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William Blake LeMaster,1 Corey J Witenko,2 Melinda K Lacy,2 Ann W Olmsted,2 Edmund J Moran,2 Donald A Mahler3,4 1Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 2Theravance Biopharma US, Inc, South San Francisco, CA, USA; 3Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 4Respiratory Services, Valley Regional Hospital, Claremont, NH, USACorrespondence: Edmund J Moran, Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA, 94080, USA, Tel +1 650 892 9229, Email emoran@theravance.comPurpose: Several lung function endpoints are utilized in clinical trials of inhaled bronchodilators for chronic obstructive pulmonary disease (COPD). Trough forced expiratory volume in 1 second (FEV1) is a commonly reported endpoint in COPD trials and can be complemented by area under the FEV1 vs time curve (FEV1 AUC), which provides information on duration and consistency of bronchodilation over a dosing interval. Revefenacin, a once-daily bronchodilator, significantly improved lung function in patients with COPD when measured by trough FEV1 in two replicate Phase 3 trials. Here, we report an FEV1 AUC substudy using data from these trials.Patients and Methods: This post hoc analysis examined substudy data from 12-week replicate Phase 3 trials (NCT02459080/NCT02512510); patients with moderate to very severe COPD were randomized 1:1 to revefenacin 175 μg or placebo once daily. The substudy patients had FEV1 AUC0– 2h assessed on Day 1, and those who continued to Day 84 also underwent 24-hour serial spirometry postdose where FEV1 AUC0– 2h, AUC0– 12h, AUC12-24h, and AUC0– 24h were evaluated.Results: Fifty and 47 patients who received revefenacin and placebo underwent 24-hour serial spirometry; most baseline characteristics were aligned between groups. At Day 84 postdose, revefenacin demonstrated sustained improvements in bronchodilation over 24 hours; differences in least squares mean vs placebo were 282, 220, 205, and 212 mL for FEV1 AUC0– 2h, AUC0– 12h, AUC12– 24h, and AUC0– 24h (all P < 0.001), respectively.Conclusion: This substudy analysis supplements previous findings that revefenacin provides sustained bronchodilation over 24 hours. Assessing additional complementary COPD clinical trial endpoints can help clinicians make treatment decisions.Keywords: Bronchodilators, long-acting muscarinic antagonist, outcome measures, spirometry, forced expiratory volume in 1 second

Introduction: Many patients with chronic obstructive pulmonary disease (COPD) may derive inadequate benefit from dry powder inhalers (DPIs) because of suboptimal peak inspiratory flow (sPIF)., Objectives: To assess the clinical burden of COPD by characterizing the clinical characteristics of participants with sPIF against medium-low resistance DPIs versus those with optimal PIF (oPIF) from two phase 3 clinical trials., Methods: Baseline data were collected from two randomized, controlled, phase 3 trials (NCT03095456; NCT02518139) in participants with moderate-to-severe COPD. oPIF (60 L/min) against the medium-low resistance DPIs was used as the threshold for defining the PIF subgroups (<60 L/min (sPIF) vs ≥60 L/min (oPIF))., Results: Most participants included in this analysis were White (92%) and male (63%); the mean (range) age was 65 (43-87) years. Participants with sPIF had significantly greater dyspnea than those with oPIF as measured using the modified Medical Research Council scoring (mean (95% CI): 2.1 (2.0-2.2) vs 1.6 (1.4-1.7); P   < 0.001) and baseline dyspnea index (mean (95% CI): 5.1 (4.9-5.4) vs 6.1 (5.8-6.3); P   < 0.001). Based on COPD Assessment Test scores, participants with sPIF had a higher COPD symptom burden than those with oPIF (mean (95% CI): 21.5 (19.7-23.3) vs 19.5 (18.6-20.4); P = 0.05)., Conclusion: In these trials, participants with COPD who had sPIF against the medium-low resistance DPIs had more dyspnea and worse health status than those with oPIF. These results demonstrate that sPIF is associated with a higher clinical burden as measured by patient-reported outcomes., Competing Interests: JAO has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GSK, Mylan Inc., Reckitt Benckiser, Sunovion Pharmaceuticals, and Theravance Biopharma US, Inc. DAM has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GSK, Mylan, Sunovion Pharmaceuticals, Theravance Biopharma US, Inc., and Teva and is on the speaker's bureau for AstraZeneca, Boehringer Ingelheim, and Teva Pharmaceuticals. GND is an employee of Theravance Biopharma US, Inc. DAL is a contract employee of Theravance Biopharma US, Inc. EJM is an employee of Theravance Biopharma US, Inc. GDC was an employee of Theravance Biopharma US, Inc., at the time these trials were conducted., (Copyright © 2024 Jill A. Ohar et al.)

