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.

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 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.

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.

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%).

The effects of growth hormone on the initial bone formation around implants.

PURPOSE: The aim of this study was to evaluate the effect of the topical application of growth hormone on the osseointegration of dental implants in beagle dogs 14 days after placement. MATERIALS AND METHODS: Maxillary and mandibular premolars and molars were extracted from 12 beagle dogs. Two months later, each mandible received cylindric screw-type 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 implantation, lyophilized powdered growth hormone was applied to one osteotomy on each side of the mandible. No growth hormone was applied at the control sites. Eight histologic sections per implant were obtained for histomorphometric analysis. RESULTS: After a 2-week treatment period, the growth hormone-treated sites showed significant (P < .0001) increases in the perimeter of bone that was in direct contact with the treated implants (40.19% +/- 2.51%), total peri-implant area (P < .001) (69.57% +/- 3.53%), and new bone formation (P < .0001) (35.18% +/- 0.31%), in comparison to control implants (25.05% +/- 2.43%, 53.40% +/- 4.58%, and 28.65% +/- 1.92%, respectively). There was no significant increase in interthread bone in growth hormone-treated implants (27.92% +/- 3.31%) in comparison to control implants (25.08% +/- 3.47%) (P > .05). CONCLUSION: Topical application of growth hormone may act as a bone stimulant in the placement of endosseous dental implants.

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 used in odontology: vasoconstrictors in local anaesthetics and anti-inflammatory and anti-microbial analgesics. The necessity for the odontologist to be aware of adverse reactions as a result of the pharmacological interactions is due to the increase in medicament consumption by the general population. There is a demographic change with greater life expectancy and patients 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 duration and depth of anaesthesia and reduces bleeding and systemic toxicity of the local anaesthetic. However, it might produce pharmacological interactions between the injected vasoconstrictors and the local anaesthetic and adrenergic medicament administered exogenically which the odontologist should be aware of, especially because of the risk of consequent adverse reactions. Therefore the importance of conducting a detailed clinical history of the general state of health and include all medicaments, legal as well as illegal, taken by the patient.

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.

Melatonin stimulates osteointegration of dental implants.

The aim of this study was to evaluate the effect of the topical application of melatonin on osteointegration of dental implants in Beagle dogs 14 days after their insertion. In preparation 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 powdered 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. After a 2-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) and inter-thread bone (P < 0.05) in comparison with control implants. Topical application of melatonin may act as a biomimetic agent in the placement of endo-osseous dental implants.

Interaction of paracetamol in chronic alcoholic patients. Importance for odontologists.

For social, cultural and historical motives alcohol (ethanol or isopenthanol) is considered to be just a beverage rather than a liquor. However, from a pharmatherapeutic point of view alcohol is a depressor of the central nervous system. The effects of alcohol consumption can range from raised loquacity to drunkenness, loss of consciousness and death as a result of insufficient respiration. Probably the most frequent pharmacological interaction is the combination of alcohol with other depressors of the central nervous system which increases the depression even further. Some medicaments which more frequently produce an interaction are antihistamines, analgesics, antidepressants and medicaments for coughs, common cold and influenza. Paracetamol or acetaminophen is an analgesic medicament similar to acetylsalicylic acid lacking anticoagulatory properties and gastric irritation. However, its major drawback is hepatic toxicity as a result of a toxic metabolite produced in the liver by cytochrome P-450, principally cytochrome CYP2E1, which is detoxified under normal conditions by hepatic glutathione. Ethanol is also detoxified by CYP2E1, which is an inducer of ethanol such that chronic ingestion increases the level of this enzyme. When the ingestion of alcohol is stopped, CYP2E1 is greatly increased and only metabolises the paracetamol giving rise to high quantities of hepatotoxic metabolites so that the hepatic glutathione is unable to detoxify resulting in irreversible hepatic damage. Therefore for odontologists it is important that in chronic alcoholic patients the consumption of alcohol should not be suspended on prescribing paracetamol.

Melatonin: potential functions in the oral cavity.

