MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Melatonin - Circadin, Agomelatin

Agomelatin

  • Nové antidepresivum
  • Látka s velkou afinitou k receptorům MT1, MT2 a MT3
  • S antagonistickou aktivitou k serotoninovým receptorům 5-HT2C [1]

Literatura:

[1] prof. MUDr. Karel Šonka, DrSc., prof. MUDr. Soňa Nevšímalová, DrSc. MELATONIN ZNÁME 50 LET. CO O NĚM VÍME MELATONIN ZNÁME 50 LET. CO O NĚM VÍME A JAK JEJ MŮŽEME POUŽÍT? A JAK JEJ MŮŽEME POUŽÍT? Neurologická klinika 1. LF UK a VFN, Praha; Neurol. pro praxi, 2008; 9(2): 104–108


N-acetylserotonin

Urinary 6-sulfatoxymelatonin

  • And total antioxidant capacity
  • Increase after the intake of a grape juice cv. Tempranillo stabilized with HHP.
  • Red grapes contain elevated amounts of antioxidant compounds (polyphenols) that may potentially prevent cell aging, cardiovascular disease and oxidation-related disorders.
  • Since functional drinks are presently one of the most dynamic sectors of the market, the present work was aimed at evaluating the possible antioxidant effect of an experimental grape juice in terms of urinary 6-sulfatoxymelatonin (aMT6-s) and total antioxidant capacity in young (20 ± 10 yr-old), middle-aged (45 ± 10 yr-old) and elderly (75 ± 10 yr-old) individuals. Grapes (Vitis vinifera cv. Tempranillo) were de-stemmed, racked and pressed. The juice was subsequently stabilized by high hydrostatic pressure (HHP). Participants consumed 200 mL of grape juice twice a day (as the lunch and dinner desserts) for 5 days. First-void morning urines were collected before treatment (basal values), the day immediately after the last ingestion of juice (assay), and one day afterwards (post-assay). aMT6-s and total antioxidant capacity were quantified using commercial ELISA and colorimetric assay kits, respectively. The intake of grape juice cv. Tempranillo induced a significant increase of urinary aMT6-s and total antioxidant capacity in the three groups of age analyzed as compared to their corresponding basal and post-assay values. These functional/nutraceutical properties may be of interest for a prospective commercialization of the grape juice. The novel technology used for juice stabilization may be suitable for introducing into the market a product with high sensory and nutritional quality, as it has been shown in this study.
  • www.semanticscholar.org/paper/Urinary-6-sulfatoxymelatonin-and-total-antioxidant-Gonz%C3%A1lez-Flores-Gamero/78b4a4ff16e906000ffa37775a8785e9fa7414e8
t least one study has noted synergistic sedative effects of melatonin and Monoamine Oxidase (MAO-A) inhibitors. In this frog study, clorgyline and moclobemide were used.[145]

Circadin

  • Contains the active substance melatonin
  • Prolonged-release tablets (2 mg) over a few hours

Indikace

  • Short-term treatment (up to 13 weeks) of primary insomnia (poor quality of sleep) in patients aged 55 years or over
    • Insomnia does not have any identified cause, including any medical, mental or environmental cause
  • One tablet a day
  • 1-2h před spaním a po jídle

Děti

  • Not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy. [2]

Těhotné a kojící

  • no clinical data on exposed pregnancies are available
  • Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probably secreted into human milk
  • Therefore, breast-feeding is not recommended in women under treatment with melatonin. [2]

Mechanismus účinku

  • melatonin, is a naturally occurring hormone produced by pineal gland
  • Older people may produce less melatonin, leading to the development of insomnia
  • Tablets release melatonin slowly over a few hours, they mimic the natural production of melatonin in the body
  • Receptor Agonists, ATC code: N05CH01
  • Structurally related to serotonin
  • melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night [2]
  • Associated with the control of circadian rhythms and entrainment to the light-dark cycle [2]
  • Associated with a hypnotic effect and increased propensity for sleep.
  • Activity of melatonin at the MT1, MT2 and MT3 receptors is believed to contribute to its sleep-promoting properties, as these receptors (mainly MT1 and MT 2) are involved in the regulation of circadian rhythms and sleep regulation. [2]

Absorpce

  • P.o. is complete in adults
  • May be decreased by up to 50% in the elderly
  • Kinetics of melatonin are linear over the range of 2-8 mg.
  • Bioavailability is in the order of 15%
    • Significant first pass effect with an estimated first pass metabolism of 85%
  • Tmax occurs after 3 hours in a fed state
  • The rate of melatonin absorption and Cmax following Circadin 2 mg oral administration is affected by food
    • Presence of food delayed the absorption of the melatonin
      • (Tmax=3.0 h versus Tmax=0.75 h)
    • Food lower peak plasma concentration in the fed state
      • (Cmax=1020pg/ml versus Cmax=1176 pg/ml)

Distribuce

  • In vitro plasma protein binding of melatonin is approximately 60%
  • Mainly bound to albumin, alpha1-acid glycoprotein and high density lipoprotein

Metabolismus

  • Isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism
  • Principal metabolite is 6-sulphatoxy-melatonin (6-S-MT)
    • Inactive
  • Excretion of the metabolite is completed within 12 hours after ingestion.
  • Terminal half life (t1) is 3.5-4 hours
  • Renal excretion of metabolites
  • 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin
  • 2% is excreted as melatonin (unchanged drug)
  • A 3-4-fold increase in Cmax is apparent for women compared to men
  • A five-fold variability in Cmax between different members of the same sex has also been observed
  • Higher AUC and Cmax levels have been reported in older subjects compared to younger subjects, reflecting the lower metabolism of melatonin in the elderly.
    • Cmax levels around 500 pg/ml in adults (18-45)
    • 1200 pg/ml in elderly (55-69)
    • AUC levels around 3,000 pg*h/mL in adults
    • 5,000 pg*h/mL in the elderly.

