Factors influencing outcomes of surgical therapy of peri-implantitis: A secondary analysis of 1-year results from a randomized clinical study.

AIM: To identify predictors of treatment outcomes following surgical therapy of peri-implantitis. MATERIALS AND METHODS: We performed a secondary analysis of data from a randomized controlled trial (RCT) comparing access flap with or without bone replacement graft. Outcomes at 12 months were probing pocket depth (PPD), bleeding on probing (BOP), soft-tissue recession (REC) and marginal bone level (MBL) change. Multilevel regression analyses were used to identify predictors. We also built an explanatory model for residual signs of inflammation. RESULTS: Baseline PPD was the most relevant predictor, showing positive associations with final PPD, REC and MBL gain, and negative association with probability of pocket closure. Smokers presented higher residual PPD. Absence of keratinized mucosa at baseline increased the probability of BOP but was otherwise not indicative of outcomes. Plaque at 6 weeks was detrimental in terms of residual PPD and BOP. Treatment allocation had an effect on REC. Final BOP was explained by residual PPD ≥6 mm and plaque at more than two sites. CONCLUSIONS: Baseline PPD was the most relevant predictor of the outcomes of surgical therapy of peri-implantitis. Pocket closure should be a primary goal of treatment. Bone replacement grafts may be indicated in aesthetically demanding cases to reduce soft-tissue recession. The importance of smoking cessation and patient-performed plaque control is also underlined.

Reconstructive surgical therapy of peri-implantitis: A multicenter randomized controlled clinical trial.

OBJECTIVE: To evaluate the potential benefit of the use of a bone substitute material in the reconstructive surgical therapy of peri-implantitis. METHODS: In this multicenter randomized clinical trial, 138 patients (147 implants) with peri-implantitis were treated surgically, randomized by coin toss to either a control (access flap surgery) or a test group (reconstructive surgery using bone substitute material). Clinical assessments, including probing pocket depth (PPD), bleeding and suppuration on probing (BOP & SOP) as well as soft tissue recession (REC), were recorded at baseline, 6 and 12 months. Marginal bone levels (MBL), measured on intra-oral radiographs, and patient-reported outcomes (PROs) were recorded at baseline and 12 months. No blinding to group allocation was performed. The primary outcome at 12 months was a composite measure including (i) implant not lost, (ii) absence of BOP/SOP at all aspects, (iii) PPD ≤5 mm at all aspects and (iv) ≤1 mm recession of mucosal margin on the buccal aspect of the implant. Secondary outcomes included (i) changes of MBL, (ii) changes of PPD, BOP%, and buccal KM, (iii) buccal REC and (iv) patient-reported outcomes. RESULTS: During follow-up, four implants (one in the test group, three in the control group) in four patients were removed due to disease progression. At 12 months, a total of 69 implants in the test and 68 implants in the control group were examined. Thus, 16.4% and 13.5% of implants in the test and control group, respectively, met all predefined criteria of the composite outcome. PPD reduction and MBL gain were 3.7 mm and about 1.0 mm in both groups. Reduction in mean BOP% varied between 45% (test) and 50% (control), without significant differences between groups. Buccal REC was less pronounced in the test group (M = 0.7, SD = 0.9 mm) when compared to controls (M = 1.1, SD = 1.5 mm). PROs were favorable in both groups without significant differences. One case of allergic reaction to the antibiotic therapy was recorded. No other adverse events were noted. CONCLUSIONS: Surgical therapy of peri-implantitis effectively improved the clinical and radiographic status at 12 months. While the use of a bone substitute material did not improve reductions of PPD and BOP, buccal REC was less pronounced in the test group. Patient satisfaction was high in both groups.

Occurrence, associated factors and soft tissue reconstructive therapy for buccal soft tissue dehiscence at dental implants: Consensus report of group 3 of the DGI/SEPA/Osteology Workshop.