BACKGROUND: Melatonin is synthesized and secreted by the pineal gland and other organs. The pattern of melatonin secretion is controlled by an endogenous circadian timing system and conveys information about the light-dark cycle to the organism, thereby organizing its seasonal and circadian rhythms. Melatonin has powerful antioxidant effects, functions in an immunomodulatory role, may protect against certain cancers, delays some age-related processes, stimulates the synthesis of type I collagen fibers, and promotes bone formation. METHODS: An extensive review was made (e.g., using PubMed, Science Direct, and Web of Knowledge) of the literature. RESULTS: Melatonin, which is released into the saliva, may have important implications for dental disorders, especially in periodontal disease. Diseases of the periodontium are known to be aggravated by free radicals and by alterations in the immune response to microorganisms that are present in plaque. In response to periodontal inflammation, the blood and salivary levels of melatonin may increase. CONCLUSION: Melatonin may play a role in protecting the oral cavity from tissue damage that is due to oxidative stress, and it may contribute to the regeneration of alveolar bone through the stimulation of type I collagen fiber production and the modulation of osteoblastic and osteoclastic activity.

Local application of melatonin into alveolar sockets of beagle dogs reduces tooth removal-induced oxidative stress.

BACKGROUND: The antioxidant and anti-inflammatory hormone melatonin is secreted by saliva into the oral cavity, where it may protect the mucosal and gingival tissues from radical damage. To date, no studies have addressed the potential beneficial role of melatonin in the acute inflammatory response that follows oral surgical interventions, especially tooth extractions. The aim of this study was to determine whether tooth extraction induces changes in plasma oxidative stress levels, and whether melatonin treatment may counteract these changes. METHODS: Maxillary and mandibular premolars and molars of 16 adult Beagle dogs were extracted under general anesthesia. Eight dogs were treated with 2 mg melatonin placed into the alveolar sockets, whereas the other eight dogs received only vehicle. Lipid peroxidation (LPO) and nitrite plus nitrate (NOx) levels were determined in plasma, whereas glutathione (GSH) and glutathione disulfide (GSSG) levels and glutathione peroxidase (GPx) and reductase (GRd) activities were measured in red blood cells before and 24 hours after tooth extraction. RESULTS: Removal of the premolars and molars caused a significant rise in plasma LPO and NOx levels and in the erythrocyte GSSG/GSH ratio, whereas melatonin treatment restored the normal values of these parameters. Also, melatonin slightly increased erythrocyte GRd activity without changing GPx activity. CONCLUSION: For the first time to our knowledge, the results show that during the immediate postoperative period following tooth extraction, there is a significant increase of oxidative stress, which is counteracted by the administration of melatonin into the alveolar sockets.

Relationship between salivary melatonin and severity of periodontal disease.

BACKGROUND: Melatonin possesses antioxidant, free-radical scavenging, and immunoenhancing properties that promote fibroblast activity and bone regeneration. The aim of this study was to examine the possible links between salivary melatonin levels and the severity of periodontal disease using the community periodontal index (CPI). METHODS: Thirty-seven patients with different degrees of periodontal disease were studied. Salivary and plasma melatonin levels (by radioimmunoassay), salivary/plasma melatonin ratio, and CPI status were collected for each patient. The Spearman correlation coefficient was used to analyze relationships among variables. RESULTS: Data showed a significant correlation between CPI and salivary/plasma melatonin ratios. When saliva volume was controlled for, a significant correlation (P<0.05) was found between lower salivary melatonin and a worse CPI. This finding suggests that melatonin may act as a protector against free radicals produced by inflammatory periodontal diseases. CONCLUSIONS: Salivary melatonin levels varied according to the degree of periodontal disease. As the degree of periodontal disease increased, the salivary melatonin level decreased, indicating that melatonin may act to protect the body from external bacterial insults. Therefore, melatonin may be potentially valuable in the treatment of periodontal diseases, although further research is required to validate this hypothesis.

Migration of implants into the maxillary sinus: two clinical cases.

Invasion of the maxillary sinus is a relatively frequent complication in dental implant treatment of patients with inadequate bone height in the posterior maxilla. This event usually occurs during surgery and sometimes produces sinusitis. There is a paucity of reports in the literature of implants migrating into the sinus cavity after a period of function. In the 2 clinical cases presented, an intraosseous apical movement of the implants was produced several years after placement of the implants. Hypotheses and possible mechanisms by which an implant may migrate into the maxillary sinus are described.

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.

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.

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.

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.