Current analytical technology and continuing maturation of -omics methodology have enabled detailed assessment of human exposure via the exposome. Topics exploring the connection between etiology of disease and toxicology were presented at the 2023 Fall American Chemical Society meeting.

Background: The public health response to COVID-19 has shifted to reducing deaths and hospitalizations to prevent overwhelming health systems. The amount of SARS-CoV-2 RNA fragments in wastewater are known to correlate with clinical data including cases and hospital admissions for COVID-19. We developed and tested a predictive model for incident COVID-19 hospital admissions in New York State using wastewater data., Methods: Using county-level COVID-19 hospital admissions and wastewater surveillance covering 13.8 million people across 56 counties, we fit a generalized linear mixed model predicting new hospital admissions from wastewater concentrations of SARS-CoV-2 RNA from April 29, 2020 to June 30, 2022. We included covariates such as COVID-19 vaccine coverage in the county, comorbidities, demographic variables, and holiday gatherings., Findings: Wastewater concentrations of SARS-CoV-2 RNA correlated with new hospital admissions per 100,000 up to ten days prior to admission. Models that included wastewater had higher predictive power than models that included clinical cases only, increasing the accuracy of the model by 15%. Predicted hospital admissions correlated highly with observed admissions (r = 0.77) with an average difference of 0.013 hospitalizations per 100,000 (95% CI = [0.002, 0.025])., Interpretation: Using wastewater to predict future hospital admissions from COVID-19 is accurate and effective with superior results to using case data alone. The lead time of ten days could alert the public to take precautions and improve resource allocation for seasonal surges., Competing Interests: The authors declare that they have not competing financial interests., (© 2023 The Authors.)

