Explore the vast range of titles available.

In two trials involving patients with hepatitis C in whom previous treatment with direct-acting antiviral agents failed, treatment for 12 weeks with sofosbuvir, velpatasvir, and voxilaprevir achieved high rates of sustained virologic response. The majority of patients who are chronically infected with hepatitis C virus (HCV) can now be successfully treated with drugs that directly target viral replication. 1 , 2 Combination regimens of direct-acting antiviral agents (DAAs) provide rates of sustained virologic response exceeding 90%, regardless of HCV genotype, disease stage, or treatment history. 3 The proportion of patients who do not have a sustained virologic response to treatment with approved regimens is small, but given the size of the infected population — estimates range up to 150 million people worldwide 4 — the absolute number of such patients is substantial and will increase as more . . .

In patients with HCV genotype 1 infection and cirrhosis, the rate of sustained virologic response was 92% with three new antiviral agents plus ribavirin for 12 weeks and 96% with the same regimen for 24 weeks. Two percent of patients discontinued treatment because of adverse events. An estimated 184 million people worldwide have hepatitis C virus (HCV) infection, 1 a leading cause of chronic liver disease and the leading indication for liver transplantation globally. 2 , 3 Approximately 25% of persons with HCV infection in the United States have cirrhosis, and this number is expected to rise to 37% by 2020. 4 , 5 Eradication of HCV with antiviral therapy reduces the risk of hepatic decompensation, hepatocellular carcinoma, and death from a liver-related cause or any cause. 6 – 10 Among patients with HCV infection and cirrhosis in whom peginterferon–ribavirin treatment has failed, rates of sustained virologic response to retreatment with interferon-containing regimens . . .

In this trial in previously untreated patients with HCV genotype 1 infection and no cirrhosis, high rates of sustained response were achieved with three new direct-acting antiviral agents and ribavirin. Serious adverse events and treatment discontinuation were infrequent. Approximately 184 million people worldwide have chronic hepatitis C virus (HCV) infection, and more than 350,000 people die of HCV-related liver disease each year. 1 , 2 Until recently, the standard of care for chronic HCV genotype 1 infection was a first-generation protease inhibitor, telaprevir or boceprevir, with peginterferon and ribavirin; this therapy resulted in rates of sustained virologic response of 67 to 75% among previously untreated patients. 3 , 4 The new standard of care is peginterferon and ribavirin combined with either the nucleotide nonstructural (NS) 5B polymerase inhibitor sofosbuvir or the protease inhibitor simeprevir. 5 Peginterferon-based treatment is associated with clinically significant systemic . . .

Among previously untreated patients with HCV genotype 1 infection, three new antiviral agents, with or without ribavirin, resulted in high rates of sustained virologic response. Omission of ribavirin resulted in reduced response in genotype 1a infection but not in genotype 1b infection. Hepatitis C virus (HCV) infection is a worldwide health issue, with 3 million to 4 million new infections yearly and infection rates as high as 5% in some countries. 1 Chronic infection leads to liver disease, cirrhosis, or liver cancer in a large proportion of infected persons, and hepatitis C accounts for 25% of all liver cancers, representing the leading indication for liver transplantation. 1 – 3 Genotype 1 is the most common HCV genotype worldwide and includes 11 subgenotypes, of which 1a and 1b are responsible for the vast majority of infections. 4 Genotype 1b infection is the most prevalent form worldwide, particularly . . .

In this trial in patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon and ribavirin, retreatment with three new oral antiviral agents and ribavirin resulted in a sustained virologic response in 96% of patients. Patients with chronic hepatitis C virus (HCV) infection are at risk for progressive liver fibrosis, cirrhosis, portal hypertension, hepatocellular carcinoma, and decompensated liver disease. HCV infection can be cured with antiviral therapy, reducing the risk of illness and death associated with end-stage liver disease. 1 – 3 For more than a decade, patients with HCV genotype 1 infection have been treated with peginterferon–ribavirin dual therapy, resulting in rates of sustained virologic response of approximately 40 to 50%. 4 – 6 Response rates among previously untreated patients have been shown to increase to 68 to 75% with peginterferon–ribavirin plus a protease inhibitor (telaprevir or boceprevir, . . .

In this phase 2 study, peginterferon-free regimens were effective in patients with hepatitis C virus genotype 1 infection. Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, liver cancer, and end-stage liver disease. 1 The current standard of care for chronic HCV genotype 1 infection is pegylated interferon (peginterferon) and ribavirin, with a protease inhibitor (boceprevir or telaprevir). 2 Although the addition of a protease inhibitor has been associated with a significant increase in response rates, only approximately one third of patients who had not had a response to prior therapy with peginterferon and ribavirin had a sustained virologic response when re-treated with the addition of a protease inhibitor. 3 , 4 Furthermore, these therapies are associated with adverse . . .

The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes 1 , 2 . Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia 3 . Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle 4 and a glucoside to insulin, thereby introducing a switch that can open and close in response to glucose and thereby equilibrate insulin between active and less-active conformations. The insulin receptor affinity for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions. NNC2215 is an insulin conjugate that can reversibly adjust its bioactivity in response to a diabetes-relevant glucose range in vivo.

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8–11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations. Medium-sized ring systems are common in natural products, however their synthesis is challenging, largely due to entropic factors. Here the authors report a radical-based method for the synthesis of medium to large functionalized, carbon or heterocyclic scaffolds.

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens 1 . These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that—if successful—will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need. A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.

PurposeEnteral feeding intolerance (EFI) is a frequent problem in the intensive care unit (ICU), but current prokinetic agents have uncertain efficacy and safety profiles. The current study compared the efficacy and safety of ulimorelin, a ghrelin agonist, with metoclopramide in the treatment of EFI.MethodsOne hundred twenty ICU patients were randomized 1:1 to ulimorelin or metoclopramide for 5 days. EFI was diagnosed by a gastric residual volume (GRV) ≥ 500 ml. A volume-based feeding protocol was employed, and enteral formulas were standardized. The primary end point was the percentage daily protein prescription (%DPP) received by patients over 5 days of treatment. Secondary end points included feeding success, defined as 80% DPP; gastric emptying, assessed by paracetamol absorption; incidences of recurrent intolerance (GRV ≥ 500 ml); vomiting or regurgitation; aspiration, defined by positive tracheal aspirates for pepsin; and pulmonary infection.ResultsOne hundred twenty patients were randomized and received the study drug (ulimorelin 62, metoclopramide 58). Mean APACHE II and SOFA scores were 21.6 and 8.6, and 63.3% of patients had medical reasons for ICU admission. Ulimorelin and metoclopramide resulted in comparable %DPPs over 5 days of treatment (median [Q1, Q3]: 82.9% [38.4%, 100.2%] and 82.3% [65.6%, 100.2%], respectively, p = 0.49). Five-day rates of feeding success were 67.7% and 70.6% when terminations unrelated to feeding were excluded, and there were no differences in any secondary outcomes or adverse events between the two groups.ConclusionsBoth prokinetic agents achieved similar rates of feeding success, and no safety differences between the two treatment groups were observed.