Evaluation of Polymeric Matrix Loaded with Melatonin for Wound Dressing.

The development of scaffolds mimicking the extracellular matrix containing bioactive substances has great potential in tissue engineering and wound healing applications. This study investigates melatonin-a methoxyindole present in almost all biological systems. Melatonin is a bioregulator in terms of its potential clinical importance for future therapies of cutaneous diseases. Mammalian skin is not only a prominent melatonin target, but also produces and rapidly metabolizes the multifunctional methoxyindole to biologically active metabolites. In our methodology, chitosan/collagen (CTS/Coll)-contained biomaterials are blended with melatonin at different doses to fabricate biomimetic hybrid scaffolds. We use rat tail tendon- and Salmo salar fish skin-derived collagens to assess biophysical and cellular properties by (i) Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR), (ii) thermogravimetric analysis (TG), (iii) scanning electron microscope (SEM), and (iv) proliferation ratio of cutaneous cells in vitro. Our results indicate that melatonin itself does not negatively affect biophysical properties of melatonin-immobilized hybrid scaffolds, but it induces a pronounced elevation of cell viability within human epidermal keratinocytes (NHEK), dermal fibroblasts (NHDF), and reference melanoma cells. These results demonstrate that this indoleamine accelerates re-epithelialization. This delivery is a promising technique for additional explorations in future dermatotherapy and protective skin medicine.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model.

With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1-13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1-13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (HT+V; n = 7); (iii) HT + Melatonin (HT+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after HI. Comparing HT+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/exchangeable phosphate were higher at 48 h in HT+M versus HT (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in HT+M (47.1 cells/mm2) compared to HT (123.8 cells/mm2) (p = 0.0003) and HT+V (97.5 cells/mm2) compared to HT (p = 0.012). Localized protection was seen in white matter for HT+M versus HT (p = 0.036) and internal capsule for HT+M compared to HT (p = 0.001) and HT+V versus HT (p = 0.006). Therapeutic melatonin levels (15-30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.

Melatonin in Medicinal and Food Plants: Occurrence, Bioavailability, and Health Potential for Humans.

Melatonin is a widespread molecule among living organisms involved in multiple biological, hormonal, and physiological processes at cellular, tissue, and organic levels. It is well-known for its ability to cross the blood-brain barrier, and renowned antioxidant effects, acting as a free radical scavenger, up-regulating antioxidant enzymes, reducing mitochondrial electron leakage, and interfering with proinflammatory signaling pathways. Detected in various medicinal and food plants, its concentration is widely variable. Plant generative organs (e.g., flowers, fruits), and especially seeds, have been proposed as having the highest melatonin concentrations, markedly higher than those found in vertebrate tissues. In addition, seeds are also rich in other substances (lipids, sugars, and proteins), constituting the energetic reserve for a potentially growing seedling and beneficial for the human diet. Thus, given that dietary melatonin is absorbed in the gastrointestinal tract and transported into the bloodstream, the ingestion of medicinal and plant foods by mammals as a source of melatonin may be conceived as a key step in serum melatonin modulation and, consequently, health promotion.

Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care.

Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care.

Different routes and formulations of melatonin in critically ill patients. A pharmacokinetic randomized study.

BACKGROUND AND OBJECTIVES: Critically ill patients present reduced endogenous melatonin blood levels, and they might benefit from its exogenous supplementation. The aim of this research was to evaluate the feasibility of different routes of administration and drug formulations of melatonin. The efficiency of absorption was assessed as well as the adequacy in achieving and maintaining the physiological nocturnal blood peak. METHODS: Twenty-one high-risk critically ill patients were randomly assigned to receive melatonin either: (a) per os, as a standard tablet (ST-OS), (b) per os, as a suspension in solid lipid nanoparticles (SLN-OS) or c) transdermal (TD), by applying a jellified melatonin microemulsion (µE) on the skin (µE-TD). SLN-OS and µE-TD were lipid-based colloidal systems. The endogenous melatonin blood values were observed for 24 hours; subsequently, melatonin 3 mg was administered and pharmacokinetics was studied for 24 hours further. RESULTS: In both groups that received ST-OS and SLN-OS, the median time-to-peak blood concentration was 0.5 hours; however, the area under the curve (AUC) after administration of SLN-OS was significantly higher than after ST-OS (157386 [65732-193653] vs 44441 [22319-90705] pg/mL*hours, P = 0.048). µE-TD presented a delayed time-to-peak blood concentration (4 hours), a lower bioavailability (AUC: 3142 [1344-14573] pg/mL*hours) and reached pharmacological peak concentration (388 [132-1583] pg/mL). CONCLUSIONS: SLN-melatonin enterally administered offers favourable pharmacokinetics in critically ill patients, with higher bioavailability with respect to the standard formulation; µE-TD provided effective pharmacological blood levels, with a time-concentration profile more similar to the physiological melatonin pattern.

