Effect of enterally administered sleep-promoting medication on the intravenous sedative dose and its safety and cost profile in mechanically ventilated patients: A retrospective cohort study.

BACKGROUND: The clinical effect of enteral administration of sleep-promoting medication (SPM) in mechanically ventilated patients remains unclear. This study aimed to investigate the relationship between enteral SPM administration and the intravenous sedative dose and examine the safety and cost of enteral SPM administration. METHODS: This single-center retrospective cohort study was conducted in a Japanese tertiary hospital intensive care unit (ICU). The exposure was enteral SPM administration during mechanical ventilation. The outcome was the average daily propofol dose per body weight administered as a continuous sedative during mechanical ventilation. Patients were divided into three groups based on the timing of SPM administration at ICU admission: "administration within 48 hours (early administration [EA])," "administration after 48 hours (late administration [LA])," and "no administration (NA)." We used multiple linear regression models. RESULTS: Of 123 included patients, 37, 50, and 36 patients were assigned to the EA, LA, and NA groups, respectively. The average daily propofol dose per body weight was significantly lower in the EA group than in the LA and NA groups (ß -5.13 [95% confidence interval (CI) -8.93 to -1.33] and ß -4.51 [95% CI -8.59 to -0.43], respectively). Regarding safety, enteral SPM administration did not increase adverse events, including self-extubation. The total cost of neuroactive drugs tended to be lower in the EA group than in the LA and NA groups. CONCLUSIONS: Early enteral SPM administration reduced the average daily propofol dose per body weight without increasing adverse events.

The Effects of Melatonin Supplementation on Sleep Quality and Assessment of the Serum Melatonin in ICU Patients: A Randomized Controlled Trial.

OBJECTIVES: To evaluate whether the use of exogenous melatonin affects sleep, reduces the prevalence of delirium, and decreases the need for analgosedation and to assess whether serum melatonin indices correlate with exogenous administration in critically ill patients. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: Multicenter ICUs of two tertiary hospitals. PATIENTS: A total of 203 adult patients who were admitted to the ICU and administered with analgesics and/or sedatives. INTERVENTIONS: Oral melatonin (10 mg) or placebo for up to seven consecutive nights. MEASUREMENTS AND MAIN RESULTS: The number of observed sleeping hours at night was assessed by the bedside nurse. Sleep quality was evaluated using the Richards Campbell Questionnaire Sleep (RCSQ). The prevalence of delirium, pain, anxiety, adverse reactions, duration of mechanical ventilation, length of ICU and hospital stays, and doses of sedative and analgesic drugs administered were recorded. The use of analgesics and sedatives was assessed daily. Melatonin levels were determined by enzyme-linked immunosorbent assay. Based on the RCSQ results, sleep quality was assessed to be better in the melatonin group than that in the placebo group with a mean (SD) of 69.7 (21.2) and 60.7 (26.3), respectively (p = 0.029). About 45.8% and 34.4% of participants in the melatonin and placebo groups had very good sleep (risk ratio, 1.33; 95% CI, 0.94-1.89), whereas 3.1% and 14.6% had very poor sleep (risk ratio, 0.21; 95% CI, 0.06-0.71), respectively. No significant difference was observed regarding the days free of analgesics or sedatives, the duration of night sleep, and the occurrence of delirium, pain, and anxiety. Melatonin serum peak levels at 2 AM were 150 pg/mL (range, 125-2,125 pg/mL) in the melatonin group and 32.5 pg/mL (range, 18.5-35 pg/mL) in the placebo group (p < 0.001). CONCLUSIONS: Melatonin was associated with better sleep quality, which suggests its possible role in the routine care of critically ill patients in the future.

Assessment of melatonergics in prevention of delirium in critically ill patients: A protocol for systematic review and meta-analysis.

