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Phytomedicine : International Journal... Sep 2019Cardiac fibrosis is a common pathological progress of cardiovascular disease resulting from the excessive accumulation of extracellular matrix (ECM). Transforming growth...
BACKGROUND
Cardiac fibrosis is a common pathological progress of cardiovascular disease resulting from the excessive accumulation of extracellular matrix (ECM). Transforming growth factor (TGF)-β/SMADs pathway is a canonical signaling pathway which directly induces expressions of ECM related genes. Qishen Granule (QSG), a traditional Chinese formula developed from Zhen-Wu Decoration for heart failure (HF), has been proven to have definite therapeutic effects on cardiac fibrosis. However, its underlying mechanisms remain unclear.
PURPOSE
To investigate the effects of QSG on TGF-β pathway and the downstream mediators including Smad3 and Glycogen synthase kinase (GSK)-3β.
METHODS
HF model was induced by ligation of left coronary artery on male Sprague-Dawley (SD) rats. Rat were randomly divided into four groups including sham group, model group, QSG group and Fosinopril control group. Rats in each group were treated for 28 days, and 2D echocardiography was adopted to evaluate the heart function. The degree of cardiac fibrosis was assessed by Hematoxylin-Eosin (HE), Masson's trichrome and Picrosirius red (PSR) staining. Contents of collagen Ⅰ and Ⅲ were assessed by immunohistochemical method. Expressions of genes and proteins in TGF-β/SMADs and PI3K-GSK-3 signaling pathways were detected by Real-time Fluorescence Quantitative PCR (RT-qPCR) and Western blot respectively. TGF-β1-treated cardiac fibroblasts of neonatal SD rats were adopted for in vitro studies.
RESULTS
28 days after the surgery, cardiac ejection fraction (EF) and fractional shortening (FS) values in the model group showed a remarkable decrease, indicating the induction of HF model. QSG and Fosinopril elevated the EF and FS values, demonstrating cardio-protective effects. Pathological staining and immunohistochemistry showed that the contents of collagen I and III dramatically increased in the cardiac tissue of the model group compared with the sham group while QSG treatment reduced collagen contents. Furthermore, expressions of TGF-β1, p-Smad3 and p-GSK-3β were significantly decreased in the QSG treatment group compared with the model group, suggesting that the QSG may attenuate cardiac fibrosis through regulating TGF-β/Smad3 pathway. In vitro study further showed that the productions of type Ⅰ and Ⅲ collagen and α-smooth muscle actin (α-SMA) of cardiac fibroblasts were significantly increased by incubation with TGF-β1. QSG could markedly reduce the secretion of collagen Ⅰ and Ⅲ and α-SMA expression. Protein expressions of p-Smad3, PI3K, p-Akt and p-GSK-3β were significantly up-regulated by stimulation of TGF-β1. Treatment with QSG could suppress the activity of Smad3 and PI3K-GSK-3β signaling pathway in cardiac fibroblasts.
CONCLUSION
QSG improves cardiac function through inhibiting cardiac fibrosis. The anti-fibrotic effects are potentially mediated by the inhibition of the TGF-β/Smad3 pathway and the phosphorylation of GSK-3β.
Topics: Animals; Collagen Type I; Drugs, Chinese Herbal; Fibroblasts; Fibrosis; Glycogen Synthase Kinase 3 beta; Heart; Heart Failure; Male; Myocardium; Phosphatidylinositol 3-Kinases; Phosphorylation; Rats, Sprague-Dawley; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta
PubMed: 31102891
DOI: 10.1016/j.phymed.2019.152949 -
Archives of Pathology & Laboratory... Nov 2003Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been... (Comparative Study)
Comparative Study
CONTEXT
Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported.
OBJECTIVE
To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril.
DESIGN
Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature.
RESULTS
The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously.
CONCLUSION
Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.
Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Chemical and Drug Induced Liver Injury, Chronic; Cholangiopancreatography, Endoscopic Retrograde; Cholestasis, Intrahepatic; Enalapril; Fosinopril; Humans; Jaundice; Liver; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Ramipril
PubMed: 14567716
DOI: 10.5858/2003-127-1493-RH -
Frontiers in Pediatrics 2023Fosinopril and amlodipine are commonly prescribed as first-line pharmacotherapeutic agents for pediatric hypertension, but there is a lack of comparative studies...
OBJECTIVE
Fosinopril and amlodipine are commonly prescribed as first-line pharmacotherapeutic agents for pediatric hypertension, but there is a lack of comparative studies regarding the efficacy of these two drugs. We aimed to evaluate and compare the efficacy of fosinopril and amlodipine monotherapy in pediatric primary hypertension.
METHODS
This was a single-center, bidirectional observational study. A total of 175 children and adolescents with primary hypertension receiving antihypertensive monotherapy from July 2020 to February 2023 were enrolled. According to antihypertensive drugs, they were divided into the fosinopril group ( = 96) and the amlodipine group ( = 79). Subgroup analysis was performed to compare the efficacy of the two groups in terms of blood pressure (BP) control rates and reductions following a 4-week treatment.