Background: The inhaled lung-selective pan-Janus kinase inhibitor nezulcitinib had favourable safety and potential efficacy signals in part 1 of a phase 2 trial in patients with severe COVID-19, supporting progression to part 2., Methods: Part 2 was a randomised, double-blind phase 2 study (NCT04402866). Hospitalised patients aged 18-80 years with confirmed symptomatic COVID-19 requiring supplemental oxygen (excluding baseline invasive mechanical ventilation) were randomised 1:1 to nebulised nezulcitinib 3 mg or placebo for up to 7 days with background standard-of-care therapy (including corticosteroids). Efficacy endpoints included respiratory failure-free (RFF) days through day 28 as the primary endpoint. Secondary endpoints included safety and change from baseline oxygen saturation (SaO2)/fraction of inspired oxygen (FiO2) ratio on day 7, and 28-day mortality rate was a prespecified exploratory endpoint., Results: Between June 2020 and April 2021, 205 patients were treated (nezulcitinib, 103; placebo, 102). There was no statistically significant difference between nezulcitinib versus placebo in the primary endpoint (RFF days; median, 21.0 vs 21.0; p=0.6137) or secondary efficacy endpoints. Nezulcitinib was generally well tolerated with a favourable safety profile., Conclusions: Although the prespecified primary, secondary and exploratory efficacy endpoints, including RFF through day 28, change from baseline SaO2/FiO2 ratio on day 7, and 28-day mortality rate, were not met, nezulcitinib was generally well tolerated and had a favourable safety profile. Further studies are required to determine if treatment with nezulcitinib confers clinical benefit in specific inflammatory biomarker-defined populations of patients with COVID-19., Competing Interests: Competing interests: JB has no conflict of interest. DLB, EK, NDP, EJM and RS are employees of Theravance Biopharma US; and shareholders of Theravance Biopharma,. TN, CGT, JW and DAL are former employees of Theravance Biopharma US; and may hold stock in Theravance Biopharma. MB is an employee of Arensia Exploratory Medicine SRL. VM is an employee of Arensia Exploratory Medicine. DS reports personal fees from Theravance Biopharma during the conduct of the study; and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance Biopharma, and Verona outside this work. BH is a former employee of Theravance Biopharma UK and may hold stock in Theravance Biopharma., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Malignant atrophic papulosis (Degos disease) is an unusual thrombotic microangiopathy of uncertain etiology. The disease characteristically involves the skin and internal organs, with nervous system involvement more common in children. We present a case with diverse neurological manifestations including cranial nerve palsies, gait instability, and urinary incontinence. The patient also developed white papular lesions on her lower extremities and back. Magnetic resonance imaging (MRI) demonstrated progressive intracranial and spinal abnormalities. Despite treatment with numerous biologic agents, the patient had persistent clinical deterioration and expired one month after admission. We highlight the extensive neurologic manifestations of Degos disease correlated with neuroradiological imaging and pathological features. Nervous system involvement in Degos disease requires careful neurologic and dermatologic exam with central nervous system (CNS) magnetic resonance imaging to distinguish it from non-organic etiologies of similar symptoms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV 1 ) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD., Methods: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV 1 , St. George's Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 μg and placebo: severe and very severe airflow limitation (percent predicted FEV 1 30%-< 50% and < 30%), 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) D, reversibility (≥ 12% and ≥ 200 mL increase in FEV 1 ) to short-acting bronchodilators, concurrent use of long-acting β agonists and/or inhaled corticosteroids, older age (> 65 and > 75 years), and comorbidity risk factors., Results: Revefenacin demonstrated significant improvements in FEV 1 versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio > 2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio > 2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged > 75 years., Conclusions: Revefenacin showed significantly greater improvements in FEV 1 versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD., Trial Registration: Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).

Although no nebulized, dual mechanism, long-acting bronchodilator is currently marketed, with the approval of once-daily long-acting muscarinic antagonist (LAMA) revefenacinefenacin, it is theoretically possible to deliver a LAMA and long-acting beta2-agonist via standard jet nebulizer. The primary and secondary objectives of our study were to characterize the safety profile of revefenacin administered sequentially before or in combination with formoterol, via standard jet nebulizer in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, 42-day trial (NCT03573817), patients received revenacin 175 µg (n=63) or placebo (n=59), followed by formoterol 20 µg in the morning and formoterol alone in the evening formoterol 21 days via standard jet nebulizer (sequential administration). For another 21 days, revefenacin/placebo and formoterol, were administered as mixed solutions via single nebulization in the morning (combined administration), and formoterol alone in the evening. The adverse events' (AEs) incidence was higher in the placebo + formoterol arms (11%-12%) than in the revefenacin + formoterol arms (5%-8%). The most common AEs were worsening/exacerbation of COPD, cough, and dizziness. There were no serious AEs or deaths reported in any arm. The least squares mean in trough forced expiratory volume in 1 second (FEV 1 ) versus baseline was higher in the revefenacin + formoterol arms (116-157 mL) than in the placebo + formoterol arms (35-53 mL). Revefenacin had a safety profile similar to formoterol alone when delivered sequentially or combined. Trough FEV 1 was similar when revefenacin was delivered sequentially or combined with formoterol, with revefenacin providing an additional 81-104 mL improvements over formoterol alone., Competing Interests: TMS received research support from West-Ward Pharmaceuticals, Theravance Biopharma US, Inc., GlaxoSmithKline, Pearl Therapeutics, Chiesi, AstraZeneca, Novartis, Boehringer Ingelheim, Forest, Compleware, Evidera, Novartis, Oncocyte, Teva, Vapotherm, Sunovion, Proterix BioPharma, Seer and Sanofi. He has also received speaker fees from GlaxoSmithKline, Mylan Inc./Theravance Biopharma US, Inc., and Sunovion, and consulting fees from Vapotherm. EJM and GDC are current employees of Theravance Biopharma US, Inc. CNB was an employee of Theravance Biopharma US, Inc., at the time this study was conducted., (JCOPDF © 2020.)

