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1.
Trials ; 21(1): 466, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493475

RESUMO

OBJECTIVES: Primary objective: to evaluate the efficacy of melatonin as a prophylactic treatment on prevention of symptomatic SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Secondary objectives: To evaluate the efficacy of melatonin as a prophylactic treatment on prevention of asymptomatic SARS-CoV-2 infection.To evaluate the efficacy of melatonin to prevent the development of severe COVID-19 in the participants enrolled in this study who develop SARS-CoV-2 infection along the trial.To evaluate the duration of COVID-19 symptoms in participants receiving melatonin before the infection.To evaluate seroconversion timing post-symptom onset. Exploratory objectives:To compare severity of COVID-19 between men and women.To evaluate the influence of sleep and diet on prevention from SARS-CoV-2 infection.To evaluate the effect of melatonin on the incidence and characteristics of lymphopenia and increase of inflammatory cytokines related to COVID-19. TRIAL DESIGN: This is a two-arm parallel randomised double-blind controlled trial to evaluate the efficacy of melatonin versus placebo in the prophylaxis of coronavirus disease 2019 among healthcare workers. PARTICIPANTS: Inclusion Criteria: Male or female participants ≥ 18 and ≤ 80 years of age.Healthcare workers from the public and private Spanish hospital network at risk of SARS-CoV 2 infection.Not having a previous COVID19 diagnosis.Understanding the purpose of the trial and not having taken any pre-exposure prophylaxis (PrEP) including HIV PrEP from March 1st 2020 until study enrolment.Having a negative SARS-CoV 2 reverse-transcription PCR (RT-PCR) result or a negative serologic rapid test (IgM/IgG) result before randomization.Premenopausal women must have a negative urinary pregnancy test in the 7 days before starting the trial treatment.Premenopausal women and males with premenopausal couples must commit to using a high efficiency anticonceptive method. EXCLUSION CRITERIA: HIV infection.Active hepatitis B infection.Renal failure (CrCl < 60 mL/min/1.73 m2) or need for hemodialysis.Osteoporosis.Myasthenia gravis.Pre-existent maculopathy.Retinitis pigmentosa.Bradycardia (less than 50 bpm).Weight less than 40 Kg.Participant with any immunosuppressive condition or hematological disease.Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days including: azithromycin, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone.Hereditary intolerance to galactose, Lapp lactase deficiency or glucose or galactose malabsorption.Treatment with fluvoxamine.Treatment with benzodiazepines or benzodiazepine analogues such as zolpidem, zopiclone or zaleplon.Pregnancy.Breastfeeding.History of potentially immune derived diseases such as: lupus, Crohn's disease, ulcerative colitis, vasculitis or rheumatoid arthritis.Insulin-dependent diabetes mellitus.Known history of hypersensitivity to the study drug or any of its components.Patients that should not be included in the study at the judgment of the research team. Participants will be recruited from the following eight hospitals in Madrid, Spain: Hospital Universitario La Paz, Hospital Ramón y Cajal, Hospital Infanta Sofía, Hospital 12 de Octubre, Hospital Clínico San Carlos, Hospital Central de la defensa Gómez Ulla,Hospital de La Princesa and Hospital Infanta Leonor. INTERVENTION AND COMPARATOR: Experimental: Melatonin (Circadin®, Exeltis Healthcare, Spain): 2 mg of melatonin orally before bedtime for 12 weeks. Comparator: Identical looking placebo (Laboratorios Liconsa, Spain) orally before bedtime for 12 weeks. MAIN OUTCOMES: Number of SARS-CoV-2 (COVID-19) symptomatic infections confirmed by polymerase chain reaction (PCR) test or serologic test or according to each centre diagnosis protocol. Primary outcome will be measured until the end of treatment for each participant (until the date of the last dose taken by each patient). RANDOMISATION: Patients who meet all inclusion and no exclusion criteria will be randomised, stratified by centres, sex and age (<50 and ≥ 50 years old). The randomisation sequence was created using SAS version 9.4 statistical software (procedure 'PROC PLAN') with a 1:1 allocation. No randomisation seed was specified. The randomisation seed was generated taking the hour of the computer where the program was executed. Randomization will be done centrally through the electronic system RedCAP® in order to conceal the sequence until interventions are assigned BLINDING (MASKING): Participants, caregivers, and those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 450 participants are planned to be enrolled in this clinical trial, 225 in the experimental arm and 225 in the placebo arm. TRIAL STATUS: Protocol version 3.0, 17th of April 2020. Recruitment ongoing. First participant was recruited on the 21st of April 2020. The final participant is anticipated to be recruited on the 31st of May 2020. As of May 18th, 2020, a total of 312 participants have been enrolled (154 at Hospital La Paz, 85 at Hospital Infanta Sofía and 73 at Hospital 12 de Octubre). TRIAL REGISTRATION: EU Clinical Trials Register: 2020-001530-35; Date of trial registration: 13th of April 2020; https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001530-35/ES FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Melatonina/administração & dosagem , Exposição Ocupacional/efeitos adversos , Saúde do Trabalhador , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Antivirais/efeitos adversos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Quimioprevenção , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Melatonina/efeitos adversos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Soroconversão , Espanha , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
Int. j. morphol ; 38(3): 737-746, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098314