OBJECTIVES: To systematically assess the literature and report on (1) the frequency of occurrence of buccal soft tissue dehiscence (BSTD) at implants, (2) factors associated with the occurrence of BSTD and (3) treatment outcomes of reconstructive therapy for the coverage of BSTD. MATERIALS AND METHODS: Two systematic reviews addressing focused questions related to implant BSTD occurrence, associated factors and the treatment outcomes of BSTD coverage served as the basis for group discussions and the consensus statements. The main findings of the systematic reviews, consensus statements and implications for clinical practice and for future research were formulated within group 3 and were further discussed and reached final approval within the plenary session. RESULTS: Buccally positioned implants were the factor most strongly associated with the risk of occurrence of BSTD, followed by thin tissue phenotype. At immediate implants, it was identified that the use of a connective tissue graft (CTG) may act as a protective factor for BSTD. Coverage of BSTD may be achieved with a combination of a coronally advanced flap (CAF) and a connective tissue graft, with or without prosthesis modification/removal, although feasibility of the procedure depends upon multiple local and patient-related factors. Soft tissue substitutes showed limited BSTD coverage. CONCLUSION: Correct three-dimensional (3D) positioning of the implant is of utmost relevance to prevent the occurrence of BSTD. If present, BSTD may be covered by CAF +CTG, however the evidence comes from a low number of observational studies. Therefore, future research is needed for the development of further evidence-based clinical recommendations.

Screening of undiagnosed hyperglycaemia in the dental setting: The DiabetRisk study. A field trial.

AIM: To evaluate the efficacy of different screening protocols for undiagnosed hyperglycaemia in a Research Network of Dental Clinics coordinated by the Spanish Society of Periodontology (SEPA). MATERIAL AND METHODS: A total of 1143 patients were included in the study. Participants filled a questionnaire considering diabetes risk factors (FINDRISC) and received a periodontal screening examination. Patients with a slightly elevated score according to the Findrisc (≥7), received a point-of-care HbA1c and were eventually referred to their physician for confirmatory diagnosis. Receiver Operating Characteristic (ROC) curves were used to assess the performance of various predictive models with confirmed hyperglycaemia as outcome. RESULTS: From this population, 97 (8.5%) were finally diagnosed of diabetes (n = 28; 2.5%) or prediabetes (n = 69; 6.0%). When only including the results from the FINDRISC questionnaire, the model reported an area under the curve (AUC) of 0.866 (95% confidence interval - CI [0.833; 0.900]). This model significantly improved when a basic periodontal examination (EPB Code; AUC = 0.876; 95% CI [0.845: 0.906]; p = .042) or a point-of-care HbA1c were added (AUC = 0.961; 95% CI [0.941; 0.980]; p < .001). CONCLUSIONS: The tested protocol, combining the FINDRISC questionnaire and a point-of-care HbA1c, showed to be feasible when carried out in a dental clinic setting and was efficient to identify subjects with undiagnosed diabetes or prediabetes.

Autologous connective tissue graft or xenogenic collagen matrix with coronally advanced flaps for coverage of multiple adjacent gingival recession. 36-month follow-up of a randomized multicentre trial.

AIM: To report the 36-month follow-up of a trial comparing the adjunct of a xenogenic collagen matrix (CMX) or connective tissue graft (CTG) to coronally advanced flaps (CAF) for coverage of multiple adjacent recessions. MATERIAL AND METHODS: 125 subjects (61 CMX) with 307 recessions in 8 centres from the parent trial were followed-up for 36 months. Primary outcome was change in position of the gingival margin. Multilevel analysis used centre, subject and tooth as levels and baseline parameters as covariates. RESULTS: No differences were observed between the randomized and the follow-up population. Average baseline recession was 2.6 ± 1.0 mm. 3-year root coverage was 1.5 ± 1.5 mm for CMX and 2.0 ± 1.0 mm for CTG (difference of 0.32 mm, 95% CI from -0.02 to 0.65 mm). The upper limit of the confidence interval was over the non-inferiority margin of 0.25 mm. No treatment differences in position of the gingival margin were observed between 6- and 36-month follow-up (difference 0.06 mm, 95% CI -0.17 to 0.29 mm). CONCLUSION: CMX was not non-inferior with respect to CTG in multiple adjacent recessions. No differences in stability of root coverage were observed between groups and in changes from 6 to 36 months. Previously reported shorter time to recovery, lower morbidity and more natural appearance of tissue texture and contour observed for CMX in this trial are also relevant in clinical decision-making.

