Effect of topical application of melatonin on serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with type 1 or type 2 diabetes and periodontal disease.

BACKGROUND: The present clinical trial study was designed to assess the effect of topical application of melatonin on serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP) in patients with diabetes and periodontal disease in comparison with healthy controls. MATERIAL AND METHODS: Serum levels of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay and CRP by nephelometry by using the proper commercial kits in 30 patients with diabetes and periodontal disease, and also in a control group of 30 healthy subjects. Periodontograms were performed using the Florida Probe®. Patients with diabetes were treated with a topical application of melatonin (1% orabase cream formula) once daily for 20 days. Healthy subjects were treated with a placebo orabase cream. RESULTS: Patients with diabetes and periodontal disease had significantly higher mean levels of serum TNF-α, IL-6 and CRP than healthy subjects (P < 0.001). Following topical melatonin application, there was a statistically significant decrease in the gingival index and pocket depth (P < 0.001) as well as a significant decrease in IL-6 and CRP serum levels (P < 0.001). Local melatonin application in patients with diabetes and periodontal disease resulted in a significant decrease in CRP and IL-6 serum levels as well as an improvement in the gingival index and pocket depth. Patients with periodontal disease had significantly higher serum CRP, IL-6 and TNF-α values by comparison with healthy subjects. CONCLUSIONS: We conclude that melatonin can modulate the inflammatory action of these molecules in periodontal patients. KEY WORDS: Melatonin, periodontal disease, diabetes mellitus, interleukin-6, tumor necrosis factor-alpha, C-reactive protein, inflammatory markers.

Action of melatonin on squamous cell carcinoma and other tumors of the oral cavity (Review).

Melatonin (MLT; N-acetyl-5-metoxy-tryptamine) is a hormone that is principally synthesized in the pineal gland. MLT has been shown to exhibit a variety of functions. The hormone, which is a free radical scavenger, plays an immunomodulatory role, stimulates the proliferation and synthesis of type I collagen and promotes bone formation. Moreover, MLT exerts oncostatic activity through several biological mechanisms, including antiproliferative functions, stimulation of anticancer immunity, modulation of oncogene expression and anti-inflammatory, antioxidant and antiangiogenic effects. In addition, MLT inhibits human cancer cell growth in culture, and previous clinical studies have also confirmed its anticancer properties in vivo. With regard to the underlying mechanisms of MLT in tumor processes, including oral cavity tumors such as epidermoid carcinoma, knowledge of the role played by the MT1 and 2 membrane receptors, MT3 and the calmodulin cytosolic binding sites, as well as the nuclear receptors of the RZR/ROR family, is increasing. It has been hypothesized that exogenous restoration of MT1 (MTNR1A) expression inhibits the growth of oral squamous cell carcinoma cells lacking the expression of the receptor. The tumor suppressing functions of MLT and the presence of the MT1 receptor in various tumors indicate that the receptor may play a pivotal role in oral carcinogenesis. The current review discusses the clinical significance of MLT in oral cancer.

The bacteremia of dental origin and its implications in the appearance of bacterial endocarditis

Numerous systemic diseases may affect the oral cavity and vice versa, in particular severe diseases that involve the heart valve. In these cases, additional measures or a modification to our dental treatment need to be taken. We are aware of various diseases that can cause the emergence of bacterial endocarditis (BE), such as; rheumatic fever, valve lesions due to intravenous drug use, Kawasaki disease and valve surgery, among others. Due to its severity when it is not taken into account in dental treatment, we intend to show the evolution of the antimicrobial prophylaxis towards this condition. Furthermore, we intend to publish the current guidelines of institutions and societies which increasingly encourage rational antimicrobial use. In addition, we intend to examine the evidence of the possible origins of this disease during dental treatment and at the same time describe the necessary considerations that need to be taken during dental treatment

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The bacteremia of dental origin and its implications in the appearance of bacterial endocarditis.

Numerous systemic diseases may affect the oral cavity and vice versa,in particular severe diseases that involve the heart valve. In these cases, additional measures or a modification to our dental treatment need to be taken. We are aware of various diseases that can cause the emergence of bacterial endocarditis (BE), such as; rheumatic fever, valve lesions due to intravenous drug use, Kawasaki disease and valve surgery, among others. Due to its severity when it is not taken into account in dental treatment, we intend to show the evolution of the antimicrobial prophylaxis towards this condition. Furthermore, we intend to publish the current guidelines of institutions and societies which increasingly encourage rational antimicrobial use. In addition, we intend to examine the evidence of the possible origins of this disease during dental treatment and at the same time describe the necessary considerations that need to be taken during dental treatment.

