Search

Background: The present study aims to evaluate the efficacy of diode laser alone and in combination with desensitizing toothpastes in occluding dentinal tubules (both partially occluded and completely occluded tubules) by scanning electron microscope (SEM). Materials and Methods: Fifty human teeth were extracted, cervical cavities were prepared and etched with 17% ethylenediaminetetraacetic acid, and smear layer was removed to expose the tubules. The teeth were divided into five groups: Group I – Application of NovaMin-formulated toothpaste, Group II – Application of Pro-Argin™-formulated toothpaste, Group III – Application of diode laser in noncontact mode, Group IV – NovaMin-formulated toothpaste followed by laser irradiation, and Group V – Pro-Argin™-formulated toothpaste followed by laser irradiation. After treatment, quantitative analysis of occluded dentinal tubules was done by SEM analysis. Results: The mean values of percentages of total occlusion of dentinal tubules in Groups I, II, III, IV, and V were 92.73% ± 1.38, 90.67% ± 1.86, 96.57% ± 0.64, 97.3% ± 0.68, and 96.9% ± 6.08, respectively. Addition of diode laser (Groups III, IV, and V) yielded a significant occlusion of the dentinal tubules when compared to desensitizing toothpastes alone (Groups I and II). Conclusion: Diode laser (Group III) has shown more efficacy in occluding dentinal tubules when compared with desensitizing toothpastes which was statistically significant (P < 0.05). Among the five groups, NovaMin + diode laser (Group IV) showed the highest percentage of occluded dentinal tubules.

One of the most common esthetic concerns associated with the periodontal tissues is gingival recession. Gingival recession is the exposure of root surfaces due to apical migration of the gingival tissue margins; gingival margin migrates apical to the cementoenamel junction. Although it rarely results in tooth loss, marginal tissue recession is associated with thermal and tactile sensitivity, esthetic complaints, and a tendency toward root caries. This paper reviews etiology, consequences, and the available surgical procedures for the coverage of exposed root surfaces, including three case reports.

Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal ( n = 10) or impaired ( n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUC inf ) and maximum concentration (C max )] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUC inf and C max were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment., Competing Interests: All authors are/were employees and/or shareholders of Gilead Sciences, Inc., at the time of this study.

Objectives: Remdesivir decreases the risk of SARS-CoV-2 infection progressing to severe disease in adults. This study evaluated remdesivir safety and pharmacokinetics in infants and children., Methods: This was a phase 2/3, open-label trial in children aged 28 days to 17 years hospitalized for polymerase chain reaction-confirmed SARS-CoV-2 infection. Participants received for ≤10 days once-daily intravenous remdesivir doses defined using physiologically based pharmacokinetic modeling (for ≥40 kg, 200 mg day 1, then 100 mg/day; for age ≥28 days and ≥3 to <40 kg, 5 mg/kg day 1, then 2.5 mg/kg/day). Sparse pharmacokinetic samples were analyzed using population-pharmacokinetic approaches for remdesivir and metabolites GS-704277 and GS-441524., Results: Among 53 participants, at enrollment the median (Q1, Q3) number of days of COVID-19 symptoms was 5 (3, 7) and hospitalization was 1 (1, 3). Underlying conditions included obesity in 19 (37%), asthma in 11 (21%), and cardiac disorders in 11 (21%). Median duration of remdesivir treatment was 5 days (range, 1-10). Remdesivir treatment had no new apparent safety trends. Two participants discontinued treatment because of adverse events including elevated transaminases; both had elevated transaminases at baseline. Three deaths occurred during treatment (and 1 after). When compared with phase 3 adult data, estimated mean pediatric parameters (area under the concentration-time curve over 1 dosing interval, AUCτ, Cmax, and Cτ) were largely overlapping but modestly increased (remdesivir, 33%-129%; GS-704277, 37%-124%; GS-441524, 0%-60%). Recovery occurred for 62% of participants on day 10 and 83% at last assessment., Conclusions: In infants and children with COVID-19, the doses of remdesivir evaluated provided drug exposure similar to adult dosing. In this study with a small sample size, no new safety concerns were observed., (Copyright © 2024 by the American Academy of Pediatrics.)

