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Mig az ev nagy reszeben a kozos etkezesek a rohano mindennapok miatt gyakran hatterbe szorulnak, karacsonykor egyutt lakmarozik a csalad. Elokerulnek a regi receptek, a feltve orzott etkeszletek vagy dekoracios elemek, amelyek tovabb emelik az unnep fenyet, es kedves emlekeket is felideznek. 

Bar a hangulat es a meghittseg leginkabb az asztal korul ulokon mulik, ilyenkor sokan kulonos gondot forditanak a teritekre is. Az egyedi reszletek, apro kedvessegek meg varazslatosabba teszik az unnepi vacsorat. 

Az asztal feldiszitesekor nem kell komolyabb dolgokra gondolni: a haztartasban vagy a termeszetben megtalalhato elemekbol egy kis kreativitassal bubajos dekoracio keszitheto, ami garantaltan mosolyt csal a csaladtagok es a vendegek arcara. Olyan otleteket mutatunk, amiket barki konnyuszerrel megvalosithat. 

(Boritokep forrasa: Getty Images Hungary. Ajanlokep forrasa: Pinterest.)

Purpose: Among other corneal biomechanical properties, Goldmann applanation tonometry (GAT) has been shown to depend on corneal edema. New tonometry devices have been designed, such as the Tono-Pen XL, iCare, and ocular response analyzer (ORA), to measure the intraocular pressure (IOP) accurately. This study aims to investigate the influence of corneal edema on the accuracy of these IOP-measuring devices in an in vitro model.

Methods: A model of an artificial anterior chamber was developed using a guided trephination system. Eight donor corneas not suitable for keratoplasty were clamped into this artificial anterior chamber. All corneas showed signs of stromal edema. Intracameral pressure (ICP) was adjusted manometrically to 10, 20, 30, 40, and 50 mm Hg. The central corneal thickness (CCT) was determined by ultrasonic pachymetry. For each manometrically defined ICP, tonometry was performed using the iCare, Tono-Pen XL, GAT, and ORA.

Results: The mean CCT increased from 616.1±29.6 µm to 626.9±36.1 µm. At 10 mm Hg, GAT yielded a higher ICP than those manometrically adjusted (10.4±3.3 mm Hg); at all other ICP levels, GAT yielded lower ICP levels than those adjusted. The Tono-Pen XL and iCare showed the greatest difference at 10 mm Hg, with the Tono-Pen XL yielding a value of 14.0±4.0 mm Hg and the iCare yielding a value of 12.5±2.6 mm Hg. All other results of the 2 devices fell within a range of ±2 mm Hg from the adjusted ICP. The ORA provided accurate results only at "physiological" ICP levels with a maximum difference of 2.6 mm Hg at 30 mm Hg. At higher ICP levels, corneal hysteresis decreased significantly with increasing ICP. None of the measurement devices revealed a statistically relevant dependence on CCT in this experimental setting.

Conclusions: The Tono-Pen XL and the iCare yielded the most accurate ICP values across all the adjusted ICP values. This may be because of their relatively small contact area with the cornea and, consequently, greater independence from corneal biomechanical properties. The ORA yielded accurate measurement results only at physiological ICP levels. As anticipated, GAT underestimated ICP. The Tono-Pen XL and the iCare should therefore be used to determine IOP in patients suffering from corneal edema, such as bullous keratopathy or Fuchs endothelial dystrophy.

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Background: To prevent irreversible vision loss in age-related macular degeneration (AMD), it is critical to detect retinal dysfunction before permanent structural loss occurs. In the current study we evaluated a series of visual function tests to identify potential endpoints to detect visual dysfunction in non-advanced AMD.

Methods: A series of visual function tests were performed on 23 non-advanced AMD subjects (AREDS grade 1-4 on simplified scale) and 34 age-matched normals (AREDS grade 0). Tests included some commonly used endpoints such as ETDRS visual acuity (VA), low luminance (LL) 2.0ND ETDRS VA, MNREAD as well as newly developed tests such as the Ora-VCF™ test, Ora-tablet reading test, color sensitivity etc. Differences between the two groups were compared for each test. Test-retest repeatability and reproducibility was assessed on a subset of subjects and percent agreement was calculated.

Results: There was no difference in standard ETDRS VA between non-advanced AMD (0.06 ± 0.02 logMAR) and normal groups (0.04 ± 0.02 logMAR) (p = 0.57). LL 2.0 ETDRS VA and MNREAD showed no difference between the groups (p > 0.05). Ora-VCF™ test was significantly worse in the non-advanced AMD group compared to normals (0.67 ± 0.07 in AMD; 0.45 ± 0.04 in normals, p = 0.005). Non-advanced AMD subjects also had significantly worse reading performance using the Ora-tablet with LL 2.0ND (114.55 ± 11.22 wpm in AMD; 145.17 ± 9.55 wpm in normals p = 0.049). No significant difference between the groups was noted using other tests. Repeatability was 82% for Ora-VCF™ test and 92% for Ora-tablet LL 2.0ND reading. Reproducibility was 89% for both Ora-VCF™ test and Ora-tablet LL 2.0ND reading.