BACKGROUND: Delirium is a commonly occurred complication in the critically ill. Melatonin is an endogenous hormone exerting multiple biological effects, mainly in regulating diurnal rhythms, also in inflammatory process and immune response. We aimed to assess the efficacy of exogenous melatonergics in prevention of delirium. METHODS: PubMed, Cochrane Library, and Embase will be searched to identify randomized controlled trials published from 1960 to April 2019. Critically ill adult patients administrated with melatonergics will be included. The primary outcome measure will be the incidence of delirium. The secondary outcome measure will be the length of stay in intensive care unit. The pooled effects of dichotomous outcomes will be analyzed as risk ratio, and that of continuous outcomes will be analyzed using weighted mean difference. Subgroup and sensitivity analyses will be conducted. Funnel plots and/or Egger test will be done for the examination of publication bias. The quality of evidence resulting from this study will be evaluated using the GRADE methodology. Trial sequential analysis (TSA) will be done to test whether the evidence in our meta-analysis is reliable and conclusive. RESULT: The evidence to date of the melatonergics in prevention of delirium will be systematically reviewed and meta-analyzed with the GRADE level reported and TSA examined. CONCLUSION: The stronger evidence for the efficacy of melatonergics in prevention of delirium in critically ill patients will be provided for intensive care physicians. PROSPERO REGISTRATION NUMBER: CRD42019138863.

Changes in feed consumption and water intake among broiler chickens subjected to melatonin treatment during the hot-dry season.

The experiment was conducted to evaluate changes in feed consumption and water intake among broiler chickens subjected to melatonin treatment during the hot-dry season. A total of 300 broiler chicks were selected and assigned into three groups, by simple random sampling, comprising 100 chicks each: group I was exposed to natural photoperiod of about 12-h light and 12-h darkness cycle (12D/12L), without melatonin supplementation; group II was kept under 24-h continuous lighting (CL), without melatonin supplementation; and group III was raised under 24-h CL and administered daily with melatonin orally at 0.5 mg/kg (CL + MEL). Live weight (LW), feed consumption, and water intake for each group were obtained at weekly intervals over a period of 8 weeks. On day 42 of age, the LW of 2420 ± 50 g/bird was obtained in group III administered with melatonin (CL + MEL), while LW values recorded in the 12D/12L and CL groups not administered with melatonin were 1470.00 ± 30.00 and 1907.00 ± 38.00 g/bird, respectively. The mean weight gain in CL + MEL (345.00 ± 21.01 g) was significantly (P < 0.05) higher than those of the 12D/12L (244.99 ± 18.67 g) and CL (307.48 ± 18.14 g) groups. Feed consumptions were significantly (P < 0.05) different in all the groups. Group II, raised on CL without melatonin supplementation, had the highest feed consumption value of 25.14 ± 0.51 g/bird from day 14, and attained the peak value of 206.77 ± 7.82 g/bird at day 56. The highest overall amount of water intake was recorded in the melatonin-treated group. In conclusion, melatonin administration to broiler chickens enhanced water intake but decreased feed consumption with increase in LW during the hot-dry season.

Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs.

Tamoxifen is used to prevent and treat estrogen receptor-positive (ER+) breast cancer (BC); however, its chronic use can increase uterine cancer risk and induce tamoxifen resistance. Novel melatonin-tamoxifen drug conjugates may be promising to treat BC and may help offset the adverse effects of tamoxifen usage alone due to the presence of melatonin. We synthesized and screened five drug conjugates (C2, C4, C5, C9, and C15 linked) for their effects on BC cell (MCF-7, tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231, and BT-549) viability, migration, and binding affinity to melatonin receptor 1 (MT1R) and estrogen receptor 1 (ESR1). C4 and C5 demonstrated the most favorable pharmacological characteristics with respect to binding profiles (affinity for ESR1 and MT1R) and their potency/efficacy to inhibit BC cell viability and migration in four phenotypically diverse invasive ductal BC cell lines. C4 and C5 were further assessed for their actions against tamoxifen-resistant MCF-7 cells and a patient-derived xenograft triple-negative BC cell line (TU-BcX-4IC) and for their mechanisms of action using selective mitogen-activated protein kinase kinase MEK1/2, MEK5, and phosphoinositide 3-kinase (PI3K) inhibitors. C4 and C5 inhibited tamoxifen-resistant MCF-7 cells with equal potency (IC50 = 4-8 µM) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC50 = 80-211 µM) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC50 = 181-304 mM; efficacy ∼80% inhibition) in TU-BcX-4IC cells. Unique pharmacokinetic profiles were observed, with C4 having greater bioavailability than C5. Further assessment of C4 and C5 demonstrates that they create novel pharmacophores within each BC cell that is context specific and involves MEK1/2/pERK1/2, MEK5/pERK5, PI3K, and nuclear factor κB. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.

Enteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial.

BACKGROUND: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. METHODS: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. RESULTS: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01). CONCLUSIONS: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01360346 . Registered on 25 March 2011.

Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): study protocol for a randomised controlled trial.

BACKGROUND: Delirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium. METHODS: This trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72 h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4 mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14 days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep. DISCUSSION: Delirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471 . Registered on 20 December 2015.

Sleep Complaints and the 24-h Melatonin Level in Individuals with Smith-Magenis Syndrome: Assessment for Effective Intervention.

AIMS: Individuals with Smith-Magenis syndrome (SMS) are reported to have a disrupted circadian rhythm. Our aim was to examine problematic sleeping in those attending our sleep clinic for the first time. METHODS: At intake, caregivers of 50 children and nine adults with SMS were surveyed about the sleep pattern and potential melatonin administration. Sampling of salivary melatonin levels was performed. RESULTS: At intake, exogenous melatonin was used by 16 children (27.1% of sample; 56.3% male) with mean age 6.8 ± 2.8 years, whereas 34 children (57.6%; 7.5 ± 4.8 years old; 64.7% male) and nine adults (15.3%; 36.8 ± 15.3 years old; 44.4% male) were not taking melatonin at intake. Participants were reported to have problems with night waking and early awakenings regardless of melatonin administration. Overall, moderate to high levels of salivary melatonin at noon were found in individuals with SMS. In particular, children with SMS showed a disrupted melatonin pattern. Furthermore, the endogenous melatonin level, age, and gender may potentially interact, yielding the severity range of sleep disturbances reported in SMS. CONCLUSION: Treatment of sleep problems in SMS is complex, and our findings may support person-centered sleep and medication management. Future clinical trials including larger groups may shed light on such approaches.

[The first results of assessment of clinical efficacy of melatonin and metformin in patients with disseminated skin melanoma receiving dacarbazine as first-line systemic therapy].

The aim of the study was to assess efficacy and safety of combined therapy with dacarbazine and melatonin or metformin in comparison with dacarbazine alone in the 1st line of therapy of cutaneous melanoma. Thirty-six patients with disseminated melanoma, therapy naïve, were included between March 2014 and December 2015. Patients received DTIC 1000 mg/m2 in day 1 of 28-day cycle either as monotherapy (group 1) or in combination with melatonin 3 mg PO daily (group 2) or metformin 850 mg 2 times a day PO daily (group 3). Thirty-four patients were randomized (15-in group 1, 8 - in group 2, 13 - in group 3) and received 119 cycles of therapy. Response rate was 11% in groups 1 and 2, and 8,3% - in group 3 (p=0,57). Median time to progression was 52, 79 and 63 days, respectively in the 1st, 2nd and 3rd group (р=0,468). Two patients from the 2nd and 3rd group showed delayed response to therapy. No adverse events of grade 3-4 were seen. Thus, DTIC with melatonin or metformin was well tolerated. No meaningful increase of adverse event incidence was seen. No benefit of either combination was shown in this interim analysis. Delayed responses in melatonin and metformin combination groups were registered. This suggests immunologic effect of both drugs and warrants further study.

[ASSESSMENT OF EFFICACY OF MELATONIN IN SURGICAL TREATMENT OF COLON TUMORS].

Melatonin is neurohormone, which is involved in regulation of many functions of an organism, including the digestive system. Therefore the authors offered to include this hormone as a preconditioner factor in surgical treatment of colon tumors using laparotomy and laparoscopy. Preoperative application of melatonin allowed shortening the terms of postoperative period and hospital stay.

Circadian rhythm disorders among adolescents: assessment and treatment options.