Background and Objective: Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function recently approved for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The purpose of this multicohort study was to evaluate the pharmacokinetics, metabolism, excretion, safety, and tolerability of LEN following a single intravenous (IV) infusion of 10 mg LEN or 20 mg [ 14 C]LEN in healthy participants., Methods: Twenty-one healthy adult participants were enrolled into the study and received either a single IV dose of 10 mg LEN (n = 8 active, n = 3 placebo; cohort 1) or a single IV dose of 20 mg [ 14 C]LEN containing 200 µCi (n = 10; cohort 2). Blood, urine, and feces samples (when applicable) were collected after dosing, and radioactivity (cohort 2) was assessed using liquid scintillation counting in both plasma and excreta. LEN in plasma was quantified by liquid chromatography (LC) tandem mass spectroscopy (MS/MS) method bioanalysis. Metabolite profiling in plasma and excreta were performed using LC-fraction collect (FC)-high-resolution MS and LC-FC-accelerator mass spectrometry in plasma., Results: Between the 10 mg and 20 mg doses of LEN, the observed plasma exposure of LEN doubled, while the elimination half-life was similar. Following administration of 20 mg [ 14 C]LEN (200 µCi), the mean cumulative recovery of [ 14 C] radioactivity was 75.9% and 0.24% from feces and urine, respectively. The mean whole [ 14 C] blood-to-plasma concentration ratio was 0.5-0.7, which showed a low distribution of LEN to red blood cells. Intact LEN was the predominant circulating species in plasma (representing 68.8% of circulating radioactivity), and no single metabolite contributed to > 10% of total radioactivity exposure through 1176 h postdose. Similarly, intact LEN was the most abundant component (32.9% of administered dose; 75.9% of recovered dose) measured in feces, with metabolites accounting for trace amounts. These results suggest metabolism of LEN is not a primary pathway of elimination. Of the metabolites observed in the feces, the three most abundant metabolites were direct phase 2 conjugates (glucuronide, hexose, and pentose conjugates), with additional metabolites formed to a lesser extent via other pathways. The administered LEN IV doses were generally safe and well-tolerated across participants in this study., Conclusions: The results of this mass balance study indicated that LEN was majorly eliminated as intact LEN via the feces. The renal pathway played a minor role in LEN elimination (0.24%). In addition, no major circulating metabolites in plasma or feces were found, indicating minimal metabolism of LEN., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: The objective of this study was to assess the pharmacokinetics, safety, and efficacy and confirm the dose of once-daily bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF; B/F/TAF) during pregnancy., Design: An open-label, multicenter, single-arm, phase 1b study (NCT03960645) was conducted in 33 virologically suppressed pregnant women with HIV-1., Methods: Participants received B/F/TAF (50/200/25 mg) from the second or third trimester through ∼16 weeks postpartum. Steady-state maternal plasma pharmacokinetic samples were collected at the second and third trimesters and 6 and 12 weeks postpartum for BIC, FTC, and TAF. Neonates ( n  = 29) were followed from birth to 4-8 weeks with sparse washout pharmacokinetic sampling for BIC and TAF. The proportion of participants with HIV-1 RNA less than 50 copies/ml at delivery (missing = excluded) was evaluated., Results: Mean areas under the concentration-time curve over the dosing interval (AUC tau ) for BIC, FTC, and TAF were lower during pregnancy versus postpartum but were closer to AUC tau values for nonpregnant adults with HIV reported in other studies. Geometric least-squares mean ratios for BIC, FTC, and TAF AUC tau during pregnancy versus postpartum ranged from 41 to 45%, 64 to 69% and 57 to 78%, respectively. Mean BIC trough concentrations during pregnancy were more than 6.5-fold greater than the protein-adjusted 95% effective concentration. In neonates, the median BIC half-life was 43 h. Virologic suppression was maintained in all adult participants throughout the study, with no virologic failure or treatment-emergent resistance to HIV-1, no discontinuations because of adverse events, and no perinatal transmission., Conclusion: Exposures to BIC, FTC, and TAF were lower during pregnancy than postpartum. However, mean BIC trough concentrations were maintained at levels indicative of efficacious exposure, and FTC/TAF data were concordant with published literature in this population. Pharmacokinetic and safety data, combined with maintenance of robust virologic suppression, suggest that once-daily B/F/TAF without dose adjustment is appropriate during pregnancy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Intravenous remdesivir (RDV) is US Food and Drug Administration-approved for hospitalized and nonhospitalized individuals with coronavirus disease 2019. RDV undergoes intracellular metabolic activation to form the active triphosphate, GS-443902, and other metabolites. Alternative administration routes, including localized pulmonary delivery, can lower systemic exposure and maximize exposure at the site of action. This study evaluated the pharmacokinetics (PK) and safety of inhaled RDV in healthy adults. This phase Ia, randomized, placebo-controlled study evaluated inhaled RDV in healthy participants randomized 4:1 to receive RDV or placebo as single doses (4 cohorts) or multiple once-daily doses (3 cohorts). Doses in cohorts 1-6 were administered as an aerosolized solution for inhalation through a sealed facemask; doses in cohort 7 were administered as an aerosolized solution for inhalation through a mouthpiece. Safety was assessed throughout the study. Seventy-two participants were enrolled (inhaled RDV, n = 58 and placebo, n = 14). Following single RDV doses, RDV, GS-704277, and GS-441524 plasma PK parameters indicated dose-proportional increases in area under the concentration-time curve (AUC) extrapolated to infinite time, AUC from time zero to last quantifiable concentration, and maximum observed concentration. Analyte plasma concentrations after multiple RDV doses were consistent with those for single-dose RDV. Analyte plasma exposures were lower when RDV was administered with a mouthpiece versus a sealed facemask. The most common adverse events included nausea, dizziness, and cough. Single- and multiple-dose inhaled RDV exhibited linear and dose-proportional plasma PK. Administration of RDV via inhalation was generally safe and well-tolerated., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Long-acting injectable (LAI) formulations can provide several advantages over the more traditional oral formulation as drug product opportunities. LAI formulations can achieve sustained drug release for extended periods of time, which results in less frequent dosing requirements leading to higher patient adherence and more optimal therapeutic outcomes. This review article will provide an industry perspective on the development and associated challenges of long-acting injectable formulations. The LAIs described herein include polymer-based formulations, oil-based formulations, and crystalline drug suspensions. The review discusses manufacturing processes, including quality controls, considerations of the Active Pharmaceutical Ingredient (API), biopharmaceutical properties and clinical requirements pertaining to LAI technology selection, and characterization of LAIs through in vitro, in vivo and in silico approaches. Lastly, the article includes a discussion around the current lack of suitable compendial and biorelevant in vitro models for the evaluation of LAIs and its subsequent impact on LAI product development and approval., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

