Morning Administration Research Articles

0114 Morning Stimulant Administration Reduces Sleep and Overnight Working Memory Improvement

Abstract Introduction The goal of cognitive enhancement is to improve mental functions using interventions including cognitive training, brain stimulation and pharmacology. Indeed, psychostimulants, commonly used for cognitive enhancement purposes, while preventing sleep, have been shown to increase working memory (WM) and attention. WM is widely believed play a core role in cognitive ability, and has been shown to correlate with broad measure of cognitive ability and fluid intelligence. Sleep, however, is also important for cognitive function; thus, understanding the interaction between stimulants, sleep and cognition may inform current approaches to cognitive enhancement. Methods We used a double-blind, placebo controlled, repeated-measure design to investigate the effect of morning administration (9am) of stimulant, dextroamphetamine (DEX, 20 mg), on within-day and overnight WM performance, and sleep in 46 (22 female) healthy young adults. We tested WM using an operation span task (OSPAN) as it engages and captures both the memory retention and online processing capacity of WM. WM was tested at 75 minutes post drug, 12 h post drug, and 24 h post drug over a night of sleep. Results Compared with placebo, DEX showed no changes to WM performance at 75min or 12-hr post-drug. After sleep, DEX performed worse than PBO and the overnight improvement in performance in the PBO condition was absent in the DEX condition. Moreover, sleep quality was negatively affected by DEX administration. Conclusion In summary, we found no cognitive boost from psychostimulants across a day of wake and a blockade of overnight WM increases with the stimulant, compared to PBO. Given the growing non-medical use of stimulants in young adults, these findings have important implications for assessing their benefit for cognitive enhancement. Support Office of Naval Research N00014-14-1-0513 (S.M.) and DoD Young Investigator Prize (S.M.)

Effect of temozolomide chronotherapy in patients with high-grade glioma.

e14525 Background: High grade gliomas (HGG) (the most common being glioblastoma) are the most common primary CNS malignancy in adults. Mainstay of therapy is surgical resection followed by concurrent radiation and temozolomide (TMZ) followed by adjuvant TMZ. Unfortunately, prognosis remains poor and optimization of current therapy is critical. Chronotherapy is defined as improvement in treatment outcomes by maximizing treatment efficacy and minimizing toxicity by administering medications in accordance with biological rhythms of the patient. In a mouse model, there was greater anti-tumor efficacy during morning administration of TMZ. This trial was designed to determine the feasibility and potential clinical impact of chrono-therapeutically administering TMZ in patients with HGG. Methods: Adult patients ( > 18 years) with HGG (WHO Grade III/IV) were eligible. Patients were screened and consented prior to initiation of monthly TMZ therapy. Eligible patients were randomized to TMZ in the morning (AM) before 10AM or in the evening (PM) after 8PM. Pill diaries were recorded for drug administration time and compliance. Fact-Br Quality of Life (QoL) surveys were administered to patients at the time of enrollment in the trial and at the end of treatment to measure differences in QoL in both groups. Circadian rhythm was recorded by Actiwatch. Adverse events (AE), overall survival (OS) and progression free survival (PFS) were measured for each group. Results: At the time of submission, a total of 28 patients were evaluated. 15 patients were in AM group and 13 in PM group. It is feasible for participants to take TMZ per study assignment. There was no significant difference in the QoL based on the Fact-Br dataset in the four main categories of physical well-being, social/family well-being, functional well-being and emotional well-being. The Friedman’s two-way nonparametric ANOVA tests were used to analyze the differences across time points. Cytopenias are a known adverse effect of TMZ. There was a trend towards worsening lymphocyte counts in the AM group compared to PM group, although not statistically significant. There was no statistical significance in PFS or OS in patients with newly diagnosed glioblastoma. Conclusions: Chronotherapy with TMZ is feasible. A trend of worsening lymphocyte counts is noted in AM treatment group compared to PM group but was not statistically significant. No difference in OS or PFS was noted, although sample size was too small to effectively assess this. A larger study will need to be conducted to effectively assess the effect of chronotherapy on survival. Clinical trial information: NCT02781792.

