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Biomedicine & Pharmacotherapy =... May 2023This study investigated the reno-protective effects of a highly selective ATR agonist peptide, β-ProAng III in a mouse model of acute kidney injury (AKI).
BACKGROUND AND PURPOSE
This study investigated the reno-protective effects of a highly selective ATR agonist peptide, β-ProAng III in a mouse model of acute kidney injury (AKI).
METHODS
C57BL/6 J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 min. IRI mice were treated with either β-ProAng III or perindopril and at 7 days post-surgery the kidneys analysed for histopathology and the development of fibrosis and matrix metalloproteinase (MMP)-2 and -9 activity. The association of the therapeutic effects of β-ProAng III with macrophage number and phenotype was determined in vivo and in vitro.
KEY RESULTS
Decreased kidney tubular injury, interstitial matrix expansion and reduced interstitial immune cell infiltration in IRI mice receiving β-ProAng III treatment was observed at day 7, compared to IRI mice without treatment. This correlated to reduced collagen accumulation and MMP-2 activity in IRI mice following β-ProAng III treatment. FACS analysis showed a reduced number and proportion of CD45CD11bF4/80 macrophages in IRI kidneys in response to β-ProAng III, correlating with a significant increase in M2 macrophage markers and decreased M1 markers at day 3 and 7 post-IR injury, respectively. In vitro analysis of cultured THP-1 cells showed that β-ProAng III attenuated lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin (IL)- 6 production but increased IL-10 secretion, compared to LPS alone.
CONCLUSION
Administration of β-ProAng III via mini-pump improved kidney structure and reduced interstitial collagen accumulation, in parallel with an alteration of macrophage phenotype and anti-inflammatory cytokine release, therefore mitigating the downstream progression of ischemic AKI.
Topics: Mice; Animals; Lipopolysaccharides; Mice, Inbred C57BL; Kidney; Acute Kidney Injury; Collagen; Reperfusion Injury; Reperfusion
PubMed: 36948137
DOI: 10.1016/j.biopha.2023.114556 -
World Journal of Clinical Cases Mar 2023Secondary hypertension is a relatively rare condition most commonly caused by renovascular disease due to atherosclerotic vascular disease or fibromuscular dysplasia....
BACKGROUND
Secondary hypertension is a relatively rare condition most commonly caused by renovascular disease due to atherosclerotic vascular disease or fibromuscular dysplasia. Although accessory renal arteries are frequent, to date, only six cases of secondary hypertension determined by their existence have been reported.
CASE SUMMARY
We describe a case of a 39-year-old female who came to the emergency department with an urgent hypertensive crisis and hypertensive encephalopathy. Despite normal renal arteries, the computed tomography angiography revealed an inferior polar artery with 50% stenosis of its diameter. Conservative treatment with amlodipine, indapamide and perindopril was adopted, leading to blood pressure control within one month.
CONCLUSION
To the best of our knowledge, there are controversies regarding accessory renal arteries as a potential etiology for secondary hypertension, but the seven similar cases already described, along with the current case, could reinforce the necessity of more studies concerning this subject.
PubMed: 36926389
DOI: 10.12998/wjcc.v11.i7.1506 -
Frontiers in Pharmacology 2023Hypertension is a major risk factor for cardiovascular diseases and the leading cause of mortality worldwide. Despite the availability of antihypertensive drugs,...
