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Journal Article 2002; 23(Suppl 1): 118-121 PubMed PMID: 12019364 Citation  Keywords:  Animals, Free Radical Scavengers, Humans, Melatonin:adverse effects, Sleep Wake Disorders:drug therapy,.   

: Report of the round table conference summarizing the International Symposium on "Melatonin: Clinical Significance and Therapeutic Applications" is presented in this article. Some sleep disorders and circadian rhythm disturbances are the widely accepted indications for melatonin treatment. However, other possibilities for use of melatonin in the therapy should be also taken into account, including a co-treatment in cancer patients and free radical-related diseases. All aspects of the possible therapeutic use of melatonin as well as its safety, dosage, side effects and contraindications are discussed herein based on the round table conference and they are presented in this paper....

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Clinical Trial 2002; 23(Suppl 1): 17-19 PubMed PMID: 12019346 Citation  Keywords:  Aged, Aged, 80 and over, Antioxidants:pharmacology, Blood Cell Count, Dehydroepiandrosterone Sulfate:blood, Estradiol:blood, Female, Humans, Hydrocortisone:blood, Melatonin:pharmacology, Pilot Projects, Sleep:drug effects, Sleep Wake Disorders:drug therap.   

OBJECTIVES: The role of melatonin is aging is still under debate. Therefore, an open pilot study on the effects of melatonin administration on some sleep parameters, routine hematological and biochemical parameters, and concentrations of hormones was performed in elderly women.

SUBJECTS AND METHODS: The study was performed on 14 women (volunteers), aged from 64 to 80 years (mean age 71+/-4.6 years). Melatonin (2 mg daily at 19:00 h) was administered during 6 months. Before and after melatonin treatment the peripheral venous blood samples were taken in the morning (approx. at 08:00 h) after the overnight fast. The total blood count, glucose, total cholesterol, LDL, HDL, and triglycerides were estimated by routine laboratory methods. The serum concentrations of the following hormones were determined: 17-beta-estradiol, dehydroepiandrosterone sulfate (DHEAS), cortisol, and somatomedin C (IGF-I). Additionally, before and after 6 months of melatonin therapy the investigated subjects answered to a questionnaire dealing with sleep parameters and self-estimation of general health status.

RESULTS: In 35.7% of investigated subjects an improvement in general sleep quality and in such sleep parameters as sleep initiation, sleep latency, number of awakenings episodes, wake time after sleep onset, was observed. A significant decrease of estradiol concentrations was observed after 6 months of the melatonin treatment in comparison to initial levels. IGF-I was found to be slightly but significantly increased after the 6 months melatonin therapy. Cortisol levels did not change significantly, during the melatonin treatment. DHEAS concentrations increased after melatonin therapy. Moreover, a tendency towards a higher DHEAS/cortisol ratio was found after 6 months of treatment. Melatonin treatment did not influence significantly either the parameters of total blood count or glucose and serum lipids levels.

CONCLUSIONS: On the basis of this preliminary open study it seems that melatonin administration may be beneficial for elderly subjects....

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Journal Article 2002; 23(Suppl 1): 3-8 PubMed PMID: 12019343 Citation  Keywords:  Animals, Antioxidants:pharmacology, Free Radical Scavengers:pharmacology, Free Radicals:adverse effects, Humans, Melatonin:pharmacology,.   

: Endogenously produced metabolites of ground state oxygen are highly reactive and destructive to intracellular and extracellular molecules. The resulting damage, referred to as oxidative stress, leads to molecular and cellular dysfunction. The destruction of essential macromolecules by oxygen-based reactants is the basis of some diseases and is believed to be involved in the processes of aging. Free radical scavengers and antioxidants neutralize and/or metabolically remove reactive species from cells before they carry out their destructive activities. Melatonin is a highly ubiquitous direct free radical scavenger and indirect antioxidant. This brief report summarizes the interactions of melatonin with reactive species and identifies the resulting products. The paper also defines the melatonin antioxidant cascade wherein not only melatonin but at least one of the products, i.e., N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, formed as a result of melatonin scavenging hydrogen peroxide is also a potent scavenger. The review summarizes the data which shows that melatonin is not only a pharmacologically useful free radical scavenger but that it functions in this capacity at physiological concentrations as well. Finally, this report identifies high oxidative stress situations in humans where melatonin has proven effective in reducing the severity of the disease state. In the last decade there have been hundreds of publications documenting melatonin's protective actions against a vast array of conditions, e.g., ischemia/reperfusion injury, toxin exposure, lipopolysaccharide exposure, etc., where free radical damage is a component of the condition....