The ideal starting dose for an oncology first-in-patient (FIP) trial should be low enough to be safe but not too far removed from therapeutically relevant doses. A low starting dose combined with small dose increments could lead to a lengthy dose escalation and could expose patients unnecessarily to sub-therapeutic dosing. In the current analyses, we reviewed 59 approved small molecule oncology drugs (SMOD) with the overarching goals to assess the current approaches of FIP starting dose selection and dose escalation, and to identify potential opportunities for improving trial efficiency and minimizing number of patients receiving sub-therapeutic dose levels. Of 59 SMODs, the majority (~ 66%) were kinase inhibitors and ~ 73% were approved for solid tumor indications. Most of the trials used a 3 + 3 design for dose escalation and had a median (range) of 4 cohorts (0-11) to reach MTD from the starting dose. The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) to starting dose ratio was highly variable with a median (range) of 8 (0.25-125). About 71% of the FIP trials had < 6 dose escalation steps to reach MTD or RP2D (with 15% ≤ 2 dose escalations), but the remaining 29% of trials had ≥ 6 dose escalation steps to reach MTD or RP2D suggesting that there is still room for increasing efficiency by reducing the number of dose escalation steps, reducing the variability in MTD to starting dose ratio, and consequently reducing significant number of patients exposed at sub-therapeutic doses in the dose escalation phase of FIP study.

