22 research outputs found
Different residues in the SARS-CoV spike protein determine cleavage and activation by the host cell protease TMPRSS2.
No full textThe spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) mediates viral entry into target cells. Cleavage and activation of SARS S by a host cell protease is essential for infectious viral entry and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease TMPRSS2 cleaves and activates SARS S in cell culture and potentially also in the infected host. Here, we investigated which determinants in SARS S control cleavage and activation by TMPRSS2. We found that SARS S residue R667, a previously identified trypsin cleavage site, is also required for S protein cleavage by TMPRSS2. The cleavage fragments produced by trypsin and TMPRSS2 differed in their decoration with N-glycans, suggesting that these proteases cleave different SARS S glycoforms. Although R667 was required for SARS S cleavage by TMPRSS2, this residue was dispensable for TMPRSS2-mediated S protein activation. Conversely, residue R797, previously reported to be required for SARS S activation by trypsin, was dispensable for S protein cleavage but required for S protein activation by TMPRSS2. Collectively, these results show that different residues in SARS S control cleavage and activation by TMPRSS2, suggesting that these processes are more complex than initially appreciated
The eschatology of Margaret Fell (1614-1702) and its place in her theology and ministry
No full textEThOS - Electronic Theses Online ServiceGBUnited Kingdo
Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial
No full textImportance: Muscle-related statin intolerance is reported by 5%to 20%of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420mg monthly) or oral ezetimibe (10mg daily). Main Outcome and Measures: Coprimary end pointswere the mean percent change in LDL-C level from baseline to the mean ofweeks 22 and 24 levels and from baseline toweek 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9]mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72]mg/dL). For the mean ofweeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7%(95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5%(95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptomswere reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drugwas stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety
Dämme, Pässe, Brücken, Schanzen und eine Heerstraße – zur Rekonstruktion mittelalterlicher und frühneuzeitlicher Infrastruktur in einer norddeutschen Grenzlandschaft
No full text
Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients:Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial
No full textStatins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co-primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.</p
Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection
No full textThe mechanism-based risk for hyperkalemia
has limited the use of
mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal
diseases. Here, we describe the structure and property-driven lead
generation and optimization, which resulted in identification of MR
modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated
equally efficacious organ protection as eplerenone after 4 weeks of
treatment in uni-nephrectomized rats on high-salt diet and aldosterone
infusion. Importantly, and in sharp contrast to eplerenone, this was
achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced
risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate
for treating MR-mediated cardio-renal diseases, including chronic
kidney disease and heart failure. On the basis of our findings, we
propose an empirical model for prediction of compounds with low risk
of affecting the urinary Na+/K+ ratio in vivo
Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection
No full textThe mechanism-based risk for hyperkalemia
has limited the use of
mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal
diseases. Here, we describe the structure and property-driven lead
generation and optimization, which resulted in identification of MR
modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated
equally efficacious organ protection as eplerenone after 4 weeks of
treatment in uni-nephrectomized rats on high-salt diet and aldosterone
infusion. Importantly, and in sharp contrast to eplerenone, this was
achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced
risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate
for treating MR-mediated cardio-renal diseases, including chronic
kidney disease and heart failure. On the basis of our findings, we
propose an empirical model for prediction of compounds with low risk
of affecting the urinary Na+/K+ ratio in vivo