The effect of long-term melatonin supplementation on psychosomatic disorders in postmenopausal women.

Different psychosomatic disorders are observed in postmenopausal women. The decrease of estrogen production is believed to be the main cause of their severity. It is nowadays evident that the decreased melatonin release in women at this age who suffer from postmenopausal disorders might also contribute to the severity of the symptoms. The aim of the study was to evaluate the effect of melatonin supplementation on female hormones release and the alteration in climacteric symptoms. The study included 60 postmenopausal women, aged 51 - 64 years, who were randomly allotted into two equal groups. Group I was recommended placebo (2 x 1 tablet) and Group II - melatonin (3 mg in the morning and 5 mg at bedtime) for 12 months. Serum levels of 17ß-estradiol, follicle-stimulating hormone (FSH), melatonin and urinary 6-sulfatoxymelatonin (aMT6s) excretion as well as Kupperman Index (KI) and body mass index (BMI) were determined before the start and at 12 months after placebo or melatonin administration. In Group I only the value of KI slightly decreased (28.4 ± 2.9 versus 25.6 ± 3.8 points, P = 0,0619). In Group II - KI decreased from 29.1 ± 2.9 to 19.7 ± 3.1 points (P < 0.001) and BMI from 30.9 ± 2.9 to 28.1 ± 2.3 kg/m2 (P < 0.05). Melatonin supplementation failed to change significantly the serum concentration of female reproductive hormones 17ß-estradiol and FSH. We conclude that melatonin supplementation therapy exerts a positive effect on psychosomatic symptoms in postmenopausal women and can be recommended as the useful adjuvant therapeutic option in treatment of these disorders.

Synergistic effects of resveratrol and melatonin on in vitro maturation of porcine oocytes and subsequent embryo development.

Resveratrol and melatonin are known for their antioxidant properties and have various biological activities. The fact that they exhibit possible synergistic effects in phytomedicine researches suggests the use of a combination of these agents to promote porcine in vitro maturation (IVM) of oocytes. Therefore, we investigated the effects of resveratrol and/or melatonin on this process; cumulus-oocyte complexes underwent IVM culture with four different conditions (control, resveratrol, melatonin or their combination). Cumulus expansion, oocyte nuclear maturation and subsequent embryo development after parthenogenetic activation (PA) and somatic cell nuclear transfer (SCNT) were evaluated. In experiment 1, all treatment groups significantly increased the proportion of complete cumulus expansion (degree 4) compared to the control, showing no difference among the treatment groups (P = 0.30). In experiment 2, oocytes matured with resveratrol and the combination had significantly higher metaphase-II (MII) rates than the control and melatonin groups, showing the highest (P < 0.05) MII rates in the combination group. In experiment 3, all treatment groups significantly increased blastocyst formation rates and total blastocyst cell numbers after PA compared to the control, but especially the combination showed the highest (P < 0.05) total cell numbers. In experiment 4, we selected the combination as the optimal condition and used this IVM system prior to SCNT. The combination treatment showed a significant (P < 0.05) increase in blastocyst formation rate and total cell numbers after SCNT. In conclusion, our results suggest that the combination of resveratrol and melatonin supported a synergistic increase in oocyte nuclear maturation and total cell numbers of PA blastocysts and improved the development of SCNT embryos.

