scholarly journals Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD

2020 ◽  
Vol 15 (11) ◽  
pp. 1566-1575
Author(s):  
Jing Chen ◽  
L. Lee Hamm ◽  
Joshua D. Bundy ◽  
Damodar R. Kumbala ◽  
Shirisha Bodana ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Adverse Events ◽  
Confidence Interval ◽  
Sodium Nitrite ◽  
Combination Treatment ◽  
Pilot Trial ◽  
Albumin Creatinine Ratio ◽  
Urine Albumin ◽  
Flow Mediated Vasodilation ◽  
And Oxidative Stress

Background and objectivesEndothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD.Design, setting, participants, & measurementsThis randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted.ResultsBaseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, −0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, −0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, −0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups.ConclusionsThis randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD.Clinical Trial registry name and registration number:Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888

Clinical study on medical value of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer (COMVI study).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 628-628
Author(s):  
Yoichiro Yoshida ◽  
Masayasu Naito ◽  
Teppei Yamada ◽  
Naoya Aisu ◽  
Daibo Kojima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Adverse Events ◽  
Adoptive Immunotherapy ◽  
Combination Treatment ◽  
Pilot Trial ◽  
Interleukin 2 ◽  
Reduction Rate ◽  
Stage Iv ◽  
Stage Iv Colorectal Cancer

628 Background: Adoptive immunotherapy of cancer is evolving with the development of novel technologies for generating a large number of activated killer cells such as αβ T cells, γδ T cells, and natural killer (NK) cells. We conducted a pilot study to evaluate the safety and feasibility of the combination treatment of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer. Methods: The COMVI study was a prospective and single-arm pilot trial. Therapy in each 21-day treatment cycle consisted of XELOX (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1–14), bevacizumab (7.5 mg/kg on day 1) and αβ T lymphocytes (over 5 ×109 on day 18) cultured ex vivo with an immobilized anti-CD3 antibody and interleukin-2. Results: A total of 6 patients were enrolled from June 2013 to September 2014. Baseline characteristics included a median age of 66 years (range: 55-75) for 2 men and 4women. Median PFS was 567 days. Overall response rate was 100 % (CR 33.3%, PR 66.7%, SD 0%, PD 0%). The tumor reduction rate was 53% (38.0–100%). The majority of adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 6 patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study. Conclusions: The combination treatment of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are warranted to confirm the safety and efficacy of this chemoimmunotherapy. Clinical trial information: UMIN000010908.

scholarly journals New-Onset Diabetes, Endothelial Dysfunction, and Cardiovascular Outcomes in Hypertensive Patients: An Illness-Event Model Analysis

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 721
Author(s):  
Raffaele Maio ◽  
Edoardo Suraci ◽  
Benedetto Caroleo ◽  
Cristina Politi ◽  
Simona Gigliotti ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Dysfunction ◽  
Confidence Interval ◽  
Cardiovascular Events ◽  
Forearm Blood Flow ◽  
Cardiovascular Outcomes ◽  
Hazard Ratio ◽  
Baseline Status ◽  
Event Model ◽  
New Onset