Effect of topical application of melatonin to the gingiva on salivary osteoprotegerin, RANKL and melatonin levels in patients with diabetes and periodontal disease.

This cross-section study was designed to assess the effect of topical application of melatonin to the gingiva on salivary RANKL, osteoprotegrin (OPG) and melatonin levels as well as plasma melatonin in 30 patients with diabetes and periodontal disease and in a control group of 30 healthy subjects. Salivary RANKL and OPG were measured by enzyme-linked immunosorbent assay and salivary and plasma melatonin by radioimmunoassay using commercial kits. Periodontograms were performed using the Florida Probe(®). Diabetic patients were treated with topical application of melatonin (1% orabase cream formula) once daily for 20 days. Patients with diabetes showed significantly higher mean levels of salivary RANKL than healthy subjects as well as significantly lower values of salivary OPG and salivary and plasma melatonin. After treatment with melatonin, there was a statistically significant decrease of the gingival index, pocket depth and salivary levels of RANKL, and a significant rise in salivary values of OPG. Changes of salivary OPG levels before and after topical melatonin treatment correlated significantly with changes in the gingival index and pocket depth. Treatment with topical melatonin was associated with an improvement in the gingival index and pocket depth, a reduction in salivary concentrations of RANKL and increase in salivary concentrations of OPG, which indicates that melatonin has a favorable effect in slowing osteoclastogenesis, improving the quality of alveolar bone and preventing the progression of periodontal disease.

Effect of gingival application of melatonin on alkaline and acid phosphatase, osteopontin and osteocalcin in patients with diabetes and periodontal disease

Objectives: To assess the effect of topical application of melatonin to the gingiva on salivary fluid concentrations of acid phosphatase, alkaline phosphatase, osteopontin, and osteocalcin. Study Design: Cross-sectional study of 30 patients with diabetes and periodontal disease and 30 healthy subjects. Diabetic patients were treated with topical application of melatonin (1% orabase cream formula) once daily for 20 days and controls with a placebo formulation. Results: Before treatment with melatonin, diabetic patients showed significantly higher mean salivary levels of alkaline and acid phosphatase, osteopontin and osteocalcin than healthy subjects (P < 0.01). After treatment with melatonin, there was a statistically significant decrease of the gingival index (15.84± 10.3 vs 5.6 ± 5.1) and pocket depth (28.3 ± 19.5 vs 11.9 ± 9.0) (P < 0.001). Also, use of melatonin was associated with a significant reduction of the four biomarkers. Changes of salivary acid phosphatase and osteopontin correlated significantly with changes in the gingival index, whereas changes of alkaline phosphatase and osteopontin correlated significantly with changes in the pocket depth. Conclusions: Treatment with topical melatonin was associated with an improvement in the gingival index and pocket depth, a reduction in salivary concentrations of acid phosphatase, alkaline phosphatase, osteopontin and osteocalcin (AU)

Effect of gingival application of melatonin on alkaline and acid phosphatase, osteopontin and osteocalcin in patients with diabetes and periodontal disease.

OBJECTIVES: To assess the effect of topical application of melatonin to the gingiva on salivary fluid concentrations of acid phosphatase, alkaline phosphatase, osteopontin, and osteocalcin. STUDY DESIGN: Cross-sectional study of 30 patients with diabetes and periodontal disease and 30 healthy subjects. Diabetic patients were treated with topical application of melatonin (1% orabase cream formula) once daily for 20 days and controls with a placebo formulation. RESULTS: Before treatment with melatonin, diabetic patients showed significantly higher mean salivary levels of alkaline and acid phosphatase, osteopontin and osteocalcin than healthy subjects (P < 0.01). After treatment with melatonin, there was a statistically significant decrease of the gingival index (15.84 ± 10.3 vs 5.6 ± 5.1) and pocket depth (28.3 ± 19.5 vs 11.9 ± 9.0) (P < 0.001). Also, use of melatonin was associated with a significant reduction of the four biomarkers. Changes of salivary acid phosphatase and osteopontin correlated significantly with changes in the gingival index, whereas changes of alkaline phosphatase and osteopontin correlated significantly with changes in the pocket depth. CONCLUSIONS: Treatment with topical melatonin was associated with an improvement in the gingival index and pocket depth, a reduction in salivary concentrations of acid phosphatase, alkaline phosphatase, osteopontin and osteocalcin.

MTNR1A receptor expression in normal and pathological human salivary glands.

