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Journal Article 2011; 32(5): 575-587 PubMed PMID: 22167140 Citation  Keywords:  Animals, Antioxidants:therapeutic use, Drug Industry:methods, Endocrine System Diseases:drug therapy, Humans, Melatonin:therapeutic use, Phytotherapy:methods, Reproduction:drug effects,.   

: Novel functions of melatonin continue to be uncovered. Those summarized in this report include actions at the level of the peripheral reproductive organs and include functions as an antioxidant to protect the maturing oocyte in the vesicular follicle and during ovulation, melatonin actions on the developing fetus particularly in relation to organizing the circadian system, its potential utility in combating the consequences of pre-eclampsia, reducing intrauterine growth restriction, suppressing endometriotic growths and improving the outcomes of in vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many cancer types have been known for decades. Until recently, however, melatonin had not been tested as a protective agent against exocrine pancreatic tumors. This cancer type is highly aggressive and 5 year survival rate in individuals with pancreatic cancer is very low. Recent studies with melatonin indicate it may have utility in the treatment of these otherwise almost untreatable pancreatic cancers. The discovery of melatonin in plants has also opened a vast new field of research which is rapidly being exploited although the specific functions(s) of melatonin in plant organs remains enigmatic. Finally, the described application of melatonin's use as a chemical reductant in industry could well serve as a stimulus to further define the utility of this versatile molecule in new industrial applications....

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Journal Article 2011; 32(5): 588-606 PubMed PMID: 22167135 Citation  Keywords:  Animals, Antioxidants:therapeutic use, Chronobiology Phenomena:drug effects, Circadian Rhythm:drug effects, Cytoprotection:drug effects, Humans, Melatonin:therapeutic use, Obesity:drug therapy, Sleep Wake Disorders:drug therapy,.   

: From a physiological perspective the sleep-wake cycle can be envisioned as a sequence of three physiological states (wakefulness, non-rapid eye movement, NREM, sleep and REM sleep) which are defined by a particular neuroendocrine-immune profile regulating the metabolic balance, body weight and inflammatory responses. Sleep deprivation and circadian disruption in contemporary "24/7 Society" lead to the predominance of pro-orexic and proinflammatory mechanisms that contribute to a pandemic metabolic syndrome (MS) including obesity, diabetes and atherosclerotic disease. Thus, a successful management of MS may require a drug that besides antagonizing the trigger factors of MS could also correct a disturbed sleep-wake rhythm. This review deals with the analysis of the therapeutic validity of melatonin in MS. Melatonin is an effective chronobiotic agent changing the phase and amplitude of the sleep/wake rhythm and having cytoprotective and immunomodulatory properties useful to prevent a number of MS sequels. Several studies support that melatonin can prevent hyperadiposity in animal models of obesity. Melatonin at a low dose (2-5 mg/day) has been used for improving sleep in patients with insomnia and circadian rhythm sleep disorders. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects (ramelteon, agomelatine, tasimelteon, TK 301). In clinical trials these analogs were employed in doses considerably higher than those usually employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin doses in the range of 50-100 mg/day are needed to assess its therapeutic value in MS....

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Journal Article 2010; 31(Suppl 1): 1-42 PubMed PMID: 20881933 Citation  Keywords:  Antineoplastic Agents:therapeutic use, Antioxidants:therapeutic use, Drug Synergism, Humans, Melatonin:therapeutic use, Neoplasms:drug therapy, Retrospective Studies, Vitamins:therapeutic use,.   

AIMS: the aim of the Di Bella Method (DBM) is to try to overcome the high toxicity level and the limited efficacy of the current medical treatments for cancer.

METHOD: using Melatonin, Retinoids, and vitamins E, D3, and C, components of the extracellular matrix, the DBM reinforces those means that Physiology considers essential for life. Acting together, these differentiating molecules also have an antiangiogenic and antiproliferative effect. Cabergoline and/or Bromocriptin negatively regulate Prolactin, the ubiquitary mitogenic hormone. This effect is reinforced by Somatostatin and/or its analogues by negatively regulating highly mitogenic molecules such as GH and GH-dependent growth factors.

RESULTS: the preliminary results are reported of a retrospective observational study on 553 patients treated with the DBM. These data show that the DBM achieved an evident improvement in the quality of life and a considerable increase in the mean survival rates for every disease and stage with respect to the data available in the literature relative to chemotherapy and/or monoclonal antibodies. The result was achieved without any of the known significant toxic effects of chemotherapy and (albeit to a lesser extent with respect to chemotherapy) of monoclonal antibodies. The invalidating causes which removed all scientific credibility from the DBM experiments carried out in Italy in 1998 are also reported.