Peri-implant radiographic bone level and associated factors in Spain.

OBJECTIVES: To evaluate radiographic bone level (RxBL) at dental implants and its associated factors in Spain. MATERIAL AND METHODS: This cross-sectional study was performed by a network of sentinel dentists from regions of Spain. RxBL was defined as the distance from the implant shoulder to the first clearly visible contact between the implant surface and the bone. Radiographic measurements were performed by two trained and experienced periodontists. Implant and patient data were also collected. Descriptive, bivariate, discriminative and multivariate analyses were done. RESULTS: A total of 49 sentinel dentists provided data 275 patients. Mean RxBL from 474 implants (5-13 years) was 1.87 mm (range: 0.00-13.17 mm). Statistically significant associations between RxBL and clinical output variables (bleeding on probing, oedema, plaque, probing depth, suppuration, keratinized tissue) were found. In the multiple regression analysis, statistically significant associations for RxBL were found for smoking habit, implant diameter, years of follow-up and type of prosthesis (p < 0.01). CONCLUSIONS: Peri-implant RxBL ranged from 0 to 13.17 mm. It was significantly associated with clinical output variables and with some potentially predictor variables, at patient- (smoking >10 cigarettes/day) and implant- (diameter, years of follow-up, Toronto bridge) levels.

Peri-implantitis: Summary and consensus statements of group 3. The 6th EAO Consensus Conference 2021.

OBJECTIVE: To evaluate the influence of implant and prosthetic components on peri-implant tissue health. A further aim was to evaluate peri-implant soft-tissue changes following surgical peri-implantitis treatment. MATERIALS AND METHODS: Group discussions based on two systematic reviews (SR) and one critical review (CR) addressed (i) the influence of implant material and surface characteristics on the incidence and progression of peri-implantitis, (ii) implant and restorative design elements and the associated risk for peri-implant diseases, and (iii) peri-implant soft-tissue level changes and patient-reported outcomes following peri-implantitis treatment. Consensus statements, clinical recommendations, and implications for future research were discussed within the group and approved during plenary sessions. RESULTS: Data from preclinical in vivo studies demonstrated significantly greater radiographic bone loss and increased area of inflammatory infiltrate at modified compared to non-modified surface implants. Limited clinical data did not show differences between modified and non-modified implant surfaces in incidence or progression of peri-implantitis (SR). There is some evidence that restricted accessibility for oral hygiene and an emergence angle of >30 combined with a convex emergence profile of the abutment/prosthesis are associated with an increased risk for peri-implantitis (CR). Reconstructive therapy for peri-implantitis resulted in significantly less soft-tissue recession, when compared with access flap. Implantoplasty or the adjunctive use of a barrier membrane had no influence on the extent of peri-implant mucosal recession following peri-implantitis treatment (SR). CONCLUSIONS: Prosthesis overcontouring and impaired access to oral hygiene procedures increases risk for peri-implantitis. When indicated, reconstructive peri-implantitis treatment may facilitate the maintenance of post-operative peri-implant soft-tissue levels.

Prevalence and risk indicators of peri-implant diseases in Spain.