RESUMO

This study aimed to evaluate changes in beige adipocytes at different times of melatonin administration, in the morning (ZT01) or in the evening (ZT11), at 30 mg/kg daily by gavage for 7 weeks or continuously with drinking water in the term of high-calorie diet-induced obesity (HCD). Melatonin received at ZT11 or with drinking water resulted in an increased area of the browning zone in the subcutaneous white adipose tissue (sWAT), even in rats with HCD (compared with Control or HCD, respectively). The beige adipocyte and lipid droplet area after melatonin use were reduced compared to those with HCD and Control, in all administration modes (group ZT01 showed smaller changes compared to ZT11 or with drinking water groups). The fibrosis level decreased and significantly differed in HCD ZT01, HCD ZT11, and HCD water compared to that in HCD; moreover, the lowest value determined in HCD water, reached the control parameters. Furthermore, the IL-1b and IL-8 level was decreased in the HCD groups under melatonin treatment at ZT11 or with drinking water compared to that in HCD. The obtained results suggest that melatonin promotes sWAT browning in rats with diet-induced obesity and influences morphological signs of normal rats depending on the time of administration. Different functional activity of beige adipocytes was observed after melatonin was used depending on the time of administration, resulting in heat production and lipolysis (the relative mass of visceral fat was likewise diminished). More rapid browning was observed when melatonin treatment was performed at 1 h before lights-off (ZT11) or continuously via drinking water. Melatonin acted on beige adipocytes of obese rats through changing some parameters such as the area of adipocytes and lipid drops, the number of lipid drops, the relative area browning of sWAT, and the level of tissue fibrosis.


Este estudio tuvo como objetivo evaluar los cambios en los adipocitos beige en diferentes momentos de la administración de melatonina, en la mañana (ZT01) o por la noche (ZT11). Se administraron 30 mg/kg diariamente por sonda durante 7 semanas o continuamente con agua potable durante el periodo de obesidad inducida por una dieta alta en calorías (HCD). La melatonina recibida en ZT11 o con agua potable resultó en un aumento de área dorada en tejido adiposo blanco subcutáneo (sWAT), incluso en ratas con HCD (en comparación con Control o HCD, respectivamente). El área de gotas de lípidos y adipocitos de color beige después del uso de melatonina se redujo en comparación con aquellos con HCD y Control, en todos los modos de administración (el grupo ZT01 mostró cambios más pequeños en comparación con ZT11 o con grupos de agua potable). El nivel de fibrosis disminuyó y difirió significativamente en HCD ZT01, HCD ZT11 y agua HCD, en comparación con el HCD; además, el valor más bajo determinado en agua HCD alcanzó los parámetros de control. Además, el nivel de IL-1b e IL-8 disminuyó en los grupos HCD bajo tratamiento con melatonina en ZT11 o con agua potable en comparación con el de HCD. Los resultados obtenidos sugieren que la melatonina promueve el dorado sWAT en ratas con obesidad inducida por la dieta e influye en los signos morfológicos de las ratas normales dependiendo del momento de la administración. Se observó una actividad funcional diferente de los adipocitos de color beige después de usar melatonina dependiendo del tiempo de administración, dando como resultado la producción de calor y lipólisis (la masa relativa de grasa visceral también disminuyó). Se observó un ennegrecimiento más rápido cuando el tratamiento con melatonina se realizó 1 h antes de apagar las luces (ZT11) o de forma continua en grupos de agua potable. La melatonina actuó en los adipocitos beige de ratas obesas al cambiar algunos parámetros, como el área de adipocitos y gotas de lípidos, el número de gotas de lípidos, el área relativa de ennegrecimiento de sWAT y el nivel de fibrosis tisular.