Renální selhání

Jaterní selhání

  • Results in higher endogenous melatonin levels.
  • With cirrhosis were significantly increased during daylight hours
  • Significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls.

Efektivita

  • 32% of the patients taking Circadin (86 out of 265) reported a significant improvement in symptoms after three weeks, compared with 19% of those taking placebo (51 out of 272) [1]
  • Circadin was more effective than placebo for at least 13 weeks [1]
  • no modifications of sleep architecture
  • no effect on REM sleep duration by Circadin
  • Modifications in diurnal functioning did not occur with Circadin 2 mg.
  • Morning alertness was 47% in the Circadin group as compared to 27% in the placebo group
  • Quality of sleep and morning alertness significantly improved with Circadin compared to placebo
  • no increase in withdrawal symptoms
  • Morning alertness was 26% in the Circadin group as compared to 15% in the placebo group
  • Circadin shortened patients’ reported sleep latency by 24.3 minutes vs 12.9 minutes with placebo [2]

Interakce

Melatonin indukuje

  • CYP3A in vitro at supra-therapeutic concentrations
  • Metabolism is mainly mediated by CYP1A enzymes

Melatonin je zvyšován

  • fluvoxamine
    • Increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19
    • The combination should be avoided.
  • 5- or 8-methoxypsoralen (5 and 8-MOP)
    • Increases melatonin levels by inhibiting its metabolism.
  • cimetidine
    • CYP2D inhibitor increases plasma melatonin levels
  • oestrogens
    • Increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2.
  • quinolones
  • CYP1A2 inhibitors

Melatonin je snižován

    • Due to induction of CYP1A2
  • cigarette smoking
  • carbamazepine
  • rifampicin

Snížení účinků melatoninu

  • adrenergic agonists/antagonists
    • alcohol
      • Alcohol should not be taken with Circadin, because it reduces the effectiveness of Circadin on sleep.

Zesílení účinků

  • Opiate agonists/antagonists
  • Antidepressant medicinal products
  • Prostaglandin inhibitors
  • Benzodiazepines
    • Circadin may enhance the sedative properties of benzodiazepines
  • Zaleplon
  • Zolpidem
  • Zopiclone
    • Circadin and zolpidem 1 h following co-dosing
      • Increased impairment of attention
      • Zhoršená memory and co-ordination compared to zolpidem alone.
    • tryptophan
  • Thioridazine and imipramine
    • No clinically significant pharmacokinetic interactions were found
    • Circadin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone.

NÚ

  • Are not common
  • Between 1 and 10 patients in 1,000
    • Irritability, nervousness, restlessness, insomnia, abnormal dreams, anxiety, migraine, lethargy, psychomotor hyperactivity, dizziness, somnolence, hypertension, abdominal pain, dyspepsia, mouth ulcers, dry mouth, hyperbilirubinaemia, dermatitis, night sweats, pruritus, rash, dry skin, pain in the extremities, symptoms of the menopause, asthenia, chest pain, glycosuria, proteinuria, abnormal liver function tests and increased weight,...
  • Circadin can cause drowsiness
    • Used with caution if this could pose a risk to safety, including in people who need to drive or use machines
    • Patients should avoid alcohol before, during and after taking Circadin
  • Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine. [2]

Předávkování

  • No case of overdose has been reported
  • Administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported.
  • Daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature.
  • If overdose occurs, drowsiness is to be expected
  • Clearance of the active substance is expected within 12 hours after ingestion. -No special treatment is required. [2]

Literatura:

[1] Circadin : melatonin. EPAR [online]. 10/06/2010 , , [cit. 2011-03-30]. Dostupný z WWW: < www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000695/human_med_000701.jsp&murl=menus/medicines/medicines.jsp&jsenabled=true >. 1995-2010 EMA, 7 Westferry Circus, Canary Wharf, London E14 4HB,Tel: +44 (0)20 7418 8400, Fax +44 (0)20 7418 8416, All questions and queries to: info@ema.europa.eu, This medicine is approved for use in the European Union, EPAR - Scientific Discussion 11/07/2007
[2] ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS : Circadin 2 mg prolonged-release tablets . Česká republika Lundbeck Česká republika s.r.o. Bozděchova 7 CZ-150 00 Praha 5 Tel: +420 225 275 600 [online]. [cit. 2011-03-30]. Dostupný z WWW: < www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000695/WC500026811.pdf >.