Hypertension is a major risk factor for cardiovascular diseases and the leading cause of mortality worldwide. Despite the availability of antihypertensive drugs, alternative treatments are needed due to the adverse events associated with their use. Previous studies have shown that SABP, a combination of aqueous active metabolites of DSS, Sal-A, Sal-B and PAL, has a significant antihypertensive effect. However, the underlying mechanisms remain unknown. This study aimed to determine the effects of SABP on vascular inflammation, oxidative stress, and vascular remodeling in spontaneously hypertensive rats (SHRs). Additionally, the response of adventitial fibroblasts in SHRs to SABP treatment was also studied, including their proliferation, differentiation, and migration. SABP or perindopril (positive control) were administered intraperitoneally to SHRs, and systolic blood pressure was measured using a tail-cuff approach. The effects of SABP on oxidative stress, inflammation, and vascular remodeling were investigated by transmission electron microscopy, histochemical staining, and Western blot. Adventitial fibroblasts were isolated and cultured from the adventitia of thoracic aorta in SHR and WKY rats. CCK8 assay, wound healing method and immunostaining were used to observe the effect of SABP on fibroblasts proliferation, migration and transformation into myofibroblasts. Moreover, Western blot analysis was also performed to detect the proteins related to oxidative stress, inflammation and fibrosis in adventitial fibroblasts. SHRs displayed higher blood pressure with significant vascular remodeling compared to WKY rats. The thoracic aorta and adventitial fibroblasts of SHRs exhibited significant oxidative stress, inflammation and fibrosis. SABP treatment repressed oxidative stress, inflammatory reaction and vascular remodeling of thoracic aorta in SHR through the ROS/TLR4/NF-κB signaling pathway, and inhibited fibrosis of thoracic aorta. Additionally, SABP inhibited the proliferation and migration of adventitial fibroblasts and their transformation to myofibroblasts through the TGFβ/Smad3 signaling pathway. These findings suggest that SABP have potential as an alternative treatment for hypertension by ameliorating oxidative stress, inflammation and fibrosis. Further research is needed to fully understand the mechanisms underlying the effects of SABP.
PubMed: 36925635
DOI: 10.3389/fphar.2023.1093669 -
Heliyon Mar 2023The fixed-dose combination of Amlodipine Besylate (ADB) with Perindopril Tertbutylamine (PTBA) drug is used to treat patients with mild-to-moderate hypertension. In...
The fixed-dose combination of Amlodipine Besylate (ADB) with Perindopril Tertbutylamine (PTBA) drug is used to treat patients with mild-to-moderate hypertension. In recent times researchers are interested to find the efficient analytical method development and validation for the simultaneous determination of ADB and PTBA in a fixed-dose, film-coated tablet. Therefore, the current study was performed with a reverse-phase liquid chromatography method developed to simultaneously analyze ADB and PTBA in film-coated tablets as fixed-dose combinations. The linearity of the proposed method was calculated by preparing six different mixtures of both ADB and PTBA in the mobile phase. The concentration of both the analytes was analyzed at 56mg/100 mL to 84mg/100 mL and 32mg/100 mL to 48mg/100 mL, respectively. The ratio of acetonitrile and phosphate buffer was 35:65. The flow rate was adjusted to 1.5 ml per minute to reduce the retention time. The validation study was performed for the parameters specificity, linearity, precision, range, limit of detection, limit of quantification, accuracy/biasness, and robustness. The relative percentage standard deviation for Perindopril Tertbutyl amine was 0.148%, and for Amlodipine is 0.312%. These results show that the advanced analysis method for simultaneous analysis of fixed-dose is precise. The theoretical IR spectra were also calculated by Gaussian 9.2 by employing the B3LYP functional at density functional theory (DFT) level study. All these parameters studied in this work authenticate the effectiveness of the developed validation method and ensure its repeatability/reproducibility accordingly. To the best of our knowledge, this is the first time to develop a new fast, and easy method for simultaneous identification and quantification of ADB and PTBA by high-performance liquid chromatography (HPLC) with a time-efficient and cost-effective approach.
PubMed: 36923897
DOI: 10.1016/j.heliyon.2023.e14209 -
Advances in Therapy Apr 2023Single-pill combination therapy for hypertension is recognized to improve adherence to treatment. However, less is known about the benefits of triple single-pill... (Observational Study)
Observational Study
INTRODUCTION
Single-pill combination therapy for hypertension is recognized to improve adherence to treatment. However, less is known about the benefits of triple single-pill combinations. This retrospective observational analysis aimed to assess changes in adherence when treatment was switched from perindopril (PER)/indapamide (IND) + amlodipine (AML) to PER/IND/AML single-pill combination, in Italian clinical practice.
METHODS
This analysis used data extracted from administrative databases of Italian healthcare entities. Adult patients receiving PER/IND/AML were selected, and the prescription date was considered as the index date. Among them, those who had a prescription for PER/IND + AML during the 12 months before the index date and a prescription of PER/IND/AML during 6 months of follow-up were included. Adherence was calculated as the proportion of days covered (PDC: PDC < 40%, non-adherent; PDC = 40-79%, partially adherent; PDC ≥ 80%, adherent).