185 The Safety and Tolerability of Lumateperone 42 mg for the Treatment of Schizophrenia: A Pooled Analysis of 3 Randomized Placebo-Controlled Trials

Lumateperone (ITI-007) is in late-phase clinical development for schizophrenia. Lumateperone has a unique mechanism of action that modulates serotonin, dopamine, and glutamate neurotransmission. This pooled analysis of lumateperone in 3 randomized, double-blind, placebo-controlled studies was conducted to evaluate the safety and tolerability of lumateperone 42mg (ITI-007 60mg). Data were pooled from the 3 controlled late-phase studies of lumateperone 42mg in patients with acute exacerbation of schizophrenia. Safety assessments of all patients who received at least one dose of any treatment included treatment-emergent adverse events (TEAEs), changes in laboratory parameters, extrapyramidal symptoms (EPS), and vital signs. The safety population comprised 1,073 patients (placebo [n=412], lumateperone 42mg [n=406], risperidone [n=255]). TEAEs that occurred in the lumateperone 42mg group at a rate of ≥5% and twice placebo were somnolence/sedation (24.1% vs 10.0%) and dry mouth (5.9% vs 2.2%). Rates of discontinuation due to TEAEs with lumateperone 42mg (0.5%) were similar to placebo (0.5%) and lower than risperidone (4.7%). Mean change in weight and rates of EPS-related TEAEs were less for lumateperone 42mg and placebo patients than risperidone patients. Mean change from baseline in metabolic parameters were similar or smaller for lumateperone 42mg vs placebo. Mean changes were notably higher in risperidone patients vs lumateperone 42mg and placebo for glucose, cholesterol, triglycerides, and prolactin. In this pooled analysis, lumateperone 42mg showed good tolerability with potential benefits over risperidone for metabolic, prolactin, and EPS risks. The only TEAE that occurred in >10% of lumateperone patients was somnolence/sedation, which was impacted by morning administration; in subsequent studies that administered lumateperone in the evening, somnolence/sedation rates were markedly reduced. These results suggest that lumateperone 42mg may be a promising new treatment for schizophrenia. Supported by funding from Intra-Cellular Therapies, Inc.

Changes in the Inflammatory Status in White Adipose Tissue of Rats with Diet-Induced Obesity at Different Regimens of Melatonin Administration

The effects of different regimens (morning and evening) of melatonin administration (30 mg/kg/day during 7 weeks) on the course of inflammation processes in visceral white adipose tissue (the presence of macrophages that formed crown-like structures around the adipocytes, fibrosis level and mast cell numbers in white adipose tissue, and the content of proinflammatory (IL-1β, IL-8, tumor necrosis factor α, and interferon γ) and anti-inflammatory (IL-4 and IL-10) cytokines in blood serum) was analyzed in rats with obesity induced by a high-calorie diet. Melatonin administration was followed by changes in the numbers of macrophages and mast cells in white adipose tissue of obese rats, and decreases of collagen fiber content (fibrosis) and the area of adipocytes were also demonstrated. Melatonin administration in the evening (1 h before the lights off) turned out to be more efficient than the morning administration (1 h after the lights on). Moreover, the level of anti-inflammatory cytokines increased in the blood serum of obese rats after melatonin administration, whereas the level of proinflammatory cytokines decreased at the same time. This demonstrates the anti-inflammatory effects of melatonin in the context of obesity development and serves as a theoretical prerequisite for further consideration of the possible use of melatonin in obesity treatment.

Evaluation of evening versus morning levothyroxine intake in elderly (MONIALE)