AIM: To analyze and compare the expression of MTNR1A receptor in normal and pathological major and minor salivary glands. MATERIALS AND METHODS: Twenty samples of major and minor salivary glands and 10 with Warthin's tumor were studied. Expression of the MTNR1A receptor (goat polyclonal antibody raised against a peptide mapping at the N-terminus of MEL-1A R of human origin) was analyzed. RESULTS: The excretory ducts of major salivary glands demonstrated intense intracytoplasmic positivity but scant cytoplasmic membrane positivity for MTNR1A. The studied Warthin's tumors showed intense cytoplasmic positivity for MT1 receptor in all cylindrical epithelial cells lining spaces and a less intense positivity in basal cells. The lymphoid component accompanying the tumor was negative for MT1 receptor. CONCLUSION: Intense intracytoplasmic positivity for the MTNR1A receptor in the excretory ducts of human major and minor salivary glands and Warthin's tumor was found. The intense expression of MTNR1A receptors observed in this study in the excretory ducts of major and minor salivary glands may be related to salivary regulation.

Role of melatonin in cancer treatment.

Melatonin has revealed itself to be a pleiotropic and multitasking molecule. The mechanisms that control its synthesis and the biological clock processes that modulate the circadian production of melatonin in the pineal gland have been well-characterized. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. Research has implicated the pineal gland and melatonin in the processes of both aging and age-related diseases. The decline in the production of melatonin with age is thought to contribute to immunosenescence and potential development of neoplastic diseases. Melatonin has been shown to inhibit growth of different tumors under both in vitro and in vivo conditions. There is evidence that the administration of melatonin alone or in combination with interleukin-2 in conjunction with chemoradiotherapy and/or supportive care in cancer patients with advanced solid tumors, has been associated with improved outcomes of tumor regression and survival. Moreover, chemotherapy has been shown to be better tolerated in patients treated with melatonin.

Topical application of melatonin and growth hormone accelerates bone healing around dental implants in dogs.

BACKGROUND: Growth hormone (GH) and melatonin belong to the group of growth factors. These substances have been proposed to improve and accelerate osseous healing using topical applications. PURPOSE: The aim of this study was to evaluate the effect of the topical administration of GH and melatonin on osseointegration of dental implants in Beagle dogs 2, 5, and 8 weeks after their insertion. MATERIALS AND METHODS: Twelve adult Beagle dogs and 48 implants were used in the study. The maxillary and mandibular premolars and molars were extracted. Each mandible received cylindrical screw implants of 3.25 mm in diameter and 10 mm in length. Prior to implanting, 4 IU of recombinant human GH and 1.2 mg of lyophilized powdered melatonin was applied to one osteotomy at each side of the mandible. None was applied at the control sites. The implants were retrieved at 2, 5, and 8 weeks for light microscopic examination, energy-dispersive x-ray microanalysis, and histomorphometric measurements in ground sections. RESULTS: At week 2, BIC was significantly higher in the melatonin-growth hormone group than in the implant control one (34.20 vs 25.05%; p = .010). The M-GH group also increased significantly the peri-implant bone area (64.72 vs 53.20%; p = .038) and interthread bone area (35.62 vs 25.08%; p = .02). At weeks 5 and 8, BIC and bone density around implants were similar to both groups. Significant differences were detected in bone neoformation at 8 weeks in ML-GH group (9.04 vs 7.53%; p = .05). Regarding the mineral composition, in ML-GH group increments in concentrations of phosphorus (10.70 vs 10.34; p = .013) were observed at 2 weeks and of magnesium (0.29 vs 0.25; p = .019) 5 weeks after implantation. CONCLUSION: The present study confirms that GH and melatonin synergistically enhance new bone formation around titanium implants in early stages of healing.

A new perspective in Oral health: potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity.

BACKGROUND: Melatonin is involved in many physiological processes in mammals, amongst others; it is implicated in sleep-wake regulation. It has antioxidant and anti-inflammatory properties. It also acts as an immunomodulator, stimulates bone metabolism and inhibits various tumours. Additionally an abnormal melatonin rhythm may contribute to depression and insomnia. The mechanisms of action of melatonin include the involvement of membrane receptors (MT1, MT2), cytosolic binding sites (MT3 and calmodulin), and nuclear receptors of the RZR/ROR family. Melatonin also has receptor-independent activity and can directly scavenge free radicals. The current review addresses the functions of melatonin in the oral cavity in relation to its receptors. METHODS: An extensive search was conducted on the following scientific databases Pub Med, Science Direct, ISI Web of Knowledge and Cochrane database in order to review all pertinent literature. RESULTS: Melatonin from the blood into the saliva may play an important role in suppressing oral diseases. It may have beneficial effects in periodontal disease, herpes and oral cancer, amongst others. CONCLUSIONS: Melatonin contributes to protecting of oral cavity from tissue damage due to its action of different receptors. From the reviewed literature it is concluded that experimental evidence suggests that melatonin can be useful in treating several common diseases of the oral cavity. Specific studies are necessary to extend the therapeutic possibilities of melatonin to other oral diseases.

