Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol.

An assessment of the rhythmic characteristics of melatonin secretion in man and other species requires the determination of 24-h secretion profiles. Measurement of a major excreted metabolite would allow noninvasive study of pineal function, applicable in particular to pediatric and long term circadian rhythm studies. This report describes a simple and rapid RIA for 6-hydroxymelatonin sulfate in human plasma and urine. Physiological studies revealed that both plasma and urinary levels of 6-hydroxymelatonin sulfate were closely related to plasma melatonin, and that the urinary 24-h rhythm was abolished by the beta 1-adrenergic anagonist atenolol.

Evidence for a functional role of alpha-1 adrenoceptors in the regulation of melatonin secretion in man.

Nocturnal plasma melatonin concentrations were reduced following administration of the alpha 1 adrenoceptor antagonist, prazosin (2 mg orally at 1900h), to 10 normal men. These data indicate that alpha 1 adrenoceptors are involved in the physiological control of melatonin secretion in man.

Clinical studies of the effect of (+) and (-)-oxaprotiline upon noradrenaline uptake.

In six normal male subjects the mydriatic effect of tyramine eye drops was inhibited by 1 day's treatment with desipramine and the (+)- but not the (-)-enantiomer of oxaprotiline. In the same experiment, the secretion of melatonin was increased after treatment with (+)- but not with (-)-oxaprotiline. The effects of (+)-oxaprotiline and of desipramine treatment were similar, as were those of (-)-oxaprotiline and placebo. These findings extend to clinical studies the demonstration in animal experiments of stereo-specificity for the effects of (+)- and (-)-oxaprotiline upon noradrenaline uptake. A comparison of the effects of the two enantiomers should provide an ideal strategy for studying effects of noradrenaline uptake blockade in clinical studies.

The effects of chronic, small doses of melatonin given in the late afternoon on fatigue in man: a preliminary study.

In a double-blind cross-over study, melatonin (2 mg) or placebo, was administered daily for 4 weeks to 12 volunteers (10 men and 2 women) at 17.00 h during February and March. Self-rated fatigue (tiredness) was significantly increased in the evening during melatonin treatment. No other consistent effects on sleep ratings or mood parameters were observed and the dose was well tolerated.

Drug users' spiritual beliefs, locus of control and the disease concept in relation to Narcotics Anonymous attendance and six-month outcomes.

Narcotics Anonymous (NA) is an important support network for drug users emerging from abstinence based treatments. However, the views of NA on 'spirituality' and the 'disease' nature of addiction could be seen as encouraging an external attributional style and have been cited as reasons for non-attendance. After 6 months ninety percent of 101 drug users in treatment were followed up. Narcotics Anonymous attendance was inversely related to drug use for those who had left residential care. We found that spiritual beliefs and disease concept beliefs were not prerequisites for attendance of NA. Spiritual beliefs were not found to cause external attributions for previous drug use or possible future lapse events. It emerged that the most powerful predictors of non-attendance were positive attitudes to the use of alcohol. Treatment implications are discussed.

Effects of a phosphodiesterase inhibitor (Rolipram) on the urinary excretion of 6-sulphatoxy melatonin in man.

The urinary excretion of 6-sulphatoxymelatonin (aMT6s) from 2400 to 0600 h was significantly increased following the treatment of ten normal volunteers with a phospho diesterase inhibitor (rolipram 1 mg 8 h for 24 h). The urinary excretion of the metabolite from 0600 to 1200 h was significantly reduced after treatment with rolipram.

Treatment and services for drug users in Britain.

The pattern of British drug service provision was transformed during the late 1980s. Policy makers and service providers recognised the need for a more flexible response to changing drug trends and client needs; consequently community-based services proliferated. HIV has had considerable impact on the working approach of many agencies, where harm minimisation is now the immediate goal. This article provides an overview of patterns of drug use and drug service provision in Britain.

Recent trends and clinical features of childhood vitamin D deficiency presenting to a children's hospital in Glasgow.

BACKGROUND: The incidence of vitamin D deficiency is unclear in the context of continuing demographic changes and the introduction of new public health measures. METHODS: All cases in which vitamin D deficiency was suspected as the primary cause of the clinical presentation were studied. RESULTS: Between 2002 and 2008, 160 cases of symptomatic vitamin D deficiency were identified with twice as many cases in 2008 (n, 42) as in the previous years. The median age of the cohort was 24 months (range 2 weeks-14 years).Three cases were recorded in children of European background, whereas the rest were in children of South Asian, Middle Eastern or sub-Saharan ethnic background. Presenting features included bowed legs in 64 (40%) and a fit in 19 (12%). In one infant, concerns were raised following a presentation with cardiac failure and hypocalcaemia. SUMMARY: Symptomatic vitamin D deficiency remains prevalent in the West of Scotland. There is a need for effective public health education, action and surveillance.