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Journal Article 2002; 23(2): 155-160 PubMed PMID: 12011802 Citation  Keywords:  Aged, Aged, 80 and over, Alzheimer Disease:blood, Estradiol:blood, Estrone:blood, Female, Folic Acid:blood, Humans, Logistic Models, Mental Status Schedule, Testosterone:blood,.   

OBJECTIVES: In vitro and in vivo animal studies suggest that sex steroids, such as estrogens and testosterone, could protect the brain. However, estrogen replacement therapy (ERT) for Alzheimer's disease (AD) in women has not been successful. We hypothesised that the lack of effect of ERT might be related to an interaction between estrogens and some other factor(s) associated with AD.

DESIGN, SETTING AND METHODS: We analysed total estrogen (TE) and testosterone (TT) levels in women diagnosed with AD and controls of the Oxford Project To Investigate Memory and Ageing. Because estradiol (TE2) after the menopause is largely derived from estrone (TE1), we computed the ratio TE2/(TE1+TE2) and a total steroid index (TT+TE2+TE1).

RESULTS: Women with AD (n=66) had significantly higher levels of TE2 (27+/-13 vs. 21+/-13) and a higher TE2/(TE1+TE2) ratio. Stepwise logistic regression analyses showed that the TE2/(TE1+TE2) ratio was the main sex steroid predictor for AD (O.R.=1.06, 95% C.I.=1.01-1.11, p<0.01). Multiple regression analyses revealed that dementia severity was associated with an interaction between the TE2/(TE1+TE2) ratio and serum folate (B=4.59 (SE=1.48), beta=1.22, 95% C.I.=1.62-7.56, p<0.005). None of the other potential mediators of this association (body mass index, sex hormone binding globulin, homocysteine levels, ApoE genotype, smoking, diabetes, blood pressure) was significant.

MAIN FINDINGS: A high ratio of estradiol to total estrogens is associated with AD but, in subjects with a high ratio, the dementia severity was lower in those with high serum folate levels.

CONCLUSIONS: If this association is causal, then supplementation with folic acid might be considered in future studies on ERT in AD....

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Journal Article 2001; 22(5): 332-336 PubMed PMID: 11600882 Citation  Keywords:  17-alpha-Hydroxyprogesterone:blood, Adolescent, Adrenal Hyperplasia, Congenital, Adrenocorticotropic Hormone, Adult, Dehydroepiandrosterone Sulfate:blood, Estradiol:blood, Fasting, Female, Follicle Stimulating Hormone:blood, Follicular Phase, Humans, Hype.   

OBJECTIVES: To determine melatonin production in hyperandrogenic women.

MATERIAL AND METHODS: Seventeen women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency (LOCAH) and 15 control women were studied in early follicular phase of the menstrual cycle. Fasting serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E(2)), testosterone, dihydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP) as well as the peak 17-OHP response to ACTH (250 microg IV) and 24h urinary 6-sulfatoxymelatonin (aMT6s) were determined in all participants.

RESULTS: All 17 hyperandrogenic women were carrying mutations of the CYP21 gene. Women with LOCAH had significantly higher serum testosterone, DHEA-S, 17-OHP and ACTH stimulated 17-OHP values compared with controls. Their aMT6s values (44.6+/-20.3 microg/24h) were significantly higher than the values in control women (31.5+/-20.3) (p<0.03). The urinary aMT6s values were positively correlated with testosterone (p<0.04), DHEA-S (p<0.02) and peak 17-OHP (p<0.04).

CONCLUSIONS: Women with LOCAH have increased melatonin production. There is a relationship between adrenal androgens and melatonin in these women....

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Journal Article 2001; 22(5): 349-355 PubMed PMID: 11600877 Citation  Keywords:  Animals, Appetite Regulation:drug effects, Energy Metabolism:drug effects, Estradiol:blood, Female, Follicle Stimulating Hormone:blood, Galanin:blood, Hormones:blood, Leptin:analysis, Luteinizing Hormone:blood, Neuropeptide Y:blood, Neuropeptides:blood, P.   

OBJECTIVES: Some hormonal disturbances were demonstrated in starvation. Leptin, NPY and galanin play an important role in the control of appetite and in the mechanism of hormone release.

METHODS: In order to evaluate the effect of starvation on the relationship between leptin, neuropeptide Y (NPY) galanin and pituitary and gonadal hormones release, plasma leptin, NPY and galanin as well as serum LH, FSH, prolactin (PRL), estradiol, progesterone levels in non-starved female rats (in diestrus) and after 72 hrs of starvation were measured with RIA methods. Effects of leptin, NPY and galanin administration on pituitary and gonadal hormones were investigated in vivo and in vitro experiments.

