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Background Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). Methods Patients with moderate to severe RA who had received ≥12 weeks’ stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. Results A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group ( n  = 3 b.i.d; n  = 10 t.i.d.) and 20 (61%) in the GSK2982772 group ( n  = 3 b.i.d; n  = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. Conclusions These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. Trial registration ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.

GSK2982772 is a highly selective inhibitor of receptor‐interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first‐in‐human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo‐controlled, double‐blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1‐120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open‐label relative bioavailability study comparing 20‐mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24‐hour period for the 60‐mg and 120‐mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.

GSK 2982772 is a highly selective inhibitor of receptor‐interacting protein kinase 1 ( RIPK 1) being developed to treat chronic inflammatory diseases. This first‐in‐human study evaluated safety, tolerability, pharmacokinetics ( PK ), and exploratory pharmacodynamics ( PD ) of GSK 2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo‐controlled, double‐blind study. In Part A, subjects received single ascending doses of GSK 2982772 (0.1‐120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK 2982772 (20 mg once daily [ QD ] to up to 120 mg twice daily [ BID ]) or placebo for 14 days. Part C was an open‐label relative bioavailability study comparing 20‐mg tablets vs capsules. Safety, tolerability, pharmacokinetics ( PK ), RIPK 1 target engagement ( TE ), and pharmacodynamics ( PD ) were assessed. The most common adverse events ( AE s) were contact dermatitis and headache. Most AE s were mild in intensity, and there were no deaths or serious AE s. The PK of GSK 2982772 was approximately linear over the dose range studied (up to 120 mg BID ). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK 1 TE was achieved over a 24‐hour period for the 60‐mg and 120‐mg BID dosing regimens. Single and repeat doses of GSK 2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK 1 TE support progression into Phase II clinical trials for further clinical development.

IntroductionPer and polyfluoroalkyl substances (PFAS), including perfluorononanoic acid (PFNA) and perfluorooctanoic acid (PFOA), were detected in the community water supply of Paulsboro New Jersey in 2009.MethodsA cross-sectional study enrolled 192 claimants from a class-action lawsuit, not affiliated with this study, who had been awarded a blood test for 13 PFAS. Study participants provided their blood test results and completed a survey about demographics; 105 participants also completed a health survey. Geometric means, 25th, 50th, 75th, and 95th percentiles of exposure of PFNA blood serum concentrations were compared to that of the 2013–2014 NHANES, adjusted for reporting level. Associations between PFNA, PFOA, PFOS, and PFHxS and self-reported health outcomes were assessed using logistic regression.ResultsPFNA serum levels were 285% higher in Paulsboro compared with U.S. residents. PFNA serum levels were higher among older compared with younger, and male compared to female, Paulsboro residents. After adjustment for potential confounding, there was a significant association between increased serum PFNA levels and self-reported high cholesterol (OR: 1.15, 95% CI: 1.02, 1.29).Discussion/ConclusionFurther investigation into possible health effects of PFAS exposure in Paulsboro and other community settings is warranted. Since exposure has ceased, toxicokinetics of PFAS elimination should be explored.

There are evidences for exposure to vehicular emissions and adverse cardiopulmonary health effects. This study attempted to further explore these effects on elderly. This study monitored personal PM 2.5 concentrations and ambulatory electrocardiograms continuously for 24 h on 1 working day in 3 separate weeks for 11 school crossing guards. Spirometry was also performed before and after the morning shift. The traffic at each work location was video recorded during one of the three morning shifts. The increases in the average personal PM 2.5 concentrations (baseline PM 2.5 was subtracted) of 1.2–87 and 1.1–98  μ g/m 3 were observed during the 1-h morning (ΔPM 2.5-ave-m ) and afternoon shift (ΔPM 2.5-ave-a ), respectively. Traffic count was not a significant predictor of the ΔPM 2.5-ave-m ( P =0.78). Mean heart rate variability (HRV), measured as 5-min standard deviation of normal-to-normal (SDNN) beats during the 10-min rest periods, decreased 18–26% ( P <0.02) 15 min, 2 and 4 h after the morning shift, but changes in SDNN (ΔSDNN) were insignificant post-afternoon exposure (−0.3 to −7% with P >0.53). ΔSDNN were negatively associated with ΔPM 2.5-ave-m , with the strongest association at 2 h after the morning shift ( P <0.01) but insignificant 4 h after the morning exposure. The peak PM 2.5 concentration (ΔPM 2.5-peak , baseline PM 2.5 was subtracted) was not a significant predictor for ΔSDNN, and no clear effect of PM 2.5 exposure on heart rate was observed. There was no effect of PM exposure on lung function ( P >0.16), either. In conclusion, acute exposure to the PM 2.5 resulting from mobile sources can cause acute decline in HRV in healthy older adults, suggesting one of the biological mechanisms for the adverse cardiovascular health effects associated with traffic-related air pollution. Traffic count may not be an appropriate surrogate measure of acute personal exposure to vehicular emission in traffic congested areas.

There are evidences for exposure to vehicular emissions and adverse cardiopulmonary health effects. This study attempted to further explore these effects on elderly. This study monitored personal PM sub(2.5) concentrations and ambulatory electrocardiograms continuously for 24h on 1 working day in 3 separate weeks for 11 school crossing guards. Spirometry was also performed before and after the morning shift. The traffic at each work location was video recorded during one of the three morning shifts. The increases in the average personal PM sub(2.5) concentrations (baseline PM sub(2.5) was subtracted) of 1.2-87 and 1.1-98kg/m super(3) were observed during the 1-h morning (PM sub(2.5-ave-m)) and afternoon shift (PM sub(2.5-ave-a)), respectively. Traffic count was not a significant predictor of the PM sub(2.5-ave-m) (P=0.78). Mean heart rate variability (HRV), measured as 5-min standard deviation of normal-to-normal (SDNN) beats during the 10-min rest periods, decreased 18-26% (P<0.02) 15min, 2 and 4h after the morning shift, but changes in SDNN (SDNN) were insignificant post-afternoon exposure (-0.3 to -7% with P>0.53). SDNN were negatively associated with PM sub(2.5-ave-m), with the strongest association at 2h after the morning shift (P<0.01) but insignificant 4h after the morning exposure. The peak PM sub(2.5) concentration (PM sub(2.5-peak), baseline PM sub(2.5) was subtracted) was not a significant predictor for SDNN, and no clear effect of PM sub(2.5) exposure on heart rate was observed. There was no effect of PM exposure on lung function (P>0.16), either. In conclusion, acute exposure to the PM sub(2.5) resulting from mobile sources can cause acute decline in HRV in healthy older adults, suggesting one of the biological mechanisms for the adverse cardiovascular health effects associated with traffic-related air pollution. Traffic count may not be an appropriate surrogate measure of acute personal exposure to vehicular emission in traffic congested areas.Journal of Exposure Science and Environmental Epidemiology (2009) 19, 525-533; doi:10.1038/jes.2008.46; published online 8 October 2008