Assuntos
Animais , Masculino , Ratos , Adipócitos Bege/efeitos dos fármacos , Melatonina/administração & dosagem , Obesidade , Fatores de Tempo , Fibrose , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Interleucina-8/efeitos dos fármacos , Dieta , Interleucina-1beta/efeitos dos fármacos
3.
Int J Nanomedicine ; 15: 1321-1333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161461

RESUMO

Introduction: Currently, the unsatisfactory treatment of cardiac hypertrophy is due to the unbridled myocardial fibrosis. Melatonin has been demonstrated to ameliorate cardiac hypertrophy and its accompanied fibrosis in previous studies. But it is not clinically appealing due to its short-lasting time against the hostile microenvironment when administered orally. Methods: Herein, to address this, poly (lactide) polycarboxybetaine (PLGA-COOH) accompanied by cardiac homing peptide (CHP) and superparamagnetic iron oxide nanoparticles (SPIONs) were used to establish a novel drug delivery and transportation strategy for melatonin via a facile two-step emulsion method. This study characterized these nanoparticles (CHP-mel@SPIONs) and tested their delivery to the hypertrophied heart and their effect on myocardial hypertrophy and fibrosis in an animal model of pressure overload-induced cardiac hypertrophy. Results: The engineered magnetic nanoparticles of CHP-mel@SPIONs were spherical (diameter = 221 ± 13 nm) and had a negative zeta potential of -19.18 ± 3.27 mV. The CHP-mel@SPIONs displayed excellent drug encapsulation capacities of SPIONs (75.27 ± 3.1%) and melatonin (77.69 ± 6.04%) separately, and their magnetic properties were characterized by constructing magnetic hysteresis curves and exhibited no remnant magnetization or coercivity. The animal experiments showed that compared with mel@SPIONs, CHP-mel@SPIONs accumulated more in the heart, especially in the presence of an external magnetic field, with in vivo echocardiography and RT-PCR and histological assessments confirming the amelioration of the myocardial hypertrophy and fibrosis with low drug doses. Conclusion: This simple biocompatible dual-targeting nanoagent may be a potential candidate for the guided clinical therapy of heart disease.


Assuntos
Cardiomegalia/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas de Magnetita/química , Melatonina/administração & dosagem , Miocárdio/patologia , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Óxido Ferroso-Férrico/química , Fibrose , Coração/efeitos dos fármacos , Campos Magnéticos , Melatonina/farmacologia , Nanoestruturas , Peptídeos/química , Pressão , Ratos Sprague-Dawley
4.
PLoS One ; 15(2): e0228943, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040524

RESUMO

INTRODUCTION: Age-related hearing loss (ARHL) is a consequence of aging of the auditory system. The best known mechanism of cell death in ARHL is apoptosis due to increased production of reactive oxygen species. In this context, it is hypothesized that melatonin, owing to its high antioxidant potential and its action in the mitochondria, helps prevent or delay outer hair cell dysfunction (HCD). AIMS: To evaluate the effect of melatonin on the prevention of HCD dysfunction in the ARHL process in a susceptible murine C57BL/6J model. METHOD: C57BL/6J animals were divided into two groups: control (CG) and melatonin (MG). The CG received a saline and ethanol solution and the MG, melatonin (10 mg/kg/day). The solutions were offered daily (50 µl) orally over a 10-month period. Distortion Product Otoacoustic Emissions (DPOAE) measurements were conducted once a month. RESULTS: There was a decrease in DPOAE values in both groups over time and a differentiation between them from the 10th month of life onwards. At 10 months, the MG maintained higher DPOAE values than the CG at all frequencies tested. CONCLUSION: The use of melatonin has otoprotective effects on HCD in the ARHL process in the C57BL/6J model.


Assuntos
Melatonina/administração & dosagem , Presbiacusia/prevenção & controle , Administração Oral , Animais , Antioxidantes/administração & dosagem , Caderinas/genética , Modelos Animais de Doenças , Células Ciliadas Auditivas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Emissões Otoacústicas Espontâneas/efeitos dos fármacos , Presbiacusia/genética , Presbiacusia/fisiopatologia
5.
Medicine (Baltimore) ; 99(2): e18700, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914074

RESUMO

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.


Assuntos
Estado Terminal , Delírio/prevenção & controle , Melatonina/administração & dosagem , Projetos de Pesquisa , Humanos , Unidades de Terapia Intensiva , Tempo de Internação
6.
J Pineal Res ; 68(1): e12613, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31583753

RESUMO

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg-1 for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K+ , TX2 , and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.