Děti a hormony

  • In older people with primary insomnia, melatonin (2mg of a slow release formula) has shown efficacy in improving sleep quality.[139][140] Melatonin has also shown efficacy for children suffering from insomnia that affects development.[141] In this latter study, kids with an average age of 12 (8.6-15.7yrs), using melatonin in ranges of 0.3-10mg (average dose of 2.69mg), for an average of 3.1 years, did not significantly differ from a non-supplemented control when assessed by Tanner stages, three questions used to assess physical maturation of puberty.[142][143] No differences in mental maturity were seen.[141] Benefits to insomnia have also been noted for people who suffer from insomnia and also experience migraines with auras, which may be correlated.[124]

Due to melatonin shortening the time it takes to fall asleep (sleep latency) it shows most efficacy in insomnia treatment and, despite being used in all age groups, is surprisingly free of withdrawal and other side-effects at the doses used.


Dopamin

  • Melatonin appears to inhibit dopamine release in the ventral hippocampus, medulla pons, preoptic area, and the hypothalamus (posterior and median)
  • no inhibition occurs in the cerebral cortex, striatum, cerebellum, or dorsal hippocampus.
  • Inhibition appears to be mediated by inhibiting calcium influx into co-stimulated nerves.
  • In accordance to this inhibition, active in physiologically relevant nM ranges (although maximal potency is at pharmacological mM ranges),
    • Dopamine experiences a diurnal rhythm of release,
  • This inhibition of dopamine release appears to apply to amphetamine-induced dopamine release, which may be of concern to ephedrine supplementation
  • melatonin appears to be a negative regulator of dopamine release in neurons.
  • examine.com/supplements/melatonin/research/#4J45jl9-sources-and-composition-1_4J45jl9-formulations-and-variants-1

Epithalamin

  • Is a hormone secreted from the pineal gland (similar to melatonin) that has been implicated in prolonging lifespan in Drosophilia, certain strains of mice, and rats. No influence was found in spontaneously hypertensive (SHR) mice.[46][47] For those that saw an improvement in lifespan, the values ranged from 10-35%, with rats experiencing a 57% reduction in mortality. In these tested animals, epithalamin administration increased melatonin secretion.[46]
One study administering epithalamin (6 courses of treatment of 10mg every third day for 15 days, spanning 3 years) to people aged 60-69 with aged cardiovascular systems and low serum melatonin noted that, 12 years after cessation of epithalamin treatment and during follow-up, some parameters associated with aging appeared to be either attenuated or reversed. The epithalamin group outperformed placebo on cycling power, improved lipid and glucose metabolism, and appeared to normalize the suppressed nightly spike of melatonin in the aged control.[48]

Epithalamin is a peptide hormone related to melatonin that seems to be able to prolong lifespan in research animals, and improve biomarkers in elderly humans.

GIT

  • Enterochromaffin (EC) cells are widely distributed in the GI tract mucosa, and are a rich source of this hormone, with the total amount of melatonin greatly exceeding that in the pineal gland[1,2]. Melatonin displays endocrine, paracrine and autocrine properties, which may account in part for its neuroprotective action, and melatonin and its metabolites are powerful antioxidants[3-5]. The hormone also plays a role in the modulation of prostaglandin secretion and nitric oxide generation, as well as stimulation of bicarbonate secretion in the duodenum and pancreas[6-8]. Melatonin exerts an inhibitory effect on gastric acid secretion and myorelaxation effects on the smooth muscles of the GI tract[9,10]. Melatonin anti-inflammatory and immunomodulatory properties may also play a role in its general protective action in the GI tract[11,12].
An obvious question is whether the protective actions of MEL are exerted only in the case of a threat, or whether they are indispensible under physiological conditions. A growing body of evidence suggests the latter possibility and it has become clear that melatonin deficiency plays an important role in the pathogenesis of certain GI diseases[13,14]. Moreover, melatonin may protect gastric mucosa from stress-mediated lesions at a level comparable to or better than ranitidine and omeprazole[15,16].
Patients with duodenal ulcer disease have lower melatonin concentrations in the blood than healthy individuals have. The difference is most pronounced in the autumn and at night, but they it does not depend on the clinical phase (exacerbation or remission) of peptic ulcer disease[17-19]. It has been suggested that fasting and night abdominal pain in ulcer-like dyspepsia could be associated with lower than normal melatonin secretion, but there are some contradictory data[20,21]. Thus, an unequivocal link between melatonin deficiency and occurrence of disease symptoms in the GI tract has not been established. In our previous study, we recommended that patients with GI pain syndromes took 5 mg/d melatonin for 12 wk. In most patients (56.6%), the symptoms resolved after melatonin treatment; in 30% there was some amelioration of symptoms; while only 13.6% reported no clinical effect[22]. These results prompted us to carry out the present study.
The clinical picture of functional dyspepsia (FD) is rather complex. According to the Rome III criteria, there are two major forms of this disease: epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). In patients with EPS, abdominal pain in the epigastrium dominates, but fasting and nocturnal pain also occur. On the other hand, PDS patients rarely suffer from epigastric pain, but they complain of discomfort and distension in the epigastrium after meals, and they often have morning satiety and nausea.
In the present work, we determined the level of melatonin in serum and measured urinary excretion of the main and immediate metabolite of melatonin, 6-sulfatoxymelatonin (6-OHMS), in patients with EPS or PDS.
Chojnacki C, Poplawski T, Klupinska G, Blasiak J, Chojnacki J, Reiter RJ. Secretion of melatonin and 6-sulfatoxymelatonin urinary excretion in functional dyspepsia. World J Gastroenterol 2011; 17(21): 2646-2651 [PMID: 21677834 DOI: 10.3748/wjg.v17.i21.2646]

