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Archive for the ‘Circadian Rhythm and Sleep’ Category


NSPR1 and DEC2 genes: Survival on 4.5 hours of Sleep per night: A mutation in the β1-adrenergic receptor gene in humans who require fewer hours of sleep than most, ADRB1 + neurons are active during rapid eye movement (REM) sleep and wakefulness

 

Reporter: Aviva Lev-Ari, PhD, RN

 

10/2019 RESEARCH ARTICLE SLEEP

Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation

 See all authors and affiliations

Science Translational Medicine  16 Oct 2019:
Vol. 11, Issue 514, eaax2014
DOI: 10.1126/scitranslmed.aax2014

Abstract

Sleep is a crucial physiological process for our survival and cognitive performance, yet the factors controlling human sleep regulation remain poorly understood. Here, we identified a missense mutation in a G protein–coupled neuropeptide S receptor 1 (NPSR1) that is associated with a natural short sleep phenotype in humans. Mice carrying the homologous mutation exhibited less sleep time despite increased sleep pressure. These animals were also resistant to contextual memory deficits associated with sleep deprivation. In vivo, the mutant receptors showed increased sensitivity to neuropeptide S exogenous activation. These results suggest that the NPS/NPSR1 pathway might play a critical role in regulating human sleep duration and in the link between sleep homeostasis and memory consolidation.

It is possible that drugs could be developed to target either the NSPR1 or DEC2 genes, as a treatment for insomnia or other sleep disorders. However, further understanding of exactly how these genes function would be required before this stage. Both are involved in brain function, so targeting them could lead to negative neural side effects.

 

Neuron

Volume 103, Issue 6, 25 September 2019, Pages 1044-1055.e7

A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors

Highlights

  • A mutation in ADRB1 leads to natural short sleep trait in humans
  • Mice engineered with same mutation have similar short sleep behavior as humans
  • Activity of dorsal pons ADRB1 + neurons associates with REM sleep and wakefulness
  • Mutation increases the population activity of dorsal pons ADRB1 + neurons

Summary

Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with poor sleep, a greater understanding of sleep regulation is necessary. We have identified a mutation in the β 1-adrenergic receptor gene in humans who require fewer hours of sleep than most. In vitro, this mutation leads to decreased protein stability and dampened signaling in response to agonist treatment. In vivo, the mice carrying the same mutation demonstrated short sleep behavior. We found that this receptor is highly expressed in the dorsal pons and that these ADRB1 + neurons are active during rapid eye movement (REM) sleep and wakefulness. Activating these neurons can lead to wakefulness, and the activity of these neurons is affected by the mutation. These results highlight the important role of β 1-adrenergic receptors in sleep/wake regulation.

Keywords

Additional SOURCES

Second Gene Mutation that Lets People Survive on Less Sleep

 

Other related articles on Circadian Rhythm and Sleep published in this Open Access Online Scientific Journal include the following:

 

2017 Nobel Prize in Physiology or Medicine jointly to Jeffrey C. Hall (ex-Brandeis, University of Maine), Michael Rosbash (Brandeis University) and Michael W. Young (Rockefeller University in New York) for their discoveries of molecular mechanisms controlling the circadian rhythm

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/10/02/2017-nobel-prize-in-physiology-or-medicine-jointly-to-jeffrey-c-hall-michael-rosbash-and-michael-w-young-for-their-discoveries-of-molecular-mechanisms-controlling-the-circadian-rhythm/

 

Patient-Reported Outcomes Study, Presented at SLEEP 2018, Provides Confirmatory Real-World Evidence of the Previously Presented 7-hour Action of REMfresh®, the First Continuous Release and Absorption Melatonin™

Reporter: Gail S. Thornton, PhD(c)

https://pharmaceuticalintelligence.com/2018/06/10/patient-reported-outcomes-study-presented-at-sleep-2018-provides-confirmatory-real-world-evidence-of-the-previously-presented-7-hour-action-of-remfresh-the-first-continuous-release-and-absorp/

 

Clinically Studied, Continuous Release and Absorption Melatonin, REMfresh, Designed to Give Patients Up to 7 Hours of Sleep Support

Reporter: Gail S. Thornton, M.A.

https://pharmaceuticalintelligence.com/2019/06/19/clinically-studied-continuous-release-and-absorption-melatonin-remfresh-designed-to-give-patients-up-to-7-hours-of-sleep-support/

 

2017 award recipients including Thomas S. Kilduff, PhD, Director, Center for Neuroscience at SRI International in Menlo Park, California

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/04/28/sleep-research-society-announces-2017-award-recipients-including-thomas-s-kilduff-phd-director-center-for-neuroscience-at-sri-international-in-menlo-park-california/

 

Sleep and Memory

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/26/sleep-and-memory/

 

Sleep Science

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/16/sleep-science/

 

Genetic Link to Sleep and Mood Disorders

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

 

Sleep Apnea Insular Glutamate and GABA Levels

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/02/12/sleep-apnea-insular-glutamate-and-gaba-levels/

 

Fat, Sleep and the Gut

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/02/06/fat-sleep-and-the-gut/

 

23andMe Genome-Wide Association Study on Human propensity to Get up early or Sleep in the Morning

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/02/02/23andme-genome-wide-association-study-on-human-propensity-to-get-up-early-or-sleep-in-the-morning/