BackgroundThe aging population is associated with increased multimorbidity and polypharmacy. Older adults are at a higher risk of adverse events and reduced therapeutic response. This phenomenon is partially explained by drug interactions and treatment adherence. Most randomized clinical trials have found no significant differences between morning and evening levothyroxine (LT4) administration in young adults, but there is little evidence regarding alternative LT4 regimens in older populations. Thus, the MONIALE trial aims to test an alternative schedule for LT4 administration in older adults.Methods/designThis randomized crossover clinical trial will include participants aged 60 years or older with primary hypothyroidism. The trial groups will consist of morning LT4 intake (60 min before breakfast) or evening LT4 intake (60 min after supper). The primary outcome will be variation in serum thyrotropin (TSH) levels after 24 weeks of the LT4 protocol. The secondary outcomes will be the prevalence of drugs that potentially interact with LT4 and hypothyroidism control according to interaction status. The sample size was calculated to detect a minimum mean difference of 1 mUI/L in serum TSH level between the groups with 80% power and a 5% probability of type I error, resulting in 91 patients per group. The project was approved by the Hospital de Clínicas de Porto Alegre Ethics Committee.DiscussionConsidering the aging population, the increased prevalence of multimorbidity and polypharmacy, as well as potential drug interactions and treatment adherence difficulties, an alternative LT4 protocol could be useful for hypothyroidism treatment in the elderly. Prior studies comparing alternative LT4 administration protocols have mainly included young adult populations and have not addressed potential drug interactions.Trial registrationClinicalTrials.gov, NCT03614988. Registered 30 July 2018.

Chronopharmacology of high blood pressure—a critical review of clinical evidence

Abstract Physiological functions of cardiovascular system (CVS) are exhibiting circadian patterns regulated by complex system of endogenous factors. Preserving this rhythmicity is important for its normal function, whereas disturbing the synchronization with natural day–night cycle can increase the risk of cardiovascular damage. Cardiovascular pathophysiology also follows cyclic variation; time susceptibility and period with maximum risk associated with elevated blood pressure (BP) can be predicted. Given this rhythmic nature, significant changes in efficacy between morning and evening administration of the drug may occur; appropriate timing of pharmacological intervention in therapy of hypertension may affect the efficacy of the treatment.

Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration.

The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects. Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65-80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily. Absorption was quick with a median time to maximum concentration of ∼ 1.0 h. The mean elimination half-life was 8.5-9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8-12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies. ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia. Clinicaltrials.gov: NCT02571855.

Bioavailability and Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets in Healthy Volunteers: Results from Three Randomized, Crossover, Open-Label, Phase 1 Studies.

IntroductionIn February 2018, OS320—an amantadine extended-release (ER) tablet formulation with once-daily morning administration—was approved for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers.MethodsStudy 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup.ResultsAmantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup.ConclusionThe PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily.FundingOsmotica Pharmaceutical US LLC.

Chronotherapy for the Treatment of Hypertension among Patients with Obstructive Sleep Apnea: A Systematic Review

Hypertension (HTN) and obstructive sleep apnea (OSA) are associated with increased risk for adverse cardiovascular events. Comorbid HTN with OSA is often resistant to pharmacologic treatment. Chronotherapy, the timing of treatment based on circadian rhythms, may prove to be a valuable, cost-effective tool for improving blood pressure (BP) control among those with OSA. This Systematic Review appraises the existing literature regarding morning (a.m.) vs. evening (p.m.) administration of antihypertensives among this population.

The impact of psychostimulants on sustained attention over a 24-h period

The off-label use of psychostimulants is a growing trend in healthy adults with many turning to these medications to increase alertness, attentional focus, and to help them study. However, the empirical literature on the efficacy of these medications for cognitive enhancement is controversial and the longer-term impact of these drugs on health and cognitive processing has not been thoroughly examined. Specifically, sleep supports daytime alertness, vigilance, and sustained attention, yet stimulants significantly disrupt sleep. Here, using a double-blind, placebo-controlled, crossover design, we tested the impact morning administration of psychostimulants (dextroamphetamine; DEX) had on: (1) tests of attention 75-min and 12-h after drug ingestion, (2) nighttime sleep and (3) post-sleep attention in healthy, young adults. First, we found that repeated testing led to significant decreases in performance from baseline in the placebo condition, and that DEX, compared to placebo, prevented deterioration at the 75-min test, and selectively for visual field at the 12 h and 24 h tests. We also found that stimulants, compared to placebo, benefitted attentional processing 75-min post-drug but this did not persist to the delayed test 12-h after drug administration. Additionally, morning stimulant administration resulted in robust nighttime sleep disruptions, yet post-sleep sustained attention was equivalent in the stimulant and placebo conditions, indicating that the initial boost to performance dissipated at 24 h, but the decrease was not significantly worse than placebo. Together, these results suggest that stimulant medications, commonly used off-label for cognitive enhancement may prevent deterioration of sustained attention brought on by repeated within-day testing. Additionally, these medications substantially disrupt nighttime sleep; which while coming at little cost to next-day attentional processing, may have steeper consequences for other cognitive domains.

