Stronger Effect of Azilsartan on Reduction of Proteinuria Compared to Candesartan in Patients with CKD: A Randomized Crossover Trial

Introduction: Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial. Methods: A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR). Results: Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m2 and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was −3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups. Conclusion: A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients.

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Angiotensin receptor blockers and angiogenesis: clinical and experimental evidence

Clinical Science ◽

10.1042/cs20100389 ◽

2010 ◽

Vol 120 (8) ◽

pp. 307-319 ◽

Cited By ~ 45

Author(s):

Lauren M. Willis ◽

Azza B. El-Remessy ◽

Payaningal R. Somanath ◽

David L. Deremer ◽

Susan C. Fagan

Keyword(s):

Molecular Mechanisms ◽

Science Studies ◽

Angiotensin Receptor Blockers ◽

Vascular Density ◽

Angiotensin Receptor ◽

Renal Protection ◽

Converting Enzyme Inhibitors ◽

Cellular Models ◽

Published Evidence ◽

Receptor Blockers

Angiotensin II type 1 receptor antagonists [ARBs (angiotensin receptor blockers)] are indicated for BP (blood pressure)-lowering, renal protection and cardioprotection in patients unable to tolerate ACEIs (angiotensin-converting enzyme inhibitors). A recent meta-analysis revealed an association between ARBs and tumour development, possibly due to enhancement of angiogenesis. However, published evidence is conflicting on the effects of ARBs on angiogenesis or the expansion of the existing vascular network. ARBs have been shown to exert primarily anti-angiogenic effects in basic science studies of cancer, retinopathy, peripheral artery disease and some models of cardiovascular disease. In animal and cellular models of myocardial infarction and stroke, however, ARB administration has been associated with robust increases in vascular density and improved recovery. The aim of the present review is to examine the angiogenic effects of ARBs in animal and cellular models of relevant disease states, including proposed molecular mechanisms of action of ARBs and the clinical consequences of ARB use.

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Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248418788334 ◽

2018 ◽

Vol 23 (6) ◽

pp. 524-531 ◽

Cited By ~ 5

Author(s):

Robert A. Kloner ◽

Coleman Gross ◽

Jinwei Yuan ◽

Ansgar Conrad ◽

Pablo E. Pergola

Keyword(s):

Adverse Events ◽

Serum Potassium ◽

Common Adverse Event ◽

Open Label ◽

Serious Adverse Events ◽

End Point ◽

The Mean ◽

Baseline Characteristics ◽

Raas Inhibitors ◽

Post Hoc

Introduction: Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin–angiotensin–aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. Methods: Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. Results: Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was −0.67 (0.08) mEq/L in patients taking RAASi and −0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. Conclusions: Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.

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Automated Needle Targeting (ANT) Device-Assisted Renal Access during Percutaneous Nephrolithotripsy (PCNL) Puncture: A Pilot Study to Assess the Safety and Efficacy of a Novel Technique

10.21203/rs.3.rs-32132/v1 ◽

2020 ◽

Author(s):

Chu Ann Chai ◽

W.S Yeoh ◽

A.N Fadzli ◽

T.A Ong ◽

S Kuppusamy ◽

...

Keyword(s):

Adverse Events ◽

Radiation Exposure ◽

Renal Stones ◽

Open Label ◽

Primary Endpoints ◽

Ethical Approval ◽

The Mean ◽

Set Up ◽

Surgical Duration ◽

Mean Time

Abstract Background: To explore the use of an automated needle targeting (ANT) device as an assistive intraoperative navigation modality during PCNL for the treatment of large renal stones, with the aim of reducing surgical durations and radiation exposure.Methods: This open-label, single-surgeon clinical trial included patients with a diagnosis of renal stones for whom PCNL using the ANT device via the percutaneous access technique was indicated. Ethical approval was obtained from the UMMC ethics review board (Ref. 20118105-6740). The ANT was assembled after an initial motor calibration, and the image calibration was performed using the patient’s fluoroscopic images. Subsequently, the ANT software calculated a bullseye alignment before percutaneous puncture. Accurate renal access was confirmed by the efflux of urine in the Chiba biopsy needle, as well as by imaging with the C-arm intensifier at different angles. The primary endpoints were the time to successful renal access (from ANT set-up to urine efflux) and adverse events.Results: In all cases, successful renal access was achieved with a single attempt. The mean time to renal access was 6 minutes, 8 seconds. The mean fluoroscopy duration was 101 seconds, with a mean radiation dose of 23.46 mGy. No adverse events were documented.Conclusion: The ANT device enabled successful, safe and efficient renal access for PCNL in this study. Further research is needed to justify the effectiveness of this device in terms of enabling accurate renal access while reducing the surgical duration and radiation exposure to both surgeons and patients.