 

Sleep Quality, Amyloid and Cognitive Decline

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

 

Study Shows Learning Is Best Enhanced During Sleep – Jewish Business News

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/02/study-shows-learning-is-best-enhanced-during-sleep-jewish-business-news/

 

Beta-Blockers Cause Lack Of Restful Sleep – Life Extension

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/08/04/beta-blockers-cause-lack-of-restful-sleep-life-extension/

 

Topical Antispasmodics conducive for Uninterrupted Sleep – A Potential Cardiovascular Chrono-therapeutics

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/13/topical-antispasmodics-conducive-for-uninterrupted-sleep-a-potential-cardiovascular-chrono-therapeutics/

 

Prolonged Wakefulness: Lack of Sufficient Duration of Sleep as a Risk Factor for Cardiovascular Diseases – Indications for Cardiovascular Chrono-therapeutics

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/02/prolonged-wakefulness-lack-of-sufficient-duration-of-sleep-as-a-risk-factor-for-cardiovascular-diseases-indications-for-cardiovascular-chrono-therapeutics/

 

Sleep Apnea and Non-invasive positive Pressure Breathing

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/06/11/sleep-apnea-and-non-invasive-positive-pressure-breathing/

 

How Might Sleep Apnea Lead to Serious Health Concerns like Cardiac and Cancer?

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/03/20/how-might-sleep-apnea-lead-to-serious-health-concerns-like-cardiac-and-cancers/

 

2019 Warren Alpert Foundation Award goes to Four Scientists for Seminal Discoveries in OptoGenetics – Illuminating the Human Brain

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/07/18/2019-warren-alpert-foundation-award-goes-to-four-scientists-for-seminal-discoveries-in-optogenetics-illuminating-the-human-brain/

 

 

 

 

 

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Novel delivery system in REMfresh mimics the way the body naturally releases and maintains melatonin over a 7-hour period

Real-world evidence confirms previous clinical data on improved sleep duration and sleep quality with REMfresh

Reporter: Gail S. Thornton, M.A.

Chronic disorders of sleep and wakefulness affect an estimated 50-70 million adults in the United States.[i] The cumulative long term effects of sleep loss have been associated with a wide range of damaging health consequences, including obesity, diabetes, impaired glucose tolerance, cardiovascular disease, hypertension, anxiety and depression.[ii]In terms of preventing health consequences, sleeping 6-8 hours per night consistently may provide optimal health outcomes.[iii]

This month, real-world evidence from two recently completed patient-reported outcomes (PRO) studies presented at SLEEP 2019 in San Antonio, Texas, confirms previous clinical data demonstrating statistically significant improvements in sleep onset, sleep duration, sleep maintenance and sleep quality with REMfresh®, the first and only continuous release and absorption melatonin (CRA-Melatonin™). This data supports and reinforces the benefits of REMfresh, which is designed to give patients up to 7 hours of sleep support. PRO studies of this kind, which more closely address real-world patient experience, are increasingly being recognized by regulatory authorities and academia in evaluating new therapies.

The REMfresh Duration Validation (REMVAL) study provides further evidence of a correlative relationship between the 7-hour pharmacokinetic profile observed in the earlier clinical study, REM Absorption Kinetics Trial (REMAKT), and the hypnotic effects of REMfresh, observed in subsequent studies, as demonstrated by improvements in sleep onset, sleep duration, sleep maintenance, sleep quality and patient satisfaction. This latest study further validates the findings of past studies that have been presented and undergone peer review at major sleep conferences:  

  • REMfresh Patient Reported Outcomes DURation (REMDUR), the first, 500-patient, PRO study of this sleep brand, presented at the annual meeting for sleep specialists, SLEEP 2018, which demonstrated that more than 77 percent of patients achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh (p<.0001)[iv], and
  • REM Absorption Kinetics Trial (REMAKT), a pharmacokinetic study presented at SLEEP 2017 and 2018, which demonstrated that REMfresh mimics the body’s own seven-hour Mesa-Wave® release profile, a natural pattern of melatonin blood levels during a normal night’s sleep cycle.[v] 

An additional PRO subset study, part of REMVAL, called the REMfresh Short Sleep Cohort Assessment (REMSS), assessed improvements in sleep duration and sleep maintenance among 311 patients with morbid or extreme short sleep duration of 4 hours or less.

These two PRO studies (REMVAL and REMSS) were presented at SLEEP 2019, the 33rd Annual Meeting of the Associated Professional Sleep Societies (APSS), which is a joint meeting of the American Academy of Sleep Medicine and the Sleep Research Society, held in San Antonio, Texas, from June 8-12.

“These latest findings provide further confirmation of the potential for nonprescription REMfresh to help address the public health issue of  the cumulative effects of sleep loss,” said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology — Head and Neck Surgery as well as Sleep Medicine, Founder and Principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician’s Seal, LLC. “Based on a novel Ion Powered Pump® (IPP®) delivery system that provides a pharmacokinetic (PK) profile that more closely aligns with the body’s own natural sleep pattern, REMfresh has demonstrated once again promising results and high levels of satisfaction in a real-world population of patients who have had chronic difficulties sleeping, providing up to seven hours of sleep support,” said Dr. Brodner.

