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Frontiers in Pharmacology 2024[This corrects the article DOI: 10.3389/fphar.2023.1156655.].
[This corrects the article DOI: 10.3389/fphar.2023.1156655.].
PubMed: 38903988
DOI: 10.3389/fphar.2024.1426608 -
World Journal of Clinical Cases Jun 2024Current treatments for chronic heart failure (CHF) are therapeutically ineffective. The optimization of treatments for this disease needs to be explored and analyzed.
BACKGROUND
Current treatments for chronic heart failure (CHF) are therapeutically ineffective. The optimization of treatments for this disease needs to be explored and analyzed.
AIM
To analyze the effect of using Luhong Formula in the cardiac rehabilitation of patients with CHF and its influence on cardiopulmonary function (CPF) and prognosis.
METHODS
In total, 160 patients with CHF admitted between June 2022 and June 2023 were selected, including 75 receiving perindopril (control group) and 85 receiving Luhong Formula (research group). We conducted comparative analyses on the curative effects of traditional Chinese medicine (TCM) syndromes and cardiac function, CPF [oxygen consumption at the anaerobic threshold (VO AT) and at peak exercise (peak VO)], echocardiographic indexes [left atrial volume index (LAVI), left ventricular muscle mass index (LVMI), left ventricular ejection fraction (LVEF)], and prognosis [major adverse cardiovascular events (MACEs) at 6 months follow-up].
RESULTS
The research group showed markedly higher curative effects of TCM syndromes and cardiac function than the control group. In addition, post-treatment VO AT, peak VO, LVMI and LVEF in the research group were significantly higher, whereas LAVI was significantly lower, than those of the control group. Furthermore, fewer patients in the research group developed MACEs at the 6-month follow-up.
CONCLUSION
Luhong Formula is more therapeutically effective than perindopril for the cardiac rehabilitation of patients with CHF, specifically in enhancing CPF and prognosis.
PubMed: 38898832
DOI: 10.12998/wjcc.v12.i17.3027 -
European Journal of Pharmacology Jun 2024Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed...
Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.
Topics: Animals; Male; Mice; Angiotensin-Converting Enzyme Inhibitors; Antiparkinson Agents; Astrocytes; Captopril; Disease Models, Animal; Dyskinesia, Drug-Induced; Enalapril; Levodopa; Mice, Inbred C57BL; Microglia; Oxidopamine; Parkinson Disease; Perindopril
PubMed: 38642669
DOI: 10.1016/j.ejphar.2024.176573 -
Diabetes, Metabolic Syndrome and... 2024This study aimed to investigate the intervention mechanism of Jiawei Shengjiangsan (JWSJS) on kidney injury in diabetic nephropathy mice.
PURPOSE
This study aimed to investigate the intervention mechanism of Jiawei Shengjiangsan (JWSJS) on kidney injury in diabetic nephropathy mice.
METHODS
Thirty 8-week-old db/db mice were randomly divided into five groups: model group, Perindopril group, and JWSJS low-, medium-, and high-dose groups (n=6 per group) based on body weight. Additionally, a blank control group was established consisting of 6 db/m mice aged 8 weeks. The blank and model groups received daily intragastric administration of 7g/kg/d pure water. The remaining groups were assigned to JWSJS low (3.5g/kg/d), medium (7g/kg/d), high (14g/kg/d) dosage groups, and perindopril positive control group (0.48mg/kg/d) for 12 weeks. Post-experiment, serum creatinine (SCr) and blood urea nitrogen (BUN) were analyzed using an automatic biochemical analyzer. Enzyme-linked immunosorbent assay (ELISA) measured 24-hour urinary albumin, neutrophil gelatinase-associated lipocalin (NGAL), TNF-α, IL-1β, VCAM-1, MCP-1, and HbA1c. Western blot assessed the protein expressions of p-PI3K, p-Akt, and p-NF-κB p65, while pathological kidney changes were observed.
RESULTS
Compared to the blank group, the model group exhibited increased SCr, BUN, 24-hour urinary albumin, serum NGAL, TNF-α, IL-1β, VCAM-1, MCP-1, HbA1c, p-PI3K, and p-Akt, alongside increased p-NF-κB p65 expression, indicating significant kidney pathology. After treatment, the JWSJS group showed decreased SCr, BUN, 24-hour urinary microalbumin, NGAL, HbA1c, TNF-α, IL-1β, VCAM-1, MCP-1 levels, increased p-PI3K and p-Akt expression (P<0.05), and reduced p-NF-κB p65 content (P<0.05). Histopathological analysis revealed that JWSJS ameliorated renal tubular epithelial cell damage, glomerular capillary and basement membrane injuries, and facilitated the repair of damaged podocytes in diabetic nephropathy mice.
CONCLUSION
JWSJS demonstrated efficacy in reducing renal inflammation in diabetic nephropathy mice, with its mechanism likely associated with the inhibition of the PI3K/Akt/NF-κB signaling pathway.
PubMed: 38629025
DOI: 10.2147/DMSO.S456205 -
Cardiovascular Research May 2024Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors...
Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks.
AIMS
Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown.
METHODS AND RESULTS
In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys.
CONCLUSION
Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks.
Topics: Animals; Renin-Angiotensin System; Rats, Inbred SHR; Kidney; Losartan; Hypertension; Gene Regulatory Networks; DNA Methylation; Male; Disease Models, Animal; Antihypertensive Agents; Renin; Angiotensin-Converting Enzyme Inhibitors; Angiotensin II Type 1 Receptor Blockers; Perindopril; Time Factors; Epigenesis, Genetic; Gene Expression Regulation; Arterial Pressure; Transcriptome; Rats; Blood Pressure
PubMed: 38501595
DOI: 10.1093/cvr/cvae053 -
Poultry Science Apr 2024At the onset of sexual maturity, the increasing circulating estrogen stimulates the formation of medullary bone, which provides available calcium for eggshell formation....