Background: Revefenacin is a long-acting muscarinic antagonist that was recently approved for the nebulized treatment of chronic obstructive pulmonary disease (COPD). Although shorter duration studies have documented the efficacy of revefenacin in COPD, longer-term efficacy has not been described. In a recent 52-week safety trial, revefenacin was well tolerated and had a favorable benefit-risk profile. Here we report exploratory efficacy and health outcomes in patients receiving revefenacin 175 μg or 88 μg daily during the 52-week trial., Methods: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 175 μg or 88 μg in a double-blind manner, or open-label active control tiotropium., Results: Over the 52-week treatment period, both doses of revefenacin, as well as tiotropium, elicited significant (all p < 0.0003) improvements from baseline in trough forced expiratory volume in 1 s (FEV 1 ). The trough FEV 1 profile (least squares mean change from baseline) for revefenacin 175 μg ranged from 52.3-124.3 mL and the trough FEV 1 profile for tiotropium ranged from 79.7-112.8 mL. In subgroup comparisons, the effect of revefenacin on trough FEV 1 was comparable in patients taking concomitant long-acting β-agonists, with or without inhaled corticosteroids, with patients who were not taking these medications. There were statistically significant (p < 0.05) improvements in all measured health status outcomes (evaluated using St. George's Respiratory Questionnaire, COPD Assessment Test, Clinical COPD Questionnaire and Baseline and Transition Dyspnea Index) from 3 months onward, in all treatment arms., Conclusions: Significant sustained improvements from baseline in trough FEV 1 and respiratory health outcomes were demonstrated for 175-μg revefenacin over 52 weeks, further supporting its use as a once-daily bronchodilator for the nebulized treatment of patients with COPD., Trial Registration: NCT02518139 ; Registered 5 August 2015.

Background: Patients with chronic obstructive pulmonary disease (COPD) and suboptimal peak inspiratory flow rate (sPIFR) may not benefit optimally from dry powder inhalers (DPI) because of inadequate inspiratory flow. Nebulized bronchodilators may provide a better alternative. We compared bronchodilation with the long-acting muscarinic antagonist (LAMA) revefenacin for nebulization versus the DPI LAMA tiotropium, in patients with COPD and sPIFR (< 60 L/min against the resistance of Diskus®)., Methods: This was a randomized, double-blind, double-dummy, 28-day Phase 3b study in patients with COPD enrolled based on sPIFR. The primary endpoint was trough forced expiratory volume in 1 second (FEV 1 ) on Day 29 for revefenacin for nebulization versus tiotropium HandiHaler® DPI., Results: We enrolled 206 patients with mean (standard deviation) age, 65 (8) years; percent predicted FEV 1 , 37 (16)%; PIFR, 45 (12) L/min. In the intent-to-treat (ITT) population, revefenacin improved trough FEV 1 from baseline; however, the difference versus tiotropium was not significant (least squares [LS] mean difference [standard error], 17.0 [22.4] mL, P=0.4461). In a prespecified analysis of patients with FEV 1 < 50% predicted, revefenacin produced an LS mean difference (95% confidence interval [CI]), 49.1 (6.3-91.9) mL in trough FEV 1 and 103.5 (7.7-199.3) mL in forced vital capacity versus tiotropium. Revefenacin produced >100 mL increase in FEV 1 in 41.6% versus 34.4% of patients with tiotropium in ITT and 41.4% versus 25.7% of patients in FEV 1 < 50% predicted populations., Conclusions: Revefenacin did not produce significant improvements in FEV1 versus tiotropium in the ITT population, but increased trough FEV 1 in patients with FEV 1 < 50% predicted and sPIFR. Clinical Trial Registration (www.Clinicaltrials.gov): Study 0149 (NCT03095456)., Competing Interests: DAM has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc, Grifols SA, Sunovion Pharmaceuticals Inc., Theravance Biopharma, Inc., and Trevi and is on the speaker’s bureau for AstraZeneca, Boehringer Ingelheim, and Sunovion Pharmaceuticals Inc. JAO has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc, Mylan Inc, Reckitt Benckiser Group plc, Sunovion Pharmaceuticals Inc., and Theravance Biopharma, Inc. EJM and GDC are employees of Theravance Biopharma US, Inc. CNB and SP were employees of Theravance Biopharma US, Inc. at the time this study was conducted., (JCOPDF © 2019.)