Conclusion: While there was no significant difference between non-advanced AMD and normal groups using some current common endpoints such as ETDRS VA, LL 2.0 ETDRS VA or MNREAD, Ora-VCF™ test and Ora-tablet LL 2.0ND reading tests were able to identify significant visual dysfunction in non-advanced AMD subjects. These tests show promise as endpoints for AMD studies.

This study found only moderate agreement between GAT performed by nurses working in a virtual glaucoma clinic and ophthalmologists, with 95% LoA of ±5.21 mmHg. In other words, 95% of IOP measurements obtained by nurses were within ~5 mmHg of those obtained by an ophthalmologist but 5% differed by a greater margin. Differences of this magnitude are likely to have important clinical implications as management decisions are often influenced by IOP. Furthermore, there was no evidence of proportional bias, meaning a difference of ±5.21 mmHg was present across the range of IOP values.

When IOP is measured in a virtual clinic there is no direct mechanism for the ophthalmologist to verify accuracy of the measurement and therefore it is especially concerning that such disagreement in repeat measures may exist. Although it is not possible to determine whether measurements obtained by nurses or ophthalmologists were more accurate, on average IOP measured by ophthalmologists had slightly better agreement with IOPg with 95% LoA of ±4.93 mmHg compared with ±5.20 mmHg for IOP measured by nurses. This indicates only moderate agreement between repeat GAT and between IOPg and GAT performed by ophthalmologists or nurses. In contrast, there was good agreement between repeat ORA measurements with 95% LoA for IOPg of ±2.52 mmHg. IOPg also had a higher ICC than GAT measuring 0.972 and 0.863, respectively. Repeatability is an important characteristic of a good clinical measure and the results of this study suggest IOPg is more consistent across repeat measures compared with GAT performed by different operators in a normal clinical setting.

Our ±5.21 mmHg LoA between GAT performed by ophthalmologists and nurses is higher than the ±3.7 mmHg observed by Kotecha et al., who also compared nurse/technician and ophthalmologist GAT measurements in glaucoma clinics [25]. Kotecha et al. utilised 100 eyes for this comparison, providing a comparable sample size to ours and a sample size of 100 is considered good for measuring agreement with Bland–Altman plots [26]. An important difference between the studies, however, is that Kotecha et al. used a two-person technique when measuring GAT, which is not typical of normal clinical practice [27]. Furthermore, IOPg still achieved a better LoA than the results of Kotecha et al.’s study.

Our ±4.93 mmHg 95% LoA between IOPg and ophthalmologist GAT measurements fell within the range of ±4.55 to ±11.54 mmHg reported in previous studies [13, 19,20,21,22,23]. It is difficult to explain this large range of LoA in the literature, however, it may be partly due to researchers using different settings on the ORA, such as the averaging mechanism and perhaps reflects variability in GAT rather than IOPg. Our finding of an IOPg ICC of 0.972 was very similar to the ICC of 0.95 found in a previous study by Tejwani et al. [13]. Our GAT ICC of 0.863 was also consistent with previous studies reporting interobserver GAT ICC to range from 0.81 to 0.97 [7,8,9,10,11,12,13].

To interpret the relevance of the 95% LoA, it is crucial to consider what difference in IOP is clinically relevant. The Early Manifest Glaucoma Trial found a 10% reduction in risk of progression for each mmHg lower IOP [28]. Likewise, the OHT Study revealed a 10% increase risk in developing primary angle glaucoma for each mmHg higher IOP [29]. Our finding of ±5.21 mmHg 95% LoA between ophthalmologist and nurse GAT measurements is thus potentially concerning. While 95% agreement limits between IOPg and GAT IOP were better, they still only reached ±4.93 mmHg.

In contrast, agreement between repeat ORA IOPg measurements was good, with a 95% LoA of ±2.52 mmHg. In addition to providing relatively reproducible results, ORA has other potential advantages for use in the virtual clinic environment. Foremost, there is evidence that ORA IOPcc measurements are less affected by corneal properties than GAT [30]. The recent United Kingdom Glaucoma Treatment Study (ISRCTN96423140), a randomised double masked placebo-controlled study, in which newly diagnosed patients with primary open angle glaucoma were randomised to receive a topical prostaglandin analogue or placebo, found IOPcc was the best IOP predictor of VF deterioration [31]. IOPcc performed better than GAT or IOP measured using the Pascal Dynamic Contour Tonometer. In addition, ORA is non-contact, reducing the risk of infection present with GAT, and requires no local anaesthetic drops. It can also be performed after a relatively short period of training: the technicians performing ORA measurements in this study required training for one morning. Lastly, the ORA quality score provides an objective measure of quality that could be recorded in the virtual clinic chart.