Topline findings of these studies are as follows:

  • The 1,116 patient-reported outcomes (PRO) study, REMfresh Duration Validation (REMVAL), found that after taking 99 percent ultra-pure, continuous release and absorption melatonin (REMfresh®, CRA-melatonin™), the majority (78.8 percent) of patients involved achieved a sleep duration of greater than or equal to 6 hours (p<.0001), while more than 91 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001).  Of the 30.7 percent of patients (342 in total), who reported never having taken other brands of melatonin, 99.4 percent indicated they were likely or very likely to continue taking CRA-melatonin for their sleep issues (p<.0001).
  • REMVAL provides further real-world evidence of a correlative relationship between the originally observed 7-hour pharmacokinetic profile in the REM Absorption Kinetics Trial (REMAKT) and the strong observed hypnotic effects of CRA-melatonin, as demonstrated by improvements in sleep onset, sleep duration, sleep maintenance and sleep quality.
  • A second PRO subset study, REMfresh Short Sleep Cohort Assessment (REMSS), involving 311 patients who reported sleeping four hours or less nightly from the REMVAL study, found that 95.8 percent of patients who previously experienced daily, morbid short sleep duration of less than or equal to 4 hours reported an improvement in sleep duration (p<.0001), including more than 46 percent who achieved a sleep duration of greater than or equal to 6 hours (p<.0001). More than 93 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001).
  • REMVAL and REMSS also provides validation of the results from the previously peer-reviewed and presented clinical study, REMAKT, which demonstrated that REMfresh mimics the body’s own 7-hour Mesa Wave®, a natural pattern of melatonin blood levels during a normal night’s sleep cycle and the 500-patient, peer-reviewed and presented  REMfresh® Patient Reported Outcomes DURation (REMDUR) study, that demonstrated statistically significant improvements in sleep onset, sleep maintenance and sleep quality.

REMVAL Study Describes Improvements in Sleep Duration and Sleep Quality

The poster entitled, “Observed Hypnotic Effects with a Continuous-Release Ion Powered Pump Melatonin Delivery System: Self-Reported Patient Outcomes Study Results Demonstrating Improvement in Sleep Duration and Quality,” reported findings provides further real-world evidence of a correlative relationship between the originally observed 7-hour pharmacokinetic profile in the REM Absorption Kinetics Trial (REMAKT) and the strong hypnotic effects of CRA-melatonin observed in subsequent studies and may offer a new low-dose, drug-free alternative to prescription hypnotics to treat chronic sleep disturbances.

The 1,116-patient REMVAL study was designed to obtain clinically relevant information about patients’ past usage of melatonin and non-melatonin sleep aids, sleep patterns prior to taking CRA-melatonin, sleep duration before and after taking CRA-melatonin, frequency of CRA-melatonin usage, improvement in sleep onset, sleep maintenance and sleep quality after taking CRA-melatonin, and overall satisfaction with CRA-melatonin.

In the study, patients with sleep disturbances in the general population received a sample of REMfresh from their physicians and were invited to complete a 13-question online survey. After taking REMfresh, the majority (78.8 percent) of patients achieved a sleep duration of greater than or equal to 6 hours (p<.0001). More than 91 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001). Of the 30.7 percent of patients (342 in total), who reported never having taken other brands of melatonin, 99.4 percent indicated they were likely or very likely to continue taking REMfresh for their sleep issues (p<.0001).

REMSS Study Shows Improvement in Patients with Chronic, Extreme Short Sleep

The poster entitled, “Improvement in Sleep Duration and Maintenance with Ion Powered Continuous Release and Absorption Melatonin in a Cohort of Patients with Chronic Short Sleep Duration: Results from a Patient-Reported Outcomes Study,” highlighted findings from the REMfresh Short Sleep Cohort Assessment (REMSS), involving a cohort of 311 patients from the REMVAL study who reported sleeping four hours or less nightly. This cohort analysis was designed to obtain clinically relevant information from these patients experiencing morbid short sleep disturbances, including sleep patterns and melatonin usage before taking REMfresh, sleep duration before and after taking REMfresh, improvement in sleep onset, sleep maintenance and sleep quality after taking REMfresh, and overall product satisfaction.

Data from this cohort show that 95.8 percent of patients who previously experienced daily, morbid short sleep duration of less than or equal to 4 hours reported an improvement in sleep duration (p<.0001), including more than 46 percent who achieved a sleep duration of greater than or equal to 6 hours (p<.0001). This increase from less than or equal to 4 hours to greater than or equal to 6 hours represents a major sleep duration upgrade in this group facing morbid sleep disturbances. More than 93 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001). Ninety-nine percent of the patients suffering with morbid short sleep (27.2 percent of whom had never previously tried a melatonin brand) reported that they were very likely or likely to continue using CRA-melatonin. These results provide real-world evidence that CRA-melatonin with its extended 7-hour pharmacokinetic  plateau time and benign safety-profile may be a practical baseline therapy to improve sleep duration and other key sleep parameters, including, sleep maintenance and sleep quality in this group of patients who have a higher risk of all-cause mortality.[vi]˒[vii]˒[viii]˒[ix]

Statistics & Data Corporation (SDC), a top-tier clinical data services provider, has independently determined that the number of participants in the study provides adequate power (>90%) to detect even small improvements in sleep outcomes. This high power, or probability of seeing statistically significant results if CRA-melatonin is truly working to improve sleep outcomes, applies to the overall study population (REMVAL) as well as the cohort of short sleepers (REMSS). SDC has subsequently independently validated the statistical results achieved, (e.g., p-values and statistical language).

