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Kidney International Reports Apr 2020Focal segmental glomerulosclerosis (FSGS), a histologic lesion in the kidney caused by varied pathophysiological processes, leads to end-stage kidney disease in a large...
INTRODUCTION
Focal segmental glomerulosclerosis (FSGS), a histologic lesion in the kidney caused by varied pathophysiological processes, leads to end-stage kidney disease in a large proportion of patients. Sparsentan is a first-in-class orally active compound combining endothelin type A (ET) receptor blockade with angiotensin II type 1 (AT) receptor antagonism in a single molecule. A Randomized, Multicenter, Double-Blind, Parallel, Active-Control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS (DUPLEX) study evaluates the long-term antiproteinuric efficacy, nephroprotective potential, and safety profile of sparsentan compared with an AT receptor blocker alone in patients with FSGS.
METHODS
DUPLEX is a multicenter, international, phase 3, randomized, double-blind, active-controlled study of sparsentan in patients with FSGS. Approximately 300 patients aged 8 to 75 years, inclusive (United States), and 18 to 75 years, inclusive (outside United States) will be randomized 1:1 to daily treatment with sparsentan or irbesartan. After renin-angiotensin-aldosterone system inhibitor washout, treatment will be administered for 108 weeks, with the final assessment at week 112, four weeks after withdrawal of study drug.
RESULTS
The primary endpoint will be the slope of estimated glomerular filtration rate from week 6 to week 108. A novel surrogate efficacy endpoint, the proportion of patients achieving urinary protein-to-creatinine (UP/C) ratio of ≤1.5 g/g and >40% reduction from baseline in UP/C (FSGS partial remission endpoint: FPRE), will be evaluated at a planned interim analysis at week 36. Safety and tolerability of sparsentan will also be assessed.
CONCLUSION
The phase 3 DUPLEX study will characterize the long-term antiproteinuric efficacy and nephroprotective potential of dual ET and AT receptor blockade with sparsentan in patients with FSGS.
PubMed: 32274453
DOI: 10.1016/j.ekir.2019.12.017 -
BMJ Open Apr 2023To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first...
OBJECTIVES
To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first Angiotensin-Receptor-Blocker (ARB) (valsartan) was recalled.
DESIGN
Retrospective cohort study.
SETTING
USA, Canadian administrative healthcare data, Danish National Prescription Registry and UK primary care electronic health records.
PARTICIPANTS
Patients aged 18 years and older between January 2014 and December 2020.
INTERVENTION
Valsartan, losartan and irbesartan.
MAIN OUTCOME
Monthly percentages of individual ARB episodes, new users and switches to another ARB, ACE inhibitors (ACEI) or calcium channel blockers containing products.
RESULTS
We identified 10.8, 3.2, 1.8 and 1.2 million ARB users in the USA, UK, Canada and Denmark, respectively. Overall proportions of valsartan, losartan and irbesartan use were 18.4%, 67.9% and 5.2% in the USA; 3.1%, 48.3% and 10.2% in the UK, 16.3%, 11.4% and 18.3% in Canada, 1%, 93.5% and 0.6% in Denmark. In July 2018, we observed an immediate steep decline in the proportion of valsartan use in the USA and Canada. A similar trend was observed in Denmark; however, the decline was only minimal. We observed no change in trends of ARB use in the UK. Accompanying the valsartan decline was an increase in switching to other ARBs in the USA, Canada and Denmark. There was a small increase in switching to ACEI relative to the valsartan-to-other-ARBs switch. We also observed increased switching from other affected ARBs, losartan and irbesartan, to other ARBs throughout 2019, in the USA and Canada, although the usage trends in the USA remained unchanged.
CONCLUSION
The first recall notice for valsartan resulted in substantial decline in usage due to increased switching to other ARBs. Subsequent notices for losartan and irbesartan were also associated with increased switching around the time of the recall, however, overall usage trends remained unchanged.