Melatonin treatment reduces chilling injury in peach fruit through its regulation of membrane fatty acid contents and phenolic metabolism.

Effects of 0.1 mM melatonin (MT) on chilling injury (CI), membrane fatty acid content and phenolic metabolism in peach fruit were studied during storage at 1°C for 28 days. MT treatment delayed the development of CI in peach fruit, as was illustrated by MT-treated fruit showing lower CI incidence, CI index and firmness loss than the control. MT treatment prevented membrane lipid peroxidation and contributed to maintaining a higher ratio of unsaturated to saturated fatty acids in peach fruit. MT treatment also stimulated the activities of glucose-6-phosphate dehydrogenase, shikimate dehydrogenase and phenylalanine ammonia lyase, but inhibited the activities of polyphenol oxidase and peroxidase. This would help in activating the accumulation of total phenolic and endogenous salicylic acid that might have a direct function in alleviation of CI. These results indicate that MT treatment can be an effective technique to reduce postharvest CI during low temperature storage of peach fruit.

Effects of Caffeic Acid and Quercetin on In Vitro Permeability, Metabolism and In Vivo Pharmacokinetics of Melatonin in Rats: Potential for Herb-Drug Interaction.

BACKGROUND AND OBJECTIVES: Melatonin is a popular dietary supplement and also considered as pharmaceutical product for sleep disorders. Caffeic acid and quercetin are widely distributed in leafy vegetables, fruits, tea extract, and both are used as natural antioxidant. There is an immense concern for health researchers to study the herb/food-drug interactions of melatonin. It is mainly metabolized by CYP1A2 in human so that herbs/foods containing cytochrome P450 (CYP) inhibitors can affect pharmacokinetics of melatonin. By considering pharmacokinetic aspects, the present study was undertaken to evaluate the effects of caffeic acid and quercetin on Caco-2 cells permeability, metabolism, CYP1A inhibition in vitro assay systems and a single dose pharmacokinetics of melatonin in vivo rats. METHODS: The effects of caffeic acid and quercetin on melatonin permeability were tested in Caco-2 cells. Metabolic stability and CYP1A activity were investigated in rat liver microsomes (RLMs) using probe substrates (melatonin/phenacetin in vitro). Melatonin and phenacetin were incubated in RLMs with or without caffeic acid and quercetin, and the IC50 values were determined. The pharmacokinetics of melatonin conducted in rats after a single dose (15 mg/kg) pre-treatment with caffeic acid, quercetin and caffeic acid plus quercetin followed by oral dose of melatonin at 5 mg/kg. Analysis of all samples was with LC-MS/MS. RESULTS: Caffeic acid and quercetin did not alter Caco-2 permeability of melatonin in apical to basolateral direction and vice versa. Melatonin was metabolized in rat liver microsomes, which was inhibited by both caffeic acid and quercetin through CYP1A. The concomitant oral administration of melatonin along with 15 mg/kg of caffeic acid or quercetin or caffeic acid plus quercetin significantly (p < 0.05) increased the AUC0-t of melatonin by 30.0, 66.7 and 114.0%, respectively. The apparent oral rat plasma clearance (CL/F) of melatonin also decreased significantly (p < 0.05) by 28.78, 47.87 and 50% in presence of caffeic acid, quercetin and caffeic acid plus quercetin, respectively. CONCLUSION: These findings suggest that caffeic acid and quercetin improved oral exposure of melatonin via CYP1A inhibition pathway.

Melatonin pharmacokinetics after transdermal administration changes according to the time of the day.