AIM: To evaluate the prevalence of peri-implant diseases in Spain, as well as the associated risk indicators. MATERIAL AND METHODS: This is a cross-sectional study using a network of sentinel dentists, who randomly selected 10 patients with implants (placed, at least, 5 years before), which were clinically and radiographically evaluated. Case definitions were established for peri-implant mucositis [bleeding on probing (BOP) and no bone level ≥2 mm] and peri-implantitis (BOP plus bone level ≥2 mm). Potential predictor variables, at univariate and multivariate levels, were explored by means of binary logistic regression. RESULTS: A total of 49 sentinel dentists provided complete data from 474 implants in 275 patients. At implant level, prevalences for peri-implant mucositis and peri-implantitis were 27% (95% confidence interval [CI] 22-32) and 20% (95% CI: 15-24), respectively, with 17% of implants (14-21) with bone level ≥2 mm without BOP. At patient level, prevalences were 27% (22-32), 24% (19-29) and 18% (13-22), respectively. In the multiple regression analysis, statistically significant associations for peri-implantitis (p < 0.10) were found for gender, peri-implant supportive therapy, implant location, diameter and surface, type of prosthesis and access to interproximal hygiene. CONCLUSIONS: In this representative subject sample across Spain, the prevalence of peri-implant diseases was high (51%).

Xenogenic collagen matrix or autologous connective tissue graft as adjunct to coronally advanced flaps for coverage of multiple adjacent gingival recession: Randomized trial assessing non-inferiority in root coverage and superiority in oral health-related quality of life.

AIM: To evaluate the non-inferiority of the adjunct of a xenogeneic collagen matrix (CMX) or connective tissue graft (CTG) to coronally advanced flaps (CAF) for coverage of multiple adjacent recessions and compare superiority in patient-reported outcomes (PROM). MATERIAL AND METHODS: One hundred and eighty-seven subjects (92 CMX) with 485 recessions in 14 centres were randomized and followed up for 6 months. Patients filled daily diaries for 15 days to monitor patient-reported experience. The primary outcome was changed in position of the gingival margin. Multilevel analysis used centre, subject and tooth as levels and baseline parameters as covariates. RESULTS: Average baseline recession was 2.5 ± 1.0 mm. The surgery was 15.7 min shorter (95%CI from 11.9 to 19.6, p < .0001) and perceived lighter (11.9 VAS units, 95%CI from 4.6 to 19.1, p = .0014) in CMX subjects. Time to recovery was 1.8 days shorter in CMX. Six-month root coverage was 1.7 ± 1.1 mm for CMX and 2.1 ± 1.0 mm for CTG (difference of 0.44 mm, 95%CI from 0.25 to 0.63 mm). The upper limit of the confidence interval was over the non-inferiority margin of 0.25 mm. Odds of complete root coverage were significantly higher for CTG (OR = 4.0, 95% CI 1.8-8.8). CONCLUSION: Replacing CTG with CMX shortens time to recovery and decreases morbidity, but the tested generation of devices is probably inferior to autologous CTG in terms of root coverage. Significant variability in PROMs was observed among centres.

Evaporative concentration of arsenic in groundwater: health and environmental implications, La Laguna Region, Mexico.

High arsenic concentrations in groundwater have been documented in La Laguna Region (LLR) in arid northern Mexico, where arsenic poisoning is both chronic and endemic. A heated debate has continued for decades on its origin. LLR consisted of a series of ancient connected lakes that developed at the end of a topographic depression under closed basin conditions. This study addresses the isotopic, chemical composition of the groundwater and geochemical modeling in the southeasternmost part of the LLR to determine the origin of arsenic. Groundwater samples were obtained from a carbonate and granular aquifers and from a clayey aquitard at terminal Viesca Lake. Results show that groundwater originated as meteoric water that reached the lakes mainly via abundant springs in the carbonate aquifer and perennial flooding of the Nazas-Aguanaval Rivers. Paleo-lake water underwent progressive evaporation as demonstrated by the enrichment of δ18O, δ2H and characteristic geochemical patterns in the granular aquifer and aquitard that resulted in highly saline (>90,000 mS/cm), arsenic-rich (up to 5000 µg/L) paleo-groundwater (>30,000 years BP). However, adsorption or co-precipitation on iron oxides, clay-mineral surfaces and organic carbon limited arsenic concentration in the groundwater. Arsenic-rich groundwater and other solutes are advancing progressively from the lacustrine margins toward the main granular aquifer, due to reversal of hydraulic gradients caused by intensive groundwater exploitation and the reduction in freshwater runoff provoked by dam construction on the main rivers. Desorption of arsenic will incorporate additional concentrations of arsenic into the groundwater and continue to have significant negative effects on human health and the environment.