Topics: Humans; Losartan; Irbesartan; Valsartan; Angiotensin Receptor Antagonists; Retrospective Studies; Cohort Studies; Hypertension; Tetrazoles; Biphenyl Compounds; Angiotensin-Converting Enzyme Inhibitors; Canada; Denmark; United Kingdom
PubMed: 37068898
DOI: 10.1136/bmjopen-2022-070985 -
Medicine Nov 2023There is a lack of studies comparing the risk of cardio-cerebrovascular disease between angiotensin receptor blockers (ARBs) of different half-lives. We aimed to compare...
There is a lack of studies comparing the risk of cardio-cerebrovascular disease between angiotensin receptor blockers (ARBs) of different half-lives. We aimed to compare the risks of myocardial infarction (MI), heart failure (HF), and cerebrovascular disease with the use of valsartan, losartan, irbesartan, and telmisartan with different half-lives in a national claim-based retrospective cohort of patients aged ≥ 40 years with hypertension. To establish a cohort exposed to valsartan, losartan, irbesartan, or telmisartan, we performed propensity score (PS) matching and used an as-treated approach to evaluate exposure. The Cox regression model was employed to calculate hazard ratios, which were based on the incidence rate for each newly occurring event of MI, heart failure, or cerebrovascular disease. These hazard ratios were calculated to compare the risk of MI, heart failure, and cerebrovascular disease associated with valsartan, losartan, and irbesartan in comparison to telmisartan. A PS-matched cohort of 148,229 patients was established for each of valsartan, losartan, irbesartan, or telmisartan. The matched cohort analysis showed that the adjusted hazard ratio (aHRs, 95% confidence interval) for MI was higher for valsartan use (1.39, 1.33-1.45) and losartan use (1.10, 1.05-1.15) but lower for irbesartan use (0.90, 0.86-0.94) compared with the reference (telmisartan). The aHRs for HF were not different among these ARBs (angiotensin receptor blockers). The aHR for cerebrovascular disease was lower for valsartan use (0.85, 0.83-0.87) and losartan use (0.80, 0.78-0.82) but higher for irbesartan use (1.11, 1.09-1.13) compared with the reference. We found differences in the risk of MI and cerebrovascular disease with the use of different ARBs compared to telmisartan use. Valsartan, and losartan with a short half-life, which showed a higher risk of MI, had a lower risk of cerebrovascular disease. Conversely, irbesartan with a long half-life, which showed a lower risk of MI, had a higher risk of cerebrovascular disease.
Topics: Humans; Losartan; Irbesartan; Telmisartan; Valsartan; Angiotensin Receptor Antagonists; Retrospective Studies; Tetrazoles; Biphenyl Compounds; Benzimidazoles; Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Myocardial Infarction; Cerebrovascular Disorders
PubMed: 37986329
DOI: 10.1097/MD.0000000000036098 -
Vascular Health and Risk Management 2013Hypertension represents a major health problem, affecting more than one billion adults worldwide. Irbesartan, an angiotensin II receptor blocker, is considered to be a... (Review)
Review
BACKGROUND
Hypertension represents a major health problem, affecting more than one billion adults worldwide. Irbesartan, an angiotensin II receptor blocker, is considered to be a highly effective treatment in the management of hypertension. The purpose of this review is to evaluate the efficacy, safety and tolerability profile, and cost-effectiveness of treatment with irbesartan in hypertension.
METHODS
A review of the literature was conducted using the electronic PubMed and Cochrane Library databases and the Health Economic Evaluations Database of search terms relating to irbesartan efficacy, tolerability, and cost-effectiveness, and the results were utilized.
RESULTS
Findings from the present analysis show that irbesartan either as monotherapy or in combination with other antihypertensive agents can achieve significant reductions in blood pressure, both systolic and diastolic, compared with alternative treatment options. Irbesartan was also found to have a renoprotective effect independent of its blood pressure-lowering in patients with type 2 diabetes and nephropathy. Furthermore, irbesartan demonstrated an excellent safety and tolerability profile, with either lower or equal adverse events compared with placebo and other alternative treatments. In terms of economic analyses, compared with other antihypertensive therapy alternatives, irbesartan was found to be a preferred option, that is less costly and more effective.
