Irbesartan restored aquaporin-1 levels via inhibition of NF-kB expression in acute kidney injury model.

INTRODUCTION: Acute kidney injury (AKI) is a serious pathology that progress with dysfunction of regulating blood pressure and fluid balance, concentrating urine due to decrement of aquaporin-1 (AQP) levels during the inflammation process. Irbesartan (IRN), angiotensin receptor blocker, is widely used in the treatment of hypertension, which also has anti-inflammatory, antioxidant and anti-apoptotic properties. The aim of this study is to investigate the protective effects of IRN in lipopolysaccharide (LPS)-induced kidney injury. MATERIAL AND METHODS: Twenty-four rats divided into three groups as control, LPS and LPS+IRN group. After 6h of LPS administration, rats were sacrificed. Blood samples and half of the kidney tissues were collected for biochemical analysis and remaining tissues were taken for histopathological and immunohistochemical analysis. RESULTS: In the LPS group, glomerular congestion and shrinkage, degeneration of distal tubules, mononuclear cell infiltration, cellular debris and intense proteinous accumulation in the tubules, increased expressions of Cas-3, nuclear factor kappa beta-p65 (NF-kB p65), levels of creatinin, TOS, OSI and decreased levels of TAS, AQP-1 were found significantly. IRN treatment reversed all these parameters. IRN's restorated AQP-1 levels by its anti-inflammatory, antioxidant and anti-apoptotic effects due to inhibiting NF-kB expression. CONCLUSION: This study suggests that IRN can be used in conditions affecting the kidneys such as AKI. Further studies needed for detailed molecular investigation of IRN at different doses and durations.

Effects of xenogeneic transplantation of umbilical cord-derived mesenchymal stem cells combined with irbesartan on renal podocyte damage in diabetic rats.

BACKGROUND: The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN). Podocyte damage is an early event in the development of DN. Currently, there is no effective treatment strategy that can slow the progression of DN or reverse its onset. The role of mesenchymal stem cells (MSCs) transplantation in diabetes and its complications has been extensively studied, and diabetic nephropathy has been a major focus. Irbesartan exerts reno-protective effects independent of lowering blood pressure, can reduce the incidence of proteinuria in rats, and is widely used clinically. However, it remains undetermined whether the combined utilization of the angiotensin II receptor antagonist irbesartan and MSCs could enhance efficacy in addressing DN. METHODS: A commonly used method for modeling type 2 diabetic nephropathy (T2DN) was established using a high-fat diet and a single low-dose injection of STZ (35 mg/kg). The animals were divided into the following 5 groups: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). MSCs (2 × 106 cells/rat) were injected every 10 days through the tail vein for a total of three injections; irbesartan (30 mg/kg/d) was administered by gavage. Additionally, the safety and homing of mesenchymal stem cells were verified using positron emission tomography (PET) imaging. RESULTS: The combination treatment significantly reduced the UACR, kidney index, IGPTT, HOMA-IR, BUN, serum creatine, and related inflammatory factor levels and significantly improved renal function parameters and the expression of proteins related to glomerular podocyte injury in rats. Moreover, MSCs can homing target to damaged kidneys. CONCLUSIONS: Compared to the administration of MSCs or irbesartan alone, the combination of MSCs and irbesartan exerted better protective effects on glomerular podocyte injury, providing new ideas for the clinical application of mesenchymal stem cells.

Low Natriuretic Peptide Levels and Outcomes in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Although some patients with heart failure (HF) with mildly reduced/preserved ejection fraction have low natriuretic peptide levels, there are no large-scale systematic studies of how common these individuals are or what happens to them. OBJECTIVES: The purpose of this study was to examine the proportion of patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial with an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level <125 pg/mL, their clinical characteristics, and outcomes. METHODS: I- PRESERVE enrolled patients with symptomatic HF and a LVEF ≥45% but who did not have NT-proBNP or body mass index inclusion/exclusion criteria. Baseline NT-proBNP was measured after enrollment but not reported to investigators. The primary outcome in this analysis was the composite of cardiovascular death or HF hospitalization. RESULTS: Overall, 808 of 3,480 patients (23.2%) had NT-proBNP <125 pg/mL. Patients with a low NT-proBNP were younger (68.6 years vs 72.6 years; P < 0.001), were less often men (36.1% vs 40.9%; P = 0.015), and had a higher body mass index (48.4% vs 38.7% obese; P < 0.001) than those with a higher NT-proBNP level. Patients with a low NT-proBNP had less atrial fibrillation (8.5% vs 35.1%; P < 0.001), myocardial infarction, diabetes, chronic obstructive pulmonary disease, and anemia but better kidney function. Patients with a lower NT-proBNP level had less marked echocardiographic abnormalities and were less likely to experience cardiovascular death or HF hospitalization; adjusted HR: 0.35 (95% CI: 0.27-0.46; P < 0.001). However, health status was similarly impaired in patients with lower and higher NT-proBNP levels (median Minnesota Living with Heart Failure Questionnaire 43 vs 43; P = 0.95). CONCLUSIONS: Almost one-quarter of patients with HF with mildly reduced/preserved ejection fraction had a low NT-proBNP level. Although these patients have a favorable prognosis, compared to those with a high NT-proBNP level, they have similarly impaired health status which should be a target for treatment. (Irbesartan in Heart Failure With Preserved Systolic Function [I- PRESERVE]; NCT00095238).