Tooth loss and alveolar bone crest loss during supportive periodontal therapy in patients with generalized aggressive periodontitis: retrospective study with follow-up of 8 to 15 years.

AIM: To determine the incidence of tooth loss in patients with generalized aggressive periodontitis (GAgP) during supportive periodontal therapy (SPT), identify tooth loss risk factors, and quantify alveolar crest height changes on periapical X-ray during follow-up. MATERIAL AND METHODS: This retrospective study included 25 GAgP patients with 656 teeth after periodontal treatment (baseline). Data were gathered on sociodemographic, periodontal, and radiological variables at baseline and at the end of follow-up. Linear regression models were used to assess the association of risk factors with tooth loss. RESULTS: Twenty-eight teeth were extracted during SPT. The mean tooth loss per patient was 1.12 ± 2.01 for all causes and 0.9 ± 2.0 for periodontal disease after a mean follow-up of 10.9 ± 2 years. Clinical variables were improved at the end of follow-up, with a mean reduction of -1 ± 0.8 mm in probing pocket depth (-0.7 to -1.3, 95% CI) and -0.6 ± 0.9 mm in clinical attachment loss (-0.9 to -0.2, 95% CI). Mean alveolar bone crest loss at the end of follow-up was 0.36 ± 0.56 mm (0.10-0.61, 95% CI). Smoking was associated with tooth loss (p = 0.052). CONCLUSIONS: Tooth loss rate was low in GAgP in a regular supportive care programme. Clinical variables improved, and bone loss was minimal over time. Smoking was associated with tooth loss.

Impact of baseline microbiological status on clinical outcomes in generalized aggressive periodontitis patients treated with or without adjunctive amoxicillin and metronidazole: an exploratory analysis from a randomized controlled clinical trial.

AIM: To explore whether subjects harbouring A. actinomycetemcomitans, P. gingivalis or T. forsythia at baseline showed increased clinical benefits with the adjunctive use of systemic amoxicillin and metronidazole (AMX-MET) during non-surgical treatment of generalized aggressive periodontitis (GAgP). MATERIAL AND METHODS: Forty one subjects were included in this 6-month randomized placebo-controlled clinical trial using a 7-day course of systemic AMX-MET or placebo as adjuncts to non-surgical periodontal therapy. Clinical and microbiological parameters were collected at baseline, 2 and 6 months after treatment. Microbiological cultures were processed for pooled subgingival samples and identities of isolates were determined by PCR for A. actinomycetemcomitans, P. gingivalis and T. forsythia RESULTS: At 6 months, the test treatment resulted in significant additional improvements in the primary outcome variable compared to placebo, and the effect of the adjunctive antimicrobials was not modified by the baseline microbiological status in the primary analysis. However, secondary exploratory subgroup analyses showed improved clinical outcomes in subjects harbouring A. actinomycetemcomitans at baseline compared to subjects who did not harbour this pathogen. CONCLUSIONS: All subjects benefited from the tested adjunctive antimicrobial regimen, although subjects who harboured A. actinomycetemcomitans at baseline may show greater clinical benefits. Larger appropriately powered studies are needed to confirm whether adjunctive AMX-MET is more beneficial for GAgP patients who harbour A. actinomycetemcomitans, along with other key periodontal pathogens.

Real-world KINDLE-Latin America subset data on treatment patterns and clinical outcomes in patients with stage III non-small-cell lung cancer.