Delayed sleep phase disorder (DSPD) - a circadian rhythm sleep disorder - is most commonly seen in adolescents. The differential diagnosis between DSPD and conventional psychophysiological insomnia is important for correct therapeutic intervention. Adolescent DSPD sleep duration is commonly 9 hours or more. Depression may be comorbid with DSPD. DSPD has a negative impact on adolescent academic performance. DSPD treatments include bright light therapy, chronotherapeutic regimens, and administration of melatonin as a chronobiotic (as distinct from a soporific). Attention to non-photic and extrinsic factors including healthy sleep parameters is also important to enable better sleep and mood outcomes in adolescents.

Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and Z-drugs consumption in nine European countries.

BACKGROUND: Benzodiazepines (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone, altogether Z-drugs) are most commonly prescribed for the treatment of insomnia. However, long-term use of BZD/Z-drugs is associated with major adverse events including, but not limited to, falls and fractures, domestic and traffic accidents, confusion, cognitive impairment, Alzheimer's disease and cancer. The prolonged use of these drugs is thought to be related to severe withdrawal symptoms and potential dependency. The chronic and extensive use of BZD/Z drugs has become a public health issue and has led to multiple campaigns to reduce both prescription and consumption of BZD/Z-drugs. Prolonged-release (PR) melatonin is the first of a new class of melatonin receptor agonist drugs that has demonstrated clinically relevant efficacy on improving quality of sleep and morning alertness, with a good safety profile. OBJECTIVE: This study aimed to analyze and evaluate the impact of anti-BZD/Z-drugs campaigns and the availability of alternative pharmacotherapy (PR-melatonin) on the consumption of BZD and Z-drugs in several European countries. METHODS: Annual sales data from nine European countries were extracted from the IMS sales database and analyzed to determine whether trends in use of these treatment options were attributed to campaigns and/or availability and affordability of safer alternatives on the market. RESULTS: Campaigns aiming to reduce the use of BZD/Z-drugs failed when they were not associated with the availability and market uptake of PR-melatonin. The reimbursement of PR-melatonin supports better penetration rates and a higher reduction in sales for BZD/Z-drugs.

Evaluation of management variables to advance conception and calving date of red deer (Cervus elaphus) in New Zealand venison production systems.

The ability to shift the supply of New Zealand chilled venison from farmed yearling red deer stags to obtain premium prices in seasonal European markets necessitates early calving of hinds combined with high growth rates of their calves. Two studies over a three-year period evaluated three management variables that offer potential to advance calving date. Under the conditions of the studies there was no consistent evidence that the management practices of early stag introduction, early weaning and enhanced hind nutrition prior to conception (lactation) and pre-calving (third trimester of pregnancy) advanced conception date and calving date in red deer hinds. However, the nutrition effect was diminished by the difficultly in achieving the dietary contrast necessary for the targeted 5kg differentiation in hind live weight at strategic times of the year. Across all hinds there was a significant pre-mating (mid-March) live weight effect on conception day in the one year in which a 5kg difference between nutritional regimens was achieved, but the driver was live weight and not nutrition. There were significant effects of nutrition on calf growth, with the growth rates of calves weaned in mid-March significantly higher when their dams grazed a high plane of nutrition pre-conception. There were significant and consistent inverse relationships between conception day and calving date that implied variation around gestation length, with early- and late-conceiving hinds exhibiting longer and shorter gestation lengths, respectively. Across all treatments, calving date was predicted to advance by approximately 5 days for every 10-day advance in conception date. However, there was a significant carry-over effect of nutrition pre-conception on calving date, with hinds on a high plane of nutrition pre-conception exhibiting shorter (2-4 days) gestation lengths. There were also indications that hinds may manipulate gestation length in response to live weight gain pre-calving. These findings suggest that fetal growth trajectory may be the principle driver of gestation length and calving date. Although there were no direct effects of hind nutrition pre-mating on conception dates, nutrition remains an important component of the management of hinds and their calves in venison production systems. The outcomes of the 3-year program suggest that there are limited opportunities to manipulate calving date through manipulation of management variables.