RESULTS
Among the identified patients, 158 were exposed users and were included in the analysis. When patients were compared before and after switch to triple single-pill combination, the proportion of adherent patients was significantly higher with PER/IND/AML single-pill combination (75.3%) than with PER/IND + AML combination (44.3%) (P < 0.05). Conversely, the proportion of non-adherent patients was lower with the PER/IND/AML single-pill combination (14.6%) vs PER/IND + AML (17.7%) (P < 0.001).
CONCLUSION
This real-world analysis showed that switching to a triple single-pill combination could offer an opportunity to improve adherence to antihypertensive treatment in real-life clinical practice.
Topics: Adult; Humans; Amlodipine; Perindopril; Indapamide; Retrospective Studies; Blood Pressure; Antihypertensive Agents; Hypertension; Drug Combinations; Medication Adherence; Leukemia, Myeloid, Acute
PubMed: 36829102
DOI: 10.1007/s12325-023-02451-y -
Acta Medica Academica Dec 2022The objective of this non-interventional post-marketing clinical trial was to analyze the antihypertensive effect and safety of a fixed combination of perindopril and... (Clinical Trial)
Clinical Trial
OBJECTIVE
The objective of this non-interventional post-marketing clinical trial was to analyze the antihypertensive effect and safety of a fixed combination of perindopril and indapamide in the treatment of unregulated essential hypertension.
PATIENTS AND METHODS
The prospective clinical trial included patients aged 20 to 75 years with essential hypertension and blood pressure values ≥ 140/90 mmHg at baseline. On the basis of the investigator's decision, patients received 2 mg perindopril + 0.625 mg indapamide (group 2+0.625) or 4 mg perindopril + 1.25 mg indapamide (group 4+1.25).
RESULTS
The study included 1173 patients (426 patients in group 2+0.625 and 747 patients in group 4+1.25) at 27 investigational centers in Bosnia and Herzegovina. Mean blood pressure values at baseline and visits after nine months were significantly higher in the 4+1.25 group compared to the 2+0.625 group. There was a significant drop in systolic and diastolic blood pressure in both groups. The target values of systolic and diastolic blood pressure, according to the European Society of Cardiology (2018), were reached after nine months of therapy by more than 80% of patients in the 2+0.625 group, and this number was significantly higher compared to the 4+1.25 group where more than 60% of patients reached target values. Newly diagnosed patients had a better response to therapy. The percentage of patients receiving additional antihypertensive therapy decreased by the end of the study. Age, gender and the existence of diabetes mellitus were identified as negative predictors of target blood pressure achievement. The therapy showed a good safety profile.
CONCLUSION
A fixed combination of perindopril and indapamide was effective and safe in the treatment of unregulated essential hypertension.
Topics: Humans; Antihypertensive Agents; Blood Pressure; Drug Combinations; Essential Hypertension; Hypertension; Indapamide; Perindopril; Prospective Studies; Treatment Outcome
PubMed: 36799308
DOI: 10.5644/ama2006-124.385 -
International Journal of Molecular... Jan 2023Vision loss in diabetic retinopathy features damage to the blood-retinal barrier and neovascularization, with hypertension and the renin-angiotensin system (RAS) having...
Finerenone, a Non-Steroidal Mineralocorticoid Receptor Antagonist, Reduces Vascular Injury and Increases Regulatory T-Cells: Studies in Rodents with Diabetic and Neovascular Retinopathy.
Vision loss in diabetic retinopathy features damage to the blood-retinal barrier and neovascularization, with hypertension and the renin-angiotensin system (RAS) having causal roles. We evaluated if finerenone, a non-steroidal mineralocorticoid receptor (MR) antagonist, reduced vascular pathology and inflammation in diabetic and neovascular retinopathy. Diabetic and hypertensive transgenic (mRen-2)27 rats overexpressing the RAS received the MR antagonist finerenone (10 mg/kg/day, oral gavage) or the angiotensin-converting enzyme inhibitor perindopril (10 mg/kg/day, drinking water) for 12 weeks. As retinal neovascularization does not develop in diabetic rodents, finerenone (5 mg/kg/day, i.p.) was evaluated in murine oxygen-induced retinopathy (OIR). Retinal vasculopathy was assessed by measuring gliosis, vascular leakage, neovascularization, and VEGF. Inflammation was investigated by quantitating retinal microglia/macrophages, pro-inflammatory mediators, and anti-inflammatory regulatory T-cells (Tregs). In diabetes, both treatments reduced systolic blood pressure, gliosis, vascular leakage, and microglial/macrophage density, but only finerenone lowered VEGF, ICAM-1, and IL-1ß. In OIR, finerenone reduced neovascularization, vascular leakage, and microglial density, and increased Tregs in the blood, spleen, and retina. Our findings, in the context of the FIDELIO-DKD and FIGARO-DKD trials reporting the benefits of finerenone on renal and cardiovascular outcomes in diabetic kidney disease, indicate the potential of finerenone as an effective oral treatment for diabetic retinopathy.