INTRODUCTION: Stage III non-small-cell lung cancer (NSCLC) management is challenging given the heterogeneous nature of the disease. The LATAM subset of the real-world, global KINDLE study reported the treatment patterns and clinical outcomes for LATAM from the pre-immuno-oncology era. METHODS: The study was conducted in seven countries (Argentina, Chile, Colombia, Dominican Republic, Mexico, Peru and Uruguay) in stage III NSCLC (American Joint Committee on Cancer, 7th edition) diagnosed between January 2013 and December 2017. Retrospective data from patients' medical records (index date to the end of follow-up) were collected. Summary statistics, Kaplan-Meier survival estimates and a two-sided 95% confidence interval (CI) were provided. Cox proportional hazard model was used for univariate and multi-variate analyses. RESULTS: A total of 231 patients was enrolled, the median age was 65.0 years (range 21.0-89.0), 60.6% were males, 76.6% had smoking history, 64.0% had adenocarcinoma and 28.7% underwent curative resection. Multiple treatment regimens (>25) were used; chemotherapy alone was the most common (24.8%). The overall median progression-free survival (mPFS) and median overall survival (mOS) were 14.8 months (95% CI, 12.1-18.6) and 48.6 months (95% CI, 34.7 to not calculable). Significantly better mPFS and mOS were observed for stage IIIA with curative surgery and resectable tumours and stage IIIB with an Eastern Cooperative Oncology Group score of 0/1, female gender, resectable tumours, adenocarcinoma and curative surgery (p < 0.05). CONCLUSION: Results show diversity in treatment practices and the corresponding clinical outcomes in stage III NSCLC. There is a need to streamline treatment selection and sequencing to decrease relapse rates after initial therapy.

Amoxicillin and metronidazole as an adjunctive treatment in generalized aggressive periodontitis at initial therapy or re-treatment: a randomized controlled clinical trial.

BACKGROUND: Previously, we showed that systemic metronidazole and amoxicillin significantly improved the outcomes of non-surgical debridement in generalized aggressive periodontitis patients. This study aimed to observe whether re-treatment with adjunctive antimicrobials would give the placebo group benefits comparable with the test group. METHODS: Thirty-eight of 41 subjects, from the initial 6-month trial, completed the second phase, re-treatment of sites with remaining pockets 5 mm. Subjects on placebo in phase one, received adjunctive antibiotics for 7 days. Clinical parameters were collected at 2 months posttreatment (8 months from baseline). RESULTS: Patients who received antibiotics at initial therapy, showed statistically significant improvement in pocket depth reduction and in the % of sites improving above clinically relevant thresholds, compared with patients who received antibiotics at re-treatment. In deep pockets (7 mm), the mean difference was 0.9 mm (p=0.003) and in moderate pockets (4-6 mm) it was 0.4 mm (p=0.036). For pockets converting from 5 to 4 mm, this was 83% compared with 67% (p=0.041) and pockets converting from 4 to 3 mm was 63% compared with 49% (p=0.297). CONCLUSIONS: At 8 months, patients who had antibiotics at initial therapy showed statistically significant benefits compared with those who had antibiotics at re-treatment.

Evidence for a Stereoselective Mechanism for Bitopic Activity by Extended-Length Antagonists of the D3 Dopamine Receptor.

The D3 dopamine receptor (D3R) has been suggested as a drug target for the treatment of a number of neuropsychiatric disorders, including substance use disorders (SUD). Many D3R-selective antagonists are bivalent in nature in that they engage two distinct sites on the receptor-a primary pharmacophore binds to the orthosteric site, where dopamine binds, whereas a secondary pharmacophore interacts with a unique secondary binding pocket (SBP). When engagement of the secondary pocket exerts allosteric activity, the compound is said to be bitopic. We recently reported the synthesis and characterization of two bitopic antagonists of the D3R, (±)-VK04-87 and (±)-VK05-95, which incorporated a racemic trans-cyclopropylmethyl linking chain. To gain a better understanding of the role of chirality in determining the pharmacology of such compounds, we resolved the enantiomers of (±)-VK04-87. We found that the (+)-isomer displays higher affinity for the D3R and exhibits greater selectivity versus the D2R than the (-)-isomer. Strikingly, using functional assays, we found that (+)-VK04-87 inhibits the D3R in a noncompetitive manner, while (-)-VK04-87 behaves as a purely competitive antagonist, indicating that the apparent allosteric activity of the racemate is due to the (+)-isomer. Molecular dynamic simulations of (+)-VK04-87 and (-)-VK04-87 binding to the D3R suggest that the (+)-isomer is able to interact with the SBP of the receptor whereas the (-)-isomer bends away from this pocket, thus potentially explaining their differing pharmacology. These results emphasize the importance of the linker, and its isomeric conformations, within extended-length molecules for their positioning and engagement within GPCR binding pockets.