Assuntos
Pressão Arterial/efeitos dos fármacos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/metabolismo , Melatonina , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Melatonina/administração & dosagem , Melatonina/farmacocinética , Melatonina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ovinos , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologia
7.
Eur J Pharm Sci ; 141: 105115, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31654755

RESUMO

In this study, we present the development of spray-dried pectin/hypromellose microspheres as efficient melatonin carrier for targeted nasal delivery. Different pectin to hypromellose weight ratios in the spray-dried feed were employed (i.e. 1:0, 3:1, 1:1 and 1:3) in order to optimise microsphere physicochemical properties influencing overall powder behaviour prior, during and upon nasal delivery. All microspheres assured complete melatonin entrapment and increased dissolution rate in relation to pure melatonin powder. Among all combinations tested, combining pectin with hypromellose at 1:3 wt ratio resulted in the microspheres with the highest potential for melatonin nasal delivery as they assured highest swelling ability and most prominent mucoadhesive properties. Studies on deposition profile revealed adequate turbinate and olfactory deposition of microsphere/lactose monohydrate powder blend administered nasally using MIAT® device, complementing findings relevant for their therapeutic potential. In conclusion, developed microspheres bear the potential to ensure prolonged melatonin retention at the nasal mucosa, improved bioavailability and advanced therapeutic outcome.


Assuntos
Derivados da Hipromelose , Melatonina , Microesferas , Mucosa Nasal/metabolismo , Pectinas , Adesividade , Administração Intranasal , Liberação Controlada de Fármacos , Derivados da Hipromelose/administração & dosagem , Derivados da Hipromelose/química , Melatonina/administração & dosagem , Melatonina/química , Modelos Biológicos , Mucosa Nasal/química , Pectinas/administração & dosagem , Pectinas/química
8.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597233

RESUMO

When exposed to hostile environments such as radiation, physical injuries, chemicals, pollution, and microorganisms, the skin requires protective chemical molecules and pathways. Melatonin, a highly conserved ancient molecule, plays a crucial role in the maintenance of skin. As human skin has functional melatonin receptors and also acts as a complete system that is capable of producing and regulating melatonin synthesis, melatonin is a promising candidate for its maintenance and protection. Below, we review the studies of new metabolic pathways involved in the protective functions of melatonin in dermal cells. We also discuss the advantages of the topical use of melatonin for therapeutic purposes and skin protection. In our view, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin and its metabolites, represent two of the most potent defense systems against external damage to the skin.


Assuntos
Melatonina/metabolismo , Melatonina/farmacologia , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Pele/metabolismo , Administração Tópica , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Humanos , Melatonina/administração & dosagem , Redes e Vias Metabólicas , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Pele/efeitos dos fármacos
9.
Acta Pharm ; 69(4): 635-648, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639097

RESUMO

The aim of this study was to evaluate long-term stability and assess the wound healing potential of the innovative melatonin-loaded lipid-enriched hybrid system compared to conventional melatonin-loaded chitosan microspheres. The hybrid system contained nanostructured lipid carrier incorporated in the chitosan matrix, in order to modify melatonin release and alter physicochemical characteristics of the delivery system. Stability testing was performed during a six-month period under two conditions: refrigerated (5 ± 3 °C) and at room temperature (25 ± 2 °C/60 ± 5 % RH). Samples stored at both conditions were analyzed in terms of particle size, zeta potential, moisture content and thermal properties. At the end of testing, drug content was determined in all samples. Dressings wound healing potential was assessed by in vitro scratch test using human skin fibroblast cell line. Although both systems showed good stability characteristics, the addition of lipids in the system has improved its wound healing potential.


Assuntos
Quitosana/química , Lipídeos/química , Melatonina/química , Cicatrização/efeitos dos fármacos , Materiais Biocompatíveis/química , Linhagem Celular , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Fibroblastos/efeitos dos fármacos , Humanos , Melatonina/administração & dosagem , Microesferas , Nanopartículas/química , Nanoestruturas/química , Tamanho da Partícula , Pele/efeitos dos fármacos
10.
Int J Pharm ; 572: 118713, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31593809

