scholarly journals Divergent Importance of Chronobiological Considerations in High- and Low-dose Melatonin Therapies

Diseases ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 18
Author(s):  
Rüdiger Hardeland
Keyword(s):  
Phase Response Curve ◽  
Sleep Onset ◽  
Melatonin Receptors ◽  
Duration Of Action ◽  
Circadian Oscillators ◽  
Protective Actions ◽  
Circadian Control ◽  
Dim Light ◽  
Poor Individual ◽  
Specific Phase

Melatonin has been used preclinically and clinically for different purposes. Some applications are related to readjustment of circadian oscillators, others use doses that exceed the saturation of melatonin receptors MT1 and MT2 and are unsuitable for chronobiological purposes. Conditions are outlined for appropriately applying melatonin as a chronobiotic or for protective actions at elevated levels. Circadian readjustments require doses in the lower mg range, according to receptor affinities. However, this needs consideration of the phase response curve, which contains a silent zone, a delay part, a transition point and an advance part. Notably, the dim light melatonin onset (DLMO) is found in the silent zone. In this specific phase, melatonin can induce sleep onset, but does not shift the circadian master clock. Although sleep onset is also under circadian control, sleep and circadian susceptibility are dissociated at this point. Other limits of soporific effects concern dose, duration of action and poor individual responses. The use of high melatonin doses, up to several hundred mg, for purposes of antioxidative and anti-inflammatory protection, especially in sepsis and viral diseases, have to be seen in the context of melatonin’s tissue levels, its formation in mitochondria, and detoxification of free radicals.

N-Acetylserotonin vs Melatonin: In-Vitro Controlled Release from Hydrophilic Matrix Tablets

2019 ◽  
Vol 16 (3) ◽  
pp. 347-352 ◽  
Author(s):  
M. Vlachou ◽  
G. Stavrou ◽  
A. Siamidi ◽  
S. Flitouri ◽  
V. Ioannidou ◽  
...  
Keyword(s):  
Controlled Release ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Sleep Onset ◽  
Matrix Tablets ◽  
Melatonin Receptors ◽  
Solid Matrix ◽  
Poor Sleep ◽  
Prolonged Release ◽  
Hydrophilic Matrix

Background: N-Acetylserotonin (NAS, N-acetyl-5-hydroxytryptamine) is the immediate precursor of the neurohormone melatonin (MT, N-acetyl-5-methoxytryptamine), which regulates sleep and wake cycles. NAS is produced by the N-acetylation of serotonin and is converted to melatonin via the action of Acetylserotonin O-methyltransferase (ASMT). Like melatonin, NAS acts as an agonist on the melatonin receptors MT1, MT2, and MT3. However, as NAS is abundant in specific brain areas, separate from serotonin and melatonin, it may also have discrete central effects. Indicatively, it has been reported that NAS may play a role in the antidepressant effects of Selective Serotonin Reuptake Inhibitors (SSRIs) and Monoamine Oxidase Inhibitors (MAOIs). </P><P> Objective: To decipher the controlled release characteristics of the active substances (NAS and MT) in a quick initial pace, aiming at a satisfactory sleep-onset related anti-depressive profile and prolonged release, thereafter, targeting at coping with poor sleep quality problems. </P><P> Methods: A series of hydrophilic matrix tablets involving as excipients, hydroxypropylmethylcellulose (HPMC) K15M, low viscosity sodium alginate, lactose monohydrate, and polyvinylpyrrolidone (PVP) M.W.: 10.000 and 55.000) was developed and tested at two dissolution media (pH 1.2 and 7.4). </P><P> Results: The results showed that commonly used excipients with different physicochemical properties govern the controlled release of NAS and MT from solid matrix systems. </P><P> Conclusions: We have demonstrated how broadly used excipients affect the in vitro controlled release of NAS and MT from solid pharmaceutical formulations. Currently, we extend our studies on the controlled release of these drugs using various other biopolymers/formulants of different physicochemical characteristics, which will help to highlight the discrete release profiles of NAS and MT.

