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Sheldon H Preskorn
This column is the fifth in a series examining the advances being made in central nervous system drug development because of advances in molecular pharmacology and an improved understanding of the neurobiology underlying disturbances in brain function including psychiatric illnesses. This column covers the special animal and human studies conducted as part of the development of suvorexant, which is the first in the class of dual orexin 1 and 2 receptor antagonists to be approved; it has an indication for the treatment of disturbances in sleep onset and maintenance...
March 2018: Journal of Psychiatric Practice
William D Blincoe, Agustina Rodriguez-Granillo, Josep Saurí, Nicholas A Pierson, Leo A Joyce, Ian Mangion, Huaming Sheng
Benzoic acid/ester/amide derivatives are common moieties in pharmaceutical compounds and present a challenge in positional isomer identification by traditional tandem mass spectrometric analysis. A method is presented for exploiting the gas-phase neighboring group participation (NGP) effect to differentiate ortho-substituted benzoic acid/ester derivatives with high resolution mass spectrometry (HRMS1 ). Significant water/alcohol loss (>30% abundance in MS1 spectra) was observed for ortho-substituted nucleophilic groups; these fragment peaks are not observable for the corresponding para and meta-substituted analogs...
February 27, 2018: Journal of the American Society for Mass Spectrometry
Tobias Atkin, Stefano Comai, Gabriella Gobbi
Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs...
April 2018: Pharmacological Reviews
Qifeng Bai, Horacio Pérez-Sánchez, Zhuoyu Shi, Lanlan Li, Danfeng Shi, Huanxiang Liu, Xiaojun Yao
The FDA approved drug suvorexant binds to the horseshoe shape pocket of OX 2 R with the boat conformation. The horseshoe shape pocket plays an important role on the biological activity of OX 2 R in the cell membrane. To study the binding mechanism between the horseshoe shape pocket of OX 2 R and boat conformation of suvorexant, the crystal structures of wild type and N324A mutant of OX 2 R in complex with antagonist suvorexant are chosen to perform molecular dynamics (MD) simulations, QM/MM and MMGBSA calculations...
February 16, 2018: Chemical Biology & Drug Design
Rajesh R Tampi, Geetha Manikkara, Silpa Balachandran, Piyush Taparia, Stephanie Hrisko, Shilpa Srinivasan, Deena J Tampi
The aim of this review was to identify published randomized control trials (RCTs) that evaluated the efficacy and tolerability of suvorexant for the treatment of insomnia among older adults (≥65 years). A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases for RCTs in any language evaluating suvorexant for the treatment of insomnia in older adults. Additionally, references of full-text articles that were included in this review were searched for further studies...
2018: Drugs in Context
Tomoyuki Masuyama, Masamitsu Sanui, Naoto Yoshida, Yusuke Iizuka, Kunio Ogi, Satoko Yagihashi, Kanae Nagatomo, Yusuke Sasabuchi, Alan K Lefor
BACKGROUND: Benzodiazepine use is a risk factor for the development of delirium in adult intensive care unit (ICU) patients. Suvorexant is an alternative to benzodiazepines to induce sleep, but the incidence of delirium in critically ill patients is unknown. We undertook this retrospective study to investigate the incidence of delirium in patients who receive suvorexant in the ICU. METHODS: This retrospective cohort study was conducted in a closed 12-bed ICU at a tertiary teaching hospital...
February 8, 2018: Psychogeriatrics: the Official Journal of the Japanese Psychogeriatric Society
Sheldon H Preskorn
This is the fourth in a series of columns discussing the rational and targeted development of drugs to affect specific central nervous system (CNS) circuits in specific ways based on knowledge gained by molecular biology and the human genome project. The first column in this series described 6 CNS drugs with novel mechanisms of action developed over the last 25 years. The second column discussed differences between syndromic diagnoses as exemplified by the third through the fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM III through DSM-5) and the new approach to psychiatric diagnoses championed by the National Institute of Mental Health in their Research Domain Criteria Initiative...