RESUMO

Inflammatory Bowel Disease (IBD) is a group of chronic disorders of the gastrointestinal tract, which two main types are Crohn's disease and ulcerative colitis. Although conventional therapeutic strategies have demonstrated to be effective in the IBD treatment, it is necessary to incorporate novel therapeutic agents that target other mechanisms involved in the pathogenesis of the disease, such as oxidative stress. For this reason, the efficacy in vivo of two antioxidant compounds, melatonin and resveratrol, has been investigated in an animal model of TNBS (2, 4, 6-trinitrobenzenesulfonic acid) induced colitis. PET/CT (Positron emission tomography/Computer Tomography) scans were performed to assess disease activity and evaluate treatment response. SUVmax (Standardized Uptake Value) values, body weight changes and histological evaluation were used as inflammatory indices to measure the efficacy of both treatments. SUVmax values increased rapidly after induction of colitis, but after the beginning of the treatment (day 3) a statistically significant decrease was observed on days 7 and 10 in treated animals compared to the non-treated group. This remission of the disease was also confirmed by histological analysis of the colon tissue using the Nancy histological index (p value < 0.05 for differences between non-treated and both groups of treated animals). Moreover, statistical analysis showed a correlation (R2 = 65.52%) between SUVmax values and weight changes throughout the treatment. Overall, this study demonstrates the potential of resveratrol, and melatonin in lower extent, as therapeutic agents in the IBD treatment.


Assuntos
Antioxidantes/administração & dosagem , Colite/tratamento farmacológico , Melatonina/administração & dosagem , Resveratrol/administração & dosagem , Animais , Colite/induzido quimicamente , Colite/diagnóstico por imagem , Colite/patologia , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico
11.
Forensic Sci Int ; 304: 109962, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31610334

RESUMO

Melatonin (MEL) is a neurohormone in humans produced in a number of locations. Starting with the amino acid tryptophan, MEL is produced through a number of enzymatic steps that includes serotonin as an intermediate compound. The primary production of MEL is in the pineal gland located in the brain. It is directly associated with the the suprachiasmatic nucleus (SCN) located in the hypothalamus. In young and adult humans, the blood levels of MEL are typically in the picogram levels and produced in a cyclic schedule highly regulated by light detected in the retina by intrinsically photosensitive retinal ganglion cells (ipRGCs), resulting in production primarily during periods of darkness. During periods of light, MEL levels are typically very low or undetectable. Basal levels of MEL in infants have been observed to be either undetectable or also in the picogram levels, although some medical treatment has involved administration of exogenous MEL resulting in peak levels in the nanogram range. MEL is considered to be well tolerated and there have been limited reports of toxicity. In this case, an infant was found unresponsive and cause of death was ruled as Undetermined. Melatonin was detected in the peripheral blood at a concentration of 1,400ng/mL.


Assuntos
Depressores do Sistema Nervoso Central/envenenamento , Morte Súbita/etiologia , Melatonina/envenenamento , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/sangue , Cromatografia Líquida , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lactente , Melatonina/administração & dosagem , Melatonina/sangue , Espectrometria de Massas em Tandem , Gêmeos
12.
Ital J Pediatr ; 45(1): 122, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547831

RESUMO

INTRODUCTION: Melatonin has been studied and used for several years as a sleep-wake cycle modulator in patients with sleep disorders. Experimental evidence has demonstrated the multiple neuroprotective benefits of this indoleamine secreted by the pineal gland. Melatonin is also used in neurological investigations, for its ability to induce sleep in children. In fact, it favors falling asleep during electroencephalogram, Magnetic Resonance Imaging (MRI), and during brainstem auditory evoked potentials. Previous studies are focused on infants and children. No investigation have been performed in neonates, before or during instrumental assessments. MATERIAL AND METHODS: One hundred ten newborns (term and preterm) undergoing brain MRI were enrolled in the study. Thirty minutes before the planned time for the examination, we administered a single dose solution of melatonin- tryptophan-vitamin B6. Twenty minutes after the initial administration of 2 mg, a second dose of 1 mg was administered, if the baby was still awake. If after further 15 min the baby was still not sleeping, an additional dose of 1 mg was administered. RESULTS: In 106 patients we obtained adequate sedation without adverse events, allowing us to perform an adequate quality MRI, with a median time of 25 min to reach sleeping. Only in three patients MRI could not be performed. In patients having a large weight, higher doses of melatonin were necessary to reach sleeping. Considering the pro kg dose of melatonin, the average dose that induced sleepiness in neonates was 0,64 ± 0.16 mg/Kg. CONCLUSION: A solution based on Melatonin- tryptophan-vitamin B6 can be a helpful sedative to administer to neonates undergoing brain MRI, avoiding the use of anesthetics and achieving adequate assessments.