scholarly journals 0039 The Clinical Utility of Dim Light Melatonin Onset in Treatment of Delayed Sleep-Wake Phase Disorder: Preliminary Findings

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A16-A16
Author(s):  
L Swanson ◽  
J Arnedt ◽  
K DuBuc ◽  
T de Sibour ◽  
H Burgess
Keyword(s):  
Sleep Onset ◽  
Onset Time ◽  
Sleep Diary ◽  
Double Blind ◽  
Exogenous Melatonin ◽  
Research Award ◽  
Dim Light Melatonin Onset ◽  
Wrist Actigraphy ◽  
Dim Light ◽  
Delayed Sleep

Abstract Introduction Delayed sleep-wake phase disorder (DSWPD) is common, debilitating, and challenging to treat. In an ongoing randomized trial, we are comparing exogenous melatonin treatment outcomes in DSWPD participants for whom dim light melatonin onset (DLMO) is measured objectively vs. estimated. Methods Thus far, 13 participants (27±6 years old, 67% female) have completed a randomized, controlled, double-blind 4-week trial of 0.5 mg of exogenous melatonin timed to either 3 h before measured DLMO (M-DLMO, n = 6) or 3 h before DLMO estimated at 2 h before average sleep onset time based on at least 7 days of wrist actigraphy and sleep diary (E-DLMO, n = 7). All participants met International Classification of Sleep Disorders-3 diagnostic criteria for DSWPD and were otherwise healthy. Participants completed 4 weekly treatment sessions with a blinded psychologist; time of melatonin administration and bed-rise schedule were advanced up to 1 h/week. A validated home saliva collection kit measured DLMO in all participants. Between-group t-tests and Hedges’ g effect sizes (ES) were calculated at post-treatment for the following outcomes: DLMO; Pittsburgh Sleep Quality Index (PSQI) global score; Morningness-Eveningness Questionnaire (MEQ); and the actigraphy parameters sleep efficiency (SE) and clock time of sleep onset and offset. A paired-sample t-test compared the measured vs. estimated DLMO at baseline. Results The M-DLMO group had a 65±88 mins DLMO advance vs. 27±30 mins in the E-DLMO group (ES=0.51 p=.381). PSQI scores were similar between groups (M-DLMO=6.67±2.06, E-DLMO=7.1± 1.57, ES=-0.24, p=.646), as were MEQ scores (M-DLMO=43±4.98, E-DLMO=48±12.72, ES=-0.47, p=.387). Sleep onset time (M-DLMO=0:32±1:02, E-DLMO=0:31±1:38, ES=0.01, p=.98) and offset time (M-DLMO=8:05±1:03, E-DLMO=8:08±2:14, ES=-0.02, p=.968) were similar between the groups, although sleep was more efficient in M-DLMO vs. E-DLMO (84%±3% vs. 76%±10%, ES=0.94, p=.096). On average, baseline measured DLMO occurred 123±83 mins earlier than estimated DLMO (p=.001). Conclusion We are continuing to enroll participants in this trial. Preliminary results suggest some potential benefit of measuring the DLMO, but results will need to be clarified in a larger sample. Support American Sleep Medicine Foundation Strategic Research Award

scholarly journals Circadian tau differences and rhythm associations in delayed sleep–wake phase disorder and sighted non-24-hour sleep–wake rhythm disorder

SLEEP ◽  
2020 ◽  
Author(s):  
Gorica Micic ◽  
Nicole Lovato ◽  
Sally A Ferguson ◽  
Helen J Burgess ◽  
Leon Lack
Keyword(s):  
Circadian Rhythm ◽  
Core Body Temperature ◽  
Sleep Onset ◽  
Phase Relationship ◽  
Biological Rhythms ◽  
Circadian Phase ◽  
Behavioral Rhythm ◽  
Rhythm Disorder ◽  
Dim Light ◽  
Delayed Sleep

