Estudos

http://aformulabr.com.br/qrcode/melatoninaafv01.pdf
 MELATONINA
Hormônio cronobiótico, regulador metabólico e do sono

DESCRIÇÃO
A Melatonina é um neuro-hormônio produzido, principalmente pela glândula pineal a partir do triptofano, tendo sua
produção regulada pelo ciclo circadiano e não sujeita aos mecanismos de retroalimentação.

MECANISMO DE AÇÃO
A Melatonina além de ações diretas, independentes de receptores, sobre os radicais livres de oxigênio e nitrogênio,
age também através de receptores específicos (MT1, MT2 e MT3) que estão distribuídos por todo o organismo,
promovendo o efeito cronobiótico (seja da regulação do sono, ciclo vigília-sono, latência prolongada para o mesmo,
fragmentação do sono, distúrbios comportamentais do sono REM e correções do sono do idoso). Além disso, a
Melatonina age regulando cada uma das etapas do balanço energético, ou seja, a ingestão alimentar, o fluxo de
energia e o dispêndio energético; assim, sua ausência ou redução, provoca resistência insulínica, intolerância à glicose,
distúrbios na secreção de insulina, dislipidemia, distúrbios do balanço energético e obesidade.
A Melatonina é usado como um coadjuvante em doenças neurodegenerativas (como doenças do espectro do autismo,
síndrome de déficit de atenção e hiperatividade, Smith- Magenis, etc) que resultam em distúrbios do sono e dos ritmos
circadianos, além de intervir de forma acentuada na síndrome metabólica.

INDICAÇÕES
 Distúrbios do sono;
 Cronoruptura (ciclo circadiano desregulado);
 Distúrbios neurodegenerativos (coadjuvante antioxidante);
 Distúrbios metabólicos.

DOSE USUAL
Recomendação oral de 0,5 a 10mg de Melatonina ao dia.

SUGESTÕES DE FÓRMULAS

Melatonina............................................................ 2mg
Tablete sublingual qsp.................................. 1 unidade
Modo de uso: 1 unidade embaixo da língua, 1 vez ao
dia 1 hora antes de dormir.
Indicação: insônia.
Obs.: a dose pode ser ajustada entre 0,5 e 10mg.
Melatonina............................................................ 3mg
5-HTP .................................................................. 50mg
L-teanina............................................................ 100mg
Ácido fólico....................................................... 500mcg
Magnésio citrato................................................ 300mg
Vitamina B1......................................................... 10mg
Vitamina B3......................................................... 15mg
Vitamina B6......................................................... 20mg
Modo de uso: 1 dose ao dia.
Indicação: suplemento para bem estar.

PRINCIPAIS REFERÊNCIAS
RAPOPORT, S. I. et al. [Metabolic syndrome and melatonin]. Klin Med (Mosk). v. 91, n. 11 p. 8-14. 2013. Disponível em:<
https://www.ncbi.nlm.nih.gov/pubmed/25696959>. Acesso em: 03/11/2016, às 12:12.

HAYWOOD, A. et al. Stability of melatonin in an extemporaneously compounded sublingual solution and hard gelatin capsule. Int J Pharm Compd.
v. 13, n. 2, p. 170-174. 2009. Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/23970011 >. Acesso em: 03/11/2016, às 11:03.
 MELATONINA
ESTUDOS CLÍNICOS

Dose dependent sun protective effect of topical melatonin: A randomized, placebo-controlled, double-blind
study.

BACKGROUND: Ultraviolet radiation (UVR) by sunlight results in an increasing number of skin conditions. Earlier
studies have suggested a protective effect of topical treatment with the pineal hormone melatonin. However, this
protective effect has never been evaluated in natural sunlight, and the optimal dosing has not been clarified.
OBJECTIVE: The aim of this study was to investigate the sun protective effect of topical treatment with three different
doses of melatonin (0.5%, 2.5%, 12.5%) against erythema induced by natural sunlight. METHOD: The study was a
randomized, placebo-controlled, double-blind study in healthy volunteers. Twenty-three healthy volunteers, 8 male and
15 female, were enrolled. The protective effect of three different doses of melatonin cream (0.5%, 2.5%, 12.5%) against
erythema induced by natural sunlight was tested. All participants had their backs exposed to sun from 1:22 PM to 2:02
PM local time and UV-index was 9. Primary outcome was reduction in erythema evaluated by chromatography after sun
exposure, when treated with topical melatonin cream (0.5%, 2.5%, 12.5%) versus placebo and no treatment. The
erythema reaction was evaluated with chromatography and visual scoring at baseline, one, four, eight and 24h after
exposure. RESULTS: Significant difference in erythema formation was found between areas treated with melatonin
cream 12.5% and areas receiving placebo or no treatment (repeated measures ANOVA p=0.001). No differences were
found between placebo and the 0.5% and 2.5% concentrations. CONCLUSION: Application of melatonin cream 12.5%
protects against natural sunlight induced erythema.