Background. Insulin resistance and endothelial dysfunction are common findings in hypertensives, both predisposing to a higher risk of diabetes and cardiovascular events. We designed this study to evaluate the role of endothelial dysfunction in three pathogenetic pathways: (1) from baseline to cardiovascular events, (2) from baseline to diabetes, and (3) from new-onset diabetes to cardiovascular events. Methods. We enrolled 653 Caucasian never-treated hypertensives. Endothelial dysfunction was investigated by strain-gauge plethysmography; incident diabetes and cardiovascular events were evaluated by an illness-event model analysis. Results. During the follow-up (median 113 months), we documented 191 new cardiovascular events and 92 new cases of diabetes. In a multiple Cox regression analysis, acetylcholine-stimulated forearm blood flow [100% decrease, hazard ratio: 2.42 (95% confidence interval = 1.72–3.40)] and serum high-sensitivity C-reactive protein [hazard ratio: 1.30 (95% confidence interval = 1.21–1.40)] had an independent association with cardiovascular outcomes. The incidence rate of cardiovascular outcomes in diabetes-developer patients was higher than in the diabetes-free ones (34.9 vs. 2.5 events per 100 persons-year). In an illness-event model, a 100% decrease in forearm blood flow was associated with a 55.5% hazard ratio increase (hazard ratio: 1.56, 95% confidence interval: 1.33–1.82) of transition 1 (from baseline status to cardiovascular events) and to an almost doubled increase (hazard ratio: 2.54, 95% CI: 2.00–3.25) of the risk of transition 2 (from baseline status to diabetes). No such effects were found in transition 3 (from diabetes to cardiovascular events). Conclusions. Endothelial dysfunction plays a primary role in the pathways leading to diabetes and cardiovascular events in hypertensives. When diabetes is overt, endothelial dysfunction has no predictive value for subsequent cardiovascular events.

scholarly journals GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e108587 ◽  
Author(s):  
Pawel P. Wolkow ◽  
Wladyslaw Kosiniak-Kamysz ◽  
Grzegorz Osmenda ◽  
Grzegorz Wilk ◽  
Beata Bujak-Gizycka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Gene Polymorphisms ◽  
Gtp Cyclohydrolase I ◽  
And Oxidative Stress ◽  
I Gene

Mercury Exposure and Endothelial Dysfunction

2015 ◽  
Vol 34 (4) ◽  
pp. 300-307 ◽  
Author(s):  
Swati Omanwar ◽  
M. Fahim
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Endothelium ◽  
Circulatory System ◽  
Vital Role ◽  
Mercury Exposure ◽  
And Function ◽  
The Impact ◽  
And Oxidative Stress

Vascular endothelium plays a vital role in the organization and function of the blood vessel and maintains homeostasis of the circulatory system and normal arterial function. Functional disruption of the endothelium is recognized as the beginning event that triggers the development of consequent cardiovascular disease (CVD) including atherosclerosis and coronary heart disease. There is a growing data associating mercury exposure with endothelial dysfunction and higher risk of CVD. This review explores and evaluates the impact of mercury exposure on CVD and endothelial function, highlighting the interplay of nitric oxide and oxidative stress.

scholarly journals FRI0453 COMPARATIVE GENE PROFILE IN MONOCYTES FROM CHILDHOOD- AND ADULT-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS: CLUES TO DIFFERENT SYSTEMIC INVOLVEMENT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 823.2-824
Author(s):  
I. C. Aranda-Valera ◽  
A. M. Patiño-Trives ◽  
R. M. Rosa ◽  
M. A. Aguirre ◽  
P. S. Laura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Lupus Erythematosus ◽  
Association Studies ◽  
Atherogenic Index ◽  
Molecular Profile ◽  
Research Support ◽  
Systemic Involvement ◽  
Dsdna Antibodies ◽  
And Oxidative Stress