Abstract Study Objectives We investigated biological and behavioral rhythm period lengths (i.e. taus) of delayed sleep–wake phase disorder (DSWPD) and non-24-hour sleep–wake rhythm disorder (N24SWD). Based on circadian phase timing (temperature and dim light melatonin onset), DSWPD participants were dichotomized into a circadian-delayed and a circadian non-delayed group to investigate etiological differences. Methods Participants with DSWPD (n = 26, 17 m, age: 21.85 ± 4.97 years), full-sighted N24SWD (n = 4, 3 m, age: 25.75 ± 4.99 years) and 18 controls (10 m, age: 23.72 ± 5.10 years) participated in an 80-h modified constant routine. An ultradian protocol of 1-h “days” in dim light, controlled conditions alternated 20-min sleep/dark periods with 40-min enforced wakefulness/light. Subjective sleepiness ratings were recorded prior to every sleep/dark opportunity and median reaction time (vigilance) was measured hourly. Obtained sleep (sleep propensity) was derived from 20-min sleep/dark opportunities to quantify hourly objective sleepiness. Hourly core body temperature was recorded, and salivary melatonin assayed to measure endogenous circadian rhythms. Rhythm data were curved using the two-component cosine model. Results Patients with DSWPD and N24SWD had significantly longer melatonin and temperature taus compared to controls. Circadian non-delayed DSWPD had normally timed temperature and melatonin rhythms but were typically sleeping at relatively late circadian phases compared to those with circadian-delayed DSWPD. Conclusions People with DSWPD and N24SWD exhibit significantly longer biological circadian rhythm period lengths compared to controls. Approximately half of those diagnosed with DSWPD do not have abnormally delayed circadian rhythm timings suggesting abnormal phase relationship between biological rhythms and behavioral sleep period or potentially conditioned sleep-onset insomnia.

Human circadian pacemaker is sensitive to light throughout subjective day without evidence of transients

1997 ◽  
Vol 273 (5) ◽  
pp. R1800-R1809 ◽  
Author(s):  
Megan E. Jewett ◽  
David W. Rimmer ◽  
Jeanne F. Duffy ◽  
Elizabeth B. Klerman ◽  
Richard E. Kronauer ◽  
...  
Keyword(s):  
Steady State ◽  
Response Curve ◽  
Phase Response Curve ◽  
Light Exposure ◽  
Light Stimulus ◽  
Dead Zone ◽  
Bright Light ◽  
Temperature Minimum ◽  
Circadian Pacemaker ◽  
Dim Light

Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three-cycle bright-light (∼10,000 lx) stimulus against a background of very dim light (10–15 lx). The phase-response curve (PRC) to these trials was assessed for the presence of a “dead zone” of photic insensitivity and was compared with another three-cycle PRC that had used a background of ∼150 lx. To assess possible transients after the light stimulus, the trials were divided into 43 steady-state trials, which occurred after several baseline days, and 13 consecutive trials, which occurred immediately after a previous resetting trial. We found that 1) bright light induces phase shifts throughout subjective day with no apparent dead zone; 2) there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1–2 days after completion of the resetting stimulus; and 3) the timing of background room light modulates the resetting response to bright light. These data indicate that the human circadian pacemaker is sensitive to light at virtually all circadian phases, implying that the entire 24-h pattern of light exposure contributes to entrainment.

scholarly journals Pharmacotherapy of Insomnia with Ramelteon: Safety, Efficacy and Clinical Applications

2011 ◽  
Vol 3 ◽  
pp. JCNSD.S1611 ◽  
Author(s):  
Seithikurippu R. Pandi-Perumal ◽  
D. Warren Spence ◽  
Joris C. Verster ◽  
Venkatramanujam Srinivasan ◽  
Gregory M. Brown ◽  
...  
Keyword(s):  
Sleep Onset ◽  
International Study ◽  
Melatonin Receptors ◽  
Residual Effects ◽  
Synthetic Analog ◽  
Minimal Risk ◽  
Short Term ◽  
Open Label ◽  
Short Term Treatment ◽  
Circadian Rhythm Sleep Disorders