The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Irbesartan mitigates the impact of cyclophosphamide-induced acute neurotoxicity in rats: Shedding highlights on NLRP3 inflammasome/CASP-1 pathway-driven immunomodulation.

IIrbesartan (IRB), an angiotensin II type 1 receptor (AT1R) antagonist, has been widely employed in the medical field for its effectiveness in managing hypertension. However, there have been no documented investigations regarding the immunostimulatory properties of IRB. To address this gap, this study has been performed to assess the neuroprotective impact of IRB as an immunostimulatory agent in mitigating acute neurotoxicity induced by cyclophosphamide (CYP) in rats. mRNA levels of nuclear factor erythroid 2 (Nrf-2), interleukin (IL)-18, IL-1ß, and MMP-1 have been assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the levels of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) has been evaluated to assess the oxidative stress. Additionally, macrophage inflammatory protein 2 (MIP2) has been evaluated using enzyme-linked immunosorbent assay (ELISA). Western blotting has been used to investigate the protein expression of nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) and caspase-1 (CASP-1), along with an assessment of histopathological changes. Administration of IRB protected against oxidative stress by augmenting the levels of GSH and SOD as well as reducing MDA level. Also, administration of IRB led to a diminishment in the brain levels of MIP2 and MMP1. Furthermore, it led to a suppression of IL-1ß and IL-18 levels, which are correlated with a reduction in the abundance of NLRP3 and subsequently CASP-1. This study provides new insights into the immunomodulatory effects of IRB in the context of CYP-induced acute neurotoxicity. Specifically, IRB exerts its effects by reducing oxidative stress, neuroinflammation, inhibiting chemokine recruitment, and mitigating neuronal degeneration through the modulation of immune markers. Therefore, it can be inferred that the use of IRB as an immunomodulator has the potential to effectively mitigate immune disorders associated with inflammation.

Role of angiotensin pathway and its target therapy to rescue from experimental cerebral malaria.

Cerebral malaria (CM) induced by Plasmodium falciparum is a devastating neurological complication that may lead the patient to coma and death. This study aimed to protect Plasmodium-infected C57BL6 mice from CM by targeting the angiotensin II type 1 (AT1) receptor, which is considered the common connecting link between hypertension and CM. In CM, AT-1 mediates blood-brain barrier (BBB) damage through the overexpression of ß-catenin. The AT-1-inhibiting drugs, such as irbesartan and losartan, were evaluated for the prevention of CM. The effectiveness of these drugs was determined by the down regulation of ß-catenin, TCF, LEF, ICAM-1, and VCAM-1 in the drug-treated groups. The expression levels of VE-cadherin and vinculin, essential for the maintenance of BBB integrity, were found to be restored in the drug-treated groups. The pro-inflammatory cytokine levels were decreased, and the anti-inflammatory cytokine levels increased with the treatment. As a major highlight, the mean survival time of treated mice was found to be increased even in the absence of treatment with an anti-malarial agent. The combination of irbesartan or losartan with the anti-malarial agent α/ß-arteether has contributed to an 80% cure rate, which is higher than the 60% cure rate observed with α/ß-arteether alone treatment.

Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.

OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure. METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1ß and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation. CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.

Intranasal irbesartan reverts cognitive decline and activates the PI3K/AKT pathway in an LPS-induced neuroinflammation mice model.

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.

Alcohol Consumption and Antihypertensive Treatment Effect in Male Patients With Hypertension.