Assuntos
Encéfalo/diagnóstico por imagem , Depressores do Sistema Nervoso Central/administração & dosagem , Imagem por Ressonância Magnética , Melatonina/administração & dosagem , Triptofano/administração & dosagem , Vitamina B 6/administração & dosagem , Antidepressivos de Segunda Geração/administração & dosagem , Sedação Consciente , Feminino , Humanos , Hipnóticos e Sedativos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Complexo Vitamínico B/administração & dosagem
13.
Neurol Clin ; 37(4): 847-869, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31563236

RESUMO

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes all marked by unilateral headache and ipsilateral cranial autonomic features. The TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and hemicrania continua. Pathophysiology includes the trigeminal pain system, autonomic system, hypothalamus, and more recently an identified role for the vagus nerve. Diagnosis is made after looking at headache frequency, duration, and accompanying symptoms. Each TAC has its own unique treatment, which is discussed in depth.


Assuntos
Cefalalgias Autonômicas do Trigêmeo/tratamento farmacológico , Cefalalgias Autonômicas do Trigêmeo/fisiopatologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Diagnóstico Diferencial , Cefaleia/diagnóstico , Cefaleia/tratamento farmacológico , Cefaleia/fisiopatologia , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Indometacina/administração & dosagem , Carbonato de Lítio/administração & dosagem , Melatonina/administração & dosagem , Cefalalgias Autonômicas do Trigêmeo/diagnóstico , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiopatologia
14.
J Anim Sci ; 97(11): 4635-4646, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31563944

RESUMO

This study tested whether supplemental melatonin given to mimic the extended nighttime melatonin pattern observed in the higher fertility winter season could minimize infertility during summer and fall in swine. Exogenous melatonin was fed during periods coinciding with follicle selection, corpus luteum formation, pregnancy recognition, and early embryo survival. Experiments were conducted at a commercial farm in 12 sequential replicates. In Exp. 1a, mature gilts (n = 420) that had expressed a second estrus were assigned by weight to receive once daily oral Melatonin (MEL, 3 mg) or Control (CON, placebo) at 1400 h for 3 wk starting before insemination at third estrus. In Exp. 1b, parity 1 sows (n = 470) were randomly assigned by lactation length to receive MEL or CON for 3 wk, starting 2 d before weaning. Follicles, estrus, pregnancy, and farrowing data were analyzed for the main effects of treatment, season (4-wk periods), and their interaction. Environmental measures were also analyzed for reproductive responses. In Exp. 1a, there was no effect (P > 0.10) of MEL on age at third estrus (203 d), follicle size after 7 d of treatment (5.0 mm), estrous cycle length (22.6 d), return to service (9.2%), farrowing rate (FR, 80.0%), or total born pigs (TB, 13.6). However, there was an effect of season (P = 0.03) on number of follicles and on gilts expressing estrus within 23 d of the previous estrus (P < 0.005). In Exp. 1b, there was no effect of MEL (P > 0.10) on follicle measures, wean to estrous interval, FR (84.0%), or TB (13.0). But MEL (73.5%) reduced (P = 0.03) estrous expression within 7 d of weaning compared with CON (82.0%) and season (P = 0.001) decreased FR by ~14.0% during mid summer. Also, gilts and parity 1 sows exposed to low light intensity (<45 lx) during breeding had reduced conception (-8%) and farrowing (-15%) rates, compared with higher light intensity. Similarly, high temperatures (>25 °C) during breeding also reduced gilt conception rates by 7%. Although there was clear evidence of seasonal fertility failures in gilts and sows, MEL treatment did not improve fertility in gilts and reduced estrus in parity 1 sows. It is possible that differences in lighting and thermal environments before breeding could explain the differential response to MEL in sows and gilts.


Assuntos
Fertilidade/efeitos dos fármacos , Melatonina/administração & dosagem , Reprodução , Suínos/fisiologia , Animais , Cruzamento , Estro/efeitos dos fármacos , Feminino , Lactação/efeitos dos fármacos , Luz , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Paridade/efeitos dos fármacos , Gravidez , Estações do Ano
15.
Sr Care Pharm ; 34(7): 419-431, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383052

RESUMO

OBJECTIVE: To review clinical studies evaluating melatonin doses and their effects on sleep in adults 65 years of age and older. DATA SOURCES: The MEDLINE databases were searched (1946 to October 10, 2018) using the following Medical Subject Heading terms: melatonin and: sleep initiation and maintenance disorders, dyssomnia, sleep wake disorders, insomnia, sleep disorders intrinsic, and sleep disorders circadian rhythm. Sources were limited to English and human data. STUDY SELECTION/DATA EXTRACTION: An initial search resulted in 144 publications, with 25 included in this review. Studies were selected for full review based on design, mean age of participants, use of exogenous melatonin, and reports on any sleep-related outcome. DATA SYNTHESIS: Because of the side effect profiles of most prescription and nonprescription sleep aids, safe and effective alternative therapies are necessary. Based on the current literature, no dose-related response to sleep improvement has been identified for melatonin in older adults. Variations in melatonin formulation and dosages, as well as available tools to measure sleep outcomes, make it challenging to compare studies. CONCLUSIONS: This review evaluated a variety of melatonin doses, 0.5 mg to 10 mg, and their effects on sleep in older adults. The results varied, with some studies finding no difference in sleep outcomes when compared with placebo, while other studies found statistically significant improvements in sleep outcomes. Doses of melatonin between 1 mg and 6 mg appear to be effective for improving sleep in older adults; however, further studies are needed to find the optimal minimum effective dose.