CONCLUSION
The evidence indicates that treating patients with hypertension alone or with type 2 diabetes and nephropathy using irbesartan can control hypertension, prolong life, and reduce costs in relation to existing alternatives.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Costs; Humans; Hypertension; Irbesartan; Models, Economic; Quality-Adjusted Life Years; Tetrazoles; Time Factors; Treatment Outcome
PubMed: 24124375
DOI: 10.2147/VHRM.S50831 -
Vascular Health and Risk Management 2009Approximately 25% of the adult population worldwide is hypertensive and thus at risk of cardiovascular morbidity and mortality. Despite the availability of many... (Review)
Review
Approximately 25% of the adult population worldwide is hypertensive and thus at risk of cardiovascular morbidity and mortality. Despite the availability of many antihypertensive drugs, at least 50% of patients do not achieve blood pressure (BP) targets and thus remain at increased cardiovascular risk. Fixed-dose (FD) irbesartan/hydrochlorothiazide (HCTZ) is an antihypertensive combination therapy approved for the treatment of patients whose BP is not adequately controlled on monotherapy and for initial treatment of patients likely to need multiple drugs to achieve their BP goal. The efficacy and tolerability of FD irbesartan/HCTZ has been demonstrated in both patient populations in large multicenter studies. In patients failing antihypertensive monotherapy, FD irbesartan/HCTZ (150/12.5 mg) has been shown to be more effective than FD valsartan/HCTZ (80/12.5 mg) and at least comparable to FD losartan/HCTZ (50/12.5 mg). In patients with moderate or severe hypertension receiving FD irbesartan/HCTZ as initial therapy, this combination achieved more rapid BP reductions compared with irbesartan monotherapy and enabled a greater proportion of patients with severe hypertension to achieve their BP target. FD irbesartan/HCTZ is thus a valuable addition to the clinician's armamentarium for the management of hypertension and should help more patients achieve their BP target.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diuretics; Drug Combinations; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Tetrazoles; Treatment Outcome
PubMed: 19436667
DOI: 10.2147/vhrm.s3302 -
RSC Advances Oct 2020SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host. This disturbs the dynamic... (Review)
Review
SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host. This disturbs the dynamic equilibrium between the ACE/Ang II/AT1R axis and ACE2/Ang (1-7)/Mas receptor axis. Therefore, the clinically approved drugs belonging to (i) angiotensin converting enzyme (ACE) inhibitors such as captopril, and enalaprilat, (ii) angiotensin-receptor blockers (ARBs) such as losartan, candesartan, olmesartan, azilsartan, irbesartan, and telmisartan and (iii) the combination of ACE inhibitors and ARBs such as losartan with lisinopril and captopril with losartan, and (iv) recombinant ACE2, were studied for their ability to activate ACE2 in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. These clinically approved drugs were found to activate ACE2 that had been downregulated in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. Therefore, these drugs may be repurposed to re-activate the downregulated ACE2 of COVID-19 patients. These drugs either alone or in combination may be repurposed as prophylactics and therapeutics against SARS-CoV-2 virus.
PubMed: 35515386
DOI: 10.1039/d0ra08228g -
International Immunopharmacology Feb 2024New strategies are urgently needed to manage and delay the development of Alzheimer's disease (AD). Neuroinflammation is a significant contributor to cognitive decline...
BACKGROUND
New strategies are urgently needed to manage and delay the development of Alzheimer's disease (AD). Neuroinflammation is a significant contributor to cognitive decline in neurodegenerative diseases, including AD. Angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) protect hypertensive patients against AD, but the cellular and molecular mechanisms underlying these effects remain unknown. In light of this, the protective effects of three ARBs and three ACEIs against neuroinflammation and cognitive decline were investigated through comprehensive pharmacologicalin vitro/in vivoscreening.
METHODS
BV-2 microglia cells were exposed tolipopolysaccharide (LPS) and treated with ARBs and ACEIs to provide initial insights into the anti-inflammatory properties of the drugs. Subsequently, irbesartan was selected, and its efficacy was evaluated inC57/BL6 male miceintranasally administered with irbesartan and injected with LPS. Long-term memory and depressive-like behavior were evaluated; dendritic spines were measured as well as neuroinflammation, neurodegeneration and cognitive decline biomarkers.