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT1 and MT2 melatonin receptors. Ramelteon is the first melatonin receptor agonist approved by the Food and Drug Administration (FDA) for the treatment of insomnia characterized by sleep onset difficulties. Ramelteon is both a chronobiotic and a hypnotic that has been shown to promote sleep initiation and maintenance in various preclinical and in clinical trials. The efficacy and safety of ramelteon in patients with chronic insomnia was initially confirmed in short-term placebo-controlled trials. These showed little evidence of next-day residual effects, withdrawal symptoms or rebound insomnia. Other studies indicated that ramelteon lacked abuse potential and had a minimal risk of producing dependence or adverse effects on cognitive or psychomotor performance. A 6-month placebo-controlled international study and a 1-year open-label study in the USA demonstrated that ramelteon was effective and well tolerated. Other potential off-label uses of ramelteon include circadian rhythm sleep disorders such as shift-work and jet lag. At the present time the drug should be cautiously prescribed for short-term treatment only.

scholarly journals Circadian Vision in Zebrafish: From Molecule to Cell and from Neural Network to Behavior

2019 ◽  
Vol 34 (5) ◽  
pp. 451-462
Author(s):  
Lei Li
Keyword(s):  
Visual System ◽  
Visual Sensitivity ◽  
Opsin Gene ◽  
Vertebrate Species ◽  
Light Perception ◽  
Lighting Conditions ◽  
Circadian Oscillators ◽  
Circadian Control ◽  
Neural Transmission ◽  
Circadian Pacemakers

Most visual system functions, such as opsin gene expression, retinal neural transmission, light perception, and visual sensitivity, display robust day-night rhythms. The rhythms persist in constant lighting conditions, suggesting the involvement of endogenous circadian clocks. While the circadian pacemakers that control the rhythms of animal behaviors are mostly found in the forebrain and midbrain, self-sustained circadian oscillators are also present in the neural retina, where they play important roles in the regulation of circadian vision. This review highlights some of the correlative studies of the circadian control of visual system functions in zebrafish. Because zebrafish maintain a high evolutionary proximity to mammals, the findings from zebrafish research may provide insights for a better understanding of the mechanisms of circadian vision in other vertebrate species including humans.

Melatonin and retinoid orphan receptors: Demand for new interpretations after their exclusion as nuclear melatonin receptors

2018 ◽  
Vol 1 (1) ◽  
pp. 78-93 ◽  
Author(s):  
Ruediger Hardeland
Keyword(s):  
Nuclear Receptors ◽  
Retinoic Acid Receptor ◽  
Membrane Receptors ◽  
Melatonin Receptors ◽  
Sirtuin 1 ◽  
Orphan Receptor ◽  
Melatonin Receptor ◽  
Orphan Receptors ◽  
Synthetic Compound ◽  
Circadian Oscillators

The demonstrated incapability of the retinoic acid receptor-related orphan receptor-α (RORα) to bind melatonin inevitably requires consequences for interpreting numerous reports on actions of this protein as far as it was believed to be a nuclear melatonin receptor. While the synthetic compound CGP 52608 is, in fact, a ligand of RORα, effects obtained with this molecule can no longer be attributed to melatonin. Moreover, the sometimes assumed interplay between melatonin membrane receptors and RORα as nuclear receptors has to be dropped. Conclusions on melatonin’s actions via RORα that were based on a lack of demonstrable involvement of membrane receptors appear to have been precocious. Nevertheless, findings on melatonin uptake into the nucleus may still be taken as a hint for nuclear melatonin receptors, but this would require thorough characterization. Although RORα does not bind melatonin, it is interrelated to the latter in regulatory terms by involvement of cellular circadian oscillators. A mode of action seems to be the upregulation of sirtuin-1 by melatonin, deacetylation of poly ADP ribose polymerase-γ coactivator-1α (PGC-1α) by sirtuin-1, and facilitation of RORα binding to its response element by deacetylated PGC-1α, a route that had been shown to exist in circadian oscillators, thereby enhancing their amplitude. 