Aim: Aim of the present study was to evaluate the loading of clindamycin with injectable-guided tissue regeneration (GTR) will prevent the colonization of Porphyromonas gingivalis and to compare and assess the quantitative changes in P. gingivalis colony forming units (CFUs) by real-time polymerase chain reaction (PCR) analysis., Materials and Methods: Thirty microbiological samples were pooled from the deepest periodontal pockets from the thirty sites from the two groups: group I-injectable GTR placed in the defect filled with demineralized freeze-dried bone allograft (DFDBA) and group II-clindamycin loaded injectable GTR placed in the defect filled with DFDBA. The total number of P. gingivalis CFUs was estimated using real-time PCR at baseline and 4 weeks after therapy., Results: A significant reduction in P. gingivalis CFUs at the end of 4 weeks was seen in both groups. Comparative evaluations between both groups at 4 weeks were with a mean of 4.44 ± 2.28 and 4.75 ± 3.32, respectively. Though there was a significant reduction in group II, the difference was statistically insignificant., Conclusion: The results suggest that clindamycin is beneficial in reducing microbial infection and can potentiate regeneration through host modulation., Clinical Significance: Injectable GTR has the ability to mold according to the defect size and shape and eliminates the need to manipulate the membrane as required for the conventional membrane.

Aims: To evaluate the clinical and microbiological effects of local drug delivery of moxifloxacin and ibuprofen gel as an adjunct to conventional periodontal therapy in chronic periodontitis patients., Subjects and Methods: Twenty patients with moderate-to-severe chronic generalized periodontitis with probing pocket depth (PPD) of ≥5 mm and <8 mm were randomly assigned to one of the following two treatment modalities: scaling and root planing (SRP) group and moxifloxacin and ibuprofen combination gel as an adjunct to SRP group. Clinical parameters include plaque index (PI), gingival index (GI), probing depths and clinical attachment level (CAL) that were recorded at baseline and 1 and 3 months after the treatment, and microbiologic assessment was done using dark-field microscopy., Results: A statistically significant difference in mean PI and GI scores and reduction in PPD and gain in CAL were observed at different study intervals with greater difference in the test group. On microbiological examination, the percentage of cocci increased, while a statistically significant decrease in the mean percentage of bacilli and spirochetes was observed in both groups at given intervals. In-vitro dissolution showed controlled release of both the drugs., Conclusions: Among the two treatment modalities, treatment with moxifloxacin and ibuprofen local delivery as an adjunct to SRP gave superior results in clinical and microbiological parameters compared to SRP group., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Oral and Maxillofacial Pathology.)

Background: Several bone graft materials are popularized in the treatment of intrabony defects. Demineralized freeze-dried bone allograft (DFDBA) is widely used in the treatment of intrabony defects. Platelet-rich fibrin (PRF) is autologous blood preparation which helps in wound healing and regeneration. Hence, this study focuses on evaluation of PRF, DFDBA, and their combination in the regeneration of intrabony defects., Materials and Methods: A total of 39 sites with intrabony defects were randomly assigned into three groups: (Group I - Open flap debridement, Group II - DFDBA alone, and Group III- DFDBA + PRF). Parameters such as probing pocket depth (PPD), relative attachment level (RAL), and radiographic bone fill were measured at baseline, 3 months, and 6 months. Intragroup comparison at various study intervals was made using one-way ANOVA test. Intergroup comparison was made using Tukey's multiple post hoc test., Results: Reduction in the PPD and greater difference in RAL was observed over the study period in all the three groups with greater reduction in DFDBA + PRF group. Reduction in the radiographic defect depths was observed over the study period in all the three groups with the greatest reduction of 38.99% in the DFDBA + PRF group. However, no statistically significant difference was reported by DFDBA versus DFDBA + PRF group., Conclusion: Combination of DFDBA and PRF improved the clinical and radiographic parameters compared to PRF and DFDBA alone. PRF was combined with DFDBA to produce a synergistic effect for treating intrabony defects in chronic periodontitis patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Indian Society of Periodontology.)