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134 Long-Term Deutetrabenazine Treatment Is Associated with Sustained Treatment Response in Tardive Dyskinesia: Results from an Open-Label Extension Study

CNS Spectrums ◽

10.1017/s1092852920000504 ◽

2020 ◽

Vol 25 (2) ◽

pp. 284-285 ◽

Cited By ~ 1

Author(s):

Robert A. Hauser ◽

Hadas Barkay ◽

Hubert H. Fernandez ◽

Stewart A. Factor ◽

Joohi Jimenez-Shahed ◽

...

Keyword(s):

Adverse Events ◽

Percentage Change ◽

Extension Study ◽

Total Daily Dose ◽

Open Label ◽

Daily Dose ◽

Open Label Extension ◽

The Mean ◽

Over Time

Abstract:Background:In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The current open-label study evaluated the long-term efficacy and safety of deutetrabenazine in patients with TD.Methods:Patients with TD who completed ARM-TD or AIM-TD could enroll in this open-label, single-arm extension study, titrating up over 6 weeks to a maximum total daily dose of deutetrabenazine 48 mg/day on the basis of dyskinesia control and tolerability. The proportion of Abnormal Involuntary Movement Scale (AIMS; items 1-7) responders was assessed based on response rates for achieving ≥50% improvement from baseline in the open-label extension study. AlMS score was assessed by local site raters for this analysis.Results:343 patients enrolled in the extension study. At Week 54 (n=249; total daily dose [mean ± standard error]: 38.6±0.66 mg), the mean percentage change from baseline in AIMS score was –40%; 48% of patients achieved a ≥50% response and 59% of those had already achieved a ≥50% response at Week 15. Further, 34% of those who had not achieved a ≥50% response at Week 15 achieved a ≥50% response at Week 54. At Week 106 (n=169; total daily dose: 39.6±0.77 mg), the mean percentage change from baseline in AIMS score was –45%; 55% of patients achieved a ≥50% response, 59% of those patients had already achieved a ≥50% response at Week 15, and 41% of those who had not achieved a ≥50% response at Week 15 but who reached Week 106 achieved a ≥50% response. At Week 132 (n=109; total daily dose: 39.7±0.97 mg), the mean percentage change from baseline in AIMS score was –61%; 55% of patients achieved a ≥50% response, 61% of those patients had already achieved a ≥50% response at Week 15, and 43% of those who had not achieved a ≥50% response at Week 15 but who reached Week 132 achieved a ≥50% response. Completer analysis suggests that long-term efficacy was not due to dose increases over time. Treatment with deutetrabenazine was generally well tolerated. There were 623 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) of adverse events of special interest were 0.01 for akathisia and restlessness, 0.07 for somnolence and sedation, 0.04 for parkinsonism, and 0.05 for depression.Conclusions:Patients who received long-term treatment with deutetrabenazine achieved response rates that were indicative of clinically meaningful long-term benefit. Results from this open-label trial suggest the possibility of increasing benefit over time with individual dose titration of deutetrabenazine.Funding Acknowledgements:This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.

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Renal protection with angiotensin receptor blockers: where do we stand

Journal of Nephrology ◽

10.5301/jn.2011.6445 ◽

2011 ◽

Vol 24 (5) ◽

pp. 569-580 ◽

Cited By ~ 11

Author(s):

Roland E. Schmieder ◽

Luis-Miguel Ruilope ◽

Anthony H. Barnett

Keyword(s):

Angiotensin Receptor Blockers ◽

Angiotensin Receptor ◽

Renal Protection ◽

Receptor Blockers

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NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽

10.1182/blood.v108.11.1149.1149 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1149-1149

Author(s):

Bruce A. Wallin ◽

Denise Ramjit ◽

Michael Seiberling ◽

David Zopf

Keyword(s):

Adverse Events ◽

Animal Studies ◽

Phase 1 ◽

Stopping Rules ◽

Open Label ◽

Serious Adverse Events ◽

Maximal Increase ◽

The Mean ◽

Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

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An Open-Label Randomized Crossover Trial of Lyophilized Black Raspberries on Postprandial Inflammation in Older Overweight Males

American Journal of Therapeutics ◽

10.1097/mjt.0b013e3182a40bf8 ◽

2016 ◽

Vol 23 (1) ◽

pp. e86-e91 ◽

Cited By ~ 15

Author(s):

Christine L. Sardo ◽

Joseph P. Kitzmiller ◽

Glen Apseloff ◽

Robin B. Harris ◽

Denise J. Roe ◽

...