BLOOD PRESSURE LOWERING EFFICACY OF TELMISARTAN, AZILSARTAN, OLMESARTAN TAKING ON THE MORNING OR AT BEDTIME IN PATIENTS WITH MILD TO MODERATE ARTERIAL HYPERTENSION

Objective: Aim study was compared the antihypertensive effects of morning (a.m.) and evening (p.m.) dosing of olmesartan, azilsartan, telmisartan on 24-h BP. Design and method: 126 patients (57 men, 69 women) was included in 12-week study with evaluated the efficacy and safety of olmesartan 20–40 mg (n = 40), azilsartan 40–80 mg (n = 41), telmisartan 40–80 mg (n = 45), dosed a.m. or p.m., in patients with grade 1–2 hypertension. Mean ages 51,80 ± 1,31, BMI - 28,81 ± 0,39 kg/m2. Mean 24SBP – (135,60 ± 0,96) mmHg., 24DBP – (82,41 ± 0,84) mmHg., 24HR – (71,88 ± 0,89) b.p.m. Results: Mean 24-h SBP/DBP change from baseline to Weeks 12 in olmesartan group was benefit (−11,09 ± 2,30/8,38 ± 2,58 mmHg) in p.m. compared (−4,06 ± 2,25/3,38 ± 2,31mmHg) in a.m., p < 0,01 between evening and morning administration. Mean 24-h SBP/DBP change in azilsartan group was comparable in p.m. (−13,06 ± 2,65/9,76 ± 1,73 mmHg) and a.m. (−12,71 ± 1,62/7,00 ± 1,50 mmHg) in a.m., p > 0,05 between evening and morning. Mean 24-h SBP/DBP change from baseline to Weeks 12 in telmisartan group was benefit (−16,48 ± 2,86/12,56 ± 2,80 mmHg) in a.m. compared (−4,93 ± 1,53/5,40 ± 1,89 mmHg) in p.m., p < 0,01 between morning and evening administration. All treatments were well tolerated. At 24-h BP, with the administration of olmesartan, azilsartan and telmisartan, the target blood pressure levels were 71.80%, 71.05% and 75.61% respectively. Thus, all three drugs have equally effectively. Conclusions: Taking telmisartan more significantly reduced the 24-h BP in the morning compared with the evening adminisrtation, olmesartan lowered 24-h BP better in the evening administration, and the use of azilsartan equally decreased 24-h BP, regardless of the time of taking the drug.

MON-263 CHRONOTHERAPY, OPTIMAL TIMING OF MEDICATION, IN CHRONIC RENAL FAILURE: BAYESIAN ANALYSIS AND KALMAN FILTERING TO ESTABLISH INFLUENCE OF TIMING ON PROGRESSION

In 1961 24 h, blood pressure studies showed no fall at night in patients with malignant (accelerated) hypertension with renal failure or at risk of this. Wang et al (2017) provided a meta-analysis of studies including an evaluation of time of administration, concluding that evening administration was optimal when evening dosing was contrasted with morning administration, using two surrogate markers of long-term benefit: restoring ‘dipping’ in ‘non-dipping’ hypertensives and decreasing urinary albumin.

Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration

ACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability following multiple-ascending oral dose (MAD) administration in the morning, and next-day residual effects after repeated evening administration were investigated in a double-blind, placebo-controlled, randomized study. 31 healthy male and female subjects in 3 dose-groups (10, 25, and 75 mg) received study drug in the morning for 5 days (MAD part), and 20 healthy subjects received 25 mg in the evening for 1 week (evening part). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analogue scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), Digit Symbol Substitution Test (DSST), and Simple Reaction Time Test (SRTT), safety, and tolerability were assessed. ACT-541468 was absorbed with a median tmax of 1.0–2.0 h across the 3 dose groups. The geometric mean elimination half-life (t½) on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality. No accumulation and no influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. No effects were observed at 10 mg. Administration of 25 and 75 mg during the day showed clear dose-dependent effects on the PD parameters, while next-day effects were absent after evening administration of 25 mg. The drug was safe and well tolerated. In conclusion, multiple-dose PK/PD of ACT-541468 were compatible with a drug designated to treat insomnia.