Addicts' drug-related dreams: their frequency and relationship to six-month outcomes.

101 drug users were interviewed at baseline when 6-weeks abstinent. Eighty-four percent reported having drug-related dreams. More subjects reported drug dreams when abstinent than when using drugs. Ninety percent of subjects were followed-up at 6 months. Higher baseline measures of dream frequency were prospectively related to greater drug use. In the first 7 weeks of follow-up there was a rapid reduction in the number of reports, but half of the sample were still experiencing drug dreams in the sixth month. Drug dream frequency at follow-up was related to "craving" and lack of sleep.

Further ethical and social issues in using a cocaine vaccine: response to Hall and Carter.

Evaluation of the potential of a cocaine vaccine requires a detailed understanding of the intended and unintended social consequences of its use. Prospective technology assessment is always difficult, but in the case of treatment and prevention of cocaine addiction we need to understand not only the neuroscience and pharmacology of cocaine addiction, but also social attitudes to drug use and addiction, the social context of drug use, and the factors which make drug use a rational strategy for an addict and make treatment seeking or relapse more or less likely. By considering different scenarios related to differing levels of effectiveness of the vaccine, the authors argue that vaccination will be at best a useful adjunct to existing methods of treatment, rather than a substitute for them.

Plasma concentrations of melatonin in man following oral absorption of different preparations.

The plasma concentrations of melatonin in man, fasting and fed, were determined after ingestion of three different oral preparations. A dose of 2 mg was given as either a gelatine capsule, a solution in corn oil or as a slow-release pill. Gelatine capsules and the corn oil preparation gave reproducibly timed peak plasma concentrations, 30 to 60 min after ingestion regardless of nutritional status, and plasma melatonin remained at or above endogenous night-time levels for 3-4 h with mean elimination half-lives of 0.54 to 0.67 h. The slow-release preparation usefully extended high plasma melatonin concentrations for 5-7 h after ingestion but the timing of peak concentrations was very dependent on nutritional status. These preparations should be of use in the study of timed melatonin administration in man.

A comparison of melatonin secretion in depressed patients and normal subjects.

Depressed patients were carefully matched in pairs with normal subjects for the variables which are known to influence the secretion of melatonin in humans. In contrast to the previous literature, nocturnal melatonin secretion was not lower in the depressed group than in the normal group, and there was no difference in the timing of secretion; indeed, the trend was for greater melatonin secretion in the depressed group. The results are discussed in relation to previous studies, none of which has been so carefully controlled for the relevant variables.

A study of the effects of desipramine treatment alone and in combination with L-triiodothyronine on 6-sulphatoxymelatonin excretion in depressed patients.

Urinary 6-sulphatoxymelatonin (alpha MT6s) excretion was measured after one day and one, two and three weeks of desipramine treatment in eight depressed patients. There was significant increase in the urinary excretion of alpha MT6s after one week of treatment, and at no time was there any decrease in alpha MT6s excretion. These findings are opposed to the hypothesis that desipramine reduces noradrenergic neurotransmission in the human pineal. In a further five patients whose depression was resistant to desipramine alone, urinary alpha MT6s excretion was measured during treatment with adjunctive L-triiodothyronine (T3). There was no change in alpha MT6s excretion, and thus the previously reported potentiation of the efficacy of tricyclic antidepressants in combination with T3 does not appear to be mediated through an alteration in noradrenergic neurotransmission.

Plasma melatonin levels in anorexia nervosa.

Plasma melatonin levels were measured at three-hourly intervals over 24 hours in 11 women with untreated anorexia nervosa, and in nine healthy women of normal weight. The circadian rhythm was unaltered but the nocturnal secretion of melatonin was significantly greater in anorectics. It is possible that this was related to nocturnal hypoglycaemia.

Acute treatment with desipramine stimulates melatonin and 6-sulphatoxy melatonin production in man.

Acute administration of the antidepressant drug desipramine (DMI) in man, increased evening melatonin secretion, which reached peak plasma levels 2-4 h earlier than after placebo administration. The increase at set time points 21.00 h-22.00 h was directly proportional to an individual's integrated night-time secretion of melatonin. We have shown that this stimulation was not an effect of DMI inhibition on the hepatic metabolism of melatonin to 6-sulphatoxy melatonin (aMT6s), indeed aMT6s is in itself a good index of the evening melatonin rise. The stimulation of early evening melatonin by DMI might be exploited as a simple pineal function test.

