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Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin.

AbstractObjective: The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU) – a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum MT levels differently, inasmuch as the ways they inhibit cytochrome P450 (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation was to test this hypothesis. Methods: Seven healthy subjects participated in three different experiments, which were performed in random order 6–8 days apart. In experiment A, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC0–20) were compared in the three experiments, and differences were statistically evaluated. Results: FLU augmented the MT-AUC0–20 by a factor of 2.8 compared with the effect of placebo (P < 0.01), whereas CIT was without significant effect. More MT was excreted in the urine after ingestion of FLU than after placebo. In contrast, CIT did not influence the MT excretion. A clear relationship was found between serum levels of MT and plasma concentrations of FLU. Conclusion: The serum MT level increased markedly after ingestion of FLU but not after CIT. The exact mechanism behind this finding is unknown, but decreased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is probable. Although exogenous MT, causing high MT concentration in plasma, has sleep-promoting properties in man, it is at this stage unknown whether serum MT concentrations in the range found in this study have similar effects. This has to be given further attention in additional studies.

Fibromyalgia — a syndrome associated with decreased nocturnal melatonin secretion

Most patients with fibromyalgic syndrome (FMS) complain of sleep disturbances, fatigue, and pain. These symptoms might be a consequence of changed melatonin (MT) secretion, since MT is known to have sleep promoting properties. Moreover, serum concentrations of two MT precursors (tryptophan and serotonin) — affecting both sleep and pain perception — appear to be low in patients with FMS. Therefore, the objective of this investigation was to study whether serum MT (s‐MT) level is also low in these patients.

Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: A pilot study

Melatonin is a hormone that is metabolized by cytochrome P450 (CYP) 1A2 to its main primary metabolite 6‐hydroxymelatonin. We therefore evaluated the utility of oral melatonin as a marker of hepatic CYP1A2 activity.

Alcohol ingestion decreases both diurnal and nocturnal secretion of leptin in healthy individuals

OBJECTIVE Neuropeptide Y (NPY) stimulates appetite and increases food intake. Leptin inhibits NPY. It is not known whether alcohol influences any of these factors, but it has been suggested that alcohol stimulates appetite in man. The primary objective of this investigation was to determine whether ingestion of ethanol inhibits leptin secretion in normal subjects.

NOCTURNAL MELATONIN SECRETION IN THYROID DISEASE AND IN OBESITY

Summary. objective The purpose was to Investigate whether the function of the pinealocytes is changed in patients with disturbed metabolic rate or In subjects with marked obesity.

Inhibition of melatonin secretion by ethanol in man

To determine whether ethanol inhibits nocturnal melatonin (MT) secretion, three experiments (A, B, and C) were performed in seven normal subjects. In A, ethanol at a dose of 0.34 g/kg was administered orally at 6:00, 8:00, and 10:00 PM. Each dose was increased to 0.52 g/kg in B. In C, water was substituted for ethanol. Blood samples for determination of serum MT levels were drawn every second hour between 6:00 PM and 8:00 AM. Urinary excretion of MT during the night was also determined. In A, serum ethanol reached a maximal level of 13 +/- 1 mmol/L at 12 midnight. In B, the corresponding maximum was 25 +/- 1 mmol/L. The higher alcohol dose inhibited nocturnal MT secretion by 20% +/- 5% (P < .01), whereas the lower dose lacked such effect. Urinary excretion of MT was left unaffected by alcohol at both doses. Five additional normal subjects were given alcohol as described above at a dose of 0.52 g/kg (experiment D). This induced mild nocturnal hypoglycemia as evidenced by a glucose decremental area (5.9 +/- 1.8 mmol/L.h) that differed significantly from zero (P < .05). To determine whether a reduced glucose delivery to pinealocytes might contribute to the decreased MT secretion in alcohol-intoxicated subjects, two experiments (E and F) were performed in eight healthy individuals. In E, ethanol was given orally as in B; three small oral doses of glucose were also given at 8:00 PM, 10:00 PM, and 12 midnight. In F, water was substituted for ethanol and glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased IGF-I bioavailability after ethanol abuse in alcoholics: Partial restitution after short-term abstinence