Oral Care and Quality Evaluation: A Multicentric Study on Periodontal Treatment.

PURPOSE: No information is available on the perception of the quality of care in patients treated for periodontitis. The purpose of this article was to assess how periodontitis-affected patients perceive the quality of periodontal treatment (PT) and to measure the factors which may influence it. MATERIALS AND METHODS: 306 subjects who completed PT were invited to participate. Questionnaires and visual analogic scales (VAS) evaluating perception of quality of care, symptoms, and oral health related quality of life (OHRQoL) were handed out. Oral and periodontal indicators were collected before and after treatment. The impact of different factors on perception of quality was assessed with a regression model. RESULTS: Quality evaluation was high yet unrelated for both patients and clinicians (p = 0.983). Quality was negatively influenced by the number of residual oral infections (p < 0.001), patient's age (p = 0.07) and presence of residual pain at completion of PT (p = 0.02). Professionalism, kindness of the staff and communication skills were the characteristics mostly appreciated. The OHRQoL was influenced by the number of residual teeth (p < 0.001), increasing age of patients (p = 0.08), number of residual infections (p < 0.01) and pain (p = 0.04). CONCLUSIONS: Patients' quality perception appeared to be influenced by clinical and emotional aspects. Oral care providers should be aware of the impact of non-clinical factors in patients' appreciation of quality of treatment.

Lack of short-term adjunctive effect of systemic neridronate in non-surgical periodontal therapy of advanced generalized chronic periodontitis: an open label-randomized clinical trial.

AIM: To determine if the adjunctive use of intra-muscular neridronate (NE) during non-surgical periodontal treatment (PT) provides, in patients with generalized chronic periodontitis (GCP), adjunctive benefits as compared with PT alone 3 months after the completion of a 3-month NE therapy. MATERIAL AND METHODS: Sixty GCP healthy patients were randomly assigned to control (CG) or test group (TG). CG patients received PT only. Thirty subjects in TG also received adjunctive NE (12.5 mg in an i.m. injection/week for 3 months). Clinical parameters were evaluated at baseline, at the end of NE treatment (3 months after PT) and 3 months after the completion of NE treatment (6 months after the beginning of PT). RESULTS: Groups were balanced at baseline and all clinical parameters showed improvement between baseline and follow-ups. At 6 months improvements from baseline at sites with deep pocket depth (>or=7 mm) were 3.2 mm [95% confidence interval (CI): 2.7-3.9] in CG and 3.0 mm (95% CI: 2.3-3.8) in TG with a non-significant difference of 0.2 mm (95% CI: -1.0-0.5; ANCOVA; p=0.549) between groups. Secondary outcomes did not show significant differences between groups. No major adverse events were reported. CONCLUSIONS: The adjunctive use of NE during PT did not result in additional short-term improvements in periodontal conditions of GCP patients when compared with PT.

Novel and Potent Dopamine D2 Receptor Go-Protein Biased Agonists.

The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D2 receptor (D2R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D2R agonists linking the D2R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D2R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D2R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and ß-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D2Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.

Investigation of Novel Primary and Secondary Pharmacophores and 3-Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D3 Receptor Antagonists and Partial Agonists.

Dopamine D3 receptors (D3R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1-yl)butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D3R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D3R binding affinity (Ki = 0.756 nM) and was 327-fold selective for D3R over D2R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R- and S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D3R selectivity as well as drug-like features required for development as pharmacotherapeutics.

The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists.

Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D3R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.