This article contains information on the experimental design and methods on how the safety and tolerability data concerning patients with moderate to very severe chronic obstructive pulmonary disease (COPD) were obtained. This is in addition to our original research article. [1] We have also provided information on the clinical laboratory tests that were conducted. Further interpretation and discussion of the data are demonstrated in the article "Revefenacin, a Once-daily, Lung-selective, Long-acting Muscarinic Antagonist for Nebulized Therapy: Safety and Tolerability Results of a 52-week Phase 3 Trial in Moderate to Very Severe Chronic Obstructive Pulmonary Disease." [1].

Background: Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 μg and 175 μg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 μg and 175 μg over 52 weeks of treatment., Methods: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 μg or 175 μg in a double-blind manner, or open-label active control tiotropium., Results: Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 μg, 272 [74.7%]; 175 μg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 μg (73 [21.8%]) than with 88 μg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 μg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 μg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 μg or tiotropium with a concurrent long-acting β-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 μg., Conclusions: Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Revefenacin, a novel, lung-selective, long-acting muscarinic antagonist, has been developed for nebulized therapy for chronic obstructive pulmonary disease (COPD). We present the results of replicate Phase III efficacy and safety studies of revefenacin in patients with moderate to very severe COPD., Methods: In 2 double-blind, parallel-group studies, (Study 0126 and Study 0127), patients ≥ 40 years old were randomized to revefenacin 88 μg, revefenacin 175 μg or placebo administered once daily by standard jet nebulizer for 12 weeks. The primary endpoint was 24-hour trough forced expiratory volume in 1 second (FEV 1 ) on day 85. Secondary efficacy endpoints included overall treatment effect (OTE) on trough FEV 1 and peak FEV 1 (0-2 hours after first dose). Safety assessments included treatment-emergent adverse events., Results: At day 85, revefenacin 88 µg and 175 µg improved trough FEV 1 versus placebo in Study 0126 (by 79 mL [ p =0.0003] and 146 mL [ p <0.0001]) and Study 0127 (by 160 mL and 147 mL; both p <0.0001). Compared with placebo, pooled data of revefenacin 88 µg and 175 µg increased OTE trough FEV 1 by 115 mL and 142 mL (both p <0.001) and increased peak FEV 1 by 127 mL and 129 mL (both p <0.0001). Revefenacin 175 µg demonstrated greater improvements in FEV 1 in concomitant long-acting beta2-agonist patients and in more severe patients than revefenacin 88 µg. Adverse events were minor., Conclusion: Revefenacin, administered once daily for 12 weeks to patients with moderate to very severe COPD, demonstrated clinically significant improvements in trough FEV 1 and OTE FEV 1 . Revefenacin was generally well tolerated with no major safety concerns., Competing Interests: GTF has received grants, served on advisory boards, received consulting fees and/or received speaking fees from AstraZeneca, Boehringer Ingelheim, Circassia, Forest, GlaxoSmithKline, Innoviva, Meda, Mylan, Novartis, Pearl Therapeutics, Sanofi, Sunovion, Theravance Biopharma and Verona. GF and KKP have nothing to declare. CNB, EJM, BH, SP and GC are employees of Theravance Biopharma US, Inc. Mylan Inc., (Canonsburg, Pennsylvania) and Theravance Biopharma US, Inc., (South San Francisco, California) funded medical writing support., (JCOPDF © 2019.)