Melatonin is a neurohormone with multiple and different actions, such as chronobiotic or antioxidant. Melatonin is usually orally administered, but dermal administration is also useful in dermatological diseases or as adjuvant to certain skin treatments. Here, we studied the variability of the pharmacokinetics of melatonin and its metabolite AFMK, when melatonin is transdermally administered to Hairless rat at two different times of day (Zeitgeber Time 4 (ZT4) and ZT16). Moreover, in order to obtain the bioavailability, kinetics after intravenous administration was also studied. In addition, a permeation study was carried out, at both ZTs, to test the amount of melatonin retained in the skin after transdermal administration. Results showed that pharmacokinetic parameters of melatonin administered exogenously depended on the time of the day. When intravenous data were fitted to a compartmental model, the extrapolated plasma concentration at time 0 and the area under the curve were higher at ZT4, while clearance, volumes of central and peripheral compartments and volume of distribution at the steady state were higher at ZT16. Transdermal administration was best fitted to a one-compartment model and tmax, half-life of absorption and area under the curve showed higher values at ZT4, while the absorption rate and constant of absorption were higher at ZT16. AFMK was detected in all cases, but no differences between the two ZTs were observed. Transdermal administration showed better bioavailability also at ZT4. Results indicate that time of day is a variable that should be taken into account when melatonin is transdermally administered.

Nanoparticle-mediated interplay of chitosan and melatonin for improved wound epithelialisation.

Herein, we propose an innovative approach to improving wound healing. Our strategy is to deliver melatonin locally at the wound site by means of lecithin/chitosan nanoparticles. We used four types of chitosan that differed in terms of molecular weight and/or deacetylation degree. Melatonin encapsulation efficiency, nanoparticle size, zeta potential, biocompatibility and in vitro drug release were studied as a function of the type of chitosan used in preparation. The nanoparticles were evaluated in terms of their potential to promote wound epithelialisation via an in vitro scratch assay using a human keratinocyte (HaCaT) monolayer. The model wounds were treated with nanoparticle suspensions at a chitosan concentration of 5µgml(-1), which was based on preceding cell biocompatibility studies. Nanoparticles prepared with different types of chitosan showed similar effect on the keratinocyte proliferation/migration. Nanoparticle-mediated interplay of chitosan and melatonin was shown to be crucial for improved wound epithelialisation.

Pharmacokinetics of high-dose intravenous melatonin in humans.

This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study.

Evaluation of cationic nanosystems with melatonin using an eye-related bioavailability prediction model.

In this study, two types of nanosystems, namely lecithin/chitosan nanoparticles and Pluronic® F127/chitosan micelles, have been prepared and evaluated for their potential for the ocular delivery of melatonin, which is known to exert an ocular hypotensive effect. The melatonin content, particle size, zeta potential and in vitro drug release properties were studied as a function of the presence of chitosan in the nanosystem. Lecithin/chitosan nanoparticles were evaluated in terms of the mucoadhesive properties by a newly established method based on HCE-T cells, also used in in vitro biocompatibility and permeability studies. Lecithin/chitosan nanoparticles were significantly larger than the corresponding F127/chitosan micelles (mean diameter of 241.8 vs. 20.7nm, respectively) and characterised by a higher surface charge (22.7 vs. 4.3mV, respectively). The HCE-T cell viability assay did not show significant toxic effects of nanosystems investigated at the (relevant) chitosan concentration tested. The permeability study results confirmed the permeation enhancing effect of F127, which was hindered in the presence of chitosan. Lecithin/chitosan nanoparticles were characterised by prominent mucoadhesive properties and prolonged melatonin release, which was shown to control melatonin permeation across an in vitro corneal epithelial model. Such properties demonstrate the potential for nanoparticles to provide an extended pre-corneal residence time of melatonin, ensuring higher eye-related bioavailability and extended intraocular pressure reduction compared to melatonin in both aqueous and micelle solutions.

Therapeutic uses of melatonin and melatonin derivatives: a patent review (2012 - 2014).

INTRODUCTION: Melatonin is a neurohormone involved in the regulation of circadian rhythms, with potent antioxidant activity. It has a wide functional repertoire, with effects almost on all tissues and organs. It is mainly used as a dietary supplement for sleep regulation and re-synchronization of disrupted circadian rhythms. Melatonin has very low toxicity, but some pharmacokinetic issues, such as limited oral bioavailability and short half-life, limit its tissue availability. AREAS COVERED: Patents and patent applications from 2012 to September 2014 in which melatonin or synthetic analogues are claimed for the prevention or treatment of pathological conditions. EXPERT OPINION: Melatonin is considered a valuable substance that can be safely administered for the prevention and treatment of many diverse diseases. A major trend in 2012 - 2014 patents is the co-administration of melatonin with other drugs to increase the efficacy of the treatment and reduce side-effects. Two different actions have been combined in hybrid ligands (e.g., melatonin-tamoxifen and melatonin-tacrine derivatives). Further experimental evidence is needed to support the usefulness of these approaches. The number of new melatonin analogues has shown a marked decrease in the past 3 years, with claimed applications mainly as hypnotic or antioxidant agents.