The Increasing Appreciation of PRO Studies to Include Patient Experience 
Increasingly, there is an appreciation by the U.S. Congress, regulatory authorities and academia, of the substantive value that real-world patient experience brings to assessing new therapies. In addition to the traditional randomized, placebo-controlled trial studies, regulatory authorities are now incorporating the patient perspective in their decision making, including PRO studies. A PRO study is a measurement based on a report that comes directly from the patient about the status or change in their health condition and without amendment or interpretation of the patient’s response by health-care intermediaries. PRO measures can be used to capture a patient’s everyday experience outside of the clinician’s office, and the effects of a treatment on the patient’s activities of daily living.[x]˒[xi]Together, clinical measures and PRO measures can provide a fuller picture of patient benefit.

REMAKT Clinical Study Presented at Past Medical Meetings 
Pharmacokinetic data on REMfresh® was peer-reviewed and then presented in 2017 and 2018 at SLEEP, the Annual Meeting of the Associated Professional Sleep Societies LLC (APSS), and a joint meeting of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS). 

The study, REM Absorption Kinetics Trial (REMAKT), was a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin). The study found that melatonin levels with REMfresh exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and then had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours. 

Analysis presented at SLEEP 2017 and 2018 showed that REMfresh builds upon the body of evidence from prolonged-release melatonin (PR-M), approved by the European Medicines Agency (EMA) in 2007 as a prescription drug for insomnia, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep onset and quality of life in patients aged 55 years and older compared with placebo.[xv] REMfresh was designed to overcome the challenges of continuous release and absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave®, a flat-topped hill with steep sides).[xvi] There was the desirable fast time to reach the sleep threshold level, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave may help to improve sleep maintenance and morning alertness. 

Over 5,000 healthcare practitioners are estimated to have used REMfresh for their patients and about 320,000 patients are estimated to have purchased and used REMfresh. The continuing, rapid acceptance of REMfresh by patients is observable by several markers, including rapid sales growth and availability among major drug retailers.

###

Data Presented at SLEEP 2019 Poster Sessions:

Monday, June 10, 2019, 5:15-7:15pm

  • (Abstract 0398, Poster Board #135) Improvement in Sleep Duration and Maintenance with Ion Powered Continuous Release and Absorption Melatonin in a Cohort of Patients with Chronic Short Sleep Duration: Results from a Patient-Reported Outcomes Study
    • David J. Seiden, M.D., FAASM,  David Brodner, M.D., Syed M. Shah, Ph.D.
  • (Abstract 0399, Poster Board #136) Observed Hypnotic Effects with a Continuous-Release Ion Powered Pump Melatonin Delivery System: Self-Reported Patient Outcomes Study Results Demonstrating Improvement in Sleep Duration and Quality
    • David J. Brodner, M.D., David J. Seiden, M.D. FAASM, Syed M. Shah, Ph.D.

The abstracts are published in an online supplement of the journal, Sleep, which is available at https://sleepmeeting.org/wp-content/uploads/2019/04/SLEEP_42_S1-Website-Final.pdf.

REFERENCES:


[i] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617

[ii] Cappuccio, F.P., D’Elia, L., Strazzullo, P., & Miller, M.A. (2010). Sleep duration and all-cause mortality: A systemic review and meta-analysis of prospective studies. Sleep, 33(5):585-592.

[iii] Watson, N.F., Badr, M.S., Belenky, G., et al. (2015). Joint Consensus Statement of the American Academy of Sleep  Medicine and Sleep Research Society on the Recommended Amount of Sleep for the Healthy Adult, Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(6); 591-592.

[iv] Seiden,D.J., Brodner, D.C., & Shah, S.M. (2018, June 2-6). Improvement in Sleep Maintenance and Sleep Quality with Ion-Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study (Abstract #0419). Poster presented at SLEEP 2018, Baltimore, Maryland.

[v] Brodner, D.C., Shah, S.M. (2017, June 3-7). REM Absorption Kinetics Trial: A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation versus a Same Strength Immediate-Release Formulation in Healthy Adults (Abstract #0396). Poster presented at: SLEEP 2017, Boston, Massachusetts.

[vi] Knutsen, K.L., Turek,, F.W., Patel, S.R., et al (2006). The u-shaped association between sleep and health: the 2 peaks do not mean the same thing.  Comment on Patel, SR, et al. Sleep, 29(7): 878-879.

[vii] Lubetkin,, E.I., & Haomiao, J. (2018). Burden of disease due to sleep duration and sleep problems in the elderly. Sleep Health, 4; 182-187.

[viii] Hafner M, et al. (2017). Why sleep matters-the economic costs of insufficient sleep: A cross-country comparative analysis, Rand Quarterly.

[ix] Ikehara, S, et al. (2009). Association of Sleep Duration with Mortality  from Cardiovascular Disease and other Causes for Japanese Men and Women: the JACC Study. Sleep, 32(3); 295-301.

[x] U.S. Food and Drug Administration. Real World Evidence. Retrieved from https://www.fda.gov/scienceresearch/specialtopics/realworldevidence/default.htm

[xi] U.S. Food and Drug Administration. 21st Century Cures Act. Retrieved from https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/significantamendmentstothefdcact/21stcenturycuresact/default.htm.