BACKGROUND: Alcohol consumption is a proven risk factor of hypertension. In the present analysis, we investigated the use of antihypertensive medications and blood pressure control in male alcohol drinkers and non-drinkers with hypertension (systolic/diastolic blood pressure 160-199/100-119 mm Hg). METHODS: The study participants were patients enrolled in a 12-week therapeutic study and treated with the irbesartan/hydrochlorothiazide combination 150/12.5 mg once daily, with the possible up-titration to 300/12.5 mg/day and 300/25 mg/day at 4 and 8 weeks of follow-up, respectively, for blood pressure control of <140/90 mm Hg or <130/80 mm Hg in patients with diabetes mellitus. Alcohol consumption was classified as non-drinkers and drinkers. RESULTS: The 68 alcohol drinkers and 168 non-drinkers had similar systolic/diastolic blood pressure at baseline (160.8 ±â€…12.1/99.8 ±â€…8.6 vs. 161.8 ±â€…11.0/99.2 ±â€…8.6, P ≥ 0.55) and other characteristics except for current smoking (80.9% vs. 47.6%, P < 0.0001). In patients who completed the 12-week follow-up (n = 215), the use of higher dosages of antihypertensive drugs was similar at 4 weeks of follow-up in drinkers and non-drinkers (10.6% vs. 12.4%, P = 0.70), but increased to a significantly higher proportion in drinkers than non-drinkers at 12 weeks of follow-up (54.7% vs. 36.6%, P = 0.01). The control rate of hypertension tended to be lower in alcohol drinkers, compared with non-drinkers, at 4 weeks of follow-up (45.6% vs. 58.9%, P = 0.06), but became similar at 12 weeks of follow-up (51.5% vs. 54.8%, P = 0.65). CONCLUSION: Alcohol drinkers compared with non-drinkers required a higher dosage of antihypertensive drug treatment to achieve similar blood pressure control. CLINICAL TRIAL REGISTRY NUMBER: NCT00670566 at www.clinicaltrials.gov.

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker on oxidative stress and metabolism of elements in kidney of STZ-induced diabetic rats.

In diabetes, increased oxidative stress and impaired trace element metabolism play an important role in the pathogenesis of diabetic nephropathy. The objective of this research was to examine the outcomes of blocking the renin-angiotensin system, using either the angiotensin-converting enzyme inhibitor (ACEI), perindopril, or the angiotensin II type 1 (AT1) receptor blocker, irbesartan, on oxidative stress and trace element levels such as Zn, Mg, Cu, and Fe in the kidneys of diabetic rats that had been induced with streptozotocin. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as a control. The second group of rats developed diabetes after receiving a single intraperitoneal dose of STZ. The third and fourth groups of rats had STZ-induced diabetes and received daily dosages of irbesartan (15 mg/kg b.w/day) and perindopril (6 mg/kg b.w/day) treatment, respectively. Biochemical analysis of the kidneys showed a distinct increase in oxidative stress, indicated by heightened levels of malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activities, as well as reduced glutathione (GSH) levels in the kidneys of diabetic rats. In the kidneys of diabetic rats, the mean levels of Fe and Cu were found to be significantly higher than those of the control group. Additionally, the mean levels of Zn and Mg were significantly lower in the diabetic rats compared to the control rats. Both perindopril and irbesartan decreased significantly MDA content and increased SOD activities and GSH levels in the kidneys of rats with diabetes. The Zn and Mg concentrations in the kidneys of diabetic rats treated with perindopril and irbesartan were markedly higher than in untreated STZ-diabetic rats, while the Cu and Fe concentrations were significantly lower. The urinary excretion of rats treated with perindopril and irbesartan showed a pronounced increase in Cu levels, along with a significant reduction in Zn and Mg levels. Although diabetic rats demonstrated degenerative morphological alterations in their kidneys, both therapies also improved diabetes-induced histopathological modifications in the kidneys. Finally, the present results suggest that manipulating the levels of Zn, Mg, Cu, and Fe - either through ACE inhibition or by blocking AT1 receptors - could be advantageous in reducing lipid peroxidation and increasing antioxidant concentration in the kidneys of diabetic rats.

Lactobacillus induced by irbesartan on spontaneously hypertensive rat contribute to its antihypertensive effect.

OBJECTIVE: Hypertension is linked to gut dysbiosis. Here, the impact of the angiotensin receptor antagonist irbesartan on the gut microbiota of spontaneously hypertensive rats (SHR) were investigated. In addition, we assessed their contribution to its antihypertensive effect. METHODS: Eight-week-old Wistar-Kyoto (WKY) rats and SHR were administered irbesartan for 8 weeks. Fecal microbiota transplantation (FMT) was performed from SHR treated with irbesartan or untreated SHR to recipient untreated SHR. The preventive effect of Lactobacillus on hypertension in SHR was evaluated. Blood pressure (BP) was calculated using a tail-sleeve sphygmomanometer. To better assess the composition of the gut microbiota, the V3-V4 region of the 16S rRNA gene was amplified while short-chain fatty acids (SCFAs) in feces were tested by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). RESULTS: Irbesartan restored gut dysbiosis, increased the abundance of Lactobacillus , and improved anti-inflammatory ability, antioxidative ability, intestinal integrity, and intestinal inflammation in SHR. The microbiota in SHR-treated irbesartan could reduce BP and improve antioxidative ability and gut integrity in SHR. Lactobacillus johnsonii ( L. johnsonii ) and Lactobacillus reuteri ( L. reuteri ) reduced BP, restored gut dysbiosis and improved anti-inflammatory ability, antioxidative ability, intestinal integrity in SHR. Most notably, irbesartan, L. johnsonii , and L. reuteri can significantly increase SCFA content in SHR feces. CONCLUSION: The current study demonstrated that irbesartan treatment ameliorated gut dysbiosis in SHR. Irbesartan induced alterations in gut microbiota, with increased prevalence of Lactobacillus .

Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis.

BACKGROUND: An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown. METHODS: In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated. RESULTS: A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m2 with sparsentan and -12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups. CONCLUSIONS: Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.).

Efficacy of single-pill combination in uncontrolled essential hypertension: A systematic review and network meta-analysis.

This study aimed to evaluate the efficacy of single-pill combination (SPC) antihypertensive drugs in patients with uncontrolled essential hypertension. Through Searching Pubmed, EMBASE, the Cochrane Library, and Web of Science collected only randomized controlled trials on the efficacy of single-pill combination antihypertensive drugs in people with uncontrolled essential hypertension. The search period is from the establishment of the database to July 2022. The methodological quality of the included studies was assessed using the Cochrane Risk of Bias Assessment, and statistical analyses were performed using Review Manage 5.3 and Stata 15.1 software. This review ultimately included 32 references involving 16 273 patients with uncontrolled essential hypertension. The results of the network meta-analysis showed that a total of 11 single-pill combination antihypertensive drugs were included, namely: Amlodipine/valsartan, Telmisartan/amlodipine, Losartan/HCTZ, Candesartan/HCTZ, Amlodipine/benazepril, Telmisartan/HCTZ, Valsartan/HCTZ, Irbesartan/amlodipine, Amlodipine/losartan, Irbesartan/HCTZ, and Perindopril/amlodipine. According to SUCRA, Irbesartan/amlodipine may rank first in reducing systolic blood pressure (SUCRA: 92.2%); Amlodipine/losartan may rank first in reducing diastolic blood pressure (SUCRA: 95.1%); Telmisartan/amlodipine may rank first in blood pressure control rates (SUCRA: 83.5%); Amlodipine/losartan probably ranks first in diastolic response rate (SUCRA: 84.5%). Based on Ranking Plot of the Network, we can conclude that single-pill combination antihypertensive drugs are superior to monotherapy, and ARB/CCB combination has better advantages than other SPC in terms of systolic blood pressure, diastolic blood pressure, blood pressure control rate, and diastolic response rate. However, due to the small number of some drug studies, the lack of relevant studies has led to not being included in this study, which may impact the results, and readers should interpret the results with caution.

Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension.

BACKGROUND: Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis. METHODS: In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring. RESULTS: Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively. CONCLUSIONS: Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis.

BACKGROUND: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. METHODS: We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. RESULTS: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. CONCLUSIONS: Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial.

BACKGROUND: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. METHODS: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. INTERPRETATION: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. FUNDING: Travere Therapeutics.

A collaborative study of the impact of N-nitrosamines presence and ARB recall on ARB utilization - results from IQVIA™ Disease Analyzer Germany.

PURPOSE: Regulators are increasingly concerned with  the impact of recalls on drug adherence. In 2018, N-nitrosamines impurities were detected in valsartan containing medical products. Concerned products were immediately recalled in July 2018 by regulatory agencies internationally. In Germany, recalls were issued for valsartan, losartan and irbesartan from July 2018 to March 2019. This study examined angiotensin II receptor blocker (ARB) utilization trends and switching patterns in Germany before and after July 2018. METHODS: Patients prescribed ARBs from January 2014 to June 2020 in general practices in Germany were included in a collaborative framework common protocol drug utilization study led by the US Food and Drug Administration. Trends in monthly and quarterly proportions of total ARB prescribing were analysed for individual ARBs using descriptive statistics and interrupted time series analysis. The rate of switching to an alternative ARB was analysed before and after the recalls. RESULTS: The proportion of valsartan prescriptions immediately decreased from 35.9 to 17.8% following the first recalls in July 2018, mirrored by an increased proportion for candesartan. Increased switching from valsartan to candesartan was observed. No increased switching was observed after losartan recalls, whereas for irbesartan, increased switching was observed 6-12 months after the last recall. Increased switching from ARBs to angiotensin-converting enzyme (ACE) inhibitors or ARB treatment discontinuations were not observed. CONCLUSION: This study showed that patients were able to continue ARB treatment despite the July 2018-March 2019 recalls, although many patients needed to switch to an alternative ARB. The duration of the impact of ARB recalls appeared to be limited.