Meta-analysis: melatonin for the treatment of primary sleep disorders.

STUDY OBJECTIVES: To investigate the efficacy of melatonin compared to placebo in improving sleep parameters in
patients with primary sleep disorders. DESIGN: PubMed was searched for randomized, placebo-controlled trials
examining the effects of melatonin for the treatment of primary sleep disorders. Primary outcomes examined were
improvement in sleep latency, sleep quality and total sleep time. Meta-regression was performed to examine the
influence of dose and duration of melatonin on reported efficacy. PARTICIPANTS: Adults and children diagnosed with
primary sleep disorders. INTERVENTIONS: Melatonin compared to placebo. RESULTS: Nineteen studies involving
1683 subjects were included in this meta-analysis. Melatonin demonstrated significant efficacy in reducing sleep latency
(weighted mean difference (WMD) = 7.06 minutes [95% CI 4.37 to 9.75], Z = 5.15, p<0.001) and increasing total sleep
time (WMD = 8.25 minutes [95% CI 1.74 to 14.75], Z = 2.48, p = 0.013). Trials with longer duration and using higher
doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time. Overall
sleep quality was significantly improved in subjects taking melatonin (standardized mean difference = 0.22 [95% CI:
0.12 to 0.32], Z = 4.52, p<0.001) compared to placebo. No significant effects of trial duration and melatonin dose were
observed on sleep quality. CONCLUSION: This meta-analysis demonstrates that melatonin decreases sleep onset
latency, increases total sleep time and improves overall sleep quality. The effects of melatonin on sleep are modest but
do not appear to dissipate with continued melatonin use. Although the absolute benefit of melatonin compared to
placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of
insomnia given its relatively benign side-effect profile compared to these agents.

[Metabolic syndrome and melatonin].

Metabolic syndrome (MS) is characterized by the following symptoms: obesity, AH, dyslipidemia, insulin resistance.
Pathophysiologically, MS is underlain by disorders of many biochemical and physiological processes, such as elevated
levels of low density lipoproteins, hyperstimulation of pancreatic b-cells, increased insulin secretion, substitution of lipid
metabolism for carbohydrate one, overgrowth of adipose tissue, excess production of adiponectin, leptin and other
signal molecules and a rise in their local intravascular concentration, weight gain.
Endogenous and exogenous melatonin inhibits these pathophysiological mechanisms, normalizes metabolism,
equilibrates insulin secretion, prevents pancreatic hyperfunction, phosphorylates insulin receptors, inactivates active
oxygen and nitrogen species including those produced in LDLP metabolism. Melatonin has specific MT1 and MT2
receptors localized in all body cells. Due to this, it exerts combined preventive action in patients with MS. Recently,
melatonin has been reported to have therapeutic effect in MS; it may be recommended to treat this condition.

The Use of Melatonin by Children: Parents' Perspectives.

STUDY OBJECTIVES: To explore the perceptions and experiences of parents whose children were using melatonin.
METHODS: A qualitative exploratory study was undertaken using face-to-face semi-structured interviews that were
audio recorded and transcribed verbatim. Data was thematically analyzed via open coding and subsequent axial coding.
Data collection continued until theoretical saturation occurred. RESULTS: Eleven interviews with parents of children
with a neurodevelopmental disorder were conducted. Each parent perceived melatonin as effective in alleviating their
child's sleep disturbance, and in restoring family functioning after many years of hardship and stress.The perceived
"naturalness" of melatonin was valued by participants, who tended to favor it over other medications prescribed for
sleep. The cost of melatonin was also commented on by every participant; however, all perceived the benefits of
melatonin for the child and the family to outweigh the cost burden. When discussing the future, some parents were
unsure of whether their child would still be using melatonin; however, others were happy for their child to continue
melatonin indefinitely. In addition, many parents expressed a desire for prescribers to have greater knowledge about
melatonin, and to acknowledge the positive impact melatonin had had on their lives. CONCLUSIONS: Parents perceive
melatonin to be effective in alleviating their child's sleep disturbance and in improving their behavior, as well as restoring
family functioning.

Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta-analysis of randomized

clinical trials.

The purpose of this work is to investigate the efficacy of exogenous melatonin in the treatment of sleep disorders in
patients with neurodegenerative disease. We searched Pubmed, the Cochrane Library, and ClinicalTrials.gov, from
inception to July 2015. We included randomized clinical trials (RCTs) that compared melatonin with placebo and that
had the primary aim of improving sleep in people with neurodegenerative diseases, particularly Alzheimer's disease
(AD) and Parkinson's disease (PD). We pooled data with the weighted mean difference in sleep outcomes. To assess
heterogeneity in results of individual studies, we used Cochran's Q statistic and the I (2) statistic. 9 RCTs were included
in this research. We found that the treatment with exogenous melatonin has positive effects on sleep quality as assessed
by the Pittsburgh Sleep Quality Index (PSQI) in PD patients (MD: 4.20, 95 % CI: 0.92-7.48; P = 0.01), and by changes
in PSQI component 4 in AD patients (MD: 0.67, 95 % CI: 0.04-1.30; P = 0.04), but not on objective sleep outcomes in
both AD and PD patients. Treatment with melatonin effectively improved the clinical and neurophysiological aspects of
rapid eye movement (REM) sleep behavior disorder (RBD), especially elderly individuals with underlying
neurodegenerative disorders. This meta-analysis provided some evidence that melatonin improves sleep quality in
patients with AD and PD, and melatonin can be considered as a possible sole or add-on therapy in neurodegenerative
disorders patients with RBD.

Obesity and oxidative stress: potential roles of melatonin as antioxidant and metabolic regulator.

Obesity is associated with an oxidative stress status, defined as an excessive production of reactive oxygen species
(ROS) compared to the level of antioxidants acting in the natural defence systems. Several sources of ROS can be
identified in obesity (e.g., mitochondrial respiratory chain, or NADPH oxidase) and could contribute to the pathogenesis
of obesity. Indeed, these conditions favour the development of insulin resistance and metabolic syndrome through
deregulation of adipokines and pro-inflammatory cytokines, so that it could be of interest to associate antioxidant
therapeutic strategies with strategies of weight loss.
Among antioxidants, melatonin holds a special place, on the one hand for its antioxidant and anti-inflammatory
properties, and on the other hand for its role as a metabolic regulator. As melatonin modulates several processes
involved in obesity and its related metabolic alterations, it could have a therapeutic interest in the treatment of obesity.

Stability of melatonin in an extemporaneously compounded sublingual solution and hard gelatin capsule.

This study examined the stability of melatonin in a 10-mg/mL oral sublingual solution stored at 4 deg C or 25 deg C and
in 3-mg capsules stored at ambient (25 deg C; 60% relative humidity) and accelerated (40 deg C; 75% relative humidity)
conditions over a period of 90 days. A sublingual solution of melatonin 10 mg/mL was preprared with glycerin, ethyl
alcohol, stevia powder extract, and tutti-frutti flavor. Six identical solutions were prepared and stored in prescription
amber glass bottles at 4 deg C or 25 deg C. Triplicate 1-mL samples from each of the six solutions were assayed
immediately after preparation and after 7, 14, 28, 60, and 90 days with a stability-indicating high-performance liquid
chromatographic method. Six batches of 100 melatonin 3-mg capsules were prepared with Methocel E4M and lactose
anhydrous and stored in prescription amber glass bottles at ambient or accelerated conditions. A sample of 10 capsules
from each batch was assayed immediately after preparation, and additional examples from each storage condition were
assayed at 7, 14, 28, 60, and 90 days. The mean concentration of melatonin exceeded 98% of the initial concentration
throughout th 90-day study period for the sublingual solution and capsules under all storage conditions. There were no
detectable changes in color, odor, taste, or pH, and no visible microbial growth in any of the sublingual solution samples.
Compendia requirements for content uniformity were met for the extemporaneously prepared capsules. Melatonin in an
extemporaneously compounded sublingual solution (10 mg/mL) was stable for at least 90 days when stored in
prescription amber glass bottles at 4 deg C or 25 deg C. Melatonin in extemporaneously prepared capsules (3 mg) was
stable for at leaast 90 days when stored in prescription amber glass bottles at ambient or acclereated conditions.

Melatonin Delivery: Transdermal and Transbuccal Evaluation in Different Vehicles.