Morning stimulant administration reduces sleep and overnight working memory improvement

The goal of cognitive enhancement is to improve mental functions using interventions including cognitive training, brain stimulation and pharmacology. Indeed, psychostimulants, commonly used for cognitive enhancement purposes, while preventing sleep, have been shown to increase working memory (WM) and attention. Sleep, however, is also important for cognitive function; thus, understanding the interaction between stimulants, sleep and cognition may inform current approaches to cognitive enhancement. We used a double-blind, placebo controlled, repeated measure design to investigate the effect of morning administration of a commonly used stimulant, dextroamphetamine (DEX, 20 mg), on repeated, within-day and overnight WM performance, as well as on sleep in healthy young adults. Compared with placebo (PBO), we found no within-day benefit of DEX on WM. After sleep, DEX performed worse than PBO and the overnight improvement in performance in the PBO condition was absent in the DEX condition. Moreover, sleep quality was negatively affected by DEX administration. In summary, we found no cognitive boost from psychostimulants across a day of wake and a blockade of overnight WM increases with the stimulant, compared to PBO.

Blue Light Exposure In The Morning and Low-Dose Aripiprazole Administration at Night Combined to Effectively Treat Wake-Up Difficulty due to Prolonged Sleep Time

School non-attendance due to difficulty waking up is a social concern among Japanese students. Many factors result in wake-up difficulty, and it is often difficult to identify the underlying cause at the first visit to a clinic or hospital. We, therefore assessed the effect of combination treatment with morning blue light exposure, low-dose aripiprazole (dopamine D2 and/or D3 receptor partial agonist), and sleep hygiene education in a 15-year-old patient with a 2-year history of wake-up difficulty. In this study, we demonstrate a beneficial effect with a good response of this combination treatment.

Pharmacokinetics of mycophenolate mofetil in juvenile patients with autoimmune diseases

Objectives: This study aimed to determine the association between the dosage and pharmacokinetics of mycophenolate mofetil (MMF) in juvenile patients with autoimmune diseases.Methods: Totally, 29 patients were administered oral MMF. The blood concentrations of mycophenolate acid (MPA) at seven points, the area under the time–concentration curve (MPA–AUC0–12h), the peak concentration (Cmax), and the time to peak concentration (Tmax) were measured. To obtain a dose-normalized MPA–AUC0–12h value, the actual measured MPA–AUC0–12h value was divided by the dose value of the morning administration corrected for body weight (BW) or body surface area (BSA). The patients were classified into three age groups (group 1, ≤10 years; group 2, >10–≤15 years; and group 3, >15 years), and pharmacokinetic parameters were compared among the groups.Results: In total, we obtained 37 measurements. The actual measured MPA–AUC0–12h values and the MPA–AUC0–12h values corrected for dose per BW and Tmax were lower in young patients. The MPA–AUC0–12h values corrected for dose per BSA and Cmax were comparable among all the groups.Conclusion: In patients with juvenile autoimmune diseases, determining MMF administration dosage according to BSA may facilitate MPA–AUC0–12h value prediction.