IGF-I stimulates protein synthesis, lowers blood glucose, and affects cell differentiation. The main production site of IGF-I is the liver. One of its binding proteins, IGFBP-1, is also produced by the liver. It is well known that ethanol affects the function of the human liver. Long-term alcohol abuse may therefore not only cause considerable IGF-I and IGFBP-1 production changes, but also changes in IGF-I bioavailability, which at least in part is determined by the IGF-I/IGFBP-1 ratio. Not much is known about how the bioavailability of IGF-I is changed in alcohol abusers. Therefore, the objective of this investigation was to study that matter, and to elucidate how abstinence affects IGF-I bioavailability in man. Three study groups were formed: group N including normal non-addicted subjects, group E ethanol abusers without gross liver insufficiency, and group C alcohol abusers with liver cirrhosis and ascites. Serum concentrations of insulin, GH, IGF-I, and IGFBP-1 were determined in the morning in all participants, and the IGF-I/IGFBP-1 ratios were calculated. These values were compared in the three study groups. In group E comparison was also made between values recorded in the ethanol intoxicated and in the detoxicated states. Patients in group C had low IGF-I levels, high IGFBP-1 levels, and low IGF-I bioavailability as reflected by the IGF-I/IGFBP-1 ratios, which were several-fold reduced compared with subjects in group N (0.6±0.2 vs 10.2±2.3; p <0.001). Patients in group E had also a low IGF-I/IGFBP-1 ratio in the acute ethanol intoxicated state, which increased after detoxication (from 1.5±0.4 to 5.6±1.2; p <0.01). It is concluded that alcohol abuse lowers the hepatic production of IGF-I and increases the production of IGFBP-1. This results in a reduced IGF-I bioavailability. However, in patients with not yet clinically apparent liver damage the IGF-I bioavailability increases if the alcohol abuse is stopped. These findings could reflect an important, physiological adaptation, since hypoglycemia may be induced if the blood glucose-lowering power of IGF-I remains strong at a time of ethanol-induced inhibition of the hepatic gluconeogenesis. Chronic alcohol abuse, causing liver cirrhosis, also leads to markedly reduced IGF-I bioavailability, which appears to become permanent, since it prevails more than one week after stopping the alcohol abuse.

SHORT‐TERM FASTING INHIBITS THE NOCTURNAL MELATONIN SECRETION IN HEALTHY MAN

To investigate whether short‐term fasting influences hormone release from human pinealocytes, nocturnal melatonin (MT) secretion was studied before and at the end of a 2‐day fast in seven normal subjects (group A). Serum MT was measured every second hour between 1800 and 0800 h, and the nocturnal MT secretion, as reflected by the MT incremental area (MT area appearing above the 1800 h level), was calculated and compared before and during the fast. MT excretion by the urine (between 2200 and 0700 h) was also determined before, during, and after the period of food deprivation. Body weight and blood glucose concentration fell by 2.5 ± 0.2 kg (mean ± SEM, P<0.001) and 1.7 ± 0.2 mmol/l (P<0.001) respectively during the fast. Nocturnal MT secretion declined by 19 ± 3% (P<0.002), in contrast to urinary MT excretion which remained unaffected. In order to prevent blood glucose from falling significantly during the period of food deprivation, six additional normal subjects (group B) were given eight small oral doses of glucose (each dose 0.5 g/kg) at regular intervals during the 2‐day fast. This did not prevent a weight loss (2.1 ± 0.5 kg, P<0.01) of similar magnitude as in group A, but it restored a normal nocturnal MT secretion. The fact that glucose supplementation during fasting returns a decreased MT secretion to normal suggests that human pinealocytes require a certain minimal glucose delivery to function normally.