Background : PF-06438179/GP1111 (PF-SZ-IFX) is an infliximab (IFX) biosimilar. Pharmacokinetic (PK) similarity of PF-SZ-IFX and reference IFX authorized in the European Union (ref-IFX-EU) and in the US (ref-IFX-US) was demonstrated in healthy subjects. Safety and efficacy of PF-SZ-IFX were investigated in a multinational, double-blind, randomized study in rheumatoid arthritis (RA) patients. This work aims to evaluate the population pharmacokinetics (PopPK) of ref-IFX-EU and PF-SZ-IFX in RA patients. Research design and methods : Patients with moderately to severely active RA (N = 650) were randomized 1:1 to PF-SZ-IFX or ref-IFX-EU. PopPK modeling with data collected from the study was performed using a nonlinear mixed-effects approach (NONMEM 7.2.0). Results : The PK of ref-IFX-EU and PF-SZ-IFX were adequately described using a two-compartment model with linear elimination. Clearance (CL) estimates were 0.014 L/h and 0.015 L/h for PF-SZ-IFX and ref-IFX-EU, with inter-individual variability (IIV) on CL of 43.1% and 40.1%, respectively. Volumes of distribution in the central compartment (V 1 ) were 3.38 L and 3.57 L, with IIV on V 1 of 28.1% and 23.7%, respectively. The same covariates of sex and antidrug antibody titers on CL, and body weight on V 1 , influenced the PK variability of ref-IFX-EU and PF-SZ-IFX. Conclusions : PopPK analysis revealed no appreciable differences between the PK of ref-IFX-EU and PF-SZ-IFX in RA patients. Trial registration : The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02222493).

The 'totality-of-the-evidence' biosimilarity concept requires that sufficient structural, functional, nonclinical, and clinical data are acquired in a stepwise manner, to demonstrate that no clinically meaningful differences in quality, safety, or efficacy are observed compared with the reference product. We describe the totality of the evidence for PF-06438179/GP1111 (PF-SZ-IFX; IXIFI™ [infliximab-qbtx]/Zessly®) that supported its approval as an infliximab (IFX) biosimilar for all eligible indications of reference IFX (ref-IFX; Remicade®) in Europe and in the US. Analytical similarity involving in vitro assays capable of distinguishing structural or functional differences between PF-SZ-IFX and ref-IFX formed a foundation for the biosimilarity exercise. Differences identified in N-glycosylation and charge heterogeneity were found not to impact the results in in vitro biological assays reflective of the pharmacology underlying the mechanisms of action (tumor necrosis factor binding, reverse signaling, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) of IFX across disease indications. Similarity was assessed in a comparative clinical pharmacokinetic study and in a clinical efficacy and safety study in patients with rheumatoid arthritis, where therapeutic equivalence between PF-SZ-IFX and ref-IFX provided confirmatory evidence of biosimilarity, and, when coupled with the analytical similarity already established, supported extrapolation to all eligible disease indications of ref-IFX., Competing Interests: Conflict of interest statement: Joseph E. McClellan, Hugh D. Conlon, Michael W. Bolt, Vatche Kalfayan, Rameshraja Palaparthy, Muhammad I. Rehman, and Carol F. Kirchhoff are employees of and hold stock in Pfizer Inc.

Background: This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period., Methods: Patients (N = 650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ≥ 20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ± 13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (- 12.0%, 15.0%)., Results: Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (- 9.92%, 5.11%) and 90% (- 8.75%, 4.02%) CIs for the treatment difference (- 2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period., Conclusion: PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate., Trial Registration: ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.

Background: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US., Methods: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios for PK parameters, C max , AUC T , and AUC inf , were within the 80.00-125.00% pre-specified equivalence window., Results: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration-time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for C max , AUC T , and AUC inf were within 80.00-125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups., Conclusions: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles., Trial Registration: CT.gov identifier NCT01844804.