Topics: Rats; Animals; Mice; Mineralocorticoid Receptor Antagonists; Diabetic Retinopathy; Rodentia; Vascular System Injuries; Gliosis; Vascular Endothelial Growth Factor A; T-Lymphocytes, Regulatory; Naphthyridines; Diabetic Nephropathies; Neovascularization, Pathologic; Inflammation; Diabetes Mellitus, Type 2
PubMed: 36768656
DOI: 10.3390/ijms24032334 -
Biomedicine & Pharmacotherapy =... Apr 2023The hormone, relaxin (RLX), exerts various organ-protective effects independently of etiology. However, its complex two-chain and three disulphide bonded structure is a...
The single-chain relaxin mimetic, B7-33, maintains the cardioprotective effects of relaxin and more rapidly reduces left ventricular fibrosis compared to perindopril in an experimental model of cardiomyopathy.
The hormone, relaxin (RLX), exerts various organ-protective effects independently of etiology. However, its complex two-chain and three disulphide bonded structure is a limitation to its preparation and affordability. Hence, a single chain-derivative of RLX, B7-33, was developed and shown to retain the anti-fibrotic effects of RLX in vitro and in vivo. Here, we determined whether B7-33 could retain the other cardioprotective effects of RLX, and also compared its therapeutic efficacy to the ACE inhibitor, perindopril. Adult male 129sv mice were subjected to isoprenaline (ISO; 25 mg/kg/day, s.c)-induced cardiomyopathy, then s.c-treated with either RLX (0.5 mg/kg/day), B7-33 (0.25 mg/kg/day; equivalent dose corrected for MW) or perindopril (1 mg/kg/day) from days 7-14 post-injury. Control mice received saline instead of ISO. Changes in animal body weight (BW) and systolic blood pressure (SBP) were measured weekly, whilst cardiomyocyte hypertrophy and measures of vascular dysfunction and rarefaction, left ventricular (LV) inflammation and fibrosis were assessed at day 14 post-injury. ISO-injured mice had significantly increased LV inflammation, cardiomyocyte hypertrophy, fibrosis, vascular rarefaction and aortic contractility in the absence of any changes in BW or SBP at day 14 post-injury. Both B7-33 and RLX equivalently reduced LV fibrosis and normalised the ISO-induced LV inflammation and cardiomyocyte hypertrophy, whilst restoring blood vessel density and aortic contractility. Comparatively, perindopril lowered SBP and the ISO-induced LV inflammation and vascular rarefaction, but not fibrosis or hypertrophy. As B7-33 retained the cardioprotective effects of RLX and provided rapid-occurring anti-fibrotic effects compared to perindopril, it could be considered as a cost-effective cardioprotective therapy.
Topics: Mice; Animals; Male; Perindopril; Relaxin; Microvascular Rarefaction; Cardiomyopathies; Models, Theoretical; Inflammation; Hypertrophy
PubMed: 36753958
DOI: 10.1016/j.biopha.2023.114370 -
Frontiers in Cardiovascular Medicine 2022β-blockers have been recommended for patients with heart failure (HF) and atrial fibrillation (AF), but studies have shown that β-blockers do not reduce all-cause...
BACKGROUND
β-blockers have been recommended for patients with heart failure (HF) and atrial fibrillation (AF), but studies have shown that β-blockers do not reduce all-cause mortality or cardiovascular mortality in patients with HF and AF.
OBJECTIVE
To investigate the difference in efficacy between oral amiodarone and metoprolol succinate for patients with HF with reduced ejection fraction (HFrEF) and persistent atrial fibrillation (pAF) with rapid ventricular response (RVR).