Melatonin and cancer: current knowledge and its application to oral cavity tumours.

BACKGROUND: Melatonin (MLT) is a molecule secreted by the pineal gland in cyclical periods. In mammals, MLT is involved in physiological processes, such as sleep/wake regulation in the circadian cycle. It has antioxidant and anti-inflammatory properties, functions as an immunomodulator, and stimulates bone metabolism. MLT is also involved in tumour processes in breast, prostate, liver, and bone cancers, among others, and in oral cavity tumours like epidermoid carcinoma. We are gradually increasing our knowledge of the underlying mechanism of MLT action in the aforementioned tumour processes, in which MT1, MT2, MT3, and RZR receptors appear to play a highly important role. These receptors belong to a large family of G-protein-coupled transmembrane receptors, some of which have been linked to melatonin's anticancer action, to tumour growth, and to prognosis. The objective of this article is to provide a clear review of research into the range of MLT functions, focusing specifically on MT receptors. We aim to contribute interesting, new approaches to research into oral cavity tumours. METHODS: An extensive review of the research literature was conducted using PubMed, Science Direct, ISI Web of Knowledge, and the Cochrane base. RESULTS: This study highlights the growing importance of MLT in the prognosis and treatment of certain tumours, including epidermoid carcinoma in the oral cavity. Moreover, it opens up a highly original, encouraging line of research in the field of tumours. CONCLUSIONS: MLT contributes to protecting the oral cavity from tissue damage caused by receptor action. Experimental evidence suggests that it may be useful in the treatment and prognosis of tumour processes in the oral cavity.

Evaluation of effects of topic melatonin on implant surface at 5 and 8 weeks in Beagle dogs.

PURPOSE: The aim of this study was to evaluate the effect of the topical application of melatonin on osteointegration of dental implants in Beagle dogs 5 and 8 weeks after their insertion. MATERIALS AND METHODS: For subsequent insertion of dental implants, upper and lower premolars and molars were extracted from 12 Beagle dogs. Each mandible received cylindrical screw implants of 3.25 mm in diameter and 10 mm in length. The implants were randomly assigned to the mesial and distal sites on each side of the mandible. Prior to implanting, 1.2 mg lyophylized powder melatonin was applied to one bone hole at each side of the mandible. None was applied at the control sites. Eight histological sections per implant were obtained for histomorphometric studies. RESULTS: After 5- and 8-week treatment periods, melatonin significantly increased the inter-thread bone (p < 0.05) and new bone formation (p < 0.05) in comparison to control implants in both weeks. There were no significant increases in the bone-to-implant contact and peri-implant bone (p > 0.05). CONCLUSION: Topical application of melatonin may act as a biomimetic agent in the placement of endo-osseous dental implants at 5 and 8 weeks after the implantation.

Melatonin plus porcine bone on discrete calcium deposit implant surface stimulates osteointegration in dental implants.

The aim of this study was to evaluate the effect of the topical application of melatonin mixed with collagenized porcine bone to accelerate the osteointegration on the rough discrete calcium deposit (DCD) surface implants in Beagle dogs 3 months after their insertion. In preparation for subsequent insertion of dental implants, lower premolars and molars were extracted from 12 Beagle dogs. Each mandible received three parallel wall implants with discrete calcium deposit (DCD) surface of 4 mm in diameter and 10 mm in length. The implants were randomly assigned to the distal sites on each side of the mandible in three groups: group I implants alone, group II implants with melatonin and group III implants with melatonin and porcine bone. Prior to implanting, 5 mg lyophylized powdered melatonin was applied to one bone hole at each side of the mandible. None was applied at the control sites. Ten histological sections per implant were obtained for histomorphometric studies. After a 4-wk treatment period, melatonin significantly increased the perimeter of bone that was in direct contact with the treated implants (P < 0.0001), bone density (P < 0.0001), new bone formation (P < 0.0001) in comparison with control implants. Topical application of melatonin on DCD surface may act as a biomimetic agent in the placement of endo-osseous dental implants and enhance the osteointegration. Melatonin combined with porcine bone on DCD implants reveals more bone to implant contact at 12 wk (84.5 +/- 1.5%) compared with melatonin treated (75.1 +/- 1.4%) and nonmelatonin treated surface implants (64 +/- 1.4%).

Pharmacological interactions of anti-microbial agents in odontology

In this third article we describe the pharmacological interactions resulting from the use of anti-microbial agents. Although the antimicrobials prescribed in odontology are generally safe they can produce interactions with other medicaments which can give rise to serious adverse reactions which are well documented in clinical studies. Antibiotics with grave and dangerous life threatening consequences are erythromycin, clarithromycin and metronidazol and the anti-fungal agents are ketoconazol and itraconazol. Regarding the capacity of the anti-microbials to reduce the efficacy of oral anti-contraceptives the clinical studies to date are inconclusive, however, it would be prudent for the oral cavity specialist to point out the risk of a possible interaction. Therefore the specialist should be aware of possible interactions as a consequence of administering an antibiotic together with other medicaments the patient may be taking (AU)

Pharmacological interactions of anti-microbial agents in odontology.

In this third article we describe the pharmacological interactions resulting from the use of anti-microbial agents. Although the antimicrobials prescribed in odontology are generally safe they can produce interactions with other medicaments which can give rise to serious adverse reactions which are well documented in clinical studies. Antibiotics with grave and dangerous life threatening consequences are erythromycin, clarithromycin and metronidazol and the anti-fungal agents are ketoconazol and itraconazol. Regarding the capacity of the anti-microbials to reduce the efficacy of oral anti-contraceptives the clinical studies to date are inconclusive, however, it would be prudent for the oral cavity specialist to point out the risk of a possible interaction. Therefore the specialist should be aware of possible interactions as a consequence of administering an antibiotic together with other medicaments the patient may be taking.

Pharmacological interactions of anti-inflammatory-analgesics in odontology

In this second article we describe the more interesting pharmacological interactions in dental practice basedon the prescription of analgesic narcotics, paracetamol and non-selective non-steroid anti-inflammatory drugs(NSAI) (which inhibit cyclooxigenase 1 –COX 1- and cyclooxigenase 2 –COX 2-) and selective NSAIs (COX 2inhibitors). The importance of preventing the appearance of these pharmacological interactions is because theseare medicaments prescribed daily in odontology for moderate pain treatment and inflammation in the oral cavity.Paracetamol can interact with warfarin and therefore care should be taken with chronic alcoholic patients. All NSAIsreduce renal blood flow and consequently are capable of reducing the efficacy of medicaments used for treatingarterial hypertension, which act via a renal mechanism. Especial attention should be taken considering the risk ofinteraction between the antagonists of AT1 receptors of angiostensin II (ARAII) and the NSAIs (AU)

Pharmacological interactions of anti-inflammatory-analgesics in odontology.

In this second article we describe the more interesting pharmacological interactions in dental practice based on the prescription of analgesic narcotics, paracetamol and non-selective non-steroid anti-inflammatory drugs (NSAI) (which inhibit cyclooxigenase 1 -COX 1- and cyclooxigenase 2 -COX 2-) and selective NSAIs (COX 2 inhibitors). The importance of preventing the appearance of these pharmacological interactions is because these are medicaments prescribed daily in odontology for moderate pain treatment and inflammation in the oral cavity. Paracetamol can interact with warfarin and therefore care should be taken with chronic alcoholic patients. All NSAIs reduce renal blood flow and consequently are capable of reducing the efficacy of medicaments used for treating arterial hypertension, which act via a renal mechanism. Especial attention should be taken considering the risk of interaction between the antagonists of AT1 receptors of angiostensin II (ARAII) and the NSAIs.

Pharmacological interactions of vasoconstrictors

This article is the first of a series on pharmacological interactions involving medicaments commonly prescribed and/or usedin odontology: vasoconstrictors in local anaesthetics and anti-inflammatory and anti-microbial analgesics. The necessityfor the odontologist to be aware of adverse reactions as a result of the pharmacological interactions is due to the increasein medicament consumption by the general population. There is a demographic change with greater life expectancy andpatients have increased chronic health problems and therefore have increased medicament intake. The presence of adrenaline(epinephrine) and other vasoconstrictors in local odontological anaesthetics is beneficial in relation to the durationand depth of anaesthesia and reduces bleeding and systemic toxicity of the local anaesthetic. However, it might producepharmacological interactions between the injected vasoconstrictors and the local anaesthetic and adrenergic medicamentadministered exogenically which the odontologist should be aware of, especially because of the risk of consequent adversereactions. Therefore the importance of conducting a detailed clinical history of the general state of health and include allmedicaments, legal as well as illegal, taken by the patient (AU)