Aim: The aim of the study was to compare the clinical and microbiological efficacy of Group I-delmopinol dentifrice, Group II-chlorhexidine, and Group III-triclosan-containing regularly used control dentifrice on plaque formation and gingivitis., Materials and Methods: A total of 45 healthy volunteer students fulfilling the inclusion criteria are recruited for this randomized control parallel study. All the individuals were randomly assigned into 3 groups depending on the dentifrice prescribed. After the selection of individuals, thorough scaling and polishing were performed for all the individuals, and in a 4 days' washout period, they were refrained from regular oral hygiene maintenance and 0.9% NaCl (normal saline) rinse was prescribed to obtain plaque regrowth. Microbiological morphotypes were assessed using darkfield microscope., Statistical Analysis: The data were analyzed using the SPSS-software 19.00 program. The intragroup comparison of clinical parameters was done using Kruskal-Wallis ANOVA test, and intergroup comparison was done by Mann-Whitney U-test. The intragroup comparison of clinical parameters including modified staining index, the supragingival microbiota such as cocci, bacilli, and spirochetes scores was done at various study intervals using one-way ANOVA, and intergroup comparison was done using Tukey's multiple post hoc test., Results: The results showed that statistically significant correlation between Group II and Group III at 15 and 30 days and between Group I and Group II at 30 days with cocci and bacilli but not spirochetes., Conclusion: Group II showed better plaque and gingivitis reduction compared to other active groups. To validate the results of the present study, further long-term studies with larger sample size and evaluation using known and proven study designs on gingivitis patients are needed., Competing Interests: There are no conflflicts of interest.

Background: Periodontally accelerated osteogenic orthodontics is a clinical procedure that combines selective corticotomy, particulate grafting, and application of orthodontics. It reduces treatment time, increases stability of teeth, and prevents relapse of orthodontic tooth moment. The present study was aimed to explore the clinical and radiographic comparison of bone density changes, retraction time differences in buccal and palatal corticotomy with buccal corticotomy which was done by surgical bur., Materials and Methods: A split-mouth was designed in 16 patients and divided into right (buccal and palatal corticotomy) (Group I), left (buccal corticotomy) (Group II) sides. In both groups, decortication was done with surgical bur. Clinical parameters such as gingival bleeding index and probing pocket depth were recorded at baseline, 1 month, 3 months, and 6 months. Bone density changes were measured by computed tomography at baseline and after 6 months after surgery and also used for evaluating differences in bone density changes between two groups. Retraction time differences were also measured in both groups., Results: In both groups, there was significant difference between bone density changes at baseline and 6 months after surgery. However, the difference between two groups was not significant. The difference in clinical parameters between two groups was not significant. The difference in retraction time differences was not significant., Conclusion: Within limits of the study, it may be concluded that there was difference between bone density changes before and 6 months after surgery. Difference in total treatment time found to be no significant between two groups., Competing Interests: There are no conflicts of interest.

Quorum sensing helps bacteria to communicate with each other and in coordinating their behavior. Many diseases of humans, plants, and animals are mediated by communication called quorum sensing. Various approaches are being investigated to inhibit this communication to control the diseases caused by bacteria. Periodontal pathogens also communicate through quorum sensing and new approaches to treat periodontal disease using quorum sensing inhibition need to be explored.

Objective: Omecamtiv mecarbil is a novel small molecule that directly activates cardiac myosin and increases cardiac contractility without increasing cardiac myocyte intracellular calcium. This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil., Methods: This was a phase 1, randomized, open-label, 4-way crossover, incomplete block-design study evaluating 5 MR formulations of omecamtiv mecarbil vs. an immediate-release (IR) formulation., Materials: Healthy subjects were randomized to 1 of 30 possible sequences: within each sequence, subjects were assigned to receive a single 25-mg dose of 2 of the 6 possible formulations in the fasting and/or fed states., Results: 65 subjects were screened and enrolled; 5 were replacement subjects. Pharmacokinetic and safety data were analyzed from 62 and 63 subjects in the fasting and fed states, respectively. Compared with the IR formulation, median t(max) was longer (0.5 vs. 2 - 10 hours), and mean C(max) was lower for all 5 MR formulations (262 vs. 34 - 78 ng/mL); t(1/2,z) was similar (18 - 21 hours). The relative bioavailability was high (> 75%) for three MR formulations but lower (< 65%) for the other two. Overall, the effect of food on omecamtiv mecarbil pharmacokinetics was minimal for four of the MR formulations. The pharmacokinetics of the inactive metabolites M3 and M4 were similar across all formulations., Conclusions: The relative bioavailability of omecamtiv mecarbil was high (> 75%) for 3 of the five MR formulations. Food had a marginal, nonclinically meaningful effect on the pharmacokinetics of the MR formulations of omecamtiv mecarbil.