Ten adult healthy male volunteers, aged 21-33 years

  • Once after the administration of melatonin 5 mg orally for 4 days at 17 hours
  • And once after the administration of placebo, at similar times.
  • Cortisol peak was advanced and prolactin release increased after melatonin administration
    • While growth hormone was not affected
  • Vasopressin and oxytocin levels were found to increase during the night in the control study
    • Period of the nocturnal increase in vasopressin concentrations was reduced after the administration of melatonin
    • Nocturnal increase of oxytocin was absent
  • Altering the melatonin rhythm may affect neuroendocrine function
    • Nocturnal pattern of neurohypophysial hormone secretion
    • Augmenting prolactin release
    • Advancing the peak of cortisol release
  • pubmed.ncbi.nlm.nih.gov/9509065/

Interakce

  • Components of tobacco
    • May enhance the breakdown of L THEANINE+MELATONIN in the liver.
  • L THEANINE+MELATONIN may have interacted with
    • An anti-depressant medication (e.g. fluvoxamine),
    • Drug psoriasis (e.g. psoralens),
    • Antacid medications (e.g. cimetidine),
    • Hormonal medications (e.g. estrogen),
    • Antibiotic medications (e.g. rifampicin),
    • Anti-convulsant medications (e.g. carbamazepine),
    • Hypnotics (e.g. midazolam, temazepam, zaleplon, zolpidem, zopiclone),
    • Anticoagulant medications (e.g. warfarin)
Jet lag is a term used to refer to dysregulation between external regulators of time (light and darkness) and the internal clock located, in part, in the Suprachiasmatic Nuclei (SCN) of the brain.[146] Jet lag is named after plane travel between time zones causing dysregulation of hours up to half a day (depending on time zones traversed). The general phenomena of dysregulation of the circadian rhythm also applies to shift-work (due to working at a time normally reserved for sleep), fluorescent lights in the late afternoon disrupting melatonin secretion. Blind people, due their having no influence from light or darkness, may also suffer.[146][147][148]
Melatonin is investigated for its usage in solving jet lag due to its ability to 'fix’' the circadian rhythm and restore desynchronization via signalling the SCN through MT2 receptors.[149]

In situations where external stimuli (sunlight and darkness cycles) and internal stimuli (the internal clock) are not in sync, supplemental melatonin is thought to help re-establish balance.A Cochrane database meta-analysis of 10 studies that transversed at least 5 time zones found that melatonin was significantly more effective than placebo, when taken at the destination's bedtime, in normalizing the circadian rhythm and reducing the symptoms of jet lag.[150] According to the studies reviewed, there is no significant difference between 500mcg and 5mg on the effects of melatonin in reducing jet lag. Some better sleep was noted with 5mg. It should be noted that some people still experienced jet lag, as the meta-analysis[150] noted that in the two studies that reported individual statistics, about 18% of subjects still experienced jet lag after melatonin, with placebo at 67%. The one study that did not report benefits can be found here.[151]

In studies comparing melatonin against other sedatives, it appears to be less effective than zolpidem (Ambien or Sublinox are the brand names) but also associated with less side-effects.[152]
Other interventions using melatonin for jet lag (in regards to travel) indexed in Medline are found here,[153][154][155][156][157] and this phenomena as it applies to shift work is noted here.[158][159]

Melatonin, taken in the evening (sometimes 30 minutes before sleep, at times up to 4-5 hours before sleep with a higher dose) appears to normalize abnormal circadian rhythms. In order to fix jet lag, supplementation should be timed with the clock of the current time zone.Interestingly, green light treatment in the morning combined with 3g of melatonin the night prior, additively,but not synergistically, benefits correction of abnormal circadian rhythms.[160] Bright light in the morning also aids in normalizing the circadian rhythm[161] or otherwise shifting it to another time.[162] Bright light, when observed in the afternoon and combined with melatonin, partially abolishes the effects of melatonin.[163] In this study, while light treatment at 21:00 and 24:00 delayed normalization of the circadian rhythm by 0.68 hours. Supplemental melatonin at 20:40 corrected it by 0.4 hours. The combination failed to be significantly different than placebo.[163] These results also suggest that melatonin can negate the negative effects of light at night, as it applies to jet lag.

Melatonin at night works well with bright light therapy in the morning, for the purposes of lowering sleep latency, but is antagonistic with bright lights prior to sleep.

The first night effect is a delay in sleep onset due to sleeping in new settings, common during travel. Similar to Panax ginseng,[164] melatonin is effective in reducing sleep latency (time to fall asleep) and as an aid against the first night effect, which is sometimes seen in any study assessing patients in clinical settings during sleep.[165]
The opposite effect has been noted in people suffering from schizophrenia,[166] despite improving sleep quality otherwise.[167

Kvalita

  • Previous studies also found 26% of the melatonin supplements contained serotonin
    • Can have harmful effects even at relatively low levels
  • National Center for Complementary and Integrative Health, a department of the National Institutes of Health.
  • “We cannot be certain of the purity of melatonin that is available over the counter,” Robbins said.

