbury, Margaret J / Hernandez, Lisa M / O'Brien, Zhihong / Wen, Jianyun / Wang, Hua / Hoare, Samuel R J / Petroski, Robert E / Sacaan, Aida / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA. ·J Med Chem · Pubmed #19663387.

ABSTRACT: Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.

20 Article Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia. 2009

Coon, Timothy / Moree, Wilna J / Li, Binfeng / Yu, Jinghua / Zamani-Kord, Said / Malany, Siobhan / Santos, Mark A / Hernandez, Lisa M / Petroski, Robert E / Sun, Aixia / Wen, Jenny / Sullivan, Sue / Haelewyn, Jason / Hedrick, Michael / Hoare, Samuel J / Bradbury, Margaret J / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. ·Bioorg Med Chem Lett · Pubmed #19553115.

ABSTRACT: The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.

21 Article The effects of respiratory sinus arrhythmia biofeedback on heart rate variability and posttraumatic stress disorder symptoms: a pilot study. 2009

Zucker, Terri L / Samuelson, Kristin W / Muench, Frederick / Greenberg, Melanie A / Gevirtz, Richard N. ·Alliant International University, San Diego, CA, USA. terrilynz@aol.com ·Appl Psychophysiol Biofeedback · Pubmed #19396540.

ABSTRACT: Recent studies have found a significant association between PTSD and low heart rate variability (HRV), a biomarker of autonomic dysregulation. Research indicates that respiratory sinus arrhythmia (RSA) biofeedback increases HRV while reducing related pathological symptoms. This controlled pilot study compared RSA biofeedback to progressive muscle relaxation (PMR) as adjunctive interventions for 38 persons with PTSD symptoms in a residential treatment facility for a substance use disorder. Both groups were assessed at pre-intervention and 4-week post-intervention. Group x time interactions revealed significantly greater reductions in depressive symptoms and increases in HRV indices for the RSA group. Both groups significantly reduced PTSD and insomnia symptoms and a statistical trend was observed for reduced substance craving for the RSA group. Increases in HRV were significantly associated with PTSD symptom reduction. Overall, these results provide preliminary support for the efficacy of RSA biofeedback in improving physiological and psychological health for individuals with PTSD.