Soft gel capsules improve melatonin's bioavailability in humans.

OBJECTIVE: Oral bioavailability is one of the most important properties in drug design and development. A poor oral bioavailability can result in low efficacy and unpredictable response to a drug. Several dosages of melatonin have been used for various investigations to clarify its bioavailability in humans. Aiming to search for a pharmaceutical form, which is better absorbed, the pharmacokinetic (PK) profile of the new manufactured melatonin soft gelatin (soft gel) capsule form has been evaluated and compared with the commercially available melatonin powder. RESEARCH DESIGN AND METHODS: A total of 60 healthy volunteers received 1, 3 mg of melatonin powder and 1 mg of melatonin in soft gel capsules. PK profiles were obtained by analysis of melatonin plasma concentration, and the respective melatonin bioavailability was compared. RESULTS: Melatonin soft gel capsule form showed similar PK parameters compared with the highest doses of melatonin in powder form, but its bioavailability was improved. CONCLUSIONS: Soft gel capsules improved the bioavailability of melatonin in humans even when administered dose was reduced. Considering the number of conditions in which melatonin supplementation is recommended, this evidence could support a broader use of melatonin in clinical practice.

Effect of melatonin supplementation and cross-fostering on renal glutathione system and development of hypertension in spontaneously hypertensive rats

Antenatal and postnatal environments are hypothesised to influence the development of hypertension. This study investigates the synergistic effect of cross-fostering and melatonin supplementation on the development of hypertension and renal glutathione system in spontaneously hypertensive rats (SHR). In one experiment, 1-day-old male SHR pups were fostered to either SHR (shr-SHR) or Wistar-Kyoto rats, (shr-WKY). In a concurrent experiment, SHR dams were given melatonin in drinking water (10 mg/kg body weight) from day 1 of pregnancy. Immediately following delivery, 1-day-old male pups were fostered either to SHR (Mel-shr-SHR) or WKY (Mel-shr-WKY) dams receiving melatonin supplementation until weaning on day 21. Upon weaning, melatonin supplementation was continued to these pups until the age of 16 weeks. Systolic blood pressures (SBP) were recorded at the age of 4, 6, 8, 12 and 16 weeks. Renal antioxidant activities were measured. Mean SBP of shr-WKY, Mel-shr-SHR and Mel-shr-WKY was significantly lower than that in shr-SHR until the age of 8 weeks. At 12 and 16 weeks of age, mean SBP of Mel-shr-WKY was lower than those in non-treated shr-SHR and shr-WKY pups but was not significantly different from that in Mel-shr-SHR. Renal glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities were significantly higher in Mel-shr-SHR and Mel-shr-WKY at 16 weeks of age. It appears that combination of cross-fostering and melatonin supplementation exerts no synergistic effect on delaying the rise in blood pressure in SHR. The elevated GPx and GST activities are likely to be due to the effect of melatonin supplementation

Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults.

Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low-dose (<0.5mg) and high-dose (>2mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low-dose (0.4mg) and high-dose (4.0mg) melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine whether melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3hrs versus 1.5hrs), elimination half-life (1.8hrs versus 2.1hrs), and apparent total clearance (379L/hr versus 478L/hr) did not differ significantly between the low- and high-dose arms, respectively. The maximum concentration was 405 ±93pg/mL for the low-dose arm and 3999±700pg/mL for the high-dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high-dose arm maintained melatonin levels >50pg/mL for an average of 10hrs, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6wks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes.