Assuntos
Melatonina/administração & dosagem , Transtornos do Sono-Vigília , Ritmo Circadiano , Humanos , Sono
16.
Artigo em Inglês | MEDLINE | ID: mdl-31381847

RESUMO

Objective: To evaluate the pharmacokinetic and safety profile of a novel continuous release and absorption melatonin (CRA-melatonin) compared with an immediate-release melatonin (IR-melatonin) product. Methods: The REM Absorption Kinetics Trial (REMAKT), an open-label, single-center, randomized, single-dose, 2-way crossover trial, compared the pharmacokinetic and safety profile of CRA-melatonin (5 mg) with IR-melatonin (5 mg) in healthy adult volunteers. The study was conducted from March 18, 2016, to April 20, 2016. Results: Ten subjects completed REMAKT. Plasma melatonin levels exceeded the targeted maintenance threshold level of 1,000 pg/mL for a median of 6.7 hours for CRA-melatonin compared with 3.7 hours for IR-melatonin. The median Cmax was 4,690 pg/mL for CRA-melatonin and 23,352 pg/mL for IR-melatonin. In REMAKT, there were no treatment-emergent adverse events reported in the CRA-melatonin arm. Five treatment-emergent adverse events occurred with IR-melatonin. Conclusions: The novel, well-tolerated CRA-melatonin was shown to achieve quick release and then continuous release and absorption of melatonin for up to 7 hours, making it a significant advancement in the pharmacokinetic release profile of exogenous melatonin delivery and, therefore, an important potential consideration as a baseline therapy for sleep.


Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacocinética , Melatonina/administração & dosagem , Melatonina/farmacocinética , Adolescente , Adulto , Depressores do Sistema Nervoso Central/efeitos adversos , Estudos Cross-Over , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Melatonina/efeitos adversos , Adulto Jovem
17.
Food Funct ; 10(9): 5555-5565, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31429458

RESUMO

Exposure to chromium (Cr) causes a number of respiratory diseases, including lung cancer and pulmonary fibrosis. However, there is currently no safe treatment for Cr-induced lung damage. Here, we used in vivo and in vitro approaches to examine the protective effects of melatonin (MEL) on Cr-induced lung injury and to identify the underlying molecular mechanisms. We found that treatment of rats or a mouse lung epithelial cell MLE-12 with MEL attenuated K2Cr2O7-induced lung injury by reducing the production of oxidative stress and inflammatory mediators and inhibiting cell apoptosis. MEL treatment upregulated the expression of silent information regulator 1 (Sirt1), which deacetylated the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α). In turn, this increased the expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and key anti-oxidant target genes. These results suggest that melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1α/Nrf2 pathway. Dietary MEL supplement may be a potential new strategy for the treatment of Cr poisoning.


Assuntos
Cromo/toxicidade , Lesão Pulmonar/tratamento farmacológico , Melatonina/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Animais , Suplementos Nutricionais/análise , Humanos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/genética
18.
Drug Des Devel Ther ; 13: 2715-2727, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447548

RESUMO

Purpose: Melatonin and celecoxib are antioxidants and anti-inflammatory agents that exert protective effects in different experimental models. In this study, the neuroprotective effects of melatonin and celecoxib were demonstrated against ethanol-induced neuronal injury by in silico, morphological, and biochemical approaches. Methods: For the in silico study, 3-D structures were constructed and docking analysis performed. For in vivo studies, rats were treated with ethanol, melatonin, and celecoxib. Brain samples were collected for biochemical and morphological analysis. Results: Homology modeling was performed to build 3-D structures for IL1ß), TNFα, TLR4, and inducible nitric oxide synthase. Structural refinement was achieved via molecular dynamic simulation and processed for docking and postdocking analysis. Further in vivo experiments showed that ethanol induced marked neuronal injury characterized by downregulated glutathione, glutathione S-transferase, and upregulated inducible nitric oxide synthase. Additionally, ethanol increased the expression of TNFα and IL1ß. Finally, neuronal apoptosis was demonstrated in ethanol-intoxicated animals using caspase 3 and activated JNK staining. On the other hand, melatonin and celecoxib treatment ameliorated the biochemical and immunohistochemical alterations induced by ethanol. Conclusion: These results demonstrated that ethanol induced neurodegeneration by activating inflammatory and apoptotic proteins in rat brain, while melatonin and celecoxib may protect rat brain by downregulating inflammatory and apoptotic markers.