At the onset of sexual maturity, the increasing circulating estrogen stimulates the formation of medullary bone, which provides available calcium for eggshell formation. The bone loss of laying hens is caused by the continuous dynamic changes of structure bone leading to bone fragility and susceptibility. The degree of medullary bone mineralization in sexual maturity is positively correlated with bone quality in the late laying stage. This study aimed to explore the molecular regulation mechanism of bone metabolism pre- and postsexual maturity in hens based on the joint analysis of transcriptome and metabolome. A total of 50 Hy-line Sonia pullets with comparable body weight at 13 wk were selected. Eight pullets were killed at 15 wk (juvenile hens, JH) and 19 wk (laying hens, LH), and LHs were killed within 3 h after oviposition. Differentially expressed genes and metabolites in tibia were analyzed based on transcriptome and metabolome, and then combined to construct the relevant metabolisms and hub genes. In the LH hens, plasma levels of estrogen and tartrate-resistant acid phosphatase were significantly elevated by 1.7 and 1.3 times. In addition, the midpoint diameter, bone mineral density and bone mineral content of the tibia and femur were higher at 19 wk of age. A total of 580 differentially expressed genes were found between the JH and LH group in the tibia, including 280 up-regulated, and 300 down-regulated genes in the LH group. Gene set enrichment analysis (GSEA) showed that the intracellular biosynthesis and secretion of matrix vesicles were significantly enrichment in the LH hens. A total of 21 differential metabolites were identified between JH and LH group. Estradiol valerate positively correlated with L-theanine, tryptophan betaine, dopamine, and perindopril. Joint analysis showed that the top 20 hub genes were enriched in cholesterol biosynthesis and phospholipid metabolism, which played a key regulatory role in bone metabolism during pre- and postsexual maturity. These results provide a theoretical foundation for maintaining efficient egg production and reducing bone health problems in laying hens.
Topics: Female; Animals; Transcriptome; Chickens; Gene Expression Profiling; Oviposition; Estrogens
PubMed: 38417334
DOI: 10.1016/j.psj.2024.103555 -
Frontiers in Pharmacology 2023Uncontrolled blood pressure is a major risk factor for cardiovascular diseases. Fixed-dose combination (FDC) therapy offers a promising approach to addressing this... (Review)
Review
Uncontrolled blood pressure is a major risk factor for cardiovascular diseases. Fixed-dose combination (FDC) therapy offers a promising approach to addressing this challenge by providing a convenient single-tablet solution that enhances the effectiveness of blood pressure control. In our systematic review, we assess the effectiveness of perindopril/amlodipine FDC in managing blood pressure. We conducted a comprehensive search across four primary electronic databases, namely, PubMed, Virtual Health Library (VHL), Global Health Library (GHL), and Google Scholar, as of 8 February 2022. Additionally, we performed a manual search to find relevant articles. The quality of the selected articles was evaluated using the Study Quality Assessment Tools (SQAT) checklist from the National Institute of Health and the ROB2 tool from Cochrane. Our systematic review included 17 eligible articles. The findings show that the use of perindopril/amlodipine FDC significantly lowers blood pressure and enhances the quality of blood pressure control. Compared to the comparison group, the perindopril/amlodipine combination tablet resulted in a higher rate of blood pressure response and normalization. Importantly, perindopril/amlodipine FDC contributes to improved patient adherence with minimal side effects. However, studies conducted to date have not provided assessments of the cost-effectiveness of perindopril/amlodipine FDC. In summary, our analysis confirms the effectiveness of perindopril/amlodipine FDC in lowering blood pressure, with combination therapy outperforming monotherapy and placebo. Although mild adverse reactions were observed in a small subset of participants, cost-effectiveness assessments for this treatment remain lacking in the literature.
PubMed: 38410524
DOI: 10.3389/fphar.2023.1156655 -
Pharmaceutics Feb 2024Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a...
Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and C were within 0.5-2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients.
PubMed: 38399287
DOI: 10.3390/pharmaceutics16020234 -
IScience Feb 2024The molecular mechanism of ibrutinib-induced atrial fibrillation (AF) remains unclear. We here demonstrate that treating rats with ibrutinib for 4 weeks resulted in the...
The molecular mechanism of ibrutinib-induced atrial fibrillation (AF) remains unclear. We here demonstrate that treating rats with ibrutinib for 4 weeks resulted in the development of inducible AF, left atrial enlargement, atrial fibrosis, and downregulation of connexin expression, which were associated with C-terminal Src kinase (CSK) inhibition and Src activation. Ibrutinib upregulated angiotensin-converting enzyme (ACE) protein expression in human pulmonary microvascular endothelial cells (HPMECs) by inhibiting the PI3K-AKT pathway, subsequently increasing circulating angiotensin II (Ang II) levels. However, the expression of ACE and Ang II in the left atria was not affected. Importantly, we observed that perindopril significantly mitigated ibrutinib-induced left atrial remodeling and AF promotion by inhibiting the activation of the ACE and its downstream CSK-Src signaling pathway. These findings indicate that the Ibrutinib-induced activation of the ACE contributes to AF development and could serve as a novel target for potential prevention strategies.
PubMed: 38357670
DOI: 10.1016/j.isci.2024.108926 -
European Heart Journal Apr 2024Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure...
BACKGROUND AND AIMS
Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment.
METHODS
Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes.
RESULTS
Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality.
CONCLUSIONS
Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.
Topics: Humans; Blood Pressure; Atenolol; Antihypertensive Agents; Hypertension; Amlodipine; Risk Factors
PubMed: 38291599
DOI: 10.1093/eurheartj/ehad814