CONCLUSIONS: I considered it of use to inform the scientific community of the rationale, the mechanism of action, the scientific basis and clinical findings of the DBM in order to encourage interest in the prospects opened up by the DBM through innovative formulations of the vitamins and Melatonin and the use of biological molecules with a high degree of antitumoural efficacy and low toxicity such as Somatostatin and its analogues....

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Case Reports 2009; 30(4): 437-449 PubMed PMID: 20010503 Citation  Keywords:  Antioxidants:therapeutic use, Drug Therapy, Combination, Humans, Infant, Magnetic Resonance Imaging, Male, Melatonin:therapeutic use, Neuroblastoma:diagnostic imaging, Positron-Emission Tomography, Remission Induction, Retinoids:therapeutic use, Retroperi.   

OBJECTIVES: The combined use (MDB) of Somatostatin, Melatonin, Retinoids, Vitamins E, C, and D3, with Calcium, Chondroitin sulfate, and microdoses of Cyclophosphamide in a seven-month old baby affected by a voluminous retroperitoneal neuroblastoma measuring 4 x 8 cm produced a 50% objective response in six months, an almost total response in one year and a complete response at 14 months, with cure and absence of disease for over ten years.

RESULTS: This paper discusses the rationale and the molecular mechanisms of action of the treatment which has a differentiating, apoptotic and antiproliferative effect, preserving and enhancing both the trophism and functionality of organs and tissues, and the neuroimmunoendocrine and antiblastic homeostasis. This result is in agreement with the positive results already published on the use of the MDB in lymphoproliferative diseases, in stage III and IV lung cancer, in breast cancer and in cancers of the upper aerodigestive epithelia. Without the need for hospitalisation and with no toxicity, the MDB rapidly reduced and then eliminated the voluminous tumoral mass, allowing a normal quality of life and a perfectly normal psychophysical development.

CONCLUSIONS: We believe it is of use to report this case in order to invite greater interest in the oncological possibilities offered by the immunoneuroendocrine and biological-receptorial properties of the MDB treatment....

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Journal Article 2005; 26(5): 609-616 PubMed PMID: 16264393 Citation  Keywords:  Aluminum:antagonists & inhibitors, Animals, Antioxidants:therapeutic use, Apoptosis:drug effects, Brain:metabolism, Lipid Peroxidation:drug effects, Male, Malondialdehyde:metabolism, Melatonin:therapeutic use, Nerve Degeneration:pathology, Neurofibrils:pa.   

OBJECTIVE: The present study was aimed to investigate: (1) the neurotoxic oxidative damage of orally administered aluminum chloride (AlCl3) in rabbits (Biochemical and morphopathological studies). (2) The effect of melatonin as an antioxidant and free radical scavenger on oxidative neuropathic changes.

METHODS: Thirty-five male rabbits were divided into 4 groups (A, B, C [10 animals each] and D [5 animals]). Group A received AlCl3 (20 mg/l via drinking water for 3 months). Group B received AlCl3 for 3 months then administered with melatonin (10 mg/kg b.w. sc daily for 15 days). Group C received AlCl3 plus melatonin for 3 months. Group D received the solvent and served as control. Malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) as lipid peroxides as well as superoxide dismutase (SOD) as an antioxidant enzyme were measured. Aluminum residue in the brain tissue was measured spectrophotometerically. The morphopathological changes were also examined by light and electron microscopes.

RESULTS: MDA and 4-HAD were significantly increased in group A versus those of controls while significantly decreased in groups B and C compared with those of A group. SOD run in an opposite manner. Aluminum concentration was significantly increased in groups A, B and C when compared with group D while it significantly decreased in groups B and C when compared with that of group A. The neuropathlogical examination in the animals of group A revealed atrophy and apoptosis of the neurons in cerebral cortex and hippocampus. This was associated with neurofibrillary degeneration as well as argyrophilic inclusion. Schwan cell degeneration and nerve fiber demylination were also encountered. The elaboration of lipid peroxidation products, inhibition of antioxidant enzymes and the morphopathological changes were minimized in the Al/Mel treated groups and markedly improved in Al+Mel treated group

CONCLUSION: Chronic aluminum exposure in rabbits had dramatic encephalopathic morphopathological lesions. It enhances the lipid peroxidation production and inhibits the SOD enzyme. Melatonin had a good prophylactic effect as an antioxidant in aluminum encephalopathy....

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Journal Article 2003; 24(3-4): 170-172 PubMed PMID: 14523352 Citation  Keywords:  Animals, Antioxidants:therapeutic use, Male, Malondialdehyde:blood, Melatonin:therapeutic use, Rats, Rats, Sprague-Dawley, Reperfusion Injury:pathology, Spermatic Cord Torsion:pathology, Testicular Diseases:pathology, Testis:metabolism,.   