The effects of exogenous melatonin on endocrine function in man.

At two different times of year (spring and autumn) an oral preparation of the pineal neurohormone melatonin, or placebo, was administered to 12 healthy volunteers (10 men and two women in spring: the same group minus one man in autumn) daily at 1700 h for 1 month (spring), or 3 weeks (autumn) using a double-blind cross-over protocol. The daily dose was 2 mg melatonin in 5 ml corn-oil, and placebo consisted of the vehicle only. In spring the anterior pituitary hormones LH, PRL, GH together with T4, cortisol, testosterone and melatonin were measured at 1- to 6-h intervals for 24 h in plasma on the day following the last dose. In autumn PRL, cortisol and melatonin levels were measured on the last day of treatment. Subjective fatigue, mood and sleep records were kept throughout the studies. Melatonin increased early evening fatigue and actual sleep, but had no effect on mood: these results are reported in full elsewhere. Melatonin administration had no effect on the levels or 24-h rhythm of LH, GH, T4, testosterone or cortisol. An earlier fall in the nocturnal PRL was observed on both occasions. Overall PRL levels were higher in spring than in autumn. In five of the subjects, the secretion of endogenous melatonin was advanced by 1-3 h in the presence of exogenous melatonin. These observations suggest that the potential therapeutic use of melatonin as a hypnotic or in the treatment of jet lag is unlikely to be complicated by undesirable endocrine effects.

Effects of light treatment upon mood and melatonin in patients with seasonal affective disorder.

Ten patients with seasonal affective disorder received the following treatments for 5 days each: (a) artificial daylight (2500 lux) from 20.00 to 23.00 and from 07.00 to 10.00 hours; (b) red light (300 lux) from 20.00 to 23.00 and from 07.00 to 10.00 hours; (c) artificial daylight (2500 lux) from 22.00 to 23.00 and from 07.00 to 08.00 hours. The antidepressant effect of treatment (a) was superior to that of treatment (b), suggesting that the effect of light treatment in winter depression is more than that of a placebo. The antidepressant effect of treatment (a) was superior to that of treatment (c), although these two treatments equally suppressed plasma melatonin concentrations. Consequently, in these patients there is a dissociation between the effect of light treatment on melatonin and the reduction of depression ratings.

Neuroendocrine and other studies of the mechanism of antidepressant action of desipramine.

It is not known whether in depressed patients antidepressant treatment increases or reduces monoaminergic neurotransmission. Clinical studies are therefore reviewed that investigate adaptive changes at adrenoceptors in depressed patients treated with desipramine, and the net effect of these changes upon neurotransmission. Although in animals chronic desipramine treatment enhances the responsiveness of alpha 1-adrenoceptors to phenylephrine, no such effect could be demonstrated in patients upon the responsiveness of pupil diameter to phenylephrine. However, in keeping with animal studies, clinical evidence of altered responsiveness of alpha 2-adrenoceptors could be demonstrated after chronic desipramine treatment. The alpha 2-mediated growth hormone response to clonidine was increased after one week's treatment with desipramine and then reduced during the second and third weeks of treatment. No clinical measure of the responsiveness of central beta-adrenoceptors is available. However, the secretion of melatonin is a measure of neurotransmission at noradrenergic terminals in the pineal with alpha 1-, alpha 2- and beta 1-adrenoceptors. In normal volunteers the secretion of melatonin was increased by the noradrenaline uptake inhibitors desipramine and (+)-oxaprotiline; (-)-oxaprotiline had no effect. In depressed patients melatonin secretion was increased after three weeks' treatment with desipramine. These and other clinical studies suggest that antidepressant treatments increase noradrenergic neurotransmission in depressed patients.

The effect of desipramine upon melatonin and cortisol secretion in depressed and normal subjects.

Melatonin and cortisol values in plasma were measured hourly over 24 hours in six depressed patients and six normal volunteers before treatment and after one and three weeks of treatment with desipramine. The normal volunteers were further tested one week after withdrawal of desipramine. The mydriatic effects of tyramine and phenylephrine eye drops were also recorded in the normal volunteers. In neither group of subjects did desipramine treatment reduce melatonin secretion, suggesting that functionally significant down-regulation of beta andrenoceptors was not caused by this treatment. Melatonin secretion was significantly increased after three weeks of treatment in depressed patients. This increase was not found in normal subjects.

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)