Background: Revefenacin (TD-4208) is a potent, lung-selective, long-acting muscarinic antagonist currently in development as a once-daily nebulized therapy for chronic obstructive pulmonary disease (COPD). We evaluated the pharmacodynamics (bronchodilator activity), pharmacokinetics (PK) and safety of single- and multiple-dose administrations of revefenacin in two clinical trials (Study 0059 and Study 0091) in patients with moderate to severe COPD., Methods: In Study 0059, 32 patients were randomized to receive a single dose of revefenacin (350 or 700 μg), active control ipratropium (500 μg) or placebo inhalation solution administered via standard jet nebulizer in a double-blind, crossover fashion. In Study 0091, 59 patients were randomized to receive once-daily inhalations of revefenacin (22, 44, 88, 175, 350 or 700 μg) or placebo for 7 days in a double-blind, incomplete block, five-way crossover design. The primary efficacy endpoint was change from baseline in peak (0-6 h) forced expiratory volume in 1 s (FEV 1 ) in Study 0059, and trough FEV 1 after the final dose (Day 7) in Study 0091. In both studies, secondary endpoints included area under the FEV 1 -time curve (FEV 1 AUC) values from time 12-24 h post dose and FEV 1 AUC values from time zero to 24 h post dose., Results: Revefenacin demonstrated a rapid onset and sustained duration of bronchodilator action in both studies. In Study 0059, mean peak FEV 1 was significantly higher (p < 0.001) for revefenacin and ipratropium compared to placebo, with differences of 176.8 mL for 350 μg revefenacin, 162.2 mL for 700 μg revefenacin and 190.6 mL for ipratropium. In Study 0091, mean trough FEV 1 on Day 7 was significantly higher (p < 0.006) for all revefenacin doses compared to placebo, with differences ranging from 53.5 mL (22 μg dose) to 114.2 mL (175 μg dose). The results for the other spirometry endpoints were consistent with the primary endpoint for each study, demonstrating that the bronchodilator effect of revefenacin lasted more than 24 h following nebulized administration. Revefenacin was rapidly absorbed and extensively metabolized, followed by a slow apparent terminal elimination and minimal accumulation with repeated dosing. In both studies, adverse events were generally mild and occurred with similar frequencies in all groups, with no indication of significant systemic anti-muscarinic activity at any dose., Conclusions: Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Revefenacin is a once-daily long-acting muscarinic antagonist (LAMA) in clinical development for the treatment of patients with chronic obstructive pulmonary disease (COPD). In a dose-ranging study, nebulized once-daily revefenacin had a long duration of action in patients after 7 days' administration of doses up to 700 μg. In this multiple-dose study, the bronchodilation efficacy and adverse events profile were characterized in patients administered nebulized revefenacin once daily for 28 days., Methods: A total of 355 COPD patients (mean age 62 years, mean forced expiratory volume in 1 s [FEV 1 ] 44% of predicted) were randomized in a double-blind, placebo-controlled parallel group study. Inhaled corticosteroids as well as short-acting bronchodilators were permitted. Once-daily treatments (44, 88, 175 or 350 μg revefenacin or matching placebo) were administered by a standard jet nebulizer, for 28 days. The primary endpoint was change from baseline in D28 trough FEV 1 , and secondary endpoints included weighted mean FEV 1 over 0 to 24 h and rescue medication (albuterol) use. Safety evaluations included adverse events, laboratory assessments, electrocardiograms and 24-h Holter profiles., Results: Revefenacin (88, 175 and 350 μg) significantly improved D28 trough FEV 1 over placebo (187.4, 166.6 and 170.6 mL, respectively, all p < 0.001); 44 μg produced a sub-therapeutic response. At doses ≥88 μg, more than 80% of patients achieved at least a 100-mL increase from baseline FEV 1 in the first 4 h post dose compared with 33% of placebo patients. For doses ≥88 μg, D28 24 h weighted mean differences from placebo for FEV 1 were numerically similar to respective trough FEV 1 values, indicating bronchodilation was sustained for 24 h post dose. Doses ≥88 μg reduced the average number of albuterol puffs/day by more than one puff/day. The 350 μg dose did not demonstrate additional efficacy over that observed with 175 μg revefenacin. Revefenacin was generally well tolerated, with minimal reports of systemic anti-cholinergic effects., Conclusions: These data suggest that 88 and 175 μg revefenacin are appropriate doses for use in longer-term safety and efficacy trials. Revefenacin offers the potential for the first once-daily LAMA for nebulization in patients with COPD who require or prefer a nebulized drug delivery option., Trial Registration: ClinicalTrials.gov NCT02040792 . Registered January 16, 2014.