Although our primary comparison outcomes were the 95% LoA, isolated differences in measurements falling outside the 95% LoA seen in the Bland–Altman plots are also important to consider as they could have significant clinical implications. For example, the greatest disagreement in GAT IOP measurements between nurses and ophthalmologists was in a patient in whom the nurse measured an IOP of 18 mmHg and the ophthalmologist an IOP of 30 mmHg. The ORA IOPg was 25.9 mmHg and the IOPcc was 27.8 mmHg. Missing an IOP of 30 mmHg could have had significant implications for management decisions for this patient. Furthermore, the greatest difference in IOP measurements between ORA IOPg and ophthalmologists using GAT was 7.5 mmHg in a patient in whom the ophthalmologist obtained an IOP of 14 mmHg, whilst the IOPg reading was only 6.5 mmHg and the IOPcc only 8.2 mmHg (wave score = 7.3). The repeat ORA measurements in this patient were also similarly low (IOPg 6.7 mmHg and IOPcc 8.8 mmHg, wave score = 8.5). The nurse obtained an IOP of 20 mmHg. These differences may relate to true IOP fluctuations or measurement error and highlight limitations of relying on isolated measurements.

There were a number of limitations in this study. First, we did not examine the repeatability of the ophthalmologist or nurse GAT measurements independently but considered GAT performed by nurses and ophthalmologists as repeat measures for calculation of the ICC. We were therefore not able to determine whether nurses or ophthalmologists obtained more reproducible measures. Furthermore, we did not use a two-person masked technique when measuring GAT. However, this meant that the study was more of a reflection of real clinical practice. Finally, we did not collect information on the type of glaucoma or stage of disease, which may have been useful to investigate as confounding factors in agreement between devices.

In summary, a key requirement of clinical measures in virtual clinics is that they are repeatable to provide the remote ophthalmologist with reliable data. This study has shown that under normal clinical conditions measurements from GAT only have moderate agreement when performed by different operators. In contrast, repeat ORA IOPg measurements were more consistent, suggesting, along with its other advantages, that the ORA IOPg may be a more reliable tool for IOP assessment in virtual clinics. For eyes with extremes of corneal thickness on the other hand, ORA IOPcc appears to remain a more appropriate alternative as it was not statistically affected by CCT, whereas both ORA IOPg and nurse GAT measurements increased statistically with corneal thickness.

Purpose: To characterize the preoperative vectorial difference between manifest refractive astigmatism and anterior corneal astigmatism, termed ocular residual astigmatism (ORA), and to investigate its influence on topography-guided laser in situ keratomileusis (LASIK) outcomes.

Methods: Comparative retrospective analysis of 21,581 consecutive eyes treated on the manifest refractive astigmatism. Standard outcomes of the 7,180 eyes with the lowest ORA (first tercile: 0.35 ± 0.13 diopters [D]) were compared to the 7,208 eyes with the highest ORA (last tercile: 1.13 ± 0.25 D).

Results: The ORA followed a right-skewed normal distribution (R² = 0.99) with a mean ± standard deviation of 0.73 ± 0.36 D. The efficacy index of eyes with low versus high ORA was identical (0.98 ± 0.07 vs 0.98 ± 0.08; P = .99), with a similar percentage having a spherical equivalent within ±0.50 D of the intended target (94.7% vs 94.1%; P = .11). The safety index (1.00 ± 0.04 vs 1.00 ± 0.04; P = .99) and Alpins correction index (1.01 ± 0.37 vs 1.00 ± 0.43; P = .10) were identical. A greater number of eyes with high versus low ORA had postoperative residual astigmatism of 0.75 D or greater (6.1% vs 3.9%). Eyes with very high ORA (ORA ⩾ 1.50 D; 2.5% of the population) marginally reduced the efficacy index from 0.98 to 0.97 (P < .001).

Conclusions: The contribution of ORA to topography-guided clinical outcomes in most virgin eyes is negligible, with excellent efficacy, accuracy, and safety in both low ORA and high ORA groups. Myopic eyes with high ORA treated on the manifest refraction should not be excluded from topography-guided LASIK. [J Refract Surg. 2020;36(7):449-458.].