RESULTS
After 4 weeks of treatment, both groups achieved significant reductions in systolic BP (SBP) and diastolic BP (DBP) by more than 18 mmHg and 6 mmHg, respectively, with BP control rates of 61.5% in the fosinopril group and 59.5% in the amlodipine group, revealing no significant differences in the antihypertensive efficacy between the two groups except for DBP control rate (FDR adjusted > 0.05). Further subsequent subgroup analyses revealed that the reductions in SBP and DBP in the fosinopril group were significantly greater than those in the amlodipine group in patients of females and hypo-HDL-cholesterolemia (FDR adjusted < 0.05), and there was a trend of difference, although not significant, in patients with central obesity and insulin resistance (IR) (FDR adjusted 0.05 < ≤ 0.1). However, there were no significant differences in treatment efficacy in patients without these characteristics. Furthermore, hypertriglyceridemia did not exhibit a significant association with the difference in treatment efficacy between the two medications (FDR adjusted > 0.05).
CONCLUSIONS
Fosinopril and amlodipine monotherapy were both effective in pediatric primary hypertension during a short-term follow-up. Fosinopril may be particularly effective in reducing BP in hypertensive patients of females, central obesity, IR, and hypo-HDL-cholesterolemia. These findings indicate that optimizing antihypertensive medication selection based on the individualized characteristics of children with hypertension may improve the efficacy of antihypertensive treatment.
PubMed: 37964810
DOI: 10.3389/fped.2023.1247192 -
Journal of Lipid Research 2021Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple... (Review)
Review
Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple therapeutic groups. A clear mechanistic understanding of the causes and implications of this form of drug toxicity has remained elusive. We previously reported the discovery and characterization of a lysosome-specific phospholipase A2 (PLA2G15) and later reported that amiodarone, a known cause of drug-induced phospholipidosis, inhibits this enzyme. Here, we assayed a library of 163 drugs for inhibition of PLA2G15 to determine whether this phospholipase was the cellular target for therapeutics other than amiodarone that cause phospholipidosis. We observed that 144 compounds inhibited PLA2G15 activity. Thirty-six compounds not previously reported to cause phospholipidosis inhibited PLA2G15 with IC values less than 1 mM and were confirmed to cause phospholipidosis in an in vitro assay. Within this group, fosinopril was the most potent inhibitor (IC 0.18 μM). Additional characterization of the inhibition of PLA2G15 by fosinopril was consistent with interference of PLA2G15 binding to liposomes. PLA2G15 inhibition was more accurate in predicting phospholipidosis compared with in silico models based on pKa and ClogP, measures of protonation, and transport-independent distribution in the lysosome, respectively. In summary, PLA2G15 is a primary target for cationic amphiphilic drugs that cause phospholipidosis, and PLA2G15 inhibition by cationic amphiphilic compounds provides a potentially robust screening platform for potential toxicity during drug development.
Topics: Animals; Enzyme Inhibitors; Humans; Lysosomes; Phospholipases A2; Phospholipids
PubMed: 34087196
DOI: 10.1016/j.jlr.2021.100089 -
American Family Physician Aug 2002When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been... (Review)
Review
When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction. altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and nonfatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications. (Am Fam Physician 2002;66:473.)
Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Diabetic Nephropathies; Drug Costs; Enalapril; Fosinopril; Heart Failure; Humans; Hypertension; Indoles; Isoquinolines; Lisinopril; Meta-Analysis as Topic; Myocardial Infarction; Perindopril; Quinapril; Ramipril; Renin-Angiotensin System; Risk; Tetrahydroisoquinolines; United States
PubMed: 12182524
DOI: No ID Found -
BMJ Open Feb 2017Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial.
INTRODUCTION
Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ).
METHODS AND ANALYSIS
This study will be a multicentred, prospective, double-blind, randomised parallel controlled trial for hypertensive CKD patients in China. Patients will be randomised to one of two treatment groups: a combination of benidipine 4-8 mg/day and fosinopril 20 mg/day; or a combination of HCTZ 12.5-25 mg/day and fosinopril 20 mg/day. Patients will be followed up for 24 months after a month's fosinopril run-in. There will be dose-titration after 1 and 2 months. The primary endpoint is changes in estimated glomerular filtration rate (eGFR) from baseline to month 24. Secondary endpoints include changes in home blood pressure (BP), ambulatory BP, proteinuria, urinary albumin/creatinine ratio, and composite renal events in 24 months. Inclusion criteria are: age 18-80 years, non-dialysis CKD patients with eGFR >30 mL/min/1.73 m, home BP >130 mm Hg systolic or BP >80 mm Hg diastolic at the screening and randomisation, and 24 hour proteinuria <3.5 g. Principal exclusions are hypertensive crisis, transplantation, cancer, severe diabetes complications, hyperkalaemia and severe allergy. The required sample size was 511 patients for detecting a difference in the change of eGFR (one sided α=0.025, power 1-β=0.90).
ETHICS AND DISSEMINATION
BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal.
TRIAL REGISTRATION NUMBER
NCT02646397.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; China; Dihydropyridines; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Fosinopril; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension; Kidney; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Research Design; Treatment Outcome; Young Adult
PubMed: 28237959
DOI: 10.1136/bmjopen-2016-013672