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive extranodal T-cell lymphoma that can arise in patients with underlying immune disorders. Others have suggested that tumor necrosis factor (TNF)-α inhibitor therapy for immune disorders increases the risk of HSTCL. To assess for a potential relationship between HSTCL and the use of TNF-α inhibitors, we searched for patients with HSTCL and underlying immune disorders at our institution. We identified 7 patients with a median age of 38 years. Five patients had Crohn disease, 1 ulcerative colitis, and 1 rheumatoid arthritis. In 6 patients, medication history for the immune disorder was available: 6 patients received 6-mercaptopurine or azathioprine, and 2 patients received steroids; no patients received TNF-α inhibitors. In all 7 patients, the histologic, immunophenotypic, and cytogenetic findings were similar to cases of HSTCL that arise in immunocompetent patients. We reviewed the literature and identified 60 patients with immune disorders who subsequently developed HSTCL. These patients were treated with immunosuppressive drugs in 89%, TNF-α inhibitors in 56%, and both therapies in 54%, and 1 (2%) patient was treated with TNF-α inhibitors only. Our cohort and literature review indicates that TNF-α inhibitor therapy is not essential for the development of HSTCL in patients with immunodysregulatory disorders, and implies that immunosuppressive drugs or other factors (eg, genetic predisposition, chronic antigenic stimulation) may be more critical in the pathogenesis in this context. Although these data are observational, they have implications for the use of TNF-α inhibitors in patients with inflammatory bowel disease and other immunodysregulatory disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The report of an Expert Panel convened by the National Research Council (NRC) of the National Academy of Sciences (NAS), entitled Science and Decisions: Advancing Risk Assessment (National Research Council, 2009a), includes a recommendation to use, as a default approach, low-dose linear extrapolation for systemic toxicity. This recommendation represents a significant departure from long-standing risk assessment practices for non-cancer toxicity, where the most appropriate No Observed Adverse Effect Level (NOAEL) or Benchmark Dose (BMD) of the critical effect in the key study is selected, and then a "safe exposure" level is derived by applying uncertainty factors to account for dataset completeness, potential greater sensitivity of humans when compared with experimental animals, and for potential variability of sensitivity in humans. A workshop was held to "frame" issues raised by the NAS report that needed further study. Workshop objectives included the following: (1) identify the issues raised by the 2009 NRC report and discuss the extent to which existing science may (or may not) align with the NAS analyses and recommendations, and (2) identify/develop possible actions to assist in advancing deeper and broader considerations of some of the critical issues presented by the 2009 NAS Panel. Experts invited to this "Framing" Workshop encompassed a full spectrum of toxicology and risk assessment disciplines; in particular, expertise in molecular interactions and dose-response of biological systems were well represented. The recommendations developed at this Framing Workshop provide specific ideas on possible further steps to facilitate deeper and broader consideration of the issues underpinning dose-response extrapolation in the risk assessment of systemic toxicants., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28-36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.

