RANDOMIZED CONTROLLED TRIAL COMPARING MORNING VERSUS NIGHT ADMINISTRATION OF LEVOTHYROXINE IN OLDER PERSONS

OBJECTIVE: To evaluate the effectiveness of levothyroxine administration strategies in the treatment of hypothyroidism in older persons in a tertiary outpatient clinic. METHODS: A randomized controlled trial of older persons with a diagnosis of primary hypothyroidism who had been receiving levothyroxine for at least 6 months with a stable dose in the last 3 months. Patients were randomly assigned to one of two administration strategies: morning (1 hour before breakfast) or night (1 hour after the last meal). In a period ≥ 12 weeks, patients were instructed to cross over between strategies. Laboratory tests for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were performed at visit 0 (baseline), visit 1 (period ≥ 12 weeks), and visit 2 (completion — period ≥ 24 weeks); a standardized questionnaire was also applied. Preliminary analyses of the period before crossover are presented. RESULTS: The preliminary sample consisted of 98 patients, with a mean age of 71.26 (SD 7.12) years; 83.67% were women. Fifty-three patients started with the morning strategy and 45 with the night strategy, and one patient did not return for reassessment. Median TSH levels ranged from 2.74 (IQR 1.06–4.19) at baseline to 2.77 (IQR 0.75–4.41) after a 12-week follow-up in the morning group, and from 2.36 (IQR 1.48–4.85) to 2.28 (IQR 1.69–3.56) in the night group. Mean FT4 levels ranged from 1.44 (SD 0.39) to 1.42 (SD 0.36) in the morning group, and from 1.35 (SD 0.27) to 1.37 (SD 0.32) in the night group. CONCLUSIONS: The administration of levothyroxine at night was as effective as morning administration at controlling primary hypothyroidism in older persons. Therefore, this can be considered an alternative dosage strategy for the treatment of this condition.

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

Introduction: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).Methods: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.Results: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.Conclusion: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.Funding Acknowledgements:Supported by funding from Intra-Cellular Therapies, Inc.

0151 The Dual Orexin Receptor Antagonist Almorexant Blocks the Sleep-Disrupting Effects of Methamphetamine in Male Rhesus Monkeys

Introduction Individuals with stimulant use disorder show a high prevalence of sleep problems. In the laboratory, stimulant drugs have been shown to affect sleep parameters in human and nonhuman primates, even when administered many hours before bedtime. Although the mechanisms underlying the relationship between stimulant use/abuse and sleep impairment remain unclear, recent research has implicated the orexin (also called “hypocretin”) system as a critical regulator of sleep-wake states. The aim of the present study was to investigate the effects of the dual orexin receptor antagonist (DORA) almorexant on the sleep-disrupting effects of methamphetamine in rhesus monkeys. Methods Male adult rhesus monkeys (Macaca mulatta, n=4) were fitted with primate collars to which Actiwatch monitors were attached. Actigraphy recording was conducted during baseline conditions and on the night after acute morning (9h) administration of vehicle or methamphetamine (0.03, 0.1 or 0.3 mg/kg, i.m.). During a second set of treatments, vehicle or almorexant (1, 3 or 10 mg/kg, i.m.) were administered in the evening (16:30h, 1.5h before “lights off”) following morning (9h) administration of methamphetamine (0.3 mg/kg, i.m.). Results Morning methamphetamine administration dose-dependently impaired sleep in rhesus monkeys, with the dose of 0.3 mg/kg significantly increasing sleep latency and decreasing sleep efficiency. Evening administration of almorexant improved both actigraphy-based sleep measures after morning administration of methamphetamine in a dose dependent manner. Conclusion Our findings indicate that orexin receptor systems are involved in methamphetamine-induced sleep disruption. The exact role of the two orexin receptors in this effect, alone or together, remains to be determined. This study suggests that DORAs can be effective in treating sleep impairment in individuals with methamphetamine use disorder or under stimulant prescription for other sleep and psychiatric disorders. Support Supported by UMMC Research Enhancement Funds.

Structural changes in rat colon under obesity conditions and its correction by morning and evening injection of melatonin

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.

Influence of morning and evening melatonin administration on the mucosa and crypts of a small intestine in rats with obesity

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.

Bromocriptine and insulin sensitivity in lean and obese subjects

Bromocriptine is a glucose-lowering drug, which was shown to be effective in obese subjects with insulin resistance. It is usually administered in the morning. The exact working mechanism of bromocriptine still has to be elucidated. Therefore, in this open-label randomized prospective cross-over mechanistic study, we assessed whether the timing of bromocriptine administration (morning vs evening) results in different effects and whether these effects differ between lean and obese subjects. We studied the effect of bromocriptine on insulin sensitivity in 8 lean and 8 overweight subjects using an oral glucose tolerance test. The subjects used bromocriptine in randomized cross-over order for 2 weeks in the morning and 2 weeks in the evening. We found that in lean subjects, bromocriptine administration in the evening resulted in a significantly higher post-prandial insulin sensitivity as compared with the pre-exposure visit (glucose area under the curve (AUC) 742 mmol/L * 120 min (695–818) vs 641 (504–750), P = 0.036, AUC for insulin did not change, P = 0.575). In obese subjects, both morning and evening administration of bromocriptine resulted in a significantly higher insulin sensitivity: morning administration in obese: insulin AUC (55,900 mmol/L * 120 min (43,236–96,831) vs 36,448 (25,213–57,711), P = 0.012) and glucose AUC P = 0.069; evening administration in obese: glucose AUC (735 mmol/L * 120 min (614–988) vs 644 (568–829), P = 0.017) and insulin AUC, P = 0.208. In conclusion, bromocriptine increases insulin sensitivity in both lean and obese subjects. In lean subjects, this effect only occurred when bromocriptine was administrated in the evening, whereas in the obese, insulin sensitivity increased independent of the timing of bromocriptine administration.