scholarly journals Bright morning light advances the human circadian system without affecting NREM sleep homeostasis

1989 ◽  
Vol 256 (1) ◽  
pp. R106-R111 ◽  
Author(s):  
D. J. Dijk ◽  
D. G. Beersma ◽  
S. Daan ◽  
A. J. Lewy
Keyword(s):  
Rem Sleep ◽  
Process Model ◽  
Sleep Onset ◽  
Light Condition ◽  
Bright Light ◽  
Circadian Pacemaker ◽  
Sleep Regulation ◽  
Plasma Melatonin ◽  
Sleep Homeostasis ◽  
Dim Light

Eight male subjects were exposed to either bright light or dim light between 0600 and 0900 h for 3 consecutive days each. Relative to the dim light condition, the bright light treatment advanced the evening rise in plasma melatonin and the time of sleep termination (sleep onset was held constant) for an average approximately 1 h. The magnitude of the advance of the plasma melatonin rise was dependent on its phase in dim light. The reduction in sleep duration was at the expense of rapid-eye-movement (REM) sleep. Spectral analysis of the sleep electroencephalogram (EEG) revealed that the advance of the circadian pacemaker did not affect EEG power densities between 0.25 and 15.0 Hz during either non-REM or REM sleep. The data show that shifting the human circadian pacemaker by 1 h does not affect non-REM sleep homeostasis. These findings are in accordance with the predictions of the two-process model of sleep regulation.

scholarly journals 0007 Daytime Sleep in Night Shift Workers: Quantifying the Role of Circadian Misalignment

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A3-A3
Author(s):  
E Mann ◽  
C Sagong ◽  
A Cuamatzi Castelan ◽  
M Singh ◽  
T Roth ◽  
...  
Keyword(s):  
Sleep Duration ◽  
Sleep Disturbances ◽  
Night Shift ◽  
Sleep Onset ◽  
Sleep Onset Latency ◽  
Shift Workers ◽  
Circadian Misalignment ◽  
Daytime Sleep ◽  
Falling Asleep ◽  
Dim Light

Abstract Introduction Circadian misalignment is commonly cited as a culprit of daytime sleep disturbances in night shift workers; however, the specific impact and magnitude that circadian misalignment has on daytime sleep has not been well-characterized in larger samples of night shift workers. Methods Participants included fixed-night shift workers (n=52, ages 18–50) who completed an 8-hour daytime polysomnography (PSG) in the lab following a night shift. Measures of sleep disturbances included: difficulty falling asleep (sleep onset latency [SOL], latency to persistent sleep [LPS]), difficulty staying asleep (sleep efficiency [SE], wake after sleep onset [WASO]), and sleep duration (total sleep time [TST]). Melatonin samples were collected hourly for 24 hours under dim light (&lt;10 lux) and used to determine dim light melatonin offset (DLMOff). Circadian misalignment (CM) was calculated as the time difference between bedtime and DLMOff (higher values represented sleeping after DLMOff), and correlated with PSG sleep variables. Results CM was significantly associated with difficulty staying asleep (WASO: r=0.48, p&lt;0.001; SE: r=-0.45, p&lt;0.001), and sleep duration (TST: r=-0.38, p&lt;0.01). Specifically, every 3 hours of CM on average added 19.2 minutes of WASO and reduced TST by 15 minutes. In contrast, CM was not significantly correlated with sleep onset difficulties (SOL: r=-0.27; LPS: r=-0.02). Conclusion These data suggest that circadian misalignment in shift workers may be a better predictor of difficulties staying asleep and sleep duration during the day relative to difficulties falling asleep. Because longer work hours (10–12 hours) are common in night shift worker, it may be that sleep initiation difficulties associated with circadian misalignment is masked by elevated fatigue or an increased homeostatic drive from prolonged wakefulness. These results may help guide decisions about the magnitude of phase shifts required (e.g., with light therapy) for the desired improvement in daytime sleep. Support Support for this study was provided to PC by the NHLBI (K23HL138166)

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