ВПЛИВ РАНКОВОГО ТА ВЕЧІРНЬОГО ВВЕДЕННЯ МЕЛАТОНІНУ НА СТАН СЛИЗОВОЇ ОБОЛОНКИ ТА КРИПТ ТОНКОЇ КИШКИ У ЩУРІВ З ОЖИРІННЯМ

The aim of this work was to determine structural and functional changes in a small intestine of rats after morning and evening administration of melatonin in obese animals during the spring-autumn photoperiod (12L:12D). The obesity was caused with a high-calorie diet for 6 weeks. After that, morning or evening melatonin administrations were given to normal and obese animals at a dose of 30 mg/kg for 7 weeks. After that, paraffin sections of the small intestine were made, on which a state of the mucosa, enterocytes and goblet cells in crypts was morphometrically and visually examined under a microscope. It has been shown, that obesity causes swelling and an increase of thickness of a mucosa, reduction of crypts, a decrease of activity of enterocytes and goblet cells of the small intestine. Introduction of melatonin to animals without obesity causes an increase in thickness of mucosa and a decrease in area of goblet cells. Additionally, after morning melatonin administration a depth of crypts and a height of enterocytes increases. Morning administration of melatonin to obese animals partially recovers crypts and their goblet cells, but doesn't prevent mucosal edema and worsens a state of enterocytes. The evening administration of melatonin partially normalizes all structural changes, caused by obesity. It was concluded, that melatonin may partially correct morpho-functional changes in the small intestine, caused by obesity in the spring and autumn seasons. The evening administration of melatonin to animals with obesity is more effective, than morning administrations. Also, the evening administration of melatonin causes fewer changes in the small intestine of animals without obesity, compared with morning administration.

СТРУКТУРНІ ЗМІНИ У ТОВСТІЙ КИШЦІ ЩУРІВ ПРИ ОЖИРІННІ ТА ПРИ ЙОГО КОРЕКЦІЇ РАНКОВИМИ ТА ВЕЧІРНІМИ ВВЕДЕННЯМИ МЕЛАТОНІНУ

The effect of morning and evening administrations of melatonin on structural and functional changes in the large intestine of rats with obesity under conditions of the spring-autumn photoperiod (12L:12D) was studied in this work. The obesity was caused with a high-calorie diet for 6 weeks. After that, the morning or evening melatonin administrations were given to normal and obese animals at a dose of 30 mg/kg for 7 weeks. After 13 weeks, two specimens of the colon 1 cm each were taken at a distance of 3 cm from the anus; fixed in 10% formalin and in Carnua solution; paraffin sections of the large intestine were made; stained them with hematoxylin-eosin, alcian blue-carmine, or toluidine blue. Microscopic and morphometric analysis of these sections was performed. It has been shown, that obesity cause hyperactivation of the colonic mucosa, reduction of colonocytes, hypertrophy of goblet cells and overaccumulation of granules in mast cells. Morning administration of melatonin to obese animals normalizes the colonic mucosa, decreases the reduction of colonocytes, but causes the hypotrophy of goblet cells. Evening administration of melatonin significantly decreases the reduction of colonocytes, but does not eliminate other changes caused by obesity. The administration of melatonin (both morning and evening) to animals without obesity causes an activation of the mucosa, hypertrophy of goblet cells, reduction of colonocytes, and does not change the state of mast cells. Consequently, it cannot make a clear conclusion about the possibility of correction of all structural-functional changes in the large intestine during obesity by melatonin. Although, the morning administration of melatonin had some normalizing effects on the colon and it was more effective than evening administration.

WHAT WE KNOW—AND DON'T KNOW—ABOUT THE PSYCHOSOCIAL IMPACT OF PSYCHIATRIC GENETIC INFORMATION

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1–7 mg/day; morning administration) in children (aged 6–12 years) and adolescents (aged 13–17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p < 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive–impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p < 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p < 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.

Time-Dependent Hypotensive Effect of Aspirin in Mice.

Objective- Evening but not morning administration of low-dose aspirin has been reported to lower blood pressure in hypertensive patients. The present study was designed to determine whether this phenomenon could be replicated in mice, and if so, whether a time-dependent effect of aspirin on blood pressure was because of alteration of circadian clock function. Approach and Results- We recapitulated the protective effect of aspirin (50 μg/d for 7 days) at zeitgeber time 0 (active-to-rest transit), but not at zeitgeber time 12, on a high-salt diet-induced increase of blood pressure. However, the time of aspirin administration did not influence expression of canonical clock genes or their acetylation. We used mouse Bmal1 and Per2-luciferase reporters expressed in U2OS cells to determine the real-time effect of aspirin on circadian function but found that the oscillation of bioluminescence was unaltered. Timing of aspirin administration also failed to alter urinary prostaglandin metabolites or catecholamines, or the acetylation of its COX-1 (cyclooxygenase-1) target in platelets. Conclusions- The time-dependent hypotensive effect of aspirin in humans has been recapitulated in hypertensive mice. However, this does not seem to reflect a direct impact of aspirin on circadian clocks or on acetylation of platelet COX-1.