Melatonin (N-acetyl-5methoxy-tryptamin)


Syntéza melatoninu

  • Rytmus sekrece melatoninu ze suprachiasmatických jader hypotalamu (SCN)
    • Neurony SCN vlastní schopnost generovat cirkadiánní rytmus a jsou aktivní při světlé periodě dne (v době světla). Rytmus generovaný SCN je zpřesňován na 24 h vnějšími faktory, z nichž je nejdůležitější střídání světla a tmy
      • Díky spontánní aktivitě SCN si melatonin udržuje přibližně 24hodinový cyklus i v trvale tmavém prostředí.
  • Informace o osvitu je přenášena do SCN retino-hypotalamickým traktem
    • I mírná expozice světlu v průběhu noci přerušuje sekreci melatoninu.
  • Dráha informace ze SCN do glandula pinealis, vede nejdříve do paraventrikulárních hypotalamických jader, odtud descendentně do krční míchy, kde jsou synapse s pregangliovými buňkami sympatického ganglion cervicale superius
    • Vysoké léze krční míchy s kvadruplegií vedou k vymizení nočního sekrečního vrcholu melatoninu při zachovaném rytmu sekrece kortizolu.
  • Neurony z tohoto ganglia projikují do glandula pinealis a působí na její buňky noradrenalinovými synapsemi. [1]
  • Syntéza melatoninu je iniciovaná vazbou noradrenalinu na adrenergní beta1 receptory.
    • Noční sekreci melatoninu potlačují beta1 adrenergní blokátory a alfa2 blokátor klonidin.
    • Naopak syntézu melatoninu povzbuzují látky, které zvyšují množství katecholaminů v synaptické štěrbině, jako jsou inhibitory MAO a tricyklická antidepresiva.
  • Aktivace adenylát cyklázy, vzestup cAMP a de novo syntéza serotonin-N-acetyl transferázy.
  • Zároveň je indukována transkripce supresorů, které noční produkci melatoninu ukončují.
  • Messengerové RNA kódující tyto enzymy jsou exprimovány s rytmem den/noc v glandula pinealis.
  • Z tryptofanu vzniká hydroxylací a následnou dekarboxylací serotonin
    • Tvorba melatoninu je závislá na dostupnosti tryptofanu.
    • Vitamin B6, který je koenzymem při dekarboxylaci tryptofanu, může u dětí tvorbu melatoninu stimulovat.
  • Serotonin-N-acetyl transferáza (limitující enzym syntézy melatoninu)
  • Pak hydroxyindol-O metyl transferáza [1]
.ko.jpg

Plazmatické hladiny melatoninu

  • Velkou interindividuální, ale velmi nízkou intraindividuální variabilitu
.t.jpg
  • Vysoce rozpustný ve vodě i v tucích
  • Ze 70 % vázán na albumin
  • Cirkulující ke všem tělesným tkáním
    • Přestupuje hemato-encefalickou bariéru
    • Dle PET studií po i.v. v mozku svého maxima za 6–8 minut
  • Degradován v játrech
  • Jen minimální množství se vyloučí močí v nezměněné formě [1]

Symptomy po odstranění glandula pinealis:

    • Hemikranie
    • Periorbitální cefalgie s nebo bez aktivace sympatiku
    • Poruchy vizu
    • Odpolední spavost,
    • Poruchy nálady
    • Konvulze [1]

Působení melatoninu

  • Rec. MT1 a MT2
    • Svázané s G proteinem
    • MT1 tlumí aktivitu neuronů v SCN.
  • Rec. MT3
    • Je enzym (chinon reduktáza 2)
    • Význam není jasný [1]
  • Předává celému organizmu informaci, že je noc
  • Je stabilizátorem biologických rytmů
  • Posiluje noční pokles centrální teploty
    • Facilituje spánek
    • Zprostředkován periferní vazodilatací
      • Stimulací melatoninových receptorů v periferních cévách. (Rozšíření periferních cév provází všechny terapeutické hypnogenní postupy včetně behaviorálních.)
  • Nepřímé důkazy, že melatonin ovlivňuje rytmus sekrece kortizolu [1]

Délka sekrece

  • Reflektuje roční období
  • Celotělovým sezónním signálem [1]

Melatonin jako antioxidant

  • Silnější než vitamin E
  • Přímo likviduje vysoce hydroxylové radikály a ostatní radikály s kyslíkem.
  • Zvyšuje hladiny několika antioxidačních enzymů
    • Superoxid dismutázy
    • Glutation peroxidázy
    • Glutation reduktázy
  • Současně inhibuje prooxidační enzym
    • Syntetázu oxidu dusnatého [1]

Onemocnění

  • Germinomy oblasti glandula pinealis
    • Zcela utlumují sekreci melatoninu
    • Sekreční profil podle své histologické struktury
  • Tumory pineálního parenchymu
    • Ztráta cirkadiánního kolísání sekrece melatoninu
    • Vzácně přehnaná sekrece
  • Hypotalamické tumory zasahujících do SCN
  • Ischemické a hemoragické CMP
    • Omezují podle několika pozorování noční sekreci melatoninu
  • Fatální familiární insomnie
    • Postupně mizí cirkadiánní rytmus sekrece melatoninu
  • Rettův a Angelmannův syndrom
  • Smith-Magenisův syndrom
    • Rytmus melatoninu kompletně inverzní
    • Inverze spánku
    • Možno ovlivnit
      • Podáváním beta blokátorů ve dne
      • Podání melatoninu s řízeným uvolňováním večer
  • Shy Dragerův syndromu a
  • Idiopatická ortostatická hypotenze
    • Zřejmě v souvislosti s x sympatiku sekrece melatoninu omezená nebo zcela chybí
  • Chronické ischemické choroby srdeční a akutní IM