Caffeine raises the serum melatonin level in healthy subjects: An indication of melatonin metabolism by cytochrome P450(CYP)1A2

Caffeine is metabolized in the liver by cytochrome P450(CYP)1A2. Recent findings imply that this enzyme may also be of importance for the metabolism of human melatonin (MT). If caffeine and MT are metabolized by the same enzyme, one may expect to find different serum MT levels after ingestion of coffee compared with placebo. Although coffee is consumed by people all over the world, few studies have focused on whether caffeine actually affects serum MT levels in normal subjects. We decided to study that particular topic. For that purpose 12 healthy individuals were tested on two occasions, one week apart. On one of these occasions they were given a capsule containing 200 mg caffeine in the evening. On the other, they received placebo. The experimental order was randomized. Serum MT levels were determined every second hour between 22:00 h and 08:00 h, and the melatonin areas under the curve (MT-AUCs) were calculated. After caffeine the serum MT level rose from 0.09±0.03 nmol/l at 22:00 h to 0.48±0.07 nmol/l at 04:00 h. The corresponding rise after placebo was less prominent (from 0.06±0.01 to 0.35±0.06 nmol/l). This was reflected by the MT-AUC which was 32% larger after ingestion of caffeine compared with placebo (MT-AUCcaffeine 3.16±0.44 nmol/l x h vs MT-AUCplacebo 2.39±0.40 nmol/l x h; p<0.02). These findings imply that caffeine, ingested in the evening at a dose corresponding to two ordinary cups of coffee, augments the nocturnal serum MT level, which in turn supports the notion that cytochrome P450(CYP)1A2 is involved in the hepatic metabolism of human MT.

Hunger-satiety signals in patients with Graves’ thyrotoxicosis before, during, and after long-term pharmacological treatment

Patients with Graves’ thyrotoxicosis lose weight despite increased appetite and food intake, thus suggesting a disturbed balance between energy intake and expenditure. Underlying mechanisms are not fully elucidated. The objective of this study was to investigate whether hormonal factors, known to affect hunger/satiety, change significantly over time as pharmacological treatment turns hyperthyroidism into euthyroidism. For that purpose 11 patients with Graves’ thyrotoxicosis were given thiamazole and I-thyroxine for 18–20 mo. They were investigated on three occasions: Test 1: before pharmacological therapy; Test 2: during medication; Test 3: a few months after conclusion of the pharmacological treatment. Sixteen healthy subjects were also investigated for comparison. The participants were fasted overnight. Blood samples for determination of plasma glucose and serum concentrations of free T3 and T4, TSH, albumin, cortisol, insulin, GH, IGF-1, IGFBP-1, leptin, and ghrelin were drawn in the morning from an antecubital vein. Laboratory data obtained in test 1 were statistically compared with those in tests 2 and 3. The study showed that the free T3 level declined from 42.8±4.3 pmol/L in test 1 to 6.0±0.8 pmol/L in test 2 (85±2% decline), and 5.5±0.3 pmol/L in test 3 (86±2% decline). The free T4 level fell concomitantly from 65.2±4.8 to 16.6±1.7 and 14.4±1.2 pmol/L. The glucose level was significantly higher during hyperthyroidism (test 1) than during euthyroidism (tests 2 and 3), whereas cortisol, insulin, GH, IGF-1, and leptin levels were similar. The IGFBP-1 level was initially high (48.8±8.5 µg/L in test 1), but with a relative decline in free T3 of 85±2% (test 2) the IGFBP-1 level declined by 34±13%, and with a free T3 decline of 86±2% (test 3) the binding protein fell by 39±29%. This brought about increased IGF-1 bioavailability as reflected by a rising IGF-1/IGFBP-1 ratio from 5.1±1.1 to 13.8±2.9 (p<0.01). The ghrelin level was low (2454±304 ng/L) in test 1. It increased to 3127±397 ng/L in test 2 (p<0.05), and to 3348±279 ng/L in test 3 (p<0.01). Conclusion: Both ghrelin secretion and IGF-1 bioavailability are low in patients with untreated thyrotoxicosis, but increase markedly as pharmacotherapy makes them euthyroid. These metabolic changes may be caused by the transition of hyperthyroidism into euthyroidism rather than by the pharmacotherapy per se, since the metabolic changes prevailed also in the posttreatment period.