[xii] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617

[xiii] Cappuccio, F.P., D’Elia, L., Strazzullo, P., & Miller, M.A. (2010). Sleep duration and all-cause mortality: A systemic review and meta-analysis of prospective studies. Sleep, 33(5):585-592.

[xiv] Watson, N.F., Badr, M.S., Belenky, G., et al. (2015). Joint Consensus Statement of the American Academy of Sleep  Medicine and Sleep Research Society on the Recommended Amount of Sleep for the Healthy Adult, Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(6); 591-592.

[xv] European Medicines Agency.(2007). Assessment Report for CIRCADIN.

[xvi] Brodner, D.C. & Shah, S.M. (2017, June 3-7). A Continuous Release Ion Powered Pump Melatonin Delivery System that Overcomes Challenges of Release and Absorption in the Intestines (Abstract #0385). Poster presented at: SLEEP 2017,  Boston, Massachusetts.

SOURCES:

https://finance.yahoo.com/news/significant-real-world-evidence-confirms-123000247.html

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:

2018

https://pharmaceuticalintelligence.com/2018/06/10/patient-reported-outcomes-study-presented-at-sleep-2018-provides-confirmatory-real-world-evidence-of-the-previously-presented-7-hour-action-of-remfresh-the-first-continuous-release-and-absorp/

2017

https://pharmaceuticalintelligence.com/2017/10/02/2017-nobel-prize-in-physiology-or-medicine-jointly-to-jeffrey-c-hall-michael-rosbash-and-michael-w-young-for-their-discoveries-of-molecular-mechanisms-controlling-the-circadian-rhythm/

https://pharmaceuticalintelligence.com/2017/06/11/ultra-pure-melatonin-product-helps-maintain-sleep-for-up-to-7-hours/

2016

https://pharmaceuticalintelligence.com/2016/03/16/sleep-science/

2013

https://pharmaceuticalintelligence.com/2013/03/09/melatonin-and-its-effect-on-acetylcholinesterase-activity-in-erythrocytes/

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  • More than 77 percent of patients in the REMfresh® Patient Reported Outcomes DURation (REMDUR) study reported achieving 6 or more hours of sleep after taking REMfresh®, the first continuous release and absorption melatonin (CRA-melatonin)
  • More than 91 percent experienced improvements in sleep onset, sleep maintenance and total sleep quality, after taking REMfresh® (CRA-melatonin)
  • Post-marketing, patient-reported outcomes data reinforces clinical trial evidence demonstrating the potential of non-prescription REMfresh®, as a new, non-prescription, drug-free hypnotic (sleep) product designed to achieve 7-hour sleep
  • New data confirms previously presented SLEEP 2017 study showing the patented Ion Powered Pump (IPP) technology in REMfresh® helps extend melatonin-targeted sleep maintenance levels in the body from 3.7 hours (with marketed immediate-release melatonin) to 6.7 hours, while mimicking the pattern of the body’s natural melatonin blood levels during the nightly sleep cycle

Real Time Coverage at SLEEP 2018 meeting, Baltimore.

Reporters: Aviva Lev-Ari, PhD, RN, and Gail S. Thornton, MA

BALTIMORE – (June 6, 2018) – A patient-reported outcomes study presented at SLEEP 2018 provides confirmatory real-world evidence of the previously peer-reviewed and presented data showing the 7-hour action of REMfresh®, a new product for sleep. REMfresh® Ion-Powered Melatoninis the first and only, continuous release and absorption melatonin (CRA-melatonin) to mimic the body’s own 7-hour Mesa Wave, the natural pattern of melatonin blood levels during a normal night’s sleep cycle. This induces sleep onset and provides lasting and restorative sleep for up to 7 hours.

This new data shows a correlative relationship between a 7-hour Mesa Wave pharmacokinetic (PK) profile and real-world evidence of improvements in sleep duration, onset, maintenance and sleep quality after taking REMfresh® (CRA-melatonin).

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was presented at SLEEP 2018, the 32nd Annual Meeting of the Associated Professional Sleep Societies (APSS), LLC, a joint partnership of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS).

 

Brodner and Seiden

Pictured here is David C. Brodner, M.D., and David J. Seiden, M.D., FAASM, after presenting the latest study data which found REMfresh is the first and only continuous release and absorption melatonin™ to mimic the body’s own 7-hour Mesa Wave™.

 

In a sample of 500 patients on REMfresh® (CRA-melatonin) responding to an online survey, 77.6 percent achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh® (p<.0001). A vast majority of respondents also reported a major or moderate improvement in sleep onset (91.6 percent, p<.0001), sleep maintenance (94.8 percent, p<.0001) and total sleep quality (97.2 percent, p<.0001). More than three-quarters (76.6 percent) of patients indicated they take REMfresh® (CRA-melatonin) nightly. The proportion of patients reporting nightly CRA-melatonin use was significantly greater than the proportion of patients with less than nightly use (p<.0001). Most importantly, over 98 percent of patients reported they were very likely or likely to continue taking REMfresh® (CRA-melatonin) to treat their sleep complaints.