November 2017: Journal of Psychiatric Practice
Brian Waters, Kenji Hara, Natsuki Ikematsu, Mio Takayama, Aya Matsusue, Masayuki Kashiwagi, Shin-Ichi Kubo
Suvorexant (Belsomra®) is a relatively new insomnia medication that has been available in USA and Japan since 2014. It is a dual orexin receptor antagonist that promotes sleep by inhibiting the binding of orexin neurons to the OX1R and OX2R receptors. In this report, we describe the detection and quantitation of suvorexant from the postmortem specimens of three separate autopsy cases handled by our department. Suvorexant was identified by fast gas chromatography/mass spectrometry during routine screening, and quantitated by a fully validated liquid chromatography-tandem mass spectroscopy method...
December 28, 2017: Journal of Analytical Toxicology
Hiroshi Tsuneki, Tsutomu Wada, Toshiyasu Sasaoka
Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus...
December 28, 2017: Pharmacology & Therapeutics
Atsushi Hamuro, Minoru Honda, Yuya Wakaura
No abstract text is available yet for this article.
December 1, 2017: Australian and New Zealand Journal of Psychiatry
Ryoji Suno, Kanako Terakado Kimura, Takanori Nakane, Keitaro Yamashita, Junmei Wang, Takaaki Fujiwara, Yasuaki Yamanaka, Dohyun Im, Shoichiro Horita, Hirokazu Tsujimoto, Maki S Tawaramoto, Takatsugu Hirokawa, Eriko Nango, Kensuke Tono, Takashi Kameshima, Takaki Hatsui, Yasumasa Joti, Makina Yabashi, Keiko Shimamoto, Masaki Yamamoto, Daniel M Rosenbaum, So Iwata, Tatsuro Shimamura, Takuya Kobayashi
Orexin peptides in the brain regulate physiological functions such as the sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using serial femtosecond crystallography and multi-crystal data collection with a synchrotron light source, we determined structures of human orexin 2 receptor in complex with the subtype-selective antagonist EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) at 2.30-Å and 1.96-Å resolution. In comparison with the non-subtype-selective antagonist suvorexant, EMPA contacted fewer residues through hydrogen bonds at the orthosteric site, explaining the faster dissociation rate...
January 2, 2018: Structure
Vladimir Svetnik, Ellen S Snyder, Peining Tao, Thomas E Scammell, Thomas Roth, Christopher Lines, W Joseph Herring
Objectives: To examine the duration and frequency of wake bouts underlying the wakefulness-after-sleep-onset (WASO) reduction with suvorexant. Methods: We analyzed polysomnogram recordings from clinical trials involving 1518 insomnia patients receiving suvorexant (40/30mg, 20/15mg) or placebo to determine: 1) the number of, and time spent in, long or short wake bouts, 2) the association between sleep quality and bout characteristics. We also compared wake and sleep bout characteristics of suvorexant in insomnia patients versus zolpidem in healthy subjects undergoing experimentally-induced transient insomnia...
November 3, 2017: Sleep
Jeremy Petrous, Kevin Furmaga
A 59-year-old woman on daily peritoneal dialysis for end-stage renal failure received care at an outpatient psychiatric clinic for her diagnoses that include major depressive disorder, generalised anxiety disorder and insomnia disorder. Although there was partial improvement in the patient's mood and anxiety symptoms with antidepressant treatment, insomnia remained a persistent complaint despite adequate trials of different sleep medications. The novel hypnotic, suvorexant (Belsomra, Merck & Co.) was then initiated at the recommended bedtime dose of 10 mg and was followed by a 15 mg dose the following night...
October 23, 2017: BMJ Case Reports
Nicholas A Keks, Judy Hope, Simone Keogh
OBJECTIVE: Suvorexant, a new hypnotic, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance, and is used long-term. This paper will briefly review suvorexant. RESULTS: Orexin is a hypothalamic peptide which promotes wakefulness. By blocking orexin receptors, suvorexant induces sleep. Peaking 2 h after ingestion, it has a half-life of 12 h and is hepatically metabolized mainly by CYP3A. Kinetics are not affected by age but concentrations are higher in females and obese patients...