Keyword(s):

Crossover Trial ◽

Open Label ◽

Black Raspberries ◽

Randomized Crossover Trial ◽

Postprandial Inflammation

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An Open Label Trial to Assess Safety of Losartan for Treating Worsening Respiratory Illness in COVID-19

Frontiers in Medicine ◽

10.3389/fmed.2021.630209 ◽

2021 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Charles D. Bengtson ◽

Robert N. Montgomery ◽

Usman Nazir ◽

Lewis Satterwhite ◽

Michael D. Kim ◽

...

Keyword(s):

Respiratory Failure ◽

Adverse Events ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Respiratory Illness ◽

External Control ◽

Control Group ◽

Respiratory Compromise ◽

Open Label ◽

Open Label Trial

Rationale: Coronavirus disease 2019 (COVID-19) can cause disruption of the renin-angiotensin system in the lungs, possibly contributing to pulmonary capillary leakage. Thus, angiotensin receptor blockers (ARBs) may improve respiratory failure.Objective: Assess safety of losartan for use in respiratory failure related to COVID-19 (NCT04335123).Methods: Single arm, open label trial of losartan in those hospitalized with respiratory failure related to COVID-19. Oral losartan (25 mg daily for 3 days, then 50 mg) was administered from enrollment until day 14 or hospital discharge. A post-hoc external control group with patients who met all inclusion criteria was matched 1:1 to the treatment group using propensity scores for comparison.Measures: Primary outcome was cumulative incidence of any adverse events. Secondary, explorative endpoints included measures of respiratory failure, length of stay and vital status.Results: Of the 34 participants enrolled in the trial, 30 completed the study with a mean age SD of 53.8 ± 17.7 years and 17 males (57%). On losartan, 24/30 (80%) experienced an adverse event as opposed to 29/30 (97%) of controls, with a lower average number of adverse events on losartan relative to control (2.2 vs. 3.3). Using Poisson regression and controlling for age, sex, race, date of enrollment, disease severity at enrollment, and history of high-risk comorbidities, the incidence rate ratio of adverse events on losartan relative to control was 0.69 (95% CI: 0.49–0.97)Conclusions: Losartan appeared safe for COVID-19-related acute respiratory compromise. To assess true efficacy, randomized trials are needed.

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Urinary angiotensinogen as a surrogate marker predicting the antiproteinuric effects of angiotensin receptor blockers in patients with overt proteinuria: a multicenter prospective study

10.21203/rs.2.17252/v4 ◽

2020 ◽

Author(s):

Junseok Jeon ◽

Do Hee Kim ◽

Hye Ryoun Jang ◽

Jung Eun Lee ◽

Wooseong Huh ◽

...

Keyword(s):

Independent Predictor ◽

Angiotensin Receptor Blockers ◽

Surrogate Marker ◽

Creatinine Ratio ◽

Angiotensin Receptor ◽

Clinical Value ◽

Urinary Angiotensinogen ◽

Receptor Blockers ◽

The Mean ◽

Overt Proteinuria

Abstract Background: Although urinary angiotensinogen (AGT) and renin reflect intrarenal renin-angiotensin system activity and are enhanced in proteinuric chronic kidney disease, the clinical value of urinary AGT and renin levels during antiproteinuric treatment has yet to be determined. We investigated the clinical usefulness of initial urinary AGT or renin to determine the antiproteinuric effects of angiotensin receptor blockers (ARBs). Methods: This multicenter, prospective, single-arm study included 205 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] ≥ 1 mg/mg) enrolled between April 2009 and December 2011. All patients were treated with valsartan. The urinary AGT/creatinine ratio (uAGT/Cr) was measured at the baseline and 24 weeks, and the renin/creatinine ratio (uR/Cr) was measured at the baseline. Fifty-six patients were followed-up for 5 years. Results: The mean age was 47.6 years and 51.2% were male. The mean uPCR was 2.32 mg/mg and the mean eGFR was 63.2 mL/min/1.73m2. Natural logarithms (ln) (uAGT/Cr), ln(uR/Cr), and diabetes mellitus were associated with proteinuria decrement (decrease in uPCR ≥ 1 mg/mg). Ln(uAGT/Cr) was an independent predictor for proteinuria decrement (OR 1.372, 95% CI, 1.068–1.762, P = 0.013). Among the 56 patients followed-up for 5 years, Δln(uAGT/Cr) at 24 weeks was an independent predictor for uPCR < 1 mg/mg at 5 years (OR 0.379, 95% CI, 0.20–0.715, P = 0.003). Conclusions: Our study demonstrates the potential role of both baseline urinary AGT and changes in urinary AGT during the initial 24 weeks as surrogate markers predicting the antiproteinuric effects of ARBs in patients with overt proteinuria.

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