Effects of antenatal, postpartum and post-weaning melatonin supplementation on blood pressure and renal antioxidant enzyme activities in spontaneously hypertensive rats

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Although melatonin lowers blood pressure in spontaneously hypertensive rats (SHR), its effect following antenatal and postpartum supplementation on the subsequent development of hypertension in SHR pups remains unknown. To investigate this, SHR dams were given melatonin in drinking water (10 mg/kg body weight/day) from day 1 of pregnancy until day 21 postpartum. After weaning, a group of male pups continued to receive melatonin till the age of 16 weeks (Mel-SHR), while no further melatonin was given to another group of male pups (Maternal-Mel-SHR). Controls received plain drinking water. Systolic blood pressure (SBP) was measured at 4, 6, 8, 12 and 16 weeks of age, after which the kidneys were collected for analysis of antioxidant enzyme profiles. SBP was significantly lower till the age of 8 weeks in Maternal-Mel-SHR and Mel-SHR than that in the controls, after which no significant difference was evident in SBP between the controls and Maternal-Mel-SHR. SBP in Mel-SHR was lower than that in controls and Maternal-Mel-SHR at 12 and 16 weeks of age. Renal glutathione peroxidase (GPx) and glutathione s-transferase (GST) activities, levels of total glutathione and relative GPx-1 protein were significantly higher in Mel-SHR. GPx protein was however significantly higher in Mel-SHR. No significant differences were evident between the three groups in the activities of superoxide dismutase, catalase and glutathione reductase. In conclusion, it appears that while antenatal and postpartum melatonin supplementation decreases the rate of rise in blood pressure in SHR offspring, it however does not alter the tendency of offspring of SHR to develop hypertension (AU)

Effect of melatonin supplementation on food and water intake in streptozotocin-diabetic and non-diabetic male Wistar rats / Efecto de la suplementación oral con melatonina sobre la ingestión de agua y alimento en ratas Wistar macho con diabetes experimental

The effect of orally supplemented melatonin (MT) at 1mg/kg bw for 4 weeks on feeding behavior of non-diabetic and diabetic male Wistar rats has been studied by computerized meal pattern analysis. Exogenous MT has asatiating effect in non-diabetic rats, but not in diabetic animals. The changes in feeding behavior induced by MT in non-diabetic animals are related to changes in meal frequency, size and duration leading to lower total food intake during the scotophase. MT administration to diabetic rats resulted in lower drinking time and higher faecaloutput, without further behavioral effects. We conclude that the notorious metabolic changes ocurring in the streptozotocin-diabetic rat can overcome most of the underlying effects of MT supplementation. The possible MT usage for therapeutical purposes could benefit from the lack of behavioral alterations in diabetic animals (AU)

Varias líneas de evidencia señalan a la melatonina (MT) como un importante factor en el complejo entramado de la regulación de la ingestión de alimento. Puesto que la secreción de MT aumenta en la rata con diabetes tipo I, y dada la importancia de MT en el tracto gastrointestinal,es interesante comprobar los efectos de MT sobre el alterado comportamiento ingestivo de estos animales.Se ha estudiado el efecto de la suplementación oral de MT(1 mg por kg de peso corporal y día) en la escotofase sobre el comportamiento ingestivo de ratas Wistar macho diabéticas y no diabéticas durante cuatro semanas mediantea nálisis de pautas de ingestión asistido por ordenador. La administración de MT exógena indujo un efecto de saciación en ratas no diabéticas, pero no en animales diabéticos.Los cambios en comportamiento ingestivo inducidos por MT en animales no diabéticos están relacionados con cambios en frecuencia, tamaño y duración de las comidas,con el resultado de una disminución de la ingestión total de alimento durante la escotofase. La administración deMT en ratas diabéticas originó una disminución deltiempo total de actividad dípsica y aumento de la masafecal durante la escotofase, sin otros cambios comportamentales significativos. Se concluye que los notables cambios metabólicos que tienen lugar en la rata con diabetes experimental inducida por estreptozotocina provocan cambios comportamentales más potentes que los ejercidos por la suplementación oral con MT. El posible uso terapéutico de MT podría beneficiarse de la falta de alteraciones comportamentales en animales diabéticos (AU)