“The real-world evidence reported today in REMDUR provides further confirmation that REMfresh® represents a significant advance in the use of melatonin as a baseline therapy for treating sleep complaints,” said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology — Head and Neck Surgery and Sleep Medicine, founder and principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician’s Seal, LLC®.

“REMfresh® Ion-Powered Melatoninhas been shown to be an effective drug-free solution that is now available to the millions of Americans in need of a good night’s sleep, many of whom seek new therapies that will induce sleep and keep them asleep until the morning, without causing residual effects they’ll feel the next day. With its unique delivery system that imitates the body’s own natural sleep pattern, REMfresh® has revolutionized the role of melatonin, when delivered in the CRA form. It is no longer just a treatment for jet lag, but the CRA-melatonin found in REMfresh® has been shown to provide substantial relief to individuals having nightly sleep challenges,” said Dr. Brodner.

The scientifically advanced, patented delivery system in REMfresh® (CRA-melatonin), called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products. Since REMfresh® is not a drug, there is no drug hangover.

Nearly one-third of U.S. adults sleep less than the recommended seven hours daily.[1],[2] Increasing evidence suggests an association between sub-optimal sleep duration and adverse health outcomes including a higher risk of diabetes, hypertension, heart attack, stroke, obesity and depression.[3] A pooled analysis of 16 studies and over one million patients found short sleep duration corresponded with greater risk of morbidity and mortality.[4]

 REMDUR Study Design

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was designed to obtain real-world evidence about patients’ sleep patterns, duration of sleep before and after REMfresh® (CRA-melatonin), daily REMfresh® (CRA-melatonin) use, onset of action, sleep maintenance, quality of sleep, and overall satisfaction with REMfresh® (CRA-melatonin).

Patients with sleep disturbances in the general population who received a sample of CRA-melatonin (REMfresh®) from their physicians were invited to complete a 12-question survey. Survey responses were received from 500 patients.

Confirmation of the REMAKT Clinical Study

REMDUR confirmed clinical trial findings from REMAKT (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin).[5]

The study results, peer-reviewed and presented last year at SLEEP 2017, showed that melatonin levels with REMfresh® (CRA-melatonin) exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

The REMfresh® (CRA-melatonin) studies build upon the body of evidence from prolonged-release melatonin (PR-M), marketed in Europe, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency and quality of life in patients aged 55 years and older compared with placebo. REMfresh® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave, a flat-topped hill with steep sides). There was a fast time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave, may help to improve sleep maintenance and morning alertness.

Conventional melatonin products have had challenges at mimicking the profile of a Mesa Wave™. The scientific work behind REMfresh® (CRA-melatonin) sought to overcome these challenges by having the melatonin formulation in a matrix that maintains a patented, solubility-enhancing pH environment to help with the transport to the brush border of the gut and its subsequent absorption.

Designed as a hydrogel matrix tablet, REMfresh® (CRA-melatonin) provides rapid release of the melatonin from the surface of the tablet, as the hydrogel release-controlling matrix is setting up in the acidic environment (pH of 1 to 3.5) in the stomach. As the tablet moves into the higher pH (5.5 to 6.5) environment of the small-intestine, which is above the pKa of melatonin (~4.0), the acidic moiety in the tablet is designed to maintain the pH within the tablet below 4.0 for 7+ hours. The hydrogel matrix, after proper hydration, allows continuous release of the active melatonin and acidic moiety into the lumen of the intestines.

Melatonin: The Body’s Natural Sleep Ingredient

Melatonin is produced by the pineal gland in the brain and is the body’s natural sleep ingredient. Melatonin levels normally begin to rise in the mid-to late evening and remain high for the majority of the night. Levels begin to decline towards early morning, as the body’s wake cycle is triggered. As people age, melatonin levels can drop by as much as 70 percent[6] and their bodies may no longer produce enough melatonin to ensure adequate sleep.

Other available products, such as immediate-release melatonin, help initiate the onset of sleep but are usually unable to sustain prolonged sleep maintenance due to an immediate burst of melatonin, which is quickly degraded due to its relatively short half-life (60 minutes). Absorption in the lower digestive tract is limited by melatonin’s limited ability to be absorbed in a low acidity or neutral pH environment.

Importance of Sleep

Sleep is an essential part of every person’s life. The body requires a certain amount of sleep in order to properly rest, repair and renew itself. Sleep is customarily divided in four different stages, with each stage having a different effect. These four stages are:

N1, N2, deep sleep and REM sleep. The body moves among these four stages several times while asleep. If sleep is disrupted for any reason, a person’s body may not have a chance to properly restore itself, especially if it is struggling to get to the later stages, called deep sleep and REM sleep. Studies have shown that sound and sufficient sleep is important for learning, memory and a healthy immune system. A regular pattern of deep sleep and REM sleep will help a person begin the next day feeling refreshed and ready to go.

About Non-Prescription REMfresh®

REMfresh® (CRA-melatonin) is the first and only, continuous release and absorption formulation of UltraMel® melatonin (available as 2 mg and 5 mg and with a 0.5 mg anticipated in the second half of 2018). UltraMel® melatonin is a high-quality, 99 percent ultra-pure melatonin sourced from Western Europe exclusively for Physician’s Seal®.

REMfresh® (CRA-melatonin) is a dietary supplement and is regulated under the Federal Dietary Supplement Health and Education Act, which does not require pre-approval. Melatonin has been in common use for over two decades and has a well-established profile of safe use by millions of people around the world. As with all supplements, individual results may vary.