The design, synthesis and antibacterial activity of novel glycopeptide/beta-lactam heterodimers is reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, A and B respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The antibiotics 8a-f displayed remarkable potency against a wide range of Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA). Compound 8e demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and initial evidence supports a multivalent mechanism of action for this important new class of antibiotic.

Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.

Solution-phase combinatorial chemistry was applied to the optimization and development of clinical candidate OC144-093 (22), a novel and nontoxic modulator of P-glycoprotein mediated multidrug resistance.

N-4,5-Di-(4-dialkylamino)phenyl imidazoles (A) are potent modulators of P-glycoprotein mediated multidrug resistance. This manuscript describes the discovery and lead optimization of this novel class of inhibitors.

OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed multidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in human lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by OC144-093 was reversible, but the effect persisted for at least 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-gp expression or expressing a multidrug resistance-associated protein (MRP-1). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 microM. OC144-093 blocked the binding of [3H]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.-administered paclitaxel. OC144-093 increased the life span of doxorubicin-treated mice engrafted with MDR P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of paclitaxel in MDR human breast and colon carcinoma xenograft models, without a significant increase in doxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/or induction of refractory disease.

Recent regulatory efforts have devoted attention to carbon disulfide (CS2) exposure and its potential effects on the cardiovascular system. To investigate the association between CS2 exposure and ischemic heart disease (IHD) mortality, the analysis presented here had the following objectives: (i) to review historical CS2 exposure data in the viscose rayon industry and identify trends and (ii) to use these historical data to suggest a standard mortality ratio (SMR)-exposure relationship and a threshold level for occupational exposure to CS2, CS2 exposure data were extracted from published studies and used with the SMR versus exposure score relationship developed by Sweetnam et al. (Br. J. Ind. Med. 44, 220-227, 1987) to relate SMRs directly to exposure. Upper and lower bound exposure profiles were derived and used to identify exposure thresholds. For an IHD SMR equal to 100, the upper and lower bound exposures were 60 and 20 ppm, respectively. The analysis indicates that the risk of IHD mortality and its relationship to CS2 exposure is meaningful only for workers exposed to high level for many years. These high levels, which existed many years ago, are no longer found in the workplace. The results of this analysis suggest a safe regulatory exposure level for CS2 between 15 and 20 ppm.

A statistical analysis of the NIOSH (National Institute for Occupational Safety and Health) carbon disulfide (CS2) exposure database was conducted for purposes of establishing a benchmark concentration (BMC) for CS2. The analysis addressed the effects of CS2 exposure on the peripheral nervous system and on ischemic heart disease risk factors. The BMC is based on models relating response to exposure determined from statistical analysis of the continuous exposure data for individuals recorded in the NIOSH database. The results demonstrate that changes in the responses associated with increases in CS2 exposure at levels represented in the NIOSH database are relatively small after adjustment for confounders. The only response variables that had statistically significant relationships with CS2 were the peroneal nerve MCV (motor conduction velocity) and the peroneal nerve amplitude ratio. Based on these results, BMCs of 16.2 and 18.5 ppm were derived for MCV and amplitude ratio, respectively.

The solid phase synthesis and generation of libraries of "unnatural biopolymers" is described. These polymers are characterized by novel backbones and building blocks, the properties of which may modify their pharmacological and folding properties.

A highly efficient method has been developed for the solid-phase synthesis of an "unnatural biopolymer" consisting of chiral aminocarbonate monomers linked via a carbamate backbone. Oligocarbamates were synthesized from N-protected p-nitrophenyl carbonate monomers, substituted with a variety of side chains, with greater than 99 percent overall coupling efficiencies per step. A spatially defined library of oligocarbamates was generated by using photochemical methods and screened for binding affinity to a monoclonal antibody. A number of high-affinity ligands were then synthesized and analyzed in solution with respect to their inhibition concentration values, water/octanol partitioning coefficients, and proteolytic stability. These and other unnatural polymers may provide new frameworks for drug development and for testing theories of protein and peptide folding and structure.

The odds are stacked against CEOs who hope their jobs will survive embattled relations with their medical staffs. An estimated 50 to 75 percent of CEOs who are fired lose their jobs as a direct result of medical staff conflicts. Some CEOs who have survived such conflicts say that the key is finding unusual solutions to conventional problems.

The Occupational Safety and Health Administration, Washington DC, estimates that 90 percent of hospitals already comply with its proposed infection control standards. But some hospitals aren't waiting for mandates; instead, they're taking more progressive action of their own.

A growing number of hospital administrators are switching careers. Whether unable to find work, fed up with the health care system, or simply ready for a change--these people are leaving the hospital setting for what they believe are greener pastures, and some of them won't be back.

After years of competition with a neighboring hospital, you've realized that your hospital can't win. Your bottom line is red, the interests of the community are suffering, and merging is the only viable option. Only one question remains: What becomes of you? It's probably time to update your resume, even if you're the CEO spearheading the project, according to recruiters.