Background:Objectives:1. This study, developed within the Innovative Medicines Initiative Joint Undertaking project PRECISESADS framework, aimed at identify specific inflammatory and oxidative stress determinants involved in the enhanced CV-risk present in SLE patients and to analyze the relevance of the sustained positivity for anti-dsDNA on the establishment of their atherothrombotic status.Methods:One hundred and twenty-four SLE consecutive patients (not including patients with associated antiphospholipid syndrome), belonging to the PRECISESADS project, were evaluated for the presence of CVD and its association with positivity for anti-dsDNA antibodies. A second cohort of 62 SLE patients was included, of which endothelial dysfunction, lipid profile, the presence of atheroma plaques (identified by a pathologic increase in the carotid intimae media thickness -CIMT-), and the frequencies of anti-dsDNA positivity for 7 years, were evaluated. Serum inflammatory and oxidative stress biomolecules, and NETosis-derived bioproducts were further evaluated by multiplex assay and specific commercial kits, respectively. Besides, miRNnomes were identified using next-generation sequencing. Clinical significance of the biomolecules analyzed was explored by correlation/association studies with immunological and CV-risk features.Results:A significant relationship among the incidence of CVD (i.e. thrombosis or cardiac involvement) and the positivity for anti-dsDNA antibodies was recognized in the first SLE cohort. Accordingly, in the second SLE cohort, significantly impaired micro-vascular endothelial function (identified by reduction of hyperemia post-occlusion area), increased atherogenic index and pathologic increase in the CIMT were assessed in patients positive for anti-dsDNA in relation to anti-dsDNA negative patients. Around a 65% of SLE patients displayed a sustained positivity for anti-dsDNA antibodies for more than 7 years. These patients showed a distinctive and specific molecular profile compared with patients that had remained negative for anti-dsDNA, including increased inflammatory profile (IL1B, IL2, IL6, IL17, EOTAXIN, FGF, GMCSF, IFNγ, IP10, RANTES, TNF), enhanced oxidative status (lipoperoxides), and higher NETosis (nucleosomes, elastase). Levels of those biomolecules were closely interconnected and associated to their regulatory miRNAs, which accordingly exhibited differential expression in SLE anti-dsDNA(+)vsanti-dsDNA(-) patients. Finally, the frequency for positivity of anti-dsDNA significantly correlated both with markers of endothelial dysfunction and with the presence of atheroma plaques in SLE patients, pointing at the direct involvement of anti-dsDNA-Abs in the development of these processes.Conclusion:1. Positivity for anti-dsDNA antibodies confers a specific inflammatory/oxidative profile linked to an enhanced CV-risk in SLE patients. 2. Moreover, the sustained positivity for anti-dsDNA antibodies fosters the establishment of an atherothrombotic status in these autoimmune patients.Acknowledgments:Supported by the EU/EFPIA –IMI-JU PRECISESADS (n° 115565) and ISCIII (PI18/0837 and RIER RD16/0012/0015), Co-funded with FEDER.Disclosure of Interests:Inmaculada Concepcion Aranda-Valera: None declared, Alejandra M. Patiño-Trives: None declared, Roldán Molina Rosa: None declared, Maria A Aguirre: None declared, Pérez Sánchez Laura: None declared, Carlos Pérez Sánchez: None declared, María Luque-Tévar: None declared, Iván Arias de la Rosa: None declared, Maria del Carmen Abalos-Aguilera: None declared, Desiree Ruíz-Vilchez: None declared, Mario Espinosa: None declared, Nuria Barbarroja Puerto Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE and Celgene., Eduardo Collantes-Estévez Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer.

Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial

2021 ◽  
Vol 32 (4) ◽  
pp. 972-982 ◽  
Author(s):  
Francesco Scolari ◽  
Elisa Delbarba ◽  
Domenico Santoro ◽  
Loreto Gesualdo ◽  
Antonello Pani ◽  
...  
Keyword(s):  
Complete Remission ◽  
Adverse Events ◽  
Membranous Nephropathy ◽  
Partial Remission ◽  
Pilot Trial ◽  
Clinical Trial Registry ◽  
Serious Adverse Events ◽  
First Line Therapy ◽  
Registration Number ◽  
Favorable Safety

BackgroundA cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking.MethodsWe randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events.ResultsAt 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen.ConclusionsThis pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial.Clinical Trial registry name and registration number:Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO),NCT03018535

Remote Ischemic Preconditioning Protects Against Endothelial Dysfunction in a Human Model of Systemic Inflammation: A Randomized Clinical Trial

2021 ◽  
Author(s):  
Marco Orlandi ◽  
Stefano Masi ◽  
Devina Bhowruth ◽  
Yago Leira ◽  
Georgios Georgiopoulos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Systemic Inflammation ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Remote Ischemic Preconditioning ◽  
Human Model ◽  
Control Group ◽  
Flow Mediated Dilatation ◽  
And Oxidative Stress