PURPOSE: Melatonin (MLT) could be candidate drug for treatment of several diseases because of its high antioxidant
and anticarcinogenic activity and its important biological roles. The aim of this study was to assess the influence of
different vehicles on the permeation of MLT through buccal and skin tissues. METHODS: Formulations were
characterized in terms of rheology, drug release and permeation through human skin as well as porcine buccal mucosa.
Irradiation experiments were also performed. RESULTS: The lowest amount of MLT released was from oral adhesive
paste Orabase® (OB) and the highest from the emulsion system Montanov® 68 (M68). Skin permeation revealed high
pattern for Carbopol® 940 (C940) and M68, and poor for poloxamer 407 (P407) and Pluronic® lecithin organogel (PLO).
Statistical differences of MLT remaining in skin between M68 vs C940 (p < 0.05) and M68 vs PLO (p < 0.05) were
observed. Transmucosal results showed that sodium carboxymethylcellulose (NaCMC) was the best and OB the worst
vehicle. P407 and PLO followed similar behaviour. Photostability studies revealed high percentage of degradation of
MLT in solution which was also similar when was loaded in OB. The rest of formulations showed low rates of
degradation. CONCLUSIONS: C940 or M68 and NaCMC can be proposed as formulations for a potential systemic
effect of MLT by skin and buccal mucosa routes, respectively. However, if the intended objective is to obtain local action
in the skin and buccal mucosa, the proposed formulations are M68 or P407 and PLO.

Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review.

BACKGROUND: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study
aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of
melatonin. METHODS: A systematic literature search was performed and included experimental or clinical studies,
investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes
were defined as all administration routes except oral and intravenous. RESULTS: 10 studies were included in the review.
Intranasal administration exhibited a quick absorption rate and high bioavailability. Transdermal administration displayed
a variable absorption rate and possible deposition of melatonin in the skin.
Oral transmucosal administration of melatonin exhibited a high plasma concentration compared to oral administration.
Subcutaneous injection of melatonin displayed a rapid absorption rate compared to oral administration. CONCLUSION:
Intranasal administration of melatonin has a large potential, and more research in humans is warranted. Transdermal
application of melatonin has a possible use in a local application, due to slow absorption and deposition in the skin. Oral
transmucosal administration may potentially be a clinically relevant due to avoiding first-pass metabolism. Subcutaneous
injection of melatonin did not document any advantages compared to other administration routes.

[Sleep disorders in Parkinson's disease without dementia: a comparative randomized controlled study of
melatonin and clonazepam].

We studied 38 patients with Parkinson's disease (PD) without dementia (mean age, 67.3±4.8 years; 15 males, 23
females) with complaints on sleep disorders. Quality of sleep was assessed with the Parkinson's disease sleep scale
(PDSS) and the Epworth Sleepiness Scale (ESS) as well as with overnight polysomnographic (PSG) study at baseline
and at the end of the trial. The effectiveness of sleep was estimated as TST/TIB x100% (TIB - habitual time in bed, TST
- habitual total sleeping time). REM latency (LREM), periodic limb movements (PLM) (total number and sleep index)
were measured as well. All patients underwent neuropsychological testing using MMSE, five-word test, digit span and
the Hamilton scale (HAM-D). Patients were allocated to 2 groups. Group 1 (n=20) received melatonin in addition to the
previous dopaminergic treatment in dose 3 mg 30 minutes before bedtime for 6 weeks, group 2 (n=18) received
clonazepam 2 mg at night (with gradual titration over 4 weeks from 0,5 mg). Compared to baseline, melatonin and
clonazepam reduced sleep disorders in patients: PDSS scores from 89.9±8.9 to 129.5±9.4 (p=0.0001) and from
91.0±8.7 to 110.1±12.4 scores (p=0.03), respectively. However, the daytime sleepiness (ESS) was significantly
increased (from 3.8±1.2 to 7.3±2.2 scores; p=0.0002) in the clonazepam group. In the melatonin group, ESS scores
were 4.1±1.4 before treatment and 4.7±1.4 after treatment (p=0.06). Patients treated with melatonin had better scores
on the MMSE (p=0.00009), five-word test (p=0.009), Hamilton scale (p=0.00009) at the end of the study period as
compared with the clonazepam group. Changes in total point scores on the PSG at the end of week 6, as compared
with the beginning of the trial, were in favor of the group treated with melatonin, with significant changes in the LS
(p=0.004), total sleep time/time in bad (TST/TIB) (p=0,001) sections. The number of REM sleep epochs remained lower
in patients treated with clonazepam (p=0.0001). The data suggest high treatment efficacy of melatonin in the treatment
of sleep disorders in Parkinson's disease without dementia.

Melatonin versus midazolam premedication in children undergoing surgery: A pilot study.

AIM: Melatonin has been proposed as a premedication alternative to midazolam, preceding anaesthesia induction.
However, to our knowledge, data concerning interaction between melatonin and intravenous anaesthetic drugs in
children are not available. The aim of this prospective, randomized, double-blind pilot study was to investigate the
possible effect of melatonin premedication, in comparison to midazolam, on the required infusion of propofol in children
undergoing surgery. As a secondary outcome, the effect of oral melatonin on the preoperative sedation level and on the
post anaesthesia recovery score was evaluated. METHODS: Children between the age of 5 and 14 years, scheduled
for elective surgery, were prospectively enrolled between January 2012 and December 2013, and randomly assigned
to two groups based on whether they received oral melatonin (0.5 mg/kg) or oral midazolam (0.5 mg/kg) premedication
before induction of anaesthesia with propofol. Degree of sedation before and after anaesthesia was also evaluated.
RESULTS: Ninety-two patients were studied, 46 for each group. We found that oral administration of melatonin
significantly reduced doses of propofol required for induction of anaesthesia in paediatric patients, more than midazolam
(P < 0.001). No statistically significant differences were found in the pre- and post-anaesthesia sedation score (P =
0.387 and P = 0.525, respectively) between the two groups. CONCLUSIONS: The present study demonstrates that
melatonin enhances the potency of propofol also in paediatric patients. Moreover, considering the paediatric level of
sedation, melatonin was equally as effective as midazolam. These data support the use of melatonin as a premedicant
in paediatric surgical patients.
A double-blind, placebo-controlled intervention trial of 3 and 10 mg sublingual melatonin for post-concussion
syndrome in youths (PLAYGAME): study protocol for a randomized controlled trial.

BACKGROUND: By the age of sixteen, one in five children will sustain a mild traumatic brain injury also known as
concussion. Our research found that one in seven school children with mild traumatic brain injury suffer post-concussion
syndrome symptoms for three months or longer. Post-concussion syndrome is associated with significant disability in
the child and his/her family and yet there are no evidence-based medical treatments available. Melatonin has several
potential mechanisms of action that could be useful following mild traumatic brain injury, including neuroprotective
effects. The aim of this study is to determine if treatment with melatonin improves post-concussion syndrome in youths
following mild traumatic brain injury. Our hypothesis is that treatment of post-concussion syndrome following mild
traumatic brain injury with 3 or 10 mg of sublingual melatonin for 28 days will result in a decrease in post-concussion
syndrome symptoms compared with placebo. METHODS/DESIGN: Ninety-nine youths with mild traumatic brain injury,
aged between 13 and 18 years, who are symptomatic at 30 days post-injury will be recruited. This study will be
conducted as a randomized, double blind, placebo-controlled superiority trial of melatonin. Three parallel treatment
groups will be examined with a 1:1:1 allocation: sublingual melatonin 3 mg, sublingual melatonin 10 mg, and sublingual
placebo. Participants will receive treatment for 28 days. The primary outcome is a change on the Post-Concussion
Symptom Inventory (Parent and Youth). The secondary outcomes will include neurobehavioral function, health-related
quality of life and sleep. Neurophysiological and structural markers of change, using magnetic resonance imaging
techniques and transcranial magnetic stimulation, will also be investigated. DISCUSSION: Melatonin is a safe and well-
tolerated agent that has many biological properties that may be useful following a traumatic brain injury. This study will
determine whether it is a useful treatment for children with post-concussion syndrome. Recruitment commenced on 4
December 2014.

Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review.

BACKGROUND: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study
aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of
melatonin. METHODS: A systematic literature search was performed and included experimental or clinical studies,
investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes
were defined as all administration routes except oral and intravenous. RESULTS: 10 studies were included in the review.
Intranasal administration exhibited a quick absorption rate and high bioavailability. Transdermal administration displayed
a variable absorption rate and possible deposition of melatonin in the skin. Oral transmucosal administration of melatonin
exhibited a high plasma concentration compared to oral administration. Subcutaneous injection of melatonin displayed
a rapid absorption rate compared to oral administration. CONCLUSION: Intranasal administration of melatonin has a
large potential, and more research in humans is warranted. Transdermal application of melatonin has a possible use in
a local application, due to slow absorption and deposition in the skin. Oral transmucosal administration may potentially
be a clinically relevant due to avoiding first-pass metabolism. Subcutaneous injection of melatonin did not document
any advantages compared to other administration routes.

Melatonin for Prevention of Breast Radiation Dermatitis: A Phase II, Prospective, Double-Blind Randomized
Trial.

BACKGROUND: Radiation-induced dermatitis is commonly seen during radiotherapy for breast cancer. Melatonin-
based creams have shown a protective effect against ultraviolet-induced erythema and a radioprotective effect in rats.
OBJECTIVES: To evaluate the efficacy of melatonin-containing cream in minimizing acute radiation dermatitis.
METHODS: In this phase II, prospective, randomized, placebo-controlled double-blind study, patients who underwent
breast-conserving surgery for stage 0-2 breast cancer were randomly allocated to melatonin emulsion (26 women) or
placebo (21 women) for twice daily use during radiation treatment and 2 weeks following the end of radiotherapy. All
women received 50 Gy whole breast radiation therapy with 2 Gy/fx using computed tomography-based 3D planning.
Patients were examined and completed a detailed questionnaire weekly and 2 weeks following the end of treatment.
RESULTS: The occurrence of grade 1/2 acute radiation dermatitis was significantly lower (59% vs. 90%, P = 0.038) in
the melatonin group. Women older than 50 had significantly less dermatitis than younger patients (56% vs. 100%, P =
0.021). The maximal radiation dermatitis in the study group was grade 2 in 15% of the treated patients. CONCLUSIONS:
Patients treated with melatonin-containing emulsion experienced significantly reduced radiation dermatitis compared to
patients receiving placebo.

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Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/26956459>. Acesso em: 03/11/2016, às 13:33.

GITTO, E. et al. Melatonin versus midazolam premedication in children undergoing surgery: A pilot study. J Paediatr Child Health. v. 53, n. 2, p.
291-295. 2016. Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/26515269>. Acesso em: 24/11/2016, às 14:19.

HAYWOOD, A. et al. Stability of melatonin in an extemporaneously compounded sublingual solution and hard gelatin capsule. Int J Pharm Compd.
v. 13, n. 2, p. 170-174. 2009. Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/23970011 >. Acesso em: 03/11/2016, às 11:03.

LITVINENKO, I. V.; KRASAKOV, I. V.; TIKHOMIROVA, O. V. Sleep disorders in Parkinson's disease without dementia: a comparative randomized
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https://www.ncbi.nlm.nih.gov/pubmed/23388588>. Acesso em: 03/11/2016, às 13:49.

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https://www.ncbi.nlm.nih.gov/pubmed/25696959>. Acesso em: 03/11/2016, às 12:12.

SCHEUER, C. et al. Dose dependent sun protective effect of topical melatonin: A randomized, placebo-controlled, double-blind study. J Dermatol
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WALDRON, A. Y.; SPARK, M. J.; DENNIS, C. M. The Use of Melatonin by Children: Parents' Perspectives. J Clin Sleep Med. v. 12, n. 10, p. 1395-
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ZETNER, D.; ANDERSEN, L. P.; ROSENBERG, J. Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review.
Drug Res (Stuttg). v. 66, n. 4, p. 169-173. 2016. Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/26514093>. Acesso em: 03/11/2016, às
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ZHANG, W. et al. Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta-analysis of randomized clinical trials. Neurol
Sci. v. 37, n. 1, p. 57-65. 2016. Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/26255301>. Acesso em: 03/11/2016, às 11:41.

BARLOW, K. M. et al. A double-blind, placebo-controlled intervention trial of 3 and 10 mg sublingual melatonin for post-concussion syndrome in
youths (PLAYGAME): study protocol for a randomized controlled trial. Trials. doi: 10.1186/1745-6215-15-271. 2014. Disponível em:<
https://www.ncbi.nlm.nih.gov/pubmed/25001947>. Acesso em: 01/02/2017, às 13:29.

ZETNER, D.; ANDERSEN, L. P.; ROSENBERG, J. Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review.
Drug Res (Stuttg). doi: 10.1055/s-0035-1565083. 2016. Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/26514093>. Acesso em:
01/02/2017, às 13:44.

BEN-DAVID, M. A. et al. Melatonin for Prevention of Breast Radiation Dermatitis: A Phase II, Prospective, Double-Blind Randomized Trial. Isr Med
Assoc J. v. 18, n. 3-4, p. 188-192. 2016. Disponível em:< https://www.ncbi.nlm.nih.gov/pubmed/27228641>. Acesso em: 03/02/2017, às 09:44.