Assessment of effects of pinealectomy and exogenous melatonin administration on rat sciatic nerve suture repair: an electrophysiological, electron microscopic, and immunohistochemical study.

BACKGROUND: Collagen scar formation at the cut end of a nerve, an important problem in clinical practice for neurosurgeons in peripheral nerve surgery, obstructs sprouting of axons into appropriate distal fascicles, and thereby limits nerve regeneration. Researchers attempt to control collagen accumulation in the formation of neuroma by various physical and chemical methods, but these have yielded only limited functional success. This is the first experimental study investigating the effects of melatonin (MLT) on nerve repair and neuronal regeneration in rat sciatic nerve suture repair. METHODS: The hypothesis that exogenous MLT administration may inhibit the formation of neuroma in peripheral nerve surgery was investigated in rat sciatic nerve model. In this study, a total of 80 rats were used for control groups (Groups Ia, Ib, IIa, and IId), MLT group (Group Ic), surgical pinealectomy (Px) groups (Groups IIb and IIc), and group of MLT treatment following Px procedure (Group IIe). All animals underwent a surgical intervention consisting of bilateral sciatic nerve section and primary suture repair. At 8 weeks after repair, the animals were killed following completion of recording of nerve action potentials (NAPs). Then, unilateral sciatic nerve specimens including the suture repair region were carefully removed and the excised segments were processed for electron microscopy examination. Afterwards, contralateral sciatic nerve specimens from two animals from each group were removed and stained for immunohistochemical analysis. RESULTS: Results of morphometric analysis revealed that Px procedure caused an elevation of collagen content of the sciatic nerve and macroscopic neuroma formation, and that there was a statistically significant reduction in collagen content of the same region in pinealectomized animals treated with MLT (p<0.001). Accordingly, electrophysiological findings demonstrated that the stimulus intensities required to excite a NAP response were increased in surgical Px group, but the presence of a reduced threshold response was found in the group treated with MLT following Px procedure (p<0.01). Immunohistochemical staining for Type I collagen and Type III collagen was markedly more intense in the epineurium of animals after Px. Virtually no or only weak staining was observed in animals in control groups and the MLT treatment group. Results of immunohistochemical analysis revealed that surgical Px procedure caused a strong immunoreactivity for Type I collagen and Type III collagen in all connective tissue planes of the nerve, especially in the epineurium, and there was a statistically significant reduction in immunoreactivity of the repair region in animals receiving MLT treatment after Px procedure (p<0.001). CONCLUSION: This study demonstrates that exogenous MLT administration significantly inhibits collagen accumulation in the formation of neuroma in the suture repair site and thereby improves nerve regeneration. From a clinical standpoint, the positive effect of MLT administration on neuroma formation and nerve regeneration seems a particularly attractive treatment option. Therefore, we believe that nerve repair with addition of MLT may be a worthwhile option in addition to other treatment modalities in case of MLT deficiency, such as aging. However, further experimental and clinical studies using functional analysis warranted to confirm this result in future.

Behavioural assessment of pinealectomy and foetal pineal gland transplantation in rats: Part II.

Pineal gland is an endocrine organ which exerts regulatory effects on the activity of various organs and systems. The present study was undertaken to highlight in experimental animals the possible integrative function of this endocrine organ on a behavioural pattern. Pinealectomy and foetal pineal gland transplantation to a subpial cortical area close to the pinealectomized region was performed. Behaviour was defined through motor activity induced by low (2 mg/kg) and high (10 mg/kg) doses of amphetamine in rats. It was shown that pinealectomy produced significant different patterns of behaviour induced by low and high doses of amphetamine. In sham operated animals low dose amphetamine induced a significant locomotor stimulation but without stereotyped activity. High dose amphetamine induced stereotyped activity. After pinealectomy even low dose amphetamine produced the behavioural pattern of stereotyped activity resembling a high dose amphetamine-induced behaviour. This differential effect of amphetamine, seen in pinealectomized rats, was completely restored after transplantation. On the other hand, melatonin treatment did not generate a significant alteration of behavioural profile either in the control or pinealectomized group of rats. Results are discussed with regard to the general regulatory function of the pineal gland.