Objective: Inflammation, oxidative stress, and endothelial dysfunction are known to contribute to ischemia-reperfusion injury. Remote ischemic preconditioning (RIPC) protects from endothelial dysfunction and the damage induced by ischemia-reperfusion. Using intensive periodontal treatment (IPT), an established human model of acute systemic inflammation, we investigated whether RIPC prevents endothelial dysfunction and modulates systemic levels of inflammation and oxidative stress. Approach and Results: Forty-nine participants with periodontitis were randomly allocated to receive either 3 cycles of ischemia-reperfusion on the upper limb (N=25, RIPC) or a sham procedure (N=24, control) before IPT. Endothelial function assessed by flow-mediated dilatation of the brachial artery, inflammatory cytokines, markers of vascular injury, and oxidative stress were evaluated at baseline, day 1, and day 7 after IPT. Twenty-four hours post-IPT, the RIPC group had lower levels of IL (interleukin)-10 and IL-12 compared with the control group ( P <0.05). RIPC attenuated the IPT-induced increase in IL-1β, E-selectin, sICAM-3 (soluble intercellular adhesion molecule 3), and s-thrombomodulin levels between the baseline and day 1 ( P for interaction <0.1). Conversely, oxidative stress was differentially increased at day1 in the RIPC group compared with the control group ( P for interaction <0.1). This was accompanied by a better flow-mediated dilatation (mean difference 1.75% [95% CI, 0.428–3.07], P =0.011). After 7 days from IPT, most of the inflammatory markers endothelial-dependent and -independent vasodilation were similar between groups. Conclusions: RIPC prevented acute endothelial dysfunction by modulation of inflammation and oxidation processes in patients with periodontitis following exposure to an acute inflammatory stimulus. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03072342.

A Phase 2, Randomized, Open-Label Study of Irosustat Versus Megestrol Acetate in Advanced Endometrial Cancer

2017 ◽  
Vol 27 (2) ◽  
pp. 258-266 ◽  
Author(s):  
Patricia Pautier ◽  
Ignace Vergote ◽  
Florence Joly ◽  
Bohuslav Melichar ◽  
Elzbieta Kutarska ◽  
...  
Keyword(s):  
Overall Survival ◽  
Endometrial Cancer ◽  
Adverse Events ◽  
Confidence Interval ◽  
Progression Free Survival ◽  
Megestrol Acetate ◽  
Phase 2 ◽  
Open Label ◽  
Free Survival ◽  
Recurrent Endometrial Cancer

ObjectiveAdvanced/metastatic or recurrent endometrial cancer has a poor prognosis. Malignant endometrial tissue has high steroid sulphatase (STS) activity. The aim of this study was to evaluate STS as a therapeutic target in patients with endometrial cancer.MethodsThis was a phase 2, multicenter, international, open-label, randomized (1:1), 2-arm study of the STS inhibitor oral irosustat 40 mg/d versus oral megestrol acetate 160 mg/d in women with advanced/metastatic or recurrent estrogen receptor–positive endometrial cancer. The primary end point was the proportion of patients without progression or death 6 months after start of treatment. Secondary end points included progression-free survival, time to progression, overall survival, and safety.ResultsSeventy-one patients were treated (36 with irosustat, 35 with megestrol acetate). The study was prematurely stopped after futility analysis. Overall, 36.1% and 54.1% of patients receiving irosustat or megestrol acetate had not progressed or died at 6 months, respectively. There were no statistically significant differences between irosustat and megestrol acetate in response and overall survival rates. Irosustat patients had a median progression-free survival of 16 weeks (90% confidence interval, 9.0–31.4) versus 40 weeks (90% confidence interval, 16.3–64.0) in megestrol acetate patients. Treatment-related adverse events occurred in 20 (55.6%) and 13 (37.1%) patients receiving irosustat or megestrol, respectively. Most adverse events in both groups were grade 1 or 2.ConclusionsAlthough irosustat monotherapy did not attain a level of activity sufficient for further development in patients with advanced/recurrent endometrial cancer, this study confirms the activity of hormonal treatment (megestrol acetate) for this indication.

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