Objectives: To qualitatively and quantitatively review the use of melatonin as a topical/systemic formulation for the management of periodontitis. Materials and methods: PubMed; Scopus; and Web of Science databases were searched using the MesH terms “melatonin” and “periodontitis”. Title and abstracts were screened to eliminate irrelevant and duplicate articles. The full text data of the screened articles were assessed using the selection criteria. Results: Of 176 identified articles (PubMed-66; Scopus-56; Web of Science-52; Cross-reference-2), only 12 studies qualified to be included in the systematic review. Four studies assessed the independent effect of 1% topical melatonin formulation while 8 articles assessed the adjunctive use of systemic melatonin formulation (1–10 mg) following scaling and root planing (SRP). All studies showed an improvement in periodontal parameters such as pocket depth, clinical attachment loss, periodontal disease index, community periodontal index, gingival bleeding scores, and prognostic marker levels in saliva and serum. A meta-analysis of data from 2 studies revealed that 1–2 mg (systemic) melatonin supplementation reduced pocket depth; although the difference was not statistically significant and hence cannot be interpreted or used for conclusive evidence. Risk of Bias Assessment tool (RoBANS) and Cochrane Collaboration RoB tool elicited a high risk of bias in the included studies. GRADE (recommendation assessment, development, and evaluation) inferred a weak recommendation for the use of melatonin in periodontitis management. Conclusions: Melatonin supplementation (topical and systemic) in periodontitis patients improved key periodontal parameters including pocket depth and clinical attachment loss. Clinical relevance: Melatonin could be a potential host modulatory agent for periodontitis management; although the data from the present review should be interpreted carefully due to the associated high risk of bias.

Melatonin is an indoleamine molecule that is a by-product of tryptophan metabolism [9]. The pineal gland principally synthesizes and releases melatonin into the blood using enzyme machinery during the dark phase of the day [10]. Several other tissues can produce melatonin and are termed extra-pineal sites of melatonin biosynthesis. These include gingival tissues [11] and salivary glands in the oral cavity [12]. Melatonin performs numerous functions such as circadian cycle regulation [13], antioxidant defense [14], immunomodulation [15], cancer prevention [16], and regulation of bone turnover [17]. In the oral cavity, melatonin is regarded as a potent antioxidant and immunomodulatory agent [18]. Melatonin has been assayed in saliva [19], gingival crevicular fluid (GCF) [20], and gingival tissues [18], and its overall levels were found to be lowered in patients with periodontitis than healthy controls. A recently published systematic review performed by some of us, found a depletion of salivary melatonin levels in patients with periodontitis versus healthy individuals [21]. This finding is significant as it highlights the need for melatonin supplementation in the management of periodontal disease. In this regard, some in vitro studies [22] and animal studies [23,24] have been performed and have demonstrated the beneficial effects of melatonin. In human studies, melatonin has been used either in the topical formulation (TF) or systemic formulation (SF) as a monotherapy or adjunctive therapy following SRP [6,7,8,25,26,27,28,29,30,31,32,33]. However, no systematic review and meta-analysis has critically appraised the use of melatonin in periodontitis. Hence, the present systematic review and meta-analysis were performed with the aim of qualitatively and quantitatively analyzing the published literature that has assessed melatonin in TF/SF for the management of periodontitis. To address this aim, the PICOS (population, intervention, comparison, outcome and study) criteria were set based on recently published literature [34] and are outlined in .

Complete dental plaque and calculus removal form the basis of periodontal therapy as pathogens from plaque are initiators of periodontal disease [1]. However, in addition to scaling and root planing (SRP) and periodontal surgery, other adjunctive measures have been employed, such as the use of antimicrobials [2], antioxidants [3], anti-inflammatory agents [4], and antiseptics [5]. These measures have shown promising periodontal benefits [5]. In this connection, melatonin has been tested for the management of periodontitis [6,7,8].

The meta-analysis was carryout out using review manager (Rev Man) Version 5.4 (Cochrane, London, UK). The included studies were clearly assessed for homogeneity in clinical protocols and melatonin dosages used. The studies chosen after careful assessment were subjected to a meta-analysis performed using a statistical software and standardized protocol. The forest plot and statistical inferences that arose in the form of p value were evaluated for significance. Based on this a p value of <0.05 was considered significant while a p value of >0.05 was regarded as non-significant.

Steps 1 and 2 were performed independently by two reviewers (TMB—Thodur Madapusi Balaji and SV—Saranya Varadarajan). The kappa coefficient (κ) was calculated to measure the reliability between the two reviewers and was found to be 0.97 and 0.98 for the reviewers TMB and SV, respectively. Significant data about the study characteristics (first author’s name, year of publication, country of origin), study design, sample size, melatonin/placebo formulation details, method and frequency of melatonin application, samples collected, markers measured, results, and inference were extracted from each of the included studies.

The MesH terms “melatonin” AND “periodontitis” were searched in the Web of Science, PubMed, and Scopus as of November 2020. The identified articles were manually cross-referenced for further potential articles. Language filter was applied and only articles in English language were mined for data extraction and analysis. Articles published between 2000 and 2020 were chosen for the study and further subjected to application of the inclusion and exclusion criteria.

