Measurement of ultralow losses in an optical interferometer

Characterizations of low-loss mirrors by measurements of cavity-decay time and of cavity finesse are reported near 850 nm. The lowest observed mirror loss is 1.6 x 10^-6 (transmission plus absorption and scatter), which corresponds to a reflectivity of 0.9999984 and to a cavity finesse of 1.9 x 10^6

Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis

Importance Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. Objective All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. Design, Setting, and Participants The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. Interventions All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. Main Outcomes and Measures Sustained virologic response at posttreatment week 12 (SVR12). Results One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5% CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.4%-100.0%) for patients in the treatment-naive group and 87% (97.5% CI, 75.3%-98.0%) for those in the treatment-experienced group. Three serious adverse events were considered to be treatment related and there were 4 adverse event–related discontinuations. Treatment-emergent grade 3 or 4 alanine aminotransferase elevations were observed in 4 patients, of which 1 had concomitant total bilirubin elevation. Conclusions and Relevance In this open-label uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR12

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19):an investigator-initiated, randomised, open-label, phase 2 trial

Background Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. Methods We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m(2) on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. Findings Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36.5 months (95% CI 34.2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6.2 months [95% CI 4.6-8.7]) than in the supportive care group (3.2 months [2.8-4.1]; hazard ratio [HR] 0.48 [95% CI 0.33-0.71]; p=0.0002). The benefit was confirmed by masked independent central review (HR 0.49 [0.33-0.72]; p=0.0002). Grade 3-4 adverse events occurred in 33 ( 52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. Interpretation Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma

Comparison of the Safety and Pharmacokinetics of ST-246® after IV Infusion or Oral Administration in Mice, Rabbits and Monkeys

ST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (IV) formulation may be required for some hospitalized patients who are unable to take oral medication. An IV formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation. plasma concentrations. These effects were eliminated using slower IV infusions. associated toxicity. Shorter infusions at higher doses in NHP resulted in decreased clearance, suggesting saturated distribution or elimination. Elimination half-lives in all species were similar between oral and IV administration. The administration of ST-246 was well tolerated as a slow IV infusion

Antiviral Activity, Pharmacokinetics, and Safety of BMS-488043, a Novel Oral Small-Molecule HIV-1 Attachment Inhibitor, in HIV-1-Infected Subjects

ABSTRACT BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4 + lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an 8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043 concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose groups on day 8 were 0.72 and 0.96 log 10 copies/ml, respectively, compared with 0.02 log 10 copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC 50 ) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated with an antiviral response, the trough concentration ( C trough ), adjusted by the baseline EC 50 ( C trough /EC 50 ), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is warranted

Scaling Up Programmatic Management of Drug-Resistant Tuberculosis: A Prioritized Research Agenda

Frank Cobelens and colleagues outline key research questions that need to be addressed to maximize the impact of programmatic management of drug-resistant tuberculosis

Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study

Direct Binding of a Hepatitis C Virus Inhibitor to the Viral Capsid Protein

Over 130 million people are infected chronically with hepatitis C virus (HCV), which, together with HBV, is the leading cause of liver disease. Novel small molecule inhibitors of Hepatitis C virus (HCV) are needed to complement or replace current treatments based on pegylated interferon and ribavirin, which are only partially successful and plagued with side-effects. Assembly of the virion is initiated by the oligomerization of core, the capsid protein, followed by the interaction with NS5A and other HCV proteins. By screening for inhibitors of core dimerization, we previously discovered peptides and drug-like compounds that disrupt interactions between core and other HCV proteins, NS3 and NS5A, and block HCV production. Here we report that a biotinylated derivative of SL209, a prototype small molecule inhibitor of core dimerization (IC50 of 2.80 µM) that inhibits HCV production with an EC50 of 3.20 µM, is capable of penetrating HCV-infected cells and tracking with core. Interaction between the inhibitors, core and other viral proteins was demonstrated by SL209–mediated affinity-isolation of HCV proteins from lysates of infected cells, or of the corresponding recombinant HCV proteins. SL209-like inhibitors of HCV core may form the basis of novel treatments of Hepatitis C in combination with other target-specific HCV drugs such as inhibitors of the NS3 protease, the NS5B polymerase, or the NS5A regulatory protein. More generally, our work supports the hypothesis that inhibitors of viral capsid formation might constitute a new class of potent antiviral agents, as was recently also shown for HIV capsid inhibitors

Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry

Emerging viral diseases pose a threat to the global population as intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The former was the only available intervention when the current unprecedented Ebolavirus (EBOV) outbreak in West Africa began. Prior to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus has turned to re-purposing of existing, licenced medicines that may limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their ability to inhibit pseudotype viruses (PVs) of two EBOV species, Marburg virus (MARV) and avian influenza H5 (FLU-H5). We confirm the ability of chloroquine (CQ) to inhibit viral entry in a pH specific manner. The commonly used proton pump inhibitors, Omeprazole and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved in vivo. We propose CQ as a priority candidate to consider for treatment of EBOV