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European Journal of Clinical... Jun 2024To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19.
PURPOSE
To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19.
METHODS
We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders.
RESULTS
Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17-1.35] and thiazides with reduced risk (0.78; 0.69-0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found.
CONCLUSION
In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation.
PubMed: 38913169
DOI: 10.1007/s00228-024-03709-2 -
Food & Function Jun 2024Bioactive peptides derived from food are promising health-promoting ingredients that can be used in functional foods and nutraceutical formulations. In addition to the...
Bioactive peptides derived from food are promising health-promoting ingredients that can be used in functional foods and nutraceutical formulations. In addition to the potency towards the selected therapeutic target, the bioavailability of bioactive peptides is a major factor regarding clinical efficacy. We have previously shown that a low molecular weight peptide fraction (LMWPF) from poultry by-product hydrolysates possesses angiotensin-1-converting enzyme (ACE-1) and dipeptidyl-peptidase 4 (DPP4) inhibitory activities. The present study aimed to investigate the bioavailability of the bioactive peptides in the LMWPF. Prior to the investigation of bioavailability, a dipeptide YA was identified from this fraction as a dual inhibitor of ACE-1 and DPP4. Gastrointestinal (GI) stability and intestinal absorption of the bioactive peptides (, YA as well as two previously reported bioactive dipeptides (VL and IY)) in the LMWPF were evaluated using the INFOGEST static digestion model and intestinal Caco-2 cell monolayer, respectively. Analysis of peptides after digestion confirmed that the dipeptides were resistant to the simulated GI conditions. After 4 hours of incubation, the concentration of the peptide from the apical side of the Caco-2 cell monolayer showed a significant decrease. However, the corresponding absorbed peptides were not detected on the basolateral side, suggesting that the peptides were not transported across the intestinal monolayer but rather taken up or metabolized by the Caco2 cells. Furthermore, when analyzing the gene expression of the Caco-2 cells upon peptide stimulation, a down-regulation of peptide transporters, the transcription factor , and the tight junction protein-1 () was observed, suggesting the specific effects of the peptides on the Caco-2 cells. The study demonstrated that bioactive dipeptides found in the LMWPF were stable through GI digestion; however, the overall bioavailability may be hindered by inadequate uptake across the intestinal barrier.
PubMed: 38912915
DOI: 10.1039/d4fo01214c -
Cureus May 2024Acute pancreatitis is a prevalent gastrointestinal condition in the United States, with approximately 130,000 new cases annually, displaying a rising incidence. Severe...
Acute pancreatitis is a prevalent gastrointestinal condition in the United States, with approximately 130,000 new cases annually, displaying a rising incidence. Severe cases, constituting 20% of instances, necessitate intensive care unit admission, associated with elevated mortality rates. While gallstones and chronic alcohol use are primary causes, certain medications, including ACE inhibitors, statins, hormone-replacement therapies, diuretics, hypoglycemic agents, and steroids, can induce pancreatitis. Notably, recent reports link empagliflozin, an SGLT-2 inhibitor used in managing type 2 diabetes, to pancreatitis, a rare complication in this drug class. This article details a case study of a 57-year-old African American man presenting with hyperglycemic hyperosmolar syndrome due to empagliflozin-induced pancreatitis, a novel sequela. The discussion underscores the role of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in diabetes management, emphasizing their advantages and associated complications. This report adds a unique dimension to the literature, emphasizing the importance of prompt identification and cessation of culpable agents to prevent adverse outcomes. This article aims to comprehensively address the prevalence and increasing incidence of acute pancreatitis in the United States. This report aims to assist healthcare professionals in recognizing and discontinuing causative agents, thereby providing valuable insights into the comprehension of drug-induced pancreatitis.
PubMed: 38910717
DOI: 10.7759/cureus.60935 -
Cureus May 2024Angioedema is a condition characterized by non-pitting swelling of the subcutaneous or submucosal tissues in particular the face, lips, and oral cavity....
Angioedema is a condition characterized by non-pitting swelling of the subcutaneous or submucosal tissues in particular the face, lips, and oral cavity. Angiotensin-converting enzyme (ACE) inhibitors are known to contribute to the development of angioedema by increasing the levels of bradykinin and its active metabolites. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is hypothesized to contribute to the development of angioedema by modifying ACE II levels and further increasing the level of bradykinin in patients taking ACE inhibitors. African Americans may be at particular risk of developing angioedema with concomitant SARS-CoV-2 infection and ACE inhibitor use. This case involves a 31-year-old African American male diagnosed with coronavirus disease 2019 (COVID-19) who developed angioedema while taking an ACE inhibitor.
PubMed: 38910667
DOI: 10.7759/cureus.60852 -
Current Neurovascular Research Jun 2024A rupture of the intracranial aneurysm is frequently complicated, with an increase of intracranial pressure (ICP) requiring conservative and/or surgical treatment. We...
OBJECTIVE
A rupture of the intracranial aneurysm is frequently complicated, with an increase of intracranial pressure (ICP) requiring conservative and/or surgical treatment. We ana- lyzed the risk factors related to the duration of pathologic ICP increase and the relationship be- tween ICP burden and the outcome of subarachnoid hemorrhage (SAH).
METHODS
Consecutive cases with aneurysmal SAH treated at our institution between 01/2003 and 06/2016 were eligