Khác biệt giữa bản sửa đổi của “Melatonin”

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Phiên bản lúc 14:31, ngày 8 tháng 4 năm 2009

Melatonin
Dữ liệu lâm sàng
Mã ATC
Tình trạng pháp lý
Tình trạng pháp lý
  • UK: POM (chỉ bán theo đơn)
Dữ liệu dược động học
Sinh khả dụng30 – 50%
Chuyển hóa dược phẩmHepatic via CYP1A2 mediated 6-hydroxylation
Chu kỳ bán rã sinh học35 to 50 minutes
Bài tiếtUrine
Các định danh
Tên IUPAC
  • N-[2-(5-methoxy-1H-indol-3-yl)ethyl]
    ethanamide
Số đăng ký CAS
PubChem CID
DrugBank
ChemSpider
ECHA InfoCard100.000.725
Dữ liệu hóa lý
Công thức hóa họcC13H16N2O2
Khối lượng phân tử232.278 g/mol
Mẫu 3D (Jmol)
SMILES
  • CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC

Melatonin (/ ˌ mɛ lə toʊ nɪn /), còn được gọi là chất hóa học N-acetyl-5-methoxytryptamine,[1] là một hóc môn tồn tại tự nhiên ở hầu hết các động vật, bao gồm cả con người, và một số sinh vật sống khác , kể cả rong. [2] Mức độ lưu thông tuỳ thuộc vào chu kỳ sống hàng ngày, và melatonin đóng vai trò quan trọng trong việc duy trì nhịp sống bình thường của một số chức năng sinh lý.[3] Nhiều hệ quả sinh học của melatonin được tạo ra từ hoạt động của các melatonin cảm ứng,[4] trong khi các hệ quả khác có vai trò kiểm soát và chống oxi hóa mạnh[5] với chức năng chuyên biệt là bảo vệ nhânmitochondrial DNA.[6]

Products containing melatonin have been available as a dietary supplement in the United States since 1993.[7] Foods may contain trace amounts of melatonin, but no food has been found to elevate plasma melatonin levels.[8] Over-the-counter sales of the hormone remain illegal in many other countries, and the U.S. Postal Service lists melatonin among items prohibited by Germany.[9]

Biosynthesis

In higher animals, including humans, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens, GI tract and other tissues. The largest organ in humans to biosynthesize melatonin is the skin. All machinery for melatonin synthesis has been identified in skin cells and both melatonin and its biproduct, AFMK, have been found. Both of these molecules are naturally synthesized from the amino acid tryptophan (via synthesis of serotonin). Serotonin is then converted to melatonin by the enzymes N-acetyltransferase and 5-hydroxyindole-O-methyltransferase.

Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives information from the retina about the daily pattern of light and darkness. Both SCN rhythmicity and melatonin production are affected by non-image-forming light information traveling through the recently-identified retinohypothalamic tract (RHT).

The light/dark information reaches the SCN via retinal photosensitive ganglion cells, intrinsically photosensitive photoreceptor cells, distinct from those involved in image forming (that is, these light sensitive cells are a third type in the retina, in addition to rods and cones). These cells represent approximately 2% of the retinal ganglion cells in humans and express the photopigment melanopsin.[10] The sensitivity of melanopsin fits with that of a vitamin A-based photopigment with a peak sensitivity at 484 nm (blue light).[11] This photoperiod cue entrains the circadian rhythm, and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals regulates behavioral and physiological circadian rhythms.

Melatonin may also be produced by a variety of peripheral cells such as bone marrow cells,[12][13] lymphocytes and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood but it does not seem to be regulated by the photoperiod.

Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.[14][15]

History

Melatonin is related to the mechanism by which some amphibians and reptiles change the color of their skin and, indeed, it was in this connection the substance first was discovered.[16][17] McCord and Allen discovered (J Exptl Zool, 1917) that extract of the pineal glands of cows lightened frog skin, while Aaron B. Lerner is credited for naming the hormone and for defining its chemical structure in 1958.[8] In the mid-70s Lynch et al demonstrated[18] that also in humans the production of melatonin exhibits a circadian rhythm.

Distribution

Melatonin produced in the pineal gland, which is outside of the blood-brain barrier, acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.

Roles in the non-human animal kingdom

Many animals use the variation in duration and quantity of melatonin production each day as a seasonal clock.[19] In animals and humans[20] the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organisation of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behaviour, coat growth and camouflage colouring in seasonal animals.[20] In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[21] and hamsters.[22] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

During the night, melatonin regulates leptin, lowering the levels; see Leptin.

Roles in humans

Circadian rhythm

In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, located in the center of the brain but outside of the blood-brain barrier. The melatonin signal forms part of the system that regulates the circadian cycle by chemically causing drowsiness and lowering the body temperature, but it is the central nervous system (more specifically, the suprachiasmatic nucleus) that controls the daily cycle in most components of the paracrine and endocrine systems[23][24] rather than the melatonin signal (as was once postulated).

Light dependence

Production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness" and its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual's chronotype.

Until recent history, humans in temperate climates were exposed to only about six hours of daylight in the winter. In the modern world, artificial lighting reduces darkness exposure to typically eight or fewer hours per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Since it is principally blue light that suppresses melatonin,[25] wearing glasses that block blue light[26] in the hours before bedtime may avoid melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.

Antioxidant

Besides its primary function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. The discovery of melatonin as an antioxidant was made in 1993 (Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter, RJ. Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1993, 1: 57-60). In many lower life forms, it serves only this purpose.[27] Melatonin is an antioxidant that can easily cross cell membranes and the blood-brain barrier.[5] Melatonin is a direct scavenger of OH, O2, and NO.[28] Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to regain their antioxidant properties. Melatonin, on the other hand, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[29]

Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neutralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.[27]

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[30] It also has been found to be effective in protecting against brain injury caused by ROS release in experimental hypoxic brain damage in newborn rats.[31] Melatonin's antioxidant activity may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.[32][33][34]

Immune system

While it is known that melatonin interacts with the immune system,[35][36] the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to result from melatonin acting on high affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production,[37] and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease[38] including viral and bacterial infections. Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor.[39] This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes. When taken in conjunction with calcium, it is an immunostimulator[cần dẫn nguồn] and is used as an adjuvant in some clinical protocols[cần dẫn nguồn]; conversely, the increased immune system activity may aggravate autoimmune disorders. In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.[40]

Dreaming

Many supplemental melatonin users have reported an increase in vivid dreaming. Extremely high doses of melatonin (50 mg) dramatically increased REM sleep time and dream activity in both narcoleptics and those without narcolepsy. [41]However, one factor that may influence this perception is that many over-the-counter melatonin tablets also include Vitamin B6 (pyridoxine), which is also known to be capable of producing vivid dreams.[cần dẫn nguồn]

Many psychoactive drugs, such as marijuana and LSD, increase melatonin synthesis.[41] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.[41] It has been suggested that psychotropic drugs be readmitted in the field of scientific inquiry and therapy.[42] If so, melatonin may be prioritized for research in this reemerging field of psychiatry.[43]

Autism

Individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis.[44]

Current and potential medical indications

Melatonin has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), circadian rhythm sleep disorders and sexual dysfunction. Studies by Alfred J. Lewy at Oregon Health & Science University and other researchers have found that it may ameliorate circadian misalignment and SAD.[45] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[46]

Treatment of circadian rhythm disorders

Exogenous melatonin taken in the evening is, together with light therapy upon awakening, the standard treatment for delayed sleep phase syndrome and non-24-hour sleep-wake syndrome. It appears to have some use against other circadian rhythm sleep disorders as well, such as jet lag and the problems of people who work rotating or night shifts.

Taken 30 to 90 minutes before bedtime, melatonin is put into the blood earlier than the brain's own production and acts as a mild hypnotic.

A very small dose taken several hours before bedtime in accordance with the phase response curve for melatonin in humans (PRC) doesn't cause sleepiness but, acting as a chronobiotic, does advance the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and a small oral dose melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.[47]

Preventing ischemic damage

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain[48] and the heart;[49] however, this has not been tested in humans.

Learning, memory and Alzheimer's

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[50] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). The first published evidence that melatonin may be useful in Alzheimer's disease was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta protein, a neurotoxic substance that accumulates in the brains of patients with the disorder.[51] Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates which seem to underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangles, the other neuropathological landmark of Alzheimer's disease.[51]

Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer's disease.[52] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called sundowning, which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[53]

ADHD

Research shows that after melatonin is administered to ADHD patients on methylphenidate, the time needed to fall asleep is significantly reduced. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.[54]

Fertility

Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[55] However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement.[56]

Headaches

Several clinical studies indicate that supplementation with melatonin is an effective preventive treatment for migraines and cluster headaches.[57][58]

Mental disorders

Melatonin has been shown to be effective in treating one form of depression, seasonal affective disorder, [1] and is being considered for bipolar and other disorders where circadian disturbances are involved.[59] It has been observed that bipolar disorder might have a "trait marker" (something which is characteristic of being bipolar, that doesn't change with state) of supersensitivity of the melatonin receptors.[60] This could be contrasted with drug-free recovered bipolar people not showing light hypersensitivity.[61]

Cancer

A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced chance of death.[62] Another clinical trial is due to be completed in 2012.[63]

Melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes, and it has been shown that women with the brightest bedrooms have an increased risk for breast cancer.[64]

Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers.[65]

Gallbladder Stones

Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder.[66] It even decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced Cholecystitis, whether administered before or after onsent of inflammation.[66] Relatively speaking, concentration of melatonin in the bile is 2-3 times higher than daytime melatonin levels (in the brain) across many mammals, including humans.[67]

Other

Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.[68]

Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).[69]

Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms (quoted from Ross Histology and Wheather's Functional Histology).

Use as a dietary supplement

A bottle of melatonin supplement

The use of melatonin as a drug can entrain (synchronize) the circadian clock to environmental cycles and can have beneficial effects for treatment of certain forms of insomnia. Its therapeutic potential may be limited by its short biological half-life, poor bioavailability, and the fact that it has numerous non-specific actions.[70] In recent studies though, prolonged release melatonin has shown good results in treating insomnia in older adults.[71]

The primary motivation for the use of melatonin as a supplement may be as a natural aid to better sleep. Incidental benefits to health and well-being may accumulate, due to melatonin's role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.

Studies from Massachusetts Institute of Technology have said that melatonin pills sold as supplements contain three to ten times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of sleep. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses (for example 0.3 mg as opposed to 3 mg) are just as effective at improving sleep quality.[72] Large doses of melatonin can even be counterproductive: Lewy et al[73] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve" (PRC). In one of their subjects, 0.5 mg of melatonin was effective while 20 mg was not.

Safety of supplementation

Melatonin is available without prescription in most cases in the United States and Canada, while it is available only by prescription or not at all in some other countries. The hormone is available as oral supplements (capsules, tablets or liquid) and as transdermal patches.

In the USA, because it is sold as a dietary supplement and not as a drug, the Food and Drug Administration (FDA) regulations that apply to medications are not applicable to melatonin.[3] However, new FDA rules will, by June 2010, ensure that all production of dietary supplements must comply with current good manufacturing practices, and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling."[74] In addition, the industry is now required to report to the FDA "all serious dietary supplement related adverse events."

Melatonin appears to cause very few side effects in the short term, up to three months, when healthy people take it at low doses. A systematic review[75] in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances which are secondary to other diagnoses and, second, for sleep disorders such as jet lag and shift work which accompany sleep restriction. These Canadian researchers found no trials showing evidence of effects on sleep onset latency in subjects with secondary sleep disorders or in subjects with disorders accompanying sleep restriction. Seventeen randomised controlled trials with 651 participants showed no evidence of adverse effects of melatonin with short term use. The study concludes: "There is evidence that melatonin is safe with short term use." In most of their analyses they are able to state that there is no significant difference between melatonin and placebo; even the most common adverse events reported; headache, dizziness, nausea and drowsiness; did not significantly differ for melatonin vs. placebo. A similar analysis[76] by the same team a year earlier on the efficacy and safety of exogenous melatonin in the management of primary sleep disorders found that: "There is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome," and that evidence suggests that melatonin is safe with short-term use, three months or less.

Some unwanted effects in some people, especially at high doses (~more than 3 mg/day) may include: headaches, nausea, next-day grogginess or irritability, hormone fluctuations, vivid dreams or nightmares[77] and reduced blood flow (see below).

While no large, long-term studies which might reveal side effects have been conducted, there do exist case reports about patients who have taken melatonin for years.[78]

Melatonin can cause somnolence (drowsiness), and therefore caution should be shown when driving, operating machinery, etc.

In individuals with auto-immune disorders, there is concern that melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.[79][80]

Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate symptoms by reducing nerve activity in those who experience the condition, the study found.[81]

Because of concerns of transmission of viruses through melatonin derived from animal sources, melatonin derived from cow or sheep pineal glands is no longer administered. The synthetic form does not carry this risk.[3][82]

See also

References

  1. ^ http://www.sleepdex.org/melatonin.htm
  2. ^ Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti E (2003). “Melatonin in plants”. Adv Exp Med Biol. 527: 593–7. PMID 15206778.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  3. ^ a b c Altun A, Ugur-Altun B (2007). “Melatonin: therapeutic and clinical utilization”. Int. J. Clin. Pract. 61 (5): 835–45. doi:10.1111/j.1742-1241.2006.01191.x. PMID 17298593.
  4. ^ Boutin J, Audinot V, Ferry G, Delagrange P (2005). “Molecular tools to study melatonin pathways and actions”. Trends Pharmacol Sci. 26 (8): 412–9. doi:10.1016/j.tips.2005.06.006. PMID 15992934.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  5. ^ a b Hardeland R (2005). “Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance”. Endocrine. 27 (2): 119–30. doi:10.1385/ENDO:27:2:119. PMID 16217125.
  6. ^ Reiter R, Acuña-Castroviejo D, Tan D, Burkhardt S (2001). “Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system”. Ann N Y Acad Sci. 939: 200–15. PMID 11462772.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  7. ^ Ratzburg, Courtney (Undated). “Melatonin: The Myths and Facts”. Vanderbilt University. Truy cập ngày 2 tháng 12 năm 2007. Kiểm tra giá trị ngày tháng trong: |year= (trợ giúp)
  8. ^ a b Coates, Paul M. (2005). Encyclopedia of Dietary Supplements. Marc R. Blackman, Gordon M. Cragg, Mark Levine, Joel Moss, Jeffrey D. White. CRC Press. tr. 457–466. ISBN 0824755049. Truy cập ngày 31 tháng 3 năm 2009. Chú thích có tham số trống không rõ: |chapterurl= (trợ giúp)
  9. ^ USPS. “Country Conditions for Mailing — Germany”. Truy cập ngày 15 tháng 1 năm 2008. Chú thích có các tham số trống không rõ: |month=|coauthors= (trợ giúp)
  10. ^ Nayak SK, Jegla T, Panda S (2007). “Role of a novel photopigment, melanopsin, in behavioral adaptation to light”. Cell. Mol. Life Sci. 64 (2): 144–54. doi:10.1007/s00018-006-5581-1. PMID 17160354. Đã bỏ qua tham số không rõ |month= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  11. ^ Roberts JE (2005). “Update on the positive effects of light in humans”. Photochem. Photobiol. 81 (3): 490–2. doi:10.1562/2004-12-02-IR-391. PMID 15656701.
  12. ^ Maestroni GJ (2001). “The immunotherapeutic potential of melatonin”. Expert Opin Investig Drugs. 10 (3): 467–76. doi:10.1517/13543784.10.3.467. PMID 11227046. Đã bỏ qua tham số không rõ |month= (trợ giúp)
  13. ^ Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM (2000). “Evidence for melatonin synthesis in mouse and human bone marrow cells”. J. Pineal Res. 28 (4): 193–202. doi:10.1111/j.1600-079X.2000.280401.x. PMID 10831154. Đã bỏ qua tham số không rõ |doi_brokendate= (gợi ý |doi-broken-date=) (trợ giúp); Đã bỏ qua tham số không rõ |month= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  14. ^ Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter R (1995). “Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates”. Biochem Mol Biol Int. 35 (3): 627–34. PMID 7773197.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  15. ^ Uz T, Arslan A, Kurtuncu M, Imbesi M, Akhisaroglu M, Dwivedi Y, Pandey G, Manev H (2005). “The regional and cellular expression profile of the melatonin receptor MT1 in the central dopaminergic system”. Brain Res Mol Brain Res. 136 (1–2): 45–53. doi:10.1016/j.molbrainres.2005.01.002. PMID 15893586.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  16. ^ Filadelfi A, Castrucci A (1996). “Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates”. J Pineal Res. 20 (4): 175–86. doi:10.1111/j.1600-079X.1996.tb00256.x. PMID 8836950.
  17. ^ Sugden D, Davidson K, Hough K, Teh M (2004). “Melatonin, melatonin receptors and melanophores: a moving story” (HTML: full text). Pigment Cell Res. 17 (5): 454–60. doi:10.1111/j.1600-0749.2004.00185.x. PMID 15357831. Truy cập ngày 3 tháng 5 năm 2008.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  18. ^ Lynch, HJ (1975). “Daily rhythm in human urinary melatonin” (Abstract). Science. 187 (4172): 169–71. PMID 1167425. Truy cập ngày 31 tháng 3 năm 2009. Đã bỏ qua tham số không rõ |month= (trợ giúp); Đã bỏ qua tham số không rõ |coauthors= (gợi ý |author=) (trợ giúp)
  19. ^ Lincoln G, Andersson H, Loudon A (2003). “Clock genes in calendar cells as the basis of annual timekeeping in mammals — a unifying hypothesis”. J Endocrinol. 179 (1): 1–13. doi:10.1677/joe.0.1790001. PMID 14529560.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  20. ^ a b Arendt J, Skene DJ (2005). “Melatonin as a chronobiotic”. Sleep Med Rev. 9 (1): 25–39. doi:10.1016/j.smrv.2004.05.002. PMID 15649736. Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn) it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times.
  21. ^ CM Chaturvedi (1984). “Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis”. Australian Journal of Zoology. 32 (6): 803–809. doi:10.1071/ZO9840803.
  22. ^ Chen H (1981). “Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition”. Neuroendocrinology. 33 (1): 43–6. doi:10.1159/000123198. PMID 7254478.
  23. ^ Richardson G (2005). “The human circadian system in normal and disordered sleep”. J Clin Psychiatry. 66 Suppl 9: 3–9, quiz 42–3. PMID 16336035.
  24. ^ Perreau-Lenz S, Pévet P, Buijs R, Kalsbeek A (2004). “The biological clock: the bodyguard of temporal homeostasis”. Chronobiol Int. 21 (1): 1–25. doi:10.1081/CBI-120027984. PMID 15129821.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  25. ^ Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag (August 15, 2001). “Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor”. J Neurosci. 15, 21 (16): 6405–12. PMID 11487664. Kiểm tra giá trị ngày tháng trong: |date= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  26. ^ Kayumov L, Casper RF, Hawa RJ, Perelman B Chung SA, Sokalsky S, Shipiro (2005). “Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work”. J Clin Endocrinol Metab. 90 (5): 2755–61. doi:10.1210/jc.2004-2062. PMID 15713707. Đã bỏ qua tham số không rõ |month= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  27. ^ a b Dun-Xian Tan, Lucien C. Manchester, Maria P. Terron, Luis J. Flores, Russel J. Reiter (2007). “One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?”. Journal of Pineal Research. 42 (1): 28–42. doi:10.1111/j.1600-079X.2006.00407.x. PMID 17198536.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  28. ^ Poeggeler B, Saarela S, Reiter RJ; và đồng nghiệp (1994). “Melatonin--a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro”. Ann. N. Y. Acad. Sci. 738: 419–20. PMID 7832450. “Và đồng nghiệp” được ghi trong: |author= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  29. ^ Tan DX, Manchester LC, Reiter RJ, Qi W, Karbownik M, Calvo JR (2000). “Significance of melatonin in anti oxidative defense system: reactions and products”. Biol Signals Recept. 9 (3–4): 137–59. doi:10.1159/000014635. PMID 10899700.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  30. ^ Karbownik M, Reiter R, Cabrera J, Garcia J (2001). “Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage”. Mutat Res. 474 (1–2): 87–92. PMID 11239965.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  31. ^ Tütüncüler F, Eskiocak S, Başaran UN, Ekuklu G, Ayvaz S, Vatansever U (2005). “The protective role of melatonin in experimental hypoxic brain damage”. Pediatr Int. 47 (4): 434–9. doi:10.1111/j.1442-200x.2005.02085.x. PMID 16091083.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  32. ^ Ward Dean, John Morgenthaler, Steven William Fowkes (1993). Smart Drugs II: The Next Generation : New Drugs and Nutrients to Improve Your Memory and Increase Your Intelligence (Smart Drug Series, V. 2). Smart Publications. ISBN 0-9627418-7-6.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  33. ^ Anisimov V, Alimova I, Baturin D, Popovich I, Zabezhinski M, Rosenfeld S, Manton K, Semenchenko A, Yashin A (2003). “Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice”. Exp Gerontol. 38 (4): 449–61. doi:10.1016/S0531-5565(02)00240-1. PMID 12670632.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  34. ^ Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N (1995). “Effects of long-term administration of melatonin and a putative antagonist on the ageing rat”. Neuroreport. 6 (5): 785–8. doi:10.1097/00001756-199503270-00020. PMID 7605949.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  35. ^ Carrillo-Vico A, Guerrero J, Lardone P, Reiter R (2005). “A review of the multiple actions of melatonin on the immune system”. Endocrine. 27 (2): 189–200. doi:10.1385/ENDO:27:2:189. PMID 16217132.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  36. ^ Arushanian E, Beier E (2002). “Immunotropic properties of pineal melatonin”. Eksp Klin Farmakol. 65 (5): 73–80. PMID 12596522.
  37. ^ Carrillo-Vico A, Reiter RJ, Lardone PJ; và đồng nghiệp (2006). “The modulatory role of melatonin on immune responsiveness”. Curr Opin Investig Drugs. 7 (5): 423–31. PMID 16729718. “Và đồng nghiệp” được ghi trong: |author= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  38. ^ Maestroni GJ (2001). “The immunotherapeutic potential of melatonin”. Expert Opin Investig Drugs. 10 (3): 467–76. doi:10.1517/13543784.10.3.467. PMID 11227046.
  39. ^ Carrillo-Vico A, Lardone PJ, Fernández-Santos JM; và đồng nghiệp (2005). “Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system”. J. Clin. Endocrinol. Metab. 90 (2): 992–1000. doi:10.1210/jc.2004-1429. PMID 15562014. “Và đồng nghiệp” được ghi trong: |author= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  40. ^ Cutolo M, Maestroni GJ (2005). “The melatonin-cytokine connection in rheumatoid arthritis”. Ann. Rheum. Dis. 64 (8): 1109–11. doi:10.1136/ard.2005.038588. PMID 16014678.
  41. ^ a b c Lewis, Alan (1999). Melatonin and the Biological Clock. McGraw-Hill. tr. 23. ISBN 0879837349.
  42. ^ Sessa, Ben (2005). “Can psychedelics have a role in psychiatry once again?”. The British Journal of Psychiatry. 186: 457–458. doi:10.1192/bjp.186.6.457. PMID 15928353.
  43. ^ Sessa, Ben (2005). “Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine”. Med Hypotheses. 5 (64): 930–7. PMID 15780487.
  44. ^ Melke J, Botros HG, Chaste P; và đồng nghiệp (2008). “Abnormal melatonin synthesis in autism spectrum disorders”. Mol Psychiatry. 13 (1): 90–8. doi:10.1038/sj.mp.4002016. PMID 17505466. “Và đồng nghiệp” được ghi trong: |author= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  45. ^ Lewy A, Sack R, Miller L, Hoban T (1987). “Antidepressant and circadian phase-shifting effects of light”. Science. 235 (4786): 352–4. doi:10.1126/science.3798117. PMID 3798117.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  46. ^ Uz T, Akhisaroglu M, Ahmed R, Manev H (2003). “The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice”. Neuropsychopharmacology. 28 (12): 2117–23. doi:10.1038/sj.npp.1300254. PMID 12865893.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  47. ^ Mundey, K. (2005). “Phase-dependent treatment of delayed sleep phase syndrome with melatonin”. Sleep. 28 (10): 1214–6. PMID 16295212. Truy cập ngày 26 tháng 2 năm 2009. Đã bỏ qua tham số không rõ |month= (trợ giúp); Đã bỏ qua tham số không rõ |coauthors= (gợi ý |author=) (trợ giúp)
  48. ^ Lee MY, Kuan YH, Chen HY, Chen TY, Chen ST, Huang CC, Yang IP, Hsu YS, Wu TS, Lee EJ. Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats. J Pineal Res. 2007 Apr;42(3):297 – 309. PMID 17349029
  49. ^ Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Kaski JC, Reiter RJ, Jimenez-Sosa A. A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocardial infarction undergoing primary Angioplasty The Melatonin Adjunct in the acute myocardial infarction treated with Angioplasty (MARIA) trial: Study design and rationale. Contemp Clin Trials. 2006 Oct 17. PMID 17123867.
  50. ^ Larson J, Jessen R, Uz T, Arslan A, Kurtuncu M, Imbesi M, Manev H (2006). “Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice”. Neurosci Lett. 393 (1): 23–6. doi:10.1016/j.neulet.2005.09.040. PMID 16203090.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  51. ^ a b Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK. (1997). “Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide”. J Neurosci. 17 (5): 1683–1690. PMID 9030627.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết) Lỗi chú thích: Thẻ <ref> không hợp lệ: tên “Pappolla1997” được định rõ nhiều lần, mỗi lần có nội dung khác
  52. ^ Wang X, Zhang J, Yu X, Han L, Zhou Z, Zhang Y, Wang J (2005). “Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat”. Sheng Li Xue Bao. 57 (1): 7–12. PMID 15719129.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  53. ^ Volicer L, Harper D, Manning B, Goldstein R, Satlin A (2001). “Sundowning and circadian rhythms in Alzheimer's disease”. Am J Psychiatry. 158 (5): 704–11. doi:10.1176/appi.ajp.158.5.704. PMID 11329390.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  54. ^ Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG (2003). “Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study”. Eur J Pediatr. 162 (7): 554–555. doi:10.1007/s00431-003-1207-x. PMID 12783318.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  55. ^ Bellipanni G, DI Marzo F, Blasi F, Di Marzo A (2005). “Effects of melatonin in perimenopausal and menopausal women: our personal experience”. Ann N Y Acad Sci. 1057 (Dec): 393–402. doi:10.1196/annals.1356.030. PMID 16399909.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  56. ^ “Melatonin”. About.com: Sleep Disorders: 4. Đã bỏ qua tham số không rõ |link= (trợ giúp)
  57. ^ Dodick D, Capobianco D (2001). “Treatment and management of cluster headache”. Curr Pain Headache Rep. 5 (1): 83–91. doi:10.1007/s11916-001-0015-0. PMID 11252143.
  58. ^ Gagnier J (2001). “The therapeutic potential of melatonin in migraines and other headache types”. Altern Med Rev. 6 (4): 383–9. PMID 11578254.
  59. ^ Bhattacharjee, Yudhijit (14 September 2007). “Is Internal Timing Key to Mental Health?” (PDF). ScienceMag. AAAS. 317: 1488–90. Truy cập ngày 18 tháng 2 năm 2008. Kiểm tra giá trị ngày tháng trong: |date= (trợ giúp)
  60. ^ Lewy AJ, Nurnberger JI, Wehr TA; và đồng nghiệp (1985). “Supersensitivity to light: possible trait marker for manic-depressive illness”. Am J Psychiatry. 142 (6): 725–7. PMID 4003592. Đã bỏ qua tham số không rõ |month= (trợ giúp); “Và đồng nghiệp” được ghi trong: |author= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  61. ^ Whalley LJ, Perini T, Shering A, Bennie J (1991). “Melatonin response to bright light in recovered, drug-free, bipolar patients”. Psychiatry Res. 38 (1): 13–9. doi:10.1016/0165-1781(91)90048-T. PMID 1658841. Đã bỏ qua tham số không rõ |month= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  62. ^ Mills E, Wu P, Seely D,4; Guyatt G (2005). “Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis”. Journal of pineal research. 39 (4): 360. doi:10.1111/j.1600-079X.2005.00258.x.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  63. ^ CCNM. Current Research.
  64. ^ Navara, Kristen J. (2007). “The dark side of light at night: physiological, epidemiological, and ecological consequences” (Review, PDF: full text). J. Pineal Res. 43 (43): 215–224. doi:10.1111/j.1600-079X.2007.00473.x. Truy cập ngày 7 tháng 5 năm 2008. Đã bỏ qua tham số không rõ |coauthors= (gợi ý |author=) (trợ giúp)
  65. ^ Schernhammer E, Rosner B, Willett W, Laden F, Colditz G, Hankinson S (2004). “Epidemiology of urinary melatonin in women and its relation to other hormones and night work”. Cancer Epidemiol Biomarkers Prev. 13 (62): 936–43. PMID 15184249.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  66. ^ a b Koppisetti S, Jenigiri B, Terron MP; và đồng nghiệp (2008). “Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review”. Dig. Dis. Sci. 53 (10): 2592–603. doi:10.1007/s10620-007-0195-5. PMID 18338264. Đã bỏ qua tham số không rõ |month= (trợ giúp); “Và đồng nghiệp” được ghi trong: |author= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  67. ^ Tan D, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ (1999). “High physiological levels of melatonin in the bile of mammals”. Life Sci. 65 (23): 2523–9. doi:10.1016/S0024-3205(99)00519-6. PMID 10622237. Đã bỏ qua tham số không rõ |month= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  68. ^ Maestroni G (1999). “Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer”. Adv Exp Med Biol. 467: 217–26. PMID 10721059.
  69. ^ Barrenetxe J, Delagrange P, Martínez J (2004). “Physiological and metabolic functions of melatonin”. J Physiol Biochem. 60 (1): 61–72. PMID 15352385.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  70. ^ Turek FW, Gillette MU (2004). “Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists”. Sleep Med. 5 (6): 523–32. doi:10.1016/j.sleep.2004.07.009. PMID 15511698. Đã bỏ qua tham số không rõ |month= (trợ giúp)
  71. ^ Wade AG, Ford I, Crawford G; và đồng nghiệp (2007). “Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes”. Curr Med Res Opin. 23 (10): 2597–605. doi:10.1185/030079907X233098. PMID 17875243. Đã bỏ qua tham số không rõ |month= (trợ giúp); “Và đồng nghiệp” được ghi trong: |author= (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  72. ^ Zhdanova I, Wurtman R, Regan M, Taylor J, Shi J, Leclair O (2001). “Melatonin treatment for age-related insomnia”. J Clin Endocrinol Metab. 86 (10): 4727–30. doi:10.1210/jc.86.10.4727. PMID 11600532.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  73. ^ Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA (2002). “Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period”. Chronobiol Int. 19 (3): 649–58. doi:10.1081/CBI-120004546. PMID 12069043. line feed character trong |title= tại ký tự số 81 (trợ giúp)Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  74. ^ “FDA Issues Dietary Supplements Final Rule” (Thông cáo báo chí). U.S. Food and Drug Administration. 22 tháng 6 năm 2007. Truy cập ngày 10 tháng 9 năm 2008.
  75. ^ Buscemi, Nina (18 tháng 2 năm 2006). “Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis” (HTML: Full text). BMJ. 332 (7538): 385–393. doi:10.1136/bmj.38731.532766.F6. PMID 16473858. Truy cập ngày 17 tháng 5 năm 2008. Đã bỏ qua tham số không rõ |coauthors= (gợi ý |author=) (trợ giúp)
  76. ^ Buscemi, Nina (2005). “The Efficacy and Safety of Exogenous Melatonin for Primary Sleep Disorders: A Meta-Analysis” (HTML: Full text). J Gen Intern Med. Society of General Internal Medicine. 20 (12): 1151–1158. doi:10.1111/j.1525-1497.2005.0243.x. PMID 16423108. Truy cập ngày 17 tháng 5 năm 2008. Đã bỏ qua tham số không rõ |coauthors= (gợi ý |author=) (trợ giúp); Đã bỏ qua tham số không rõ |month= (trợ giúp)
  77. ^ “melatonin cautions”. www.melatonin.com.
  78. ^ Sack, Robert L. (12 October 2000). “Entrainment of Free-Running Circadian Rhythms by Melatonin in Blind People”. The NEW ENGLAND JOURNAL of MEDICINE. 343 (15): 1070–1077. doi:10.1056/NEJM200010123431503. PMID 11027741. Truy cập ngày 13 tháng 4 năm 2008. Đã bỏ qua tham số không rõ |coauthors= (gợi ý |author=) (trợ giúp); Kiểm tra giá trị ngày tháng trong: |date= (trợ giúp)
  79. ^ Morera A, Henry M, de La Varga M (2001). “Safety in melatonin use”. Actas Esp Psiquiatr. 29 (5): 334–7. PMID 11602091.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  80. ^ Terry PD, Villinger F, Bubenik GA, Sitaraman SV (2008). “Melatonin and ulcerative colitis: Evidence, biological mechanisms, and future research”. Inflamm Bowel Dis. [Epub ahead of print]. PMID 18626968.Quản lý CS1: nhiều tên: danh sách tác giả (liên kết)
  81. ^ “Study Shows Melatonin Supplements May Make Standing A Hazard For The Cardiovascular-Challenged” (DOC) (Thông cáo báo chí). Penn State College of Medicine, Milton S. Hershey Medical Center. tháng 9 năm 2003. Truy cập ngày 21 tháng 7 năm 2006. (MS Word Format)
  82. ^ “Melatonin Information from Drugs.com”.

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