December 2017: Australasian Psychiatry: Bulletin of Royal Australian and New Zealand College of Psychiatrists
Sum Lam, Lucy O Macina
OBJECTIVE: To offer an update on insomnia in older adults and treatment options. DATA SOURCES: A search of PubMed using the terms "insomnia" and "older adults" was performed. Current guidelines, review articles, and drug database and manufacturer package inserts were utilized to provide relevant information. STUDY SELECTION: All English-language articles from 2012 to February 2017 and their bibliographies were reviewed for relevance...
October 1, 2017: Consultant Pharmacist: the Journal of the American Society of Consultant Pharmacists
(no author information available yet)
No abstract text is available yet for this article.
June 2017: Australian Prescriber
Kotaro Hatta, Yasuhiro Kishi, Ken Wada, Takashi Takeuchi, Shigeo Ito, Akiko Kurata, Kazunori Murakami, Manabu Sugita, Chie Usui, Hiroyuki Nakamura
OBJECTIVE: No highly effective pharmacologic interventions to prevent delirium have been identified. We examined whether suvorexant, a potent and selective orexin receptor antagonist, is effective for the prevention of delirium. METHODS: We conducted a multicenter, rater-blinded, randomized, placebo-controlled clinical trial in intensive care units and regular acute wards between April 2015 and March 2016. Eligible patients were 65 to 89 years old, newly admitted due to emergency, and able to take medicine orally and had an expected stay or life expectancy of 48 hours or more...
September 2017: Journal of Clinical Psychiatry
Taylor A Gentile, Steven J Simmons, Mia N Watson, Krista L Connelly, Eugen Brailoiu, Yanan Zhang, John W Muschamp
Hypothalamic hypocretin (orexin) peptides mediate arousal, attention, and reward processing. Fibers containing orexins project to brain structures that govern motivated behavior, including the ventral tegmental area (VTA). A number of psychiatric conditions, including attention deficit hyperactivity disorder (ADHD) and substance use disorders, are characterized by deficits in impulse control, however the relationship between orexin and impulsive behavior is incompletely characterized. The effects of systemic or centrally administered orexin receptor (OXR) antagonists on measures of impulsive-like behavior in rats were evaluated using the five-choice serial reaction time task (5-CSRTT) and delay discounting procedures...
July 25, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Eisuke Booka, Yasuhiro Tsubosa, Teruaki Matsumoto, Mari Takeuchi, Takashi Kitani, Masato Nagaoka, Atsushi Imai, Tomoyuki Kamijo, Yoshiyuki Iida, Ayako Shimada, Katsushi Takebayashi, Masahiro Niihara, Keita Mori, Tetsuro Onitsuka, Hiroya Takeuchi, Yuko Kitagawa
BACKGROUND: Postoperative delirium is common after extensive surgery, and is known to be associated with sleeping medications. In this study, we aimed to investigate the relationships between sleeping medications and postoperative delirium after pharyngolaryngectomy with esophagectomy. METHODS: We performed a retrospective analysis of 65 patients who underwent pharyngolaryngectomy with esophagectomy at Shizuoka Cancer Center Hospital between January 2012 and March 2016...
2017: Esophagus: Official Journal of the Japan Esophageal Society
Eric Matheson, Barry L Hainer
Insomnia accounts for more than 5.5 million visits to family physicians each year. Although behavioral interventions are the mainstay of treatment, pharmacologic therapy may be necessary for some patients. Understanding the risks and benefits of insomnia medications is critical. Controlled-release melatonin and doxepin are recommended as first-line agents in older adults; the so-called z-drugs (zolpidem, eszopiclone, and zaleplon) should be reserved for use if the first-line agents are ineffective. For the general population with difficulty falling asleep, controlled-release melatonin and the z-drugs can be considered...
July 1, 2017: American Family Physician
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