AIM: Torsion of testis, which is a urologic emergency case, is generally treated by surgical detorsion procedure. However, the resulting reperfusion and both ipsilateral and contralateral testis damage caused thereby are important problems. This study aims at investigating the administration of prophylactic melatonin in order to reduce free radical damage that is caused due to reperfusion after experimental testis torsion-detorsion procedure.

MATERIAL AND METHOD: The rats used in the study were allocated to four groups, each containing 10 rats. Rats in Group I had six hours of torsion (ischemia) followed by orchiectomy. Rats in Group II had six hours of torsion, then received melatonin (10 mg/kg/IM) and after that had detorsion (reperfusion). Rats in Group III had detorsion after six hours of torsion and serum physiologic administration (the same volume as melatonin). Torsion and/or detorsion procedures were not applied in Group IV (control). Ipsilateral, contralateral testis and plasma Malondialdehyde (MDA) levels were determined in all groups.

RESULTS: Tissue and plasma MDA levels in the group which had detorsion were found to be significantly higher than those in the group that had orchiectomy only (p<0.02). Ipsilateral and contralateral testis MDA levels were identified to be significantly lower in the group receiving prophylactic melatonin in comparison to the group receiving serum physiologic (p<0.02). Plasma and contralateral MDA levels correlated positively with MDA levels identified in ipsilateral testis in all groups (rs=+0.89, n=40, p=0.000).

CONCLUSION: In cases where testis torsion is identified, administration of melatonin just before torsion may reduce local and systemic free radical damage....

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Comparative Study 2002; 23(5-6): 391-395 PubMed PMID: 12500159 Citation  Keywords:  Animals, Coloring Agents, Cytoprotection:drug effects, DNA:analysis, Disease Models, Animal, Drug Evaluation, Preclinical, Drug Therapy, Combination, Growth Hormone:therapeutic use, Heart:drug effects, Male, Melatonin:therapeutic use, Myocardial Infarctio.   

OBJECTIVE: To examine the cytoprotective effect of melatonin or recombinant human growth hormone (hGH) on the early phase of a running myocardial infarction in rats by using the Feulgen staining.

METHODS: Rats were subjected to surgical ligature of the left coronary artery or its sham-operation and were studied 1.5 3 h later. Melatonin was administered in the drinking water (100 microg/ml water) for 7 days before surgery. Recombinant hGH (2 IU/kg) was given ip at the time of surgery. Feulgen-stained histological cardiac sections were examined by light microscopy and image analysis.

RESULTS: Infarcted rats receiving vehicle exhibited large, diffuse cardiac lesions with a marked positivity for Feulgen reaction. About 18 20% of the total area recorded became injured 1.5 or 3 h after infarction, respectively. Infarcted rats treated with melatonin or hGH, or the combination of both, and killed 3 h after surgery, showed cardiac sections with scattered lesions and only a few isolated injured muscle fibers. A similar effectiveness of melatonin and hGH, alone or in combination, to decrease injured area by 86 87% and the number of cardiac lesions by 75 80% was observed.

CONCLUSION: A significant cytoprotective effect of melatonin or hGH is demonstrable in an early phase of myocardial infarction in rats....

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Journal Article 2002; 23(Suppl 1): 20-23 PubMed PMID: 12019347 Citation  Keywords:  Aged, Alzheimer Disease:complications, Antioxidants:therapeutic use, Circadian Rhythm:drug effects, Clinical Trials as Topic, Humans, Melatonin:therapeutic use, Sleep Wake Disorders:drug therapy,.   

: About 45% of Alzheimer's disease (AD) patients have disruptions in their sleep and sundowning agitation. Since melatonin secretion is greatly inhibited in AD patients we have used melatonin to treat sleep disorders in AD patients since 1995. In a first study [21] we reported, in 7 out of 10 dementia patients treated with melatonin (3 mg p.o. at bed time), a decreased sundowning. In a second study [22] we examined 14 AD patients who received 9 mg melatonin daily for 22 to 35 months, observing a significant improvement of sleep quality with stabilization of behavioral and cognitive parameters. In a third study [23] we reported two monozygotic twins with AD and similar cognitive impairment, one of them receiving 6 mg melatonin at bedtime daily for 3 years. Melatonin treatment improved sleep quality and suppressed sundowning. We now report the effect of melatonin (4-month-long treatment with 6 mg/day) in 45 AD patients with sleep disturbances. Melatonin improved sleep and suppressed sundowning, an effect seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of AD. Melatonin treatment seems to constitute a selection therapy to ameliorate sundowning and to slow evolution of cognitive impairment in AD patients....

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