Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans.

1. Acute administration of the specific serotonin uptake inhibitor, fluvoxamine (100 mg at 16.00 h), markedly increased nocturnal plasma melatonin concentrations, with high levels extending into the morning hours. 2. Acute administration of the noradrenaline uptake inhibitor, desipramine (DMI) (100 mg at 16.00 h), increased evening plasma melatonin concentrations. 3. Both drug treatments increased the duration of melatonin secretion, fluvoxamine significantly delaying the offset time and DMI significantly advancing the onset time. 4. The stimulatory effect of DMI on plasma melatonin was mirrored by increased urinary 6-sulphatoxymelatonin (aMT6s) excretion. 5. On the contrary, there was no correlation between plasma melatonin and urinary aMT6s concentrations following fluvoxamine treatment, suggesting that fluvoxamine may inhibit the metabolism of melatonin. 6. Treatment with DMI increased plasma cortisol concentrations in the evening and early morning, treatment with fluvoxamine increased plasma cortisol at 03.00 h, 10.00 h and 11.00 h. 7. The drug treatments affected different aspects of the nocturnal plasma melatonin profile suggesting that the amplitude of the melatonin rhythm may depend upon serotonin availability and/or melatonin metabolism whilst the onset of melatonin production depends upon noradrenaline availability.

Factors influencing urinary 6-sulphatoxymelatonin, a major melatonin metabolite, in normal human subjects.

6-Sulphatoxymelatonin (aMT6s) has been measured, by a direct radioimmunoassay, in urine from 130 normal volunteers aged 2-80 years. Its relationship to a number of physiological parameters has been assessed. Total urinary excretion of aMT6s did not vary in a group of 40 children aged 2-20 years (24 boys and 16 girls) except when expressed as a function of body weight. In this case, total aMT6s excretion over 24 h decreased as a function of age. In 90 adult volunteers (44 men and 46 women) aged 20-80 years, there was an age-related decline in total 24 h aMT6s excretion with significantly lower values in elderly subjects. In this same adult group no relationships were found between total aMT6s excretion and body weight or height. No sex differences were found either in the 2-20 years or the 20-80 years groups. Pineal calcification was assessed by lateral skull X-ray in 26 adult volunteers (17 men and 9 women) aged 20-50 years. No significant differences in aMT6s excretion were found as a function of pineal calcification. In 16 of these subjects plasma melatonin and aMT6s also showed no relationship to pineal calcification. These studies confirm the usefulness of aMT6s as an index of melatonin secretion in normal volunteers.

6-sulphatoxymelatonin production in breast cancer patients.

The daily pattern of the major urinary metabolite of melatonin, 6-sulphatoxymelatonin (aMT6s), was determined in women prior to having a breast biopsy. Women with malignant tumors appeared to have significantly lower 24 h concentrations of aMT6s with a decrease in the amplitude of the rhythm compared to women with benign tumors. The amount of urinary aMT6s was dependent upon the age of the subject but was not affected by either menopausal status or body mass index. However, when the women with malignant tumors were compared with a large group of normal women of the same age their aMT6s levels were not outside the normal range. The results show that a large control group and very accurate age matching are essential when investigating melatonin production in different groups of subjects.

Acrivastine in allergic rhinitis: a review of clinical experience.

Acrivastine is an antihistamine with reduced sedating potential. This comprehensive review of clinical experience with acrivastine in allergic rhinitis considers all currently available data both published and, as yet, unpublished. Unequivocal evidence of the efficacy of 8 mg acrivastine three times daily for the control of symptoms of seasonal allergic rhinitis has been provided by 11 placebo-controlled studies involving almost 1000 patients. Additional trials have generated further supportive data as well as evidence for the use of acrivastine in the treatment of perennial allergic rhinitis. In common with most antihistamines, acrivastine alone has limited effect on the symptom of blocked nose. In a further series of 11 studies, mainly conducted in the USA, the combination of 8 mg acrivastine plus 60 mg pseudoephedrine was found to control not only the histamine-mediated symptoms of allergic rhinitis but also blocked nose. There were few adverse events associated with the use of acrivastine and the small increase in incidence of drowsiness over that found with placebo was similar to that observed for terfenadine. The marked absence of other signs of significant depression of the central nervous system (or anticholinergic activity) suggests that acrivastine will be an important addition for the antihistaminic control of symptoms of allergic rhinitis.

Annual changes in 6-sulphatoxymelatonin excretion in man.