Assuntos
Celecoxib/farmacologia , Etanol/efeitos adversos , Melatonina/farmacologia , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Animais , Celecoxib/administração & dosagem , Celecoxib/química , Biologia Computacional , Modelos Animais de Doenças , Etanol/administração & dosagem , Injeções Intraperitoneais , Masculino , Melatonina/administração & dosagem , Melatonina/química , Simulação de Acoplamento Molecular , Doenças Neurodegenerativas/induzido quimicamente , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Ratos , Ratos Sprague-Dawley
19.
BMC Plant Biol ; 19(1): 289, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262259

RESUMO

BACKGROUND: Banana anthracnose, caused by Colletotrichum musae, is one of the most severe postharvest diseases in banana. Melatonin is widely known for its role in enhancing plant stress tolerance. However, little is known about the control of melatonin on anthracnose in postharvest banana fruit. RESULTS: In this study, exogenous melatonin treatment could significantly reduce the incidence of anthracnose in ripe yellow banana fruit and delay fruit senescence. However, melatonin treatment did not affect the growth of Colletotrichum musae in vitro. Transcriptomic analysis of banana peel showed that 339 genes were up-regulated and 241 were down-regulated in the peel after melatonin treatment, compared with the control. Based on GO terms and KEGG pathway, these up-regulated genes were mainly categorized into signal transduction, cell wall formation, secondary metabolism, volatile compounds synthesis and response to stress, which might be related to the anti-anthracnose of banana fruit induced by melatonin treatment. This view was also supported by the increase of volatile compounds, cell wall components and IAA content in the melatonin-treated fruit peel via the metabolomic analysis. After melatonin treatment, auxin, ethylene and mitogen-activated protein kinase (MAPK) signaling pathways were enhanced, which might be involved in the enhanced fruit resistance by regulating physiological characteristics, disease-resistant proteins and metabolites. CONCLUSIONS: Our results provide a better understanding of the molecular processes in melatonin treatment delaying banana fruit senescence and anthracnose incidence.


Assuntos
Colletotrichum/fisiologia , Genes de Plantas , Melatonina/metabolismo , Metaboloma , Musa/microbiologia , Doenças das Plantas/microbiologia , Transcriptoma , Colletotrichum/efeitos dos fármacos , Frutas/microbiologia , Perfilação da Expressão Gênica , Melatonina/administração & dosagem , Metabolômica , Musa/genética
20.
Int J Radiat Biol ; 95(11): 1472-1483, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31290706

RESUMO

Purpose: This work investigates the effect of resveratrol and melatonin on structural and functional changes of two enzymes, lactate dehydrogenase (LDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), exposed to radiation-induced reactive oxygen species.Materials and methods: Solutions of dehydrogenases with or without antioxidants (resveratrol or melatonin) were irradiated with X-rays under the atmosphere of air and at room temperature (21 ± 2 °C). In order to determine the protective effect of melatonin and resveratrol in radiation-induced damage to GAPDH and LDH spectroscopy and HPLC methods were used. Furthermore, plausible binding sites of melatonin or resveratrol to the GAPDH or LDH molecule were analysed.Results and conclusions: Resveratrol shows better protective properties in the inactivation of GAPDH when compared to melatonin. LDH does not contain ‒SH groups in its active site, and is not inactivated by water radiolysis products other than hydroxyl radicals or the secondary radicals of the studied low-molecular-weight compounds. Resveratrol and melatonin protected the structure of LDH to a greater extent than GAPDH. This difference can be attributed to the fact that LDH potentially binds more resveratrol or melatonin molecules (27 binding sites for resveratrol and 40 for melatonin) than GAPDH (10 binding sites for resveratrol and 18 for melatonin).


Assuntos
Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , L-Lactato Desidrogenase/metabolismo , Melatonina/administração & dosagem , Proteção Radiológica/métodos , Resveratrol/administração & dosagem , Ar , Animais , Antioxidantes/química , Domínio Catalítico , Cisteína/química , Relação Dose-Resposta à Radiação , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Coelhos , Espécies Reativas de Oxigênio , Temperatura , Raios X
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