57 research outputs found
Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial
Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18â85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25â75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300â5000 mg/g who had received maximum labelled or tolerated reninâangiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for â„30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for â„90 days, chronic dialysis for â„90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4â2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49â0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85â2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75â1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie
Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).
Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and â„1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (nâ=â5069) or prospectively (nâ=â5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (â€6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; pâ=â0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)
Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.
BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362
C19-Diterpenoid alkaloid arabinosides from an aqueous extract of the lateral root of Aconitum carmichaelii and their analgesic activities
Eight new C19-diterpenoid alkaloid arabinosides, named aconicarmichosides EâL (1â8), were isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii (Fu Zi). Their structures were determined by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1â8, together with the previously reported four neoline 14-O-arabinosides from the same plant, represent the only examples of glycosidic diterpenoid alkaloids so far. At a dose of 1.0âŻmg/kg (i.p.), as compared with the black control, compounds 1, 2, and 4â6 exhibited analgesic effects with >65.6% inhibitions against acetic acid-induced writhing of mice. Structureâactivity relationship was also discussed. KEY WORDS: Ranunculaceae, Aconitum carmichaelii, C19-diterpenoid alkaloid, Arabinoside, Aconicarmichosides EâL, Analgesic effect, Structureâactivity relationshi
Aconicarmisulfonine A, a Sulfonated C<sub>20</sub>-Diterpenoid Alkaloid from the Lateral Roots of <i>Aconitum carmichaelii</i>
A novel sulfonated
C<sub>20</sub>-diterpenoid alkaloid with an
unprecedented carbon skeleton and significant analgesic activity (46.7%
inhibition at 0.1 mg/kg, i.p.), named aconicarmisulfonine A (<b>1</b>), was isolated from an aqueous extract of the lateral roots
of <i>Aconitum carmichaelii</i>. Its structure was determined
by comprehensive analysis of spectroscopic data, especially by 2D
NMR spectroscopic data combined with ECD calculation and single-crystal
X-ray diffraction. The plausible biosynthetic pathways of compound <b>1</b> are also discussed
Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimerâs Disease
Neuroinflammatory reactions mediated by microglia and astrocytes have been shown to play a key role in early progression of Alzheimerâs disease (AD). Increased evidences have demonstrated that neurons exacerbate local inflammatory reactions by producing inflammatory mediators and act as an important participant in the pathogenesis of AD. Methyl salicylate lactoside (MSL) is an isolated natural product that is part of a class of novel non-steroidal anti-inflammatory drugs (NSAID). In our previous studies, we demonstrated that MSL exhibited therapeutic effects on arthritis-induced mice and suppressed the activation of glial cells. In the current study, we investigated the effects of MSL on cognitive function and neuronal protection induced by amyloid-beta peptides (AÎČ) and explored potential underlying mechanisms involved. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice were used to evaluate the effects of MSL through behavioral testing and neuronal degenerative changes. In addition, copper-injured APP Swedish mutation overexpressing SH-SY5Y cells were used to determine the transduction of cyclooxygenase (COX) and mitogen-activated protein kinase (MAPK) pathways. Our results indicated that at an early stage, MSL treatment ameliorated cognitive impairment and neurodegeneration in APP/PS1 mice. Moreover, in an in vitro AD model, MSL treatment protected injured cells by increasing cell viability, improving mitochondrial dysfunction, and decreasing oxidative damage. In addition, MSL inhibited the phosphorylated level of c-Jun N-terminal kinase (JNK) and p38 MAPK, and suppressed the expression of COX-1/2. As a novel NSAIDs and used for the treatment in early stage of AD, MSL clearly demonstrated cognitive preservation by protecting neurons via a pleiotropic anti-inflammatory effect in the context of AD-associated deficits. Therefore, early treatment of anti-inflammatory therapy may be an effective strategy for treating AD
A Light Responsive Nanoparticle-Based Delivery System Using Pheophorbide A Graft Polyethylenimine for Dendritic Cell-Based Cancer Immunotherapy
In this study, the photochemical
internalization (PCI) technique
was adopted in a nanoparticle-based antigen delivery system to enhance
antigen-specific CD8<sup>+</sup> T cell immune response for cancer
immunotherapy. Pheophorbide A, a hydrophobic photosensitizer, grafted
with polyethylenimine (PheoA-PEI) with endosome escape activity and
near-infrared imaging capability was prepared. A model antigen ovalbumin
(OVA) was then complexed with PheoA-PEI to form PheoA-PEI/OVA nanoparticles
(PheoA-PEI/OVA NPs) that are responsive to light. Flow cytometry analysis
revealed increased endocytosis in a murine dendritic cell line (DC2.4)
that was treated with PheoA-PEI/OVA NPs compared to free OVA. Generation
of reactive oxygen species (ROS) in DC2.4 cells was also confirmed
quantitatively and qualitatively using 2âČ,7âČ-dichlorodihydrofluorescein
diacetate (DCFH-DA). Confocal laser scanning microscopy (CLSM) further
demonstrated that the PheoA-PEI/OVA NPs enhanced cytosolic antigen
release after light stimulation. Moreover, PheoA-PEI/OVA NP treated
DC2.4 cells exhibited enhanced cross-presentation to B3Z T cell hybridoma <i>in vitro</i> after light irradiation, substantially increased
compared to those treated with free OVA. Consistently, <i>in
vivo</i> results revealed upregulation of CD3<sup>+</sup>CD8<sup>+</sup>T lymphocytes in tumors of mice treated with dendritic cells
plus PheoA-PEI/OVA NPs and light irradiation. The activated T cell
response is partly responsible for the inhibitory effect on E.G7 tumor
growth in mice immunized with dendritic cells plus PheoA-PEI/OVA NPs
and light irradiation. Our results demonstrate the feasibility to
enhance antigen-specific CD8<sup>+</sup> T cell immune response by
light-responsive nanoparticle-based vaccine delivery for cancer immunotherapy
Side-Chain Metallopolymers Containing Second-Order NLO-Active Bimetallic Ni-II and Pd-II Schiff-Base Complexes: Syntheses, Structures, Electrochemical and Computational Studies
International audienceUnsymmetric Schiff-base metalloligand precursor 2 is synthesized by condensation of phenol-functionalized ferrocenylenaminone 1 with 2-hydroxy-5-nitrobenzaldehyde. Heterobimetallic complexes 3 and 4 result from the N2O2-tetradentate coordination of Ni-II and Pd-II metal ions with the doubly deprotonated form of 2, respectively. Linking 3 and 4 to polyacrylic acid through an esterification reaction leads to the formation of the corresponding side-chain metallopolymers 5 and 6. The new compounds were fully characterized (IR, UV/Vis, NMR, MS, CV, SEC) and structures of 2-4 unequivocally determined by single-crystal X-ray diffraction techniques. Decomposition temperatures higher than 250 degrees C were found by DSC and TGA techniques for 3-6. Harmonic light scattering measurements showed that compounds 2-5 exhibit rather high second-order nonlinear responses, between 200x10(-30) and 970x10(-30) esu, with the hyperpolarizability (1.91) value increasing significantly on passing from Ni-II complex 3 to its respective metallopolymer 5. The structural and electronic properties of 2-4 are analyzed by DFT and TD-DFT calculations
Side-Chain Metallopolymers Containing Second-Order NLO-Active Bimetallic NiII and PdII Schiff-Base Complexes: Syntheses, Structures, Electrochemical and Computational Studies
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