RESULTS: Plasma leptin, NPY and galanin as well as serum estradiol and progesterone concentrations were significantly lower in starved rats as compared with non-starved rats. However serum prolactin level was significantly higher in starved rats. Opposite effects after leptin and NPY administration on hormone release in vivo and in vitro experiments were observed in non-starved rats. However, in starved rats we did not find changes in pituitary and gonadal hormones release after leptin, NPY and galanin injection or the hormonal response was blunted.

CONCLUSIONS: 1) The disturbances in neuropeptides activity and in hormones release were observed in starvation. 2) Leptin, NPY and galanin have direct and indirect effects on pituitary and gonadal hormones release. 3) In starvation the hormonal response to leptin, NPY and galanin is impaired....

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Journal Article 2001; 22(2): 93-99 PubMed PMID: 11335885 Citation  Keywords:  Alcoholism:complications, Animals, Autoradiography, Cell Division:drug effects, Ethanol:administration & dosage, Leydig Cells:drug effects, Male, Rats, Rats, Sprague-Dawley, Seminiferous Tubules:drug effects, Spermatogonia:drug effects, Testicular Disease.   

OBJECTIVES: Considering the possibility that alcoholism induces gonadal dysfunction, the present work was designed to investigate the morphophysiology of rat testes submitted to experimental alcoholism.

METHODS: Male Sprague-Dawley rats weighing 150+/-5 gm were chronically given 40% ethanol solution at a dose of 3 g/kg body weight for 30 days. (3)H-thymidine autoradiographic investigations and histological studies were carried out to determine the proliferative activity and/or different stages of spermatogenesis in the seminiferous tubule cycle and Leydig cells.

RESULTS: The 3H-thymidine autoradigraphic investigation revealed that there was a significant inhibition in the proliferative activity of the spermatogonia in all stages of the seminiferous tubule cycle in the alcohol-treated rats versus controls as indicated by the values of (3)H-labelling indices. The histological and numerical investigations indicated that the alcohol-treated rats presented testicular lesions including a significant decrease in the diameter of the seminiferous tubules, the number of different germ cells in all stages of the seminiferous tubule cycle and the presence of degenerative germ cells. In addition, there was a significant decrease in the number of Leydig cells.

CONCLUSION: The present work suggests the deleterious effects of alcohol on the testes. These effects may be due to the effect of alcohol on the gonadotrophic cells of the pituitary gland and/or directly on the seminiferous tubules and Leydig cells....

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Journal Article 2001; 22(1): 9-18 PubMed PMID: 11335874 Citation  Keywords:  Adult, Aged, Aged, 80 and over, Aging:drug effects, Animals, Antioxidants:metabolism, Catalase:drug effects, Drosophila melanogaster, Free Radicals:metabolism, Humans, Lipid Peroxidation:drug effects, Melatonin:metabolism, Middle Aged, Oxidation-Reduction.   

OBJECTIVES: The review on our own data on the effect of the pineal peptide preparation Epithalamin on free radical processes in rodents and humans is presented in this paper.

RESULTS: The activity of Cu, Zn-superoxide dismutase (SOD) was found decreased in the brain of aged rats (30 months old) by 46.8% as compared to young animals. Concentration of Schiff's bases in the brain also went down with age (by 13.6%), while the level of dien conjugates (DC) and protein peroxidation (PPO) remained unchanged. General antioxidation activity (AOA) in the brain also remained stable with age. The liver of aged rats showed significant increase of Schiff's bases (by 27.1%) and PPO products (by 109.2%) and considerable decrease of SOD activity. The level of DC and general AOA in the liver remained unchanged with age. Considerable elevation of protein and lipid peroxidation products contents was registered in the blood serum of aged rats. At the same time, general AOA and SOD activity remarkably decreased. The results obtained evidence from both significant age-related alterations in the activity of free radical processes in animal organism and organic peculiarities of their dynamics. Application of peptide drug epithalamin suppressed significantly the intensity of peroxide chemoluminescence in the blood serum (2.8-fold) and lipid peroxide oxidation (LPO) expressed in the considerably decreased DC contents (4,1-fold). The contents of Schiff's bases showed only a tendency towards decrease (by 14.4%, p > 0.05) and PPO level remained unchanged. Epithalamin administration was followed by considerable (by 36.6%, p < 0.01) increase of general AOA and increased SOD activity (by 19.7%) in males. Epithalamin decreased significantly the contents of conjugated hydroperoxides and ketodienes in tissues of D.melanogaster females, increased catalase activity in drosophila males and females, and increased SOD activity in males of D.melanogaster by 41%. Humans reveal significant age-related decrease of antioxidation defence indices.

CONCLUSION: Epithalamin administration to patients with age-related pathology eliminates imbalance in prooxidation and antioxidation systems....

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