Benefity

  • Chronicky dialyzovaní
    • melatoninem potlačen oxidativní stres vyvolaný železem a erytropoetinem podávanými proti anemii [1]
  • Hypretenze
    • Večerní dávka melatoninu (2,5 mg) po dobu 3 týdnů snižovala systolický a diastolický krevní tlak u neléčených hypertoniků [1]
  • Nádorová onemocnění prevence
    • Silný cirkadiánní rytmus má významnou ochrannou úlohu proti nádorovým onemocněním [1]
  • Chemoterapie
    • Adjuvantní aplikace melatoninu podpořila délku přežití i kvalitu života [1]
  • X chování v REM spánku – RBD
    • Alternativou léčby
      • Lékem první volby je klonazepam
    • Melatonin tlumí při RBD jak snovou, tak motorickou produkci v REM spánku [1]
  • Adaptace po změně časových pásem
    • Neretard. melatonin ef. hypnogenní asi 2 hodiny po p.o.
    • S dobrým efektem u osob, které mají 24 hodinový rytmus, který je ale posunut do pozdější doby proti konvenčnímu/žádanému načasování (syndromu zpožděné fáze spánku [1]
  • Poruchy cirkadiánního rytmu
    • Melatonin v krvi a ve slinách je nepochybně dobrý marker cirkadiánního biologického rytmu. [1]
  • Slepci
    • Většinou vyvine tzv. volně běžící rytmus, který má periodu lehce delší než 24 hod odpovídající spontánnímu rytmu pacemakeru v SCM
    • U některých nevidomých část zrakových funkcí zajištující potlačení sekrece melatoninu osvitem zachována
    • Extraokulární vnímání světla nebylo však prokázáno
    • Trvalá aplikace melatoninu ve večerní době u většiny nemocných zajistí stabilizaci 24hodinového rytmu a noční načasování spánku [1]
  • Intolerance směnného režimu
    • Zkušenosti s melatoninem také příznivé
    • Pomáhá k návratu do správného režimu po nočních směnách
    • K indukci odpoledního spánku před noční směnou [1]
  • Insomnie
    • Zkrátil latenci usnutí o 4,0 min.
    • Zvýšil efektivitu spánku o 2,2 %
    • Prodloužil celkové trvání spánku o 12,8 min
    • Neovlivňuje architekturu nočního spánku
    • Doporučená perorální dávka pro iniciaci spánku je 0,1–0,3 mg v době uléhání.
    • Zdá se, že děti jsou na melatonin senzitivnější než dospělí [1]

Stanovení melatoninu

  • Opakovat nejdéle po hodinách
  • Hodnocení ze slin vyžaduje buzení nemocného, ale pokud není nemocný osvětlen, není křivka významně změněna
  • Z moči metabolit melatoninu 6-sulfatoxymelatonin
    • Asi 2hodinové zpoždění
  • Marker pozice endogenního času se používá začátek sekrece melatoninu po setmění (dim light melatonin onset)
  • Konec sekrece
  • Plocha pod křivkou [1]
  • Akrofáze melatoninu
    • U člověka s normálním cirkadiánním rytmem mezi 3.–5. hodinou
    • Začátek a konec biologické noci je v zimě a v létě různý [1]
  • Aplikace melatoninu
    • Přibližně v období 6 hodin před začátkem biologické noci až 4 hodiny po jejím začátku vede k předsunutí biologické noci, doby usínání a předsunutí i endogenního rytmu melatoninu.
    • Aplikace melatoninu v období sestupné fáze křivky plazmatického melatoninu biologickou noc prodlužuje, ale tento efekt nebyl tak spolehlivě dokázán [1]

Farmaka

PR-melatonin

  • S prodlouženým uvolňováním
  • Na rozdíl od neretardovaného exogenního melatoninu podobný průběh plazmatické hladiny jako přirozená noční sekrece
  • PR-melatonin v dávce 2 mg 1–2 hodiny před ulehnutím po dobu 3 týdnů zlepšil u nemocných s chronickou primární insomnií nad 55 let subjektivní kvalitu spánku, ranní pozornost, latenci usnutí a kvalitu života
  • Po jeho vysazení nebyly zaznamenány abstinenční příznaky [1]

Ramelteon

  • První analog melatoninu
  • Specifický agonista receptorů MT1 a MT2
  • Schválen FDA pro léčení v USA pro léčení insomnie s poruchou usínání
  • Nezlepšoval kvalitu spánku a výkonnost následujícího dne dle subjektivního hodnocení pacientem [1]