The International Prospective Register of Systematic Reviews (PROSPERO) was thoroughly scrutinized for similar systematic reviews. No registered protocol could be found by reviewing the effects of melatonin TF/SF for the management of periodontitis. Thus, the protocol of the present review was formally registered with the PROSPERO database (registration number: CRD42020204144). The report was formulated according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [35,36].

Of the 12 recruited studies, a wide discrepancy was found concerning the dosage of melatonin, duration of administration, and period of evaluation. Only two studies out of the 12 studies had comparable data concerning PD and were subjected to a meta-analysis [28,31]. The meta-analysis was conducted only from a mathematical viewpoint as small sample meta-analysis are possible to perform. The meta-analysis revealed an overall trend in reduction PD in periodontitis patients receiving melatonin, although the overall difference was not statistically significant (). However, the data from the meta-analysis cannot be interpreted or taken into account due to the low sample size and lack of any statistical inferences.

The GRADE evaluation revealed an overall weak recommendation in favor of all 12 studies assessing the effects of topical/systemic melatonin formulation [6,7,8,25,26,28,29,30,31,32,33,42]. The uniform weak score was attributed to the fact that none of the studies have reported a magnitude of the estimate of effect. Only one study reported side effects such as headache, nausea, and constipation in two patients. Although the GRADE score was low, it favored the use of melatonin for the management of periodontitis. A summary of the GRADE scoring is presented in supplementary Table S6.

Based on the RoB tool [38], one study demonstrated a high risk of bias in four categories/domains [28] while the other 5 studies demonstrated a high risk of bias in only 1 category [7,29,31,33,42]. Despite this, many studies demonstrated unclear data. Hence, the overall risk of bias could still be regarded as high. The data are presented in supplementary Table S4.

Three of these six studies evaluated biomarkers in addition to periodontal parameters following systemic melatonin administration [7,29,33]. One of the studies evaluated the effects of 2 monthly doses of 10 mg melatonin versus placebo on periodontal parameters and salivary biomarker levels and found a reduction in plaque index, GI, bleeding on probing, PD, CAL, along with a reduction in salivary TNF alpha levels and an overall improvement in insomnia [29]. The other study evaluated an 8-week dose of 6 mg melatonin versus placebo in type 2 diabetes mellitus patients with severe periodontitis and found a reduction in PD, CAL, and serum levels of IL-6 and CRP in the test group along with an increase in serum melatonin levels [7]. Another study by the same group with similar melatonin dose details and on the same patient groups demonstrated a reduction in IL-1 beta, malondialdehyde, and a concomitant increase in superoxide dismutase, glutathione peroxidase, catalase, and total antioxidant capacity in the test group versus the placebo group at 8 weeks post-intervention [33].

The other study assessed the effects of 1 mg melatonin administered for 1 month versus placebo on periodontal parameters in periodontitis patients who underwent NSPT [31]. This study found a reduction in PD in both groups at 6 months following baseline. However, the melatonin group demonstrated a significant reduction in the 4–5 mm and >6 mm pockets in the test group compared to the placebo group.

Out of the eight studies assessing systemic melatonin formulation [7,28,29,30,31,32,33,42], two were reported as prospective longitudinal studies, although they can be regarded as interventional studies without randomization [30,32]. One of these assessed 3 mg of melatonin administered for 4 weeks as an adjunct to SRP in chronic periodontitis patients versus patients treated by SRP only [30]. The study revealed a significant reduction in total leukocyte counts, neutrophils, and lymphocytes in the blood of patients in the melatonin group in 90 days. Another study evaluated a 4-week 3-mg melatonin use versus vitamin E 200 IU and no supplementation as an adjunct to SRP on plasma levels of vitamin C in chronic periodontitis patients [32]. The study found significantly elevated levels of vitamin C in plasma samples of periodontitis patients who received melatonin in contrast to vitamin E/no supplementation. The other six studies assessing systemic melatonin formulation were RCTs [7,28,29,31,33,42]. Two of these six studies evaluated the effects of melatonin supplementation on periodontal parameters only in periodontitis patients who underwent non-surgical periodontal therapy (NSPT). One study evaluated a 4-week 3-mg melatonin administration versus placebo on periodontitis patients who underwent SRP and found a significant reduction in GI, PDI, and CPI at 30-, 60-, and 90-days post-intervention in the test group [42].