REMfresh® (CRA-melatonin) is non-habit forming and does not contain narcotics, hypnotics, barbiturates, sedatives, antihistamines, alcohol or other harsh or additive chemicals. The usual adult recommended dose is 1-2 tablets 30-60 minutes before bedtime. Follow specific dosing instructions found on the back of the box for proper use of supplements.

REMfresh® (CRA-melatonin) is available at Walmart, Rite Aid and CVS/pharmacy. In 2017 REMfresh® was ranked as  the #1 recommended brand for sleep management by sleep doctors[7].

About Physician’s Seal®

Physician’s Seal® is the innovator of REMfresh®, the first and only continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin) that mimics the way the body naturally releases and maintains melatonin over a 7-hour period. Physician’s Seal®, founded in 2015, is a privately held company based in Boca Raton, Florida. It is committed to bringing cutting-edge life science applications to doctors and their patients. For more information, visit www.remfresh.com and connect with us on Facebook and You Tube.

Its sister subsidiary, IM HealthScience® (IMH) is the innovator of IBgard® and FDgard® for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. IMH® is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, including conditions with a high unmet medical need, such as digestive health. The IM HealthScience® advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting® (SST®). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,  www.FDgard.com,and www.FiberChoice.com.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.remfresh.com. Individual results may vary.

Data Presented at SLEEP 2018 Poster Session on Sleep Maintenance/Sleep Quality

Tuesday, June 5, 2018, 5-7pm

  • (Abstract 0419, Poster Board #104) Improvement in Sleep Maintenance and Sleep Quality with Ion Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study
    • David J. Seiden, M.D., FAASM, David C. Brodner, M.D., Syed M. Shah, Ph.D.

Visit Physician’s Seal® at booth 220 to learn more about REMfresh®.

The abstract is published in an online supplement of the journal, Sleep, which is available at http://www.sleepmeeting.org/docs/default-source/default-document-library/abstractbook2018.pdf?sfvrsn=2

[1] Ford, E.S., Cunningham, T.J., & Croft, J.B. (2015, May 1). Trends in Self-Reported Sleep Duration among US Adults from 1985 to 2012. Sleep, 38(5):829-832. doi: 10.5665/sleep.4684.

[2] Watson, N.F., Badr, M.S., Belenky, G., Bliwise, D.L., Buxton, G.M., Buysse, D.,…Tasali, E. (2015). Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(8):931-952. doi:10.1176/appi.ajp.158.11.1856.

[3] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617.

[4] Cappuccio, F.P., D’Elia, L., Strazzullo, P.,&  Miller, M.A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5):585-592

[5] For this clinical trial, the head-to-head comparison was with the 5 mg form; a 2 mg form of the comparator was not available.

[6] Zisapel, N. (2010). Melatonin and sleep. The Open Neuroendocrinology Journal, 3: 85-95.

[7] Among primary care physicians with a certification in sleep disorders who recommended a brand of modified-release melatonin. Quintiles IMS ProVoice July-September 2017 survey.

REFERENCE/SOURCE

Physician’s Seal® and REMfresh® (www.remfresh.com)

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:

2017

Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours

https://pharmaceuticalintelligence.com/2017/06/11/ultra-pure-melatonin-product-helps-maintain-sleep-for-up-to-7-hours/

2016

Sleep Science

Genetic link to sleep and mood disorders

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

2015

Sleep quality, amyloid and cognitive decline

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

2013

Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

 

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2017 Nobel Prize in Physiology or Medicine jointly to Jeffrey C. Hall (ex-Brandeis, University of Maine), Michael Rosbash (Brandeis University) and Michael W. Young (Rockefeller University in New York) for their discoveries of molecular mechanisms controlling the circadian rhythm

 

Curator: Aviva Lev-Ari, PhD, RN

 

Press Release

2017-10-02

The Nobel Assembly at Karolinska Institutet has today decided to award

the 2017 Nobel Prize in Physiology or Medicine

jointly to

Jeffrey C. Hall, Michael Rosbash and Michael W. Young

for their discoveries of molecular mechanisms controlling the circadian rhythm

READ the Summary

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html

 

Jeffrey C. Hall was born 1945 in New York, USA. He received his doctoral degree in 1971 at the University of Washington in Seattle and was a postdoctoral fellow at the California Institute of Technology in Pasadena from 1971 to 1973. He joined the faculty at Brandeis University in Waltham in 1974. In 2002, he became associated with University of Maine.

Michael Rosbash was born in 1944 in Kansas City, USA. He received his doctoral degree in 1970 at the Massachusetts Institute of Technology in Cambridge. During the following three years, he was a postdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, he has been on faculty at Brandeis University in Waltham, USA.

Michael W. Young was born in 1949 in Miami, USA. He received his doctoral degree at the University of Texas in Austin in 1975. Between 1975 and 1977, he was a postdoctoral fellow at Stanford University in Palo Alto. From 1978, he has been on faculty at the Rockefeller University in New York.

 

Key publications

Zehring, W.A., Wheeler, D.A., Reddy, P., Konopka, R.J., Kyriacou, C.P., Rosbash, M., and Hall, J.C. (1984). P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 369–376.

Bargiello, T.A., Jackson, F.R., and Young, M.W. (1984). Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754.