Bezpečnost melatoninu

  • Jsou ale reference o více než 10letém používání bez nežádoucích účinků
  • Pochybnosti o nezávadnosti podávání melatoninu v nepravidelnou dobu (ad hoc) pro možnost rozkolísání cirkadiánního systému
  • Laboratorní zvířata, která dostávala dlouhodobě melatonin v pravidelnou dobu, dosáhla delšího dožití
    • Pevnějším cirkadiánním rytmem [1]
  • Neretardovaný melatonin
    • Je v mnoha zemích k dispozici jako potravinový doplněk
    • Není databáze nežádoucích účinků, ale obecně je snášení velmi dobré
    • K nízkým dávkám se vybízí v dětském věku. [1]

Literatura:

[1] prof. MUDr. Karel Šonka, DrSc., prof. MUDr. Soňa Nevšímalová, DrSc. MELATONIN ZNÁME 50 LET. CO O NĚM VÍME MELATONIN ZNÁME 50 LET. CO O NĚM VÍME A JAK JEJ MŮŽEME POUŽÍT? A JAK JEJ MŮŽEME POUŽÍT? Neurologická klinika 1. LF UK a VFN, Praha; Neurol. pro praxi, 2008; 9(2): 104–108


Metabolism


At the stage of 6-hydroxylation of melatonin into its main urinary metabolite (6-hydroxymelatonin), aromatase (CYP1A1/2) appears to be very important, with some metabolism by CYP1B1 and CYP2C19.[86][87][88] Metabolism of melatonin by CYP1B1 appears to be of greater relevance to central (neural) melatonin, due to it not being expressed much in the liver.[89] Due to metabolism by aromatase, co-ingestion of aromatase inhibitors (in this case, fluvoxamine) can increase melatonin AUC and overall exposure.[90][91] Habits that induce aromatase (such as tobacco smoking) appear to be correlated to reduced circulating melatonin.[44]

Memory and Learning

A study on elderly people (86+/-6yrs) with mild cognitive impairment

  • Combination supplement of melatonin (5mg), soy phospholipids (160mg), L-tryptophan (95mg), and fish oil (720mg DHA, 286mg EPA, vitamin E at 16mg)
  • Noted that nightly ingestion for 12 weeks significantly
  • Reduced the rating score of the MMSE and MNA (indicative of cognitive enhancement) without influencing short or long term memory parameters.
  • The improved score appeared a minor trend to improve with supplementation, relative to a minor deterioration seen in control.[173]

One study assessing memory with 3mg melatonin given to healthy young men

Concentrations of melatonin and prolactin over the 24-h cycle

  • Melatonin and prolactin showed a significant positive correlation
    • (P less than 0.001) for all times during the 24-h period
    • But with a greater contribution from concentrations during the nocturnal period
      • When both hormones were elevated.
  • The positive correlation for nocturnal concentrations was evident in February and March (P less than 0.01)
    • Greatest significance in June (P less than 0.001)
  • In blood samples taken at 15-min intervals during the morning (0800-1200) and evening (2000-2400),
    • melatonin and prolactin concentrations were not significantly correlated
  • Melatonin concentrations
    • Increased before prolactin during the evening
    • Decreased before prolactin in the morning
  • Oral administration of 6 mg melatonin
    • Significantly stimulated prolactin release above concentrations measured after placebo administration, in both the morning (P less than 0.05) and evening (P less than 0.01) time periods;
  • Prolactin response being greater in the evening
  • Evidence for melatonin controlling the nocturnal increase of prolactin
    • Via its ability to stimulate prolactin release
  • pubmed.ncbi.nlm.nih.gov/3367257/

Receptory

  • Expression of melatonin receptors are in[50] the Suprachiasmatic Nuclei (SCN) of the Pineal gland, where MT1 and MT2 both exist and MT1 activation suppresses neuronal firing, the hypothalamus, where both receptors suppress gonadotropin releasing hormone release, the retina, where MT2 reduces dopamine release and an MT3 receptor reduces ocular pressure, the pars tuberalis of the pituitary gland,[62] the kidneys (MT1),[63] the pancreas and beta-cells of the pancreas (both MT1 and MT2),[64] the adrenal cortex, where MT1 activation suppresses cortisol secretion, the testes, where MT1 suppresses testosterone, the pituitary, where MT1 suppresses Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), and prolactin. Expression of melatonin receptors is also present in vasculature, where each main receptor mediates either vasoconstriction (MT1) or vasodilation (MT2) and on some adipocytes where MT1 negatively regulates adipose tissue proliferation and increases leptin secretion (there is no MT2 on white adipose tissue, but there is expression of MT2 on brown adipose suppresses glucose uptake[65]).

  • GPR50 is an orphan receptor (belonging to the same GPRC family as melatonin receptors[66]), which appears to play a role in adaptive thermogenesis[67] and is expressed in humans, specifically in the dorsomedial nucleus of the hypothalamus and tanycytes that line the third ventricle.[68] Knockout of this receptor (abolishing its effects) appears to confer resistance to diet-induced obesity, yet paradoxically reduces the amount of weight lost in a fasted state. Knockout also reduced night time thermogenesis, despite 25% higher locomotion during waking hours.[69] GPR50 appears to interact with leptin signalling, as administration of leptin can improve GPR50 nuclear activity in obese mice (with seemingly suppressed levels of GPR50[67]) but not in GPR50-/- mice, suggesting leptin acts vicariously through this receptor, but only on matters related to thermogenesis (as feeding patterns appear unaltered).[67][70] In fact, after leptin was administered to rats with the standard leptin receptor but no GPR50 receptor, the amount of genes activated by leptin in control mice (2,705) is reduced by just over 50% (to 1,327).[67] It should be noted that melatonin is not a direct ligand of this receptor.[71][66]

GPR50 is an orphan receptor, which seems to mediate the aspects of leptin related to thermogenesis, but not appetite. It may mediate up to half of the effects of leptin as well.