All interventional studies were not randomized. Out of the four studies recruited, three were performed on the same patient groups together at the same time point, and the results have been published in three different journals [6,8,25]. It was found that TF 1% Orabase cream application for 20 days could significantly reduce GI and PD in diabetic patients with periodontitis. Concerning the healthy subjects receiving placebo, data are unavailable. The first study reported a reduction in salivary osteopontin, osteocalcin, acid phosphatase, and alkaline phosphatase in the melatonin test group [25]. The second study reported a significant reduction in salivary RANK L and an increase in OPG (osteoprotegerin) levels following the intervention [6]. The third study found a reduction in salivary levels of CRP (serum C-reactive protein) and IL-6 (significant) and TNF-alpha (non-significant) [8]. The fourth study was also performed on the same patients included in the other three studies. However, it comprised an extra patient group. It was found that TF significantly reported a reduction in GI and PD in diabetic patients with periodontitis. There was also a reduction in GCF levels of IL-1 beta, IL-6, and PGE2 in the test group compared to the placebo group [26]. The details of the systemically and periodontally healthy subjects receiving placebo have not been provided.

Eight studies [7,28,29,30,31,32,33,42] used melatonin for oral consumption. The details of the studies included are presented in . Of these, one study used 1 mg melatonin [31], one study prescribed 2 mg melatonin [28], three studies used 3 mg melatonin [30,32,42], two studies used 6 mg melatonin [7,33], and one study prescribed 10 mg melatonin [29]. All studies advocated melatonin at night and subjected patients to SRP. One study recommended the use of chlorhexidine mouthwash (0.12%) [29], while another study recommended the use of chlorhexidine mouthwash (0.2%) until study completion [31]. Concerning the period of melatonin consumption, four studies prescribed melatonin for 4 weeks [28,30,32,42], two studies recommended the same for 8 weeks [7,33], one study advised the intake for 2 months [29], and the other recommended use for 1 month [31]. The follow-up appointments were heterogeneous. Three studies followed up patients at 0, 30, 60, and 90 days [30,32,42], two studies at 0, 90, and 180 days [28,29], two other studies at 0 and 8 weeks [7,33], and one study at 0 and 180 days [31]. One study compared melatonin 2 mg with melatonin 2 mg and vitamin C (60/75 mg) combination [28], and another compared melatonin with vitamin E (200 IU) as an adjunct to SRP [32]. All TF studies assessed melatonin as a topical application in patients with type 1 and 2 diabetes mellitus with periodontitis versus systemically and periodontally healthy subjects [6,8,25,26]. Amongst the SF studies, two evaluated melatonin on type 2 diabetic patients with severe periodontitis [7,33] while one study evaluated the potential of melatonin in patients with insomnia and periodontitis [29].

All the studies included in the present systematic review were published between 2013 and 2020. Of the included studies, 4 were from Spain, 3 were from India, 3 were from Iran, and 1 each from Italy and Egypt. Six studies were clinical interventions without randomization, two were clinical interventional studies [6,25], two were clinical trials [8,26], and two were prospective longitudinal studies [30,32]. The other six studies were RCTs. Only four studies were randomized double-blinded placebo-controlled clinical trials [7,29,33,42], one study was a preliminary randomized triple-blind placebo-controlled clinical trial [31], and the other was a randomized single mask clinical trial [28]. One study did not administer a placebo [28], while another study did not mention placebo details [42]. The other four studies used placebo formulations [7,29,31,33] (All details available in and and Table S1, Table S2.).

A total of 176 articles (PubMed: 66, Scopus: 56, Web of Science: 52, and Cross reference: 2) were recognized. One hundred and two irrelevant/duplicate articles were excluded. Of the 74 articles scrutinized, only 12 articles satisfied the eligibility criteria and were recruited for qualitative analysis [6,7,8,25,26,28,29,30,31,32,33,42]. The kappa values for steps 1 and 2 of the review were 0.97 and 0.99, respectively. The selection strategy is depicted in the PRISMA flow chart (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) ().

The present systematic review was done with the pursuit of critically appraising the studies concerning the administration of topical/systemic melatonin formulation for the management of periodontitis [6,7,8,25,26,28,29,30,31,32,33,42]. Of all the included studies, four were based on TF [6,8,25,26] while eight studies were based on SF [7,28,29,30,31,32,33,42]. All studies used melatonin to manage periodontitis, which is an irreversible periodontal condition characterized by gingival inflammation and bleeding, periodontal pockets associated with underlying alveolar bone destruction, and loss of attachment. Periodontitis is predominantly initiated by pathogenic bacteria, such as Porphyromonas gingivalis, Tannerrella forsythia, and Treponema denticola [43]. These organisms colonize the dental plaque biofilm and use it as an ecological niche for their survival. The toxins elaborated by the dental plaque pathogens can cause a microbial challenge to the host periodontal tissues, thereby causing inflammation and eliciting a chronic immune response characterized by infiltration of neutrophils, monocytes, and lymphocytes [44] accompanied by overproduction of pro-inflammatory cytokines and mediators such as prostaglandins, leukotrienes, and acute phase reactants such as C-reactive protein [45]. If inflammation could be regarded as a key mechanism in the pathobiology of periodontitis, another important mechanism that deserves attention is the role of oxidative stress and jeopardized antioxidant defense. It has been proven that periodontitis is a free radical (FR) disorder characterized by the overexpression of reactive oxygen species (ROS) [46]. Hence, the treatment of periodontitis revolves around debridement of the plaque biofilm and calculus that accumulate around the dentition, which is regarded as the cornerstone of periodontal therapy. It is not sufficient if only the dentition is attended to. It is also pivotal to perform debridement and instill plaque control measures around dental restorations and their interface with periodontal hard and soft tissues in order to prevent the initiation and progression of periodontitis. Additionally, therapeutic strategies include the administration of antimicrobials [2], anti-inflammatory agents [4], and antioxidants [3] systemically and topically for the management of periodontitis. It is in this connection that melatonin has been tried in periodontitis management.