A recently developed RIA for 6-sulphatoxymelatonin, the major urinary metabolite of melatonin, has been used to investigate the annual change in melatonin secretion in humans. Twenty plasma samples were taken from 18 volunteers throughout a 24-h period and simultaneous 6-hourly urine samples were also collected. Plasma melatonin and urinary 6-sulphatoxymelatonin were measured by RIA. 6-Sulphatoxymelatonin assayed in the urine samples was shown to be a good index of the rhythmic characteristics of the plasma melatonin secretion. To study annual changes in excretion four sequential 6-hourly urine samples were collected at monthly intervals from 16 normal volunteers for 13 months. Cosinor curves were fitted to the 6-sulphatoxymelatonin excretion data and the 24-h rhythm was described by the cosinor parameters: amplitude, mesor and acrophase. Significant differences in the acrophase were found during the year. The summer acrophase was phase advanced relative to the winter acrophase by about 1.5 h while intermediate phase positions were observed in spring/autumn. The 24-h excretion of urinary 6-sulphatoxymelatonin was remarkably consistent and there was no annual rhythm. In contrast, the daytime 6-sulphatoxymelatonin excretion between 12.00-18.00 h showed a statistically significant seasonal rhythm, with peaks in December/January and in July.

Suppression of nocturnal plasma melatonin and 6-sulphatoxymelatonin by bright and dim light in man.

Previous studies have shown that bright light (2500 lux) suppresses nocturnal secretion of melatonin, while dim light (500 lux) has little or no effect. We have studied the effect of varying intensities of light on 5 normal male volunteers (age 18-28). The experiment was divided into 3 parts which took place at weekly intervals. Subjects remained under artificial light (fluorescent strip 150-250 lux) between 2000 h-2300 h, they then retired to bed in darkness. On each occasion, between 0030 h and 0100 h, the subjects were required to get up and were treated with light of different intensities; (a) less than 1 lux, (b) 300 lux and (c) 2500 lux respectively. Subjects returned to bed in darkness until 0700 h. Blood was sampled hourly from 2000 h-1000 h with additional samples at 2330 h, 0015 h, 0030 h, 0045 h, 0115 h and 0130 h. Plasma melatonin and 6-sulphatoxymelatonin (aMT6s), the major melatonin metabolite, were measured by radioimmunoassay. Dim (300 lux) and bright (2500 lux) light, both significantly suppressed melatonin levels compared to less than 1 lux (P less than 0.05 and P less than 0.01 respectively) at the following time points 0100 h, 0115 h and 0130 h. One subject did not show suppression with 300 lux. There was also a significant suppression of aMT6s levels, compared to less than 1 lux, after both 300 lux and 2500 lux at 0115 h (P less than 0.05, P less than 0.01), 0130 h (P less than 0.01, P less than 0.01) and 0200 h (P less than 0.01, P less than 0.001) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Melatonin secretion in humans assessed by measuring its metabolite, 6-sulfatoxymelatonin.

Comparing a direct radioimmunoassay for 6-sulfatoxymelatonin (aMT6s) with an established gas chromatographic/mass spectrometric method for 6-hydroxymelatonin, we found a good correlation r = 0.94 (P less than 0.001, n = 100). aMT6s was stable, both in urine and plasma samples, without preservative, for at least two years at -20 degrees C and for five days at room temperature. Urinary excretion of aMT6s showed considerable inter-individual differences; however, the aMT6s excretion of any one individual was consistent over a four-day period, as assessed by continuous collection from 18 normal volunteers. Total 24-h urinary excretion of aMT6s was significantly correlated with the area under the curve of the respective profiles for plasma melatonin (r = 0.75, P = 0.0002) and plasma aMT6s (r = 0.70, P = 0.0005) for 22 healthy volunteers. At 24:00 h and 03:00 h, sampling plasma at 30-s intervals provided no evidence for episodic secretion (in short pulses) of either melatonin or aMT6s.

Metabolism and pharmacokinetics of melatonin in the ewe.

The pineal hormone melatonin has been used to advance the onset of the breeding season in sheep and thus produce lambs earlier in the year. If this reproductive manipulation is to be used commercially, some knowledge of the route of metabolism and identity of possible metabolites is necessary. A major metabolite of melatonin in rodents and man is 6-hydroxymelatonin sulphate (acetyl-methoxytryptamine-6-sulphate [aMT6S]). No significant amounts of this metabolite could be found in the plasma of untreated ewes. After subcutaneous implantation of melatonin for 5 months, plasma levels of aMT6S were also insignificant. On the other hand, both a single oral dose of melatonin (3 mg) and daily oral dosing gave rise to circulating levels of aMT6S in the range of 150 to 1,500 pg/ml for at least 18 h. The profiles seen after 180 days treatment were similar to those seen after a single dose, indicating that this route of melatonin metabolism is not induced by chronic administration. Intravenous injection of melatonin (200 or 20 micrograms) gave rise to detectable levels of aMT6S in the plasma. These results indicate that the quantitative aspects of melatonin metabolism differ according to the route of administration.