Siwicki, K.K., Eastman, C., Petersen, G., Rosbash, M., and Hall, J.C. (1988). Antibodies to the period gene product of Drosophila reveal diverse tissue distribution and rhythmic changes in the visual system. Neuron 1, 141–150.

Hardin, P.E., Hall, J.C., and Rosbash, M. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536–540.

Liu, X., Zwiebel, L.J., Hinton, D., Benzer, S., Hall, J.C., and Rosbash, M. (1992). The period gene encodes a predominantly nuclear protein in adult Drosophila. J Neurosci 12, 2735–2744.

Vosshall, L.B., Price, J.L., Sehgal, A., Saez, L., and Young, M.W. (1994). Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263, 1606–1609.

Price, J.L., Blau, J., Rothenfluh, A., Abodeely, M., Kloss, B., and Young, M.W. (1998). double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95.

Keeping time on our human physiology

The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms. A large proportion of our genes are regulated by the biological clock and, consequently, a carefully calibrated circadian rhythm adapts our physiology to the different phases of the day (Figure 3). Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.

The circadian clock

Figure 3. The circadian clock anticipates and adapts our physiology to the different phases of the day. Our biological clock helps to regulate sleep patterns, feeding behavior, hormone release, blood pressure, and body temperature.

SOURCE

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html

 

Medicine Nobel awarded for work on circadian clocks, Jeffrey Hall, Michael Rosbash and Michael Young unpicked molecular workings of cells’ daily rhythms.

Ewen CallawayHeidi Ledford

02 October 2017

https://www.nature.com/news/medicine-nobel-awarded-for-work-on-circadian-clocks-1.22736?WT.ec_id=NEWSDAILY-20171002

Other Related Research 

Charles Weitz, Ph.D., M.D.
Robert Henry Pfeiffer Professor of Neurobiology

Mammalian Circadian Clocks

Circadian clocks are molecular oscillators with ~24-hour periods that drive daily biological rhythms.  Such clocks are found in all of the major branches of life, and they likely represent ancient timekeeping systems important for predicting daily environmental cycles on our rotating planet.  In mammals, circadian clocks are present in most if not all cells. These distributed clocks control a myriad of processes, in aggregate creating coherent 24-hour programs of physiology and behavior.

A picture of how circadian clocks are built has emerged in the last two decades.  The core mechanism is a transcriptional feedback loop, wherein the protein products of several clock genes build the molecular machinery to inhibit the transcription factor responsible for their own production.  The molecular components of circadian clocks are conserved from insects to humans.

The Weitz lab uses molecular biology, biochemistry, genetics, and structural biology to investigate the mammalian circadian clock.  The focus of our efforts at present is to understand the circadian clock in terms of the integrated functions of its several multi-protein machines.  This effort is principally based on the purification of endogenous circadian clock protein complexes from mouse tissues and their biochemical analysis and structural study by cryo-electron microscopy.

Fig. 1.  Class-average electron microscopy images of the mouse nuclear PER complex, a core circadian clock machine.  It is a 1.9-MDa assembly of about thirty proteins that appears as a quasi-spherical, beaded particle of 40-nm diameter. Our current work provides an initial low-resolution view of the structural organization of endogenous clock machinery from a eukaryote.  We aim to obtain high-resolution structures.

Selected papers:

Duong HA, Robles MS, Knutti K, Weitz CJ.  A molecular mechanism for circadian clock negative feedback. Science  332, 1436-1439 (2011).

Padmanabhan K, Robles MS, Westerling T, Weitz CJ.  Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science  337, 599-602 (2012).

Kim JY, Kwak PB, Weitz CJ. Specificity in circadian clock feedback from targeted reconstitution of the NuRD co-repressor.  Mol. Cell  56, 738-748 (2014).

Aryal RA, Kwak PB, Tamayo AG, Chiu PL, Walz T, Weitz CJ.  Macromolecular assemblies of the mammalian circadian clock.  Mol. Cell  (2017, in press).

SOURCE

http://neuro.hms.harvard.edu/people/faculty/charles-weitz

Circadian Clock’s Inner Gears

https://hms.harvard.edu/news/circadian-clock%E2%80%99s-inner-gears?utm_source=linkedin&utm_medium=social&utm_campaign=hms-linkedin-general

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Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours

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Alteration in Reduced Glutathione level in Red Blood Cells: Role of Melatonin

Author: Shilpa Chakrabarti, PhD

https://pharmaceuticalintelligence.com/2013/06/11/alteration-in-reduced-glutathione-level-in-red-blood-cells-role-of-melatonin/

 

Melatonin and its effect on acetylcholinesterase activity in erythrocytes

Author: S. Chakravarty, PhD

https://pharmaceuticalintelligence.com/2013/03/09/melatonin-and-its-effect-on-acetylcholinesterase-activity-in-erythrocytes/

 

Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

Author: Shilpa Chakravarty, PhD

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

 

Prolonged Wakefulness: Lack of Sufficient Duration of Sleep as a Risk Factor for Cardiovascular Diseases – – Indications for Cardiovascular Chrono-therapeutics

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/02/prolonged-wakefulness-lack-of-sufficient-duration-of-sleep-as-a-risk-factor-for-cardiovascular-diseases-indications-for-cardiovascular-chrono-therapeutics/

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