METHODS
Patients with HFrEF complicated with pAF with RVR treated in the People's Hospital of Chongqing Hechuan between March 2018 and March 2019 were enrolled in this prospective observational study. The primary outcomes were cardiovascular mortality and the first hospitalization for HF rate. The secondary outcomes were type B pro-brain natriuretic peptide (NT-proBNP) before/after treatment, left ventricular ejection fraction (LVEF) before/after treatment, average heart rate (AhR), and the rate of sinus rhythm after 1 year of follow-up.
RESULTS
A total of 242 patients with HFrEF complicated with pAF with RVR were enrolled and divided into amiodarone + perindopril + spironolactone+ routine drug (amiodarone group, = 121) and metoprolol succinate + perindopril + spironolactone +routine drug (metoprolol succinate group, = 121) according to their treatment strategy. Cardiovascular mortality (4.9 vs. 12.4%, HR: 2.500, 95%CI: 1.002-6.237, = 0.040) and first hospitalization for HF (52.9 vs. 67.8%, HR: 1.281, 95%CI: 1.033-1.589, = 0.024) were significantly lower in the amiodarone group than in the metoprolol group. The mean ventricular rate in the amiodarone group was significantly lower than in the metoprolol group (64.5 ± 3.2 vs. 72.4 ± 4.2, < 0.001). After 1 year of follow-up, the sinus rhythm rate was significantly higher in the amiodarone group than in the metoprolol group (38.8 vs. 7.4%, HR: 0.191, 95%CI: 0.098-0.374, < 0.001). The difference in proBNP (3,914.88 vs. 2,558.07, < 0.001) and LVEF (-6.89 vs. -0.98, < 0.001) before and after treatment was significantly higher in the amiodarone group than in the metoprolol group.
CONCLUSION
In conclusion, in this prospective observational study, the amiodarone group had lower risk of cardiovascular death and the first hospitalization for HF than metoprolol in HFrEF and persistent atrial fibrillation (pAF) with RVR. The mechanism may be related to improved cardiac function, rhythm control and ventricular rate control.
REGISTRATION NUMBER
ChiCTR2200057816; Registered 7 March 2022-Retrospectively registered: http://www.medresman.org.cn/pub/cn/proj/projectshshow.aspx?proj=4222.
PubMed: 36698920
DOI: 10.3389/fcvm.2022.1029012 -
Journal of Hypertension Mar 2023The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic indapamide monotherapy or in combination with perindopril as a blood pressure lowering drug in randomized controlled trials (RCTs).
METHOD
Aggregate data from four published RCTs conducted versus matching placebo were pooled: PATS, a 2-year study (indapamide), and PROGRESS, a 4-year study (indapamide and perindopril), both in patients with a history of stroke or transient ischemic attack; ADVANCE, a 4-year study in patients with type 2 diabetes and cardiovascular risk factor (single-pill combination perindopril/indapamide) and HYVET, a 2-year study in very elderly hypertensive individuals (indapamide and an option of perindopril). The pooled effect (fixed and random) estimate (hazard ratio) was reported with corresponding 95% confidence intervals and P values. Treatment discontinuations were also analysed to assess the net benefit of the treatment.
RESULTS
The population involved 24 194 patients (active: 12 113, placebo: 12 081). The fixed-effects meta-analysis of the three mortality endpoints found low statistical heterogeneity ( I2 = 0). Statistically significant risk reductions in the indapamide with or without perindopril-treated patients as compared to placebo were observed for all-cause death (-15%), cardiovascular death (-21%), fatal stroke (-36%) and all strokes (-27%). Other cardiovascular outcomes were improved (risk reduction, 22 to 36%). As expected, discontinuation rates for safety (two studies) were higher in the active group (6.4 vs. 3.9%), while they were similar when discontinuation for any reason is concerned (18.4 vs. 18.0%).
CONCLUSION
Across medium to high cardiovascular risk population, long-term indapamide, mostly combined with perindopril-based treatment, provided evidence of benefit on mortality and morbidity.
Topics: Humans; Aged; Perindopril; Indapamide; Antihypertensive Agents; Hypertension; Stroke; Drug Combinations; Blood Pressure; Randomized Controlled Trials as Topic
PubMed: 36633311
DOI: 10.1097/HJH.0000000000003368