Melatonin has been regarded as a multifaceted molecule. In the oral cavity, melatonin is synthesized by salivary glands [12] and gingival tissues [11], and it exerts antioxidant effects on the hydroxyl [47,48,49] peroxyl radicals, nitric oxide [50], and singlet oxygen molecules [51]. It should also be noted that melatonin accumulates in the mitochondria and augments mitochondrial metabolism [14]. Melatonin and its metabolites are generated after an oxidative encounter, such as AMK (N1-acetyl-5-methoxykynuramine) and AFMK, (Acetyl-N-formyl-5-methoxykynuramine) and are also equally potent FR scavengers [52]. It is also to be noted that melatonin stimulates the transcription and translation of several antioxidant enzymes [53]. Despite the short half-life of melatonin [54], it is still regarded as a natural antioxidant gift to living organisms.

The anti-inflammatory and immunomodulatory actions of melatonin have also been described in several in vitro and in vivo studies. It has been demonstrated that the pineal gland can crosstalk with the immune system [55]. It has been shown that melatonin is a double-edged sword concerning immune mechanisms [56]. It demonstrates pro-inflammatory and immunostimulatory effects by increasing neutrophil recruitment into inflammatory sites and also increases chemotaxis and neutrophilic phagocytosis [56]. Melatonin is a potent inhibitor of NF kappa B transcription, thereby reducing the production of IL-1 beta and TNF alpha [57]. Melatonin has been regarded as an anti-TNF alpha compound [58] and has been found to enhance antigen presentation by macrophages to T lymphocytes [59] that enhances the natural killer cell activity [60].

Studies on melatonin levels in periodontitis have reported significantly lower levels in saliva [19], gingival tissue samples [18], and GCF [20]. However, a recent systematic review highlighted a significantly low level of salivary melatonin in patients with periodontitis versus healthy individuals [21]. Since melatonin levels are lowered in periodontitis, an augmentation of the same by exogenous supplementation has been implemented in recent years.

In the present systematic review, four studies on TF [6,8,25,26] found effective results. It is to be reiterated at this point as earlier mentioned that three of these studies were performed on same patients [6,8,25] while the fourth study included an additional group [26]. However, there was a significant improvement in PD and GI values. This is an important finding, as in this situation, melatonin has been prescribed without plaque and calculus removal but has still been found to produce positive results. This could be justified by the fact that melatonin has high tissue penetrability property [61] and is a highly lipophilic molecule [62]. Moreover, it is highly bioavailable when topically applied. Concerning the change in GCF levels of markers, the above studies found a reduction in pro-inflammatory markers such as IL 1 beta, TNF-α, IL 6, and CRP [6,8,25,26]. This is plausible as the crevicular fluid subtly reflects the changes in the subjacent gingival tissues. A reduction in inflammatory burden in the gingival tissues and periodontium can produce changes in the marker profile in the GCF. Additionally, salivary levels of markers related to bone destruction, such as osteocalcin, osteopontin, acid phosphatase, alkaline phosphatase, RANK-L, and OPG underwent drastic changes [6,25]. There was a decrease in osteocalcin, osteopontin, acid phosphatase, alkaline phosphatase, and RANK L, and an increase in OPG levels in saliva following melatonin application. This is a point that needs elaboration as melatonin is regarded as a bone sparing agent and can significantly prevent bone resorption and increase bone anabolism [63]. The above changes reflect melatonin’s osteo-promotive properties.

All eight studies prescribed the systemic melatonin formulations for oral consumption performed SRP in patients before supplementation [7,28,29,30,31,32,33,42]. In these studies, melatonin was used as an adjunctive agent in the management of periodontitis. In six of eight studies, periodontal parameters were measured [7,28,29,31,33,42], while two studies only measured the systemic levels of leukocytes and vitamin C after melatonin supplementation [30,32]. All six studies revealed that melatonin reduced PD, GI, PDI scores, gingival bleeding scores, and improved CAL gains. It was also remarkable that melatonin administration had a significant effect on the resolution of deep periodontal pockets >5 mm. These positive effects can be explained by the fact that melatonin administered systemically in these patients would reach the periodontium and gingival tissues to exert anti-inflammatory, antioxidant, and immunomodulatory effects [18].