Introduction: Epidemiological studies show that individuals with periodontitis have a radically amplified threat to develop cardiovascular disease. CRP& TNF-α, are acute phase proteins monitored as a marker of inflammatory status, which have been identified as a major risk factor for atherosclerotic complications. Elevated CRP & TNF-α level in periodontitis patients have been reported by several groups. The present study was performed to determine whether presence of periodontitis and periodontal therapy could influence the serum levels of CRP & TNF-α in cardiovascular disease patients., Methods: Forty cardiovascular disease subjects participated in the study. They were classified into two groups. Group A (Control) where no periodontal treatment was given, Group B (Test) where periodontal treatment (scaling & root planing) was performed. Periodontal clinical parameters like OHI-S, probing pocket depth, were evaluated together with serum CRP, TNF-α, at baseline and reassessed after 8 weeks for all the subjects in both the groups., Results: The CRP & TNF-α levels in both the groups decreased but the decrease in the Group A was minimal and was not statistically significant (P > 0.05); whereas in Group B where periodontal therapy was performed, there was statistically significant decrease., Conclusion: It can be concluded from the study that there can be a possible causal relationship between pathogenesis of periodontal disease and CVD as inferred from the statistical significant outcome in the form of decreased inflammatory biomarkers after the periodontal treatment.

Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC(50); and bone-specific alkaline phosphatase on calcium EC(50) (CRIT). This exposure-response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.

Objective: This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed., Methods: Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression., Results: Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (>150μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated., Conclusion: Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p<0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans.

Paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). Proton pump inhibitors are prescribed to CKD patients to treat gastroesophageal reflux. This was a single dose, crossover study evaluating the effect of omeprazole, change in gastric pH as a result thereof, on the pharmacokinetics (PK) of paricalcitol. Twenty-six healthy subjects were administered paricalcitol capsules (16 microg) alone (regimen A), and following a single dose of OMP (40 mg) (regimen B), with a washout of at least 7 days. Plasma samples for paricalcitol concentrations were collected for 48 h post-paricalcitol dose. The plasma paricalcitol concentrations were measured using an LC-MS/MS assay (LOQ=0.02 ng/ml) and paricalcitol pharmacokinetic parameters were estimated using non-compartmental methods. The point estimates and the corresponding 90% confidence intervals for Cmax and AUC0-infinity to evaluate paricalcitol-omeprazole interaction were 1.032 [0.920-1.158] and 1.041 [0.951-1.139], respectively. No significant differences in Tmax (regimen A: 2.9 h vs regimen B: 2.6 h) or t1/2 (6.83 h vs 6.6 h) between the regimens were observed. Hence, the co-administration of omeprazole does not affect the PK of paricalcitol. Both regimens were well tolerated and no apparent differences among the regimens with respect to safety were observed., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Objective: ABT-578, a tetrazole analogue of sirolimus (rapamycin), possesses anti-restenosis activity. The aim of this study was to assess the safety and pharmacokinetics of escalating single intravenous (IV) doses of ABT-578 in a phase 1, double-blind, randomised, placebo-controlled study., Methods: Sixty adult healthy males were divided into five IV-dose groups of 100, 300, 500, 700 and 900mug. Doses were administered as IV bolus over 3 minutes, with eight subjects and four subjects receiving ABT-578 and placebo, respectively, in each dose group. Higher doses were administered after evaluating safety from the preceding lower doses. Blood concentrations of ABT-578 were sampled for 168 hours and measured using LC-MS/MS with a limit of quantification of 0.20 ng/mL., Results: The pharmacokinetics of ABT-578 were essentially linear across the 100-900microg dose range as illustrated by the dose-proportional increases in concentration at 5 minutes (C(5)) after the end of infusion and area under the concentration-time curve (AUC). The mean half-life ranged between 26.0 and 40.2h over the studied doses and was not significantly different over the 300-900mug dose range. The mean clearance values ranged from 2.90 to 3.55 L/h. Single IV bolus doses up to 900mug of ABT-578 were well tolerated and no clinically significant changes in physical examination results, vital signs or laboratory test results were observed., Conclusion: It can be concluded that the pharmacokinetics of IV ABT-578 are dose-proportional over the 100-900mug dose range. Single IV bolus doses up to 900mug were well tolerated in healthy male subjects.