RESULTS
Irbesartan mitigated memory loss and depressive-like behavior in mice treated with LPS, probably because itincreased spine density, ameliorated synapsis dysfunction and activated the PI3K/AKT pathway. Irbesartan elevated the levels of hippocampalsuperoxide dismutase2 andglutathione peroxidaseandsuppressed LPS-induced astrogliosis.
CONCLUSIONS
Overall, this study provides compelling evidence that multiple intranasal administrations of irbesartan can effectively prevent LPS-induced cognitive decline by activating pathways involved in neuroprotection and anti-inflammatory events. These findings underscore the potential of irbesartan as a preventive strategy against the development of AD and other neurodegenerative conditions associated with neuroinflammation.
Topics: Humans; Male; Mice; Animals; Irbesartan; Angiotensin-Converting Enzyme Inhibitors; Proto-Oncogene Proteins c-akt; Lipopolysaccharides; Phosphatidylinositol 3-Kinases; Neuroinflammatory Diseases; Angiotensin Receptor Antagonists; Administration, Intranasal; Alzheimer Disease; Cognitive Dysfunction; Anti-Inflammatory Agents
PubMed: 38199198
DOI: 10.1016/j.intimp.2023.111471 -
The Journal of International Medical... Aug 2020To compare the potential beneficial effects of the angiotensin converting enzyme inhibitor (ACEI) benazepril and the angiotensin II receptor 1 blocker (ARB) irbesartan...
OBJECTIVE
To compare the potential beneficial effects of the angiotensin converting enzyme inhibitor (ACEI) benazepril and the angiotensin II receptor 1 blocker (ARB) irbesartan on vaginal vascular remodeling and fibrosis in female spontaneously hypertensive rats (SHRs).
METHODS
Twelve-week-old female SHRs were treated with irbesartan or benazepril for 12 weeks. Vaginal renin angiotensin system (RAS) components were detected by polymerase chain reaction and western blot and vaginal α-smooth muscle actin (α-SMA), endothelial nitric oxide synthase (eNOS), and collagen III (Col III) were analyzed by western blot. Vaginal tissue sections were examined by hematoxylin and eosin staining, Masson trichrome staining, and immunohistochemical analysis of α-SMA and Col III.
RESULTS
Irbesartan and benazepril had different impacts on vaginal RAS components. Both agents decreased vaginal α-SMA and Col III and increased eNOS expression in SHR. The wall/lumen thickness ratio of vaginal arterioles was similarly decreased following irbesartan and benazepril treatment. Both drugs also decreased collagen deposition in SHRs. There was no difference in vaginal vascular remodeling or fibrosis between the two groups.
CONCLUSIONS
Irbesartan and benazepril have different effects on vaginal RAS expression but similar positive effects against vaginal vascular remodeling and fibrosis.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Female; Fibrosis; Hypertension; Irbesartan; Rats; Rats, Inbred SHR; Tetrazoles; Vascular Remodeling
PubMed: 32790534
DOI: 10.1177/0300060520943453 -
International Journal of Analytical... 2018Hypertension or high blood pressure is a harbinger of cardiovascular diseases. There are several classes of drugs used to treat hypertension. This review discusses the... (Review)
Review
Hypertension or high blood pressure is a harbinger of cardiovascular diseases. There are several classes of drugs used to treat hypertension. This review discusses the use of dried blood spots (DBSs) for the quantification by mass spectrometry (MS), tandem mass spectrometry (MS/MS), or, in some cases, by fluorescence detection methods the following antihypertensive medications: angiotensin-converting enzyme inhibitors (ramipril, ramiprilat, captopril, and lisinopril); angiotensin II receptor antagonists (valsartan, irbesartan, losartan, and losartan carboxylic acid); calcium channel blockers (verapamil, amlodipine, nifedipine, pregabalin, and diltiazem); blockers (guanfacine, doxazosin, and prazosin); blockers (propranolol, bisoprolol, atenolol, and metoprolol); endothelin receptor antagonists (bosentan and ambrisentan); and statins (simvastatin, atorvastatin, and rosuvastatin).
PubMed: 30154849
DOI: 10.1155/2018/3235072