GPR50 appears to heterodimerize with the melatonin receptor MT1, which results in reduced efficacy of MT1 signalling, by preventing the binding of agonists to MT1.[72] GPR50 has the capacity to heterodimerize with MT2, but does not influence the functions of MT2, similar to how MT1 and MT2 heterodimerization does not influence binding of ligands.[72] Melatonin normally has a Ki of 0.73±0.26nM, yet the heterodimerization has a Ki of 0.37±0.28nM.[72] Secondary to this, GPR50 appears to antagonize the effects of MT1.[72] Co-expression of GPR50 alongside MT1 does not affect basal MT1 actions, but reduces the maximal response of MT1 by melatonin agonism by 50%. Reducing the expression of GPR50 reverses these effects.[72]

Expression of GPR50 appears to reduce the actions of MT1, and may alter the signals sent through MT1 via melatonin.

MT1 rec.

  • Melatonin works through the MT1 receptor on the Suprachiasmatic Nuclei (SCN)
    • To inhibit cAMP element response element-binding protein (CREB) phosphorylation
      • Secondary to pituitary adenylate cyclase activating polypeptide (PACAP)

MT2 receptors

  • Of the SCN facilitate changing of the circadian rhythm - phase shifting
    • Mediated via protein kinase C (PKC)
    • Mostly through MT2
    • To a lesser extent MT1
    • melatonin acts to regulate sleep-wake cycles
  • MT2 works to regulate the phase shifts
  • MT1 exerts general suppressive actions on cell activation.
  • A 500mcg dose of melatonin appears to be able to increase secretion of oxytocin and vasopressin
    • Within 40-60 minutes of oral ingestion
  • 5mg has no significant influence on its own
    • Able to suppress an increase in vasopressin normally seen with exercise
  • 50mcg as well as 500mcg and 5mg noted that, in roughly the same population
    • 50mcg was not significantly different than placebo in regards to vasopressin
    • Barely more significant in increasing oxytocin
  • 500mcg significantly increased both neurohormones by 40 minutes after dosing
    • Levels of which appeared to normalize by 150 minutes
  • A 5mg dose showed a suppressive effect once again
    • Suppression was noted in a third study using 5mg nightly for 4 days.
  • examine.com/supplements/melatonin/research/#4J45jl9-sources-and-composition-1_4J45jl9-formulations-and-variants-1

Resveratrol

Rostlinná strava

Fasting

  • Studies on fasting people (or food restriction to less than 300 calories daily) note that circulating melatonin levels can decrease by up to 20%, with no change of urinary secretion rates over a period of 2-7 days.[37][38][39] This may be secondary to transient glucose deprivation, as supplementation with glucose at 0.5g/kg during these periods restores circulating levels of melatonin, and suggests that the pinealocytes that secrete melatonin may require glucose for optimal functioning.[39][38] However, when investigating rats undergoing caloric restriction (40% of basal metabolic rate) for the purposes of longevity, melatonin levels in serum are increased.[40]
  • examine.com/supplements/melatonin/research/#4J45jl9-sources-and-composition-1_4J45jl9-formulations-and-variants-1

Kouření

  • When comparing active smokers of tobacco against non-smoking controls, smokers appear to have approximately twice the circulating levels of melatonin when measured during the daytime (11-12h): 17.44+/-1.8 pg/ml in smokers relative to 9.77+/-1.4 pg/ml in non-smokers,[42] while a study on 21 young female smokers taking measurements of serum melatonin at night (23-24h) found that, relative to non-smokers, smokers had reduced levels of melatonin (47.9+/-14.5pg/mL) and nonsmokers 47% higher levels (70.5+/-18.9pg/mL).[43] A later study on smokers found endogenous levels of melatonin in smokers just above 2nmol/L/h, which is not significantly different from the nonsmokers in the previous study.[44] This latter study did note, however, that smokers were about half as responsive to blood increases in melatonin from supplements,[44] due to induction of the aromatase enzyme from Polyaromatic Hydrocarbons (PAHs) in cigarette smoke.[42][45]

Alterations in melatonin status and smoking are complex and understudied. There may be a normalization of the circadian rhythm, which needs to be confirmed with further studies. Smokers appear to have less response to melatonin supplementation than do nonsmokers.

Melatonin side effects

  • Headache
  • Dizziness
  • Nausea
  • Daytime drowsiness
  • Vivid dreams or nightmares
  • Short-term feelings of depression
  • Irritability
  • Stomach cramps
  • Diarrhea
  • Constipation
  • Decreased appetite
  • Urinary incontinence at night
  • Increased risk of falls
  • Increased risk of seizures
  • Confusion or disorientation
  • Mood swings
  • Reduced alertness
Melatonin has shown some efficacy in improving sleep quality for people suffering from tinnitus.[144]
O úroveň výše

Poslední aktualizace: 7. 9. 2013 17:31:25