This is possible because the GCF, which is a defense fluid of the periodontium, is an exudate of plasma and carries in it several molecules derived from systemic circulation [64]. Another possibility is through the gingival tissues, which are highly vascularized and oxygenated. In this situation, melatonin would have carried the systemic circulation to the gingival tissues and would have attained high concentrations therein. It could be argued that melatonin was only an adjunctive agent in these cases as SRP was performed and the changes in periodontal parameters could result from periodontal non-surgical therapy. However, this can be substantiated as there was a control/placebo group in all these studies compared to the melatonin group that had better periodontal changes. Concerning levels of inflammatory markers and oxidative stress markers, melatonin administration could produce a significant reduction in salivary levels of TNF alpha and serum levels of IL-6, CRP, IL 1 beta, and malondialdehyde, and a significant increase in the levels of superoxide dismutase, glutathione peroxidase, catalase, and total antioxidant capacity in addition to vitamin C levels in the blood [7,28,29,31,32,33,42]. Additionally, melatonin administration in periodontitis patients could also change the leukocyte profile and differential white blood cell counts and cause a reduction in neutrophil and lymphocyte counts [30]. All the above data only reveal the protective properties of melatonin in periodontal homeostasis. One of the eight studies also found melatonin in periodontitis patients with insomnia to cure both conditions [29]. In the above-mentioned study, there was a significant improvement in periodontal parameters, reduction in salivary TNF alpha levels, and restoration of sleep pattern, as detected by the Athens insomnia scores. This is plausible because melatonin is a principal sleep-promoting molecule that restores the biological clock in addition to its numerous other functions in the human system.

One of the studies assessed that melatonin with vitamin C combination found superior effects on periodontal parameters versus only melatonin administration [28]. This is an interesting finding, as both melatonin and vitamin C are potent antioxidants and the synergism between the two would have produced additional effects. Another study in the systemic review compared melatonin with vitamin E administration and found that the periodontal benefits of melatonin were far superior compared to vitamin E [32]. This can be justified as melatonin is superior compared to conventional antioxidants.

Within the given scope, the present systematic review highlights significant information about the use of melatonin as a therapeutic agent in periodontitis management. However this review also sheds light on several limitations that are inherent to the included studies listed hereafter. The data from the 12 studies included in this review should be interpreted with caution as melatonin doses were ranging from 1–10 mg used in the studies. The dosage was administered in different periods, and clinical assessment was also performed at different times. An RoB assessment revealed that all 12 studies had a high risk of bias. The SIGN 50 scoring criteria applied to the RCT revealed that two trials obtained a − score and four trials obtained only a + score. The GRADE assessment also revealed an overall weak recommendation for all the 12 included studies, however, in favor of using melatonin for managing periodontitis. This outcome arose because melatonin did not produce adverse effects in most of the studies, except one where nausea and vomiting were noted in two patients [29]. Moreover, a meta-analysis could be performed only by recruiting two studies [28,31]. This was because of data heterogeneity. However, the meta-analysis was still performed despite numerous inherent disadvantages since it was possible to perform the same from a mathematical viewpoint. The results of the meta-analysis revealed that melatonin had a positive influence (although non-significant) on the reduction of PD in periodontitis patients receiving 1–2 mg melatonin for oral consumption in addition to SRP. This inference cannot be considered vital as the sample size of the meta-analysis was low and moreover, statistical significance was not obtained. Hence it would be prudent on the readers part to understand that the findings of this systematic review emanate from the review protocol per se rather than the meta-analysis findings which can be read only as a part of the protocol and cannot be used for any conclusive evidence.

Based on the assessed literature, melatonin can be considered as a potential host modulatory agent in periodontal therapy due to its beneficial properties, good safety profile, and minimal side effects. However, data from this systematic review should be cautiously interpreted due to the associated high risk of bias. Only well-planned RCTs with adequate blinding that conform to the CONSORT (Consolidated Standards of Reporting Trials) guidelines should be encouraged.

It is to be reiterated that SRP should be performed before melatonin administration as it is a prerequisite for obtaining tangible periodontal benefits. Further studies should be performed after dose titration, frequency, and therapy time standardization to exploit the fullest benefits of melatonin as an adjunctive agent in periodontal therapy. Additionally, it would be worthwhile to try other formulations containing melatonin such as mouthwashes, gummies, lozenges, and targeted local drug delivery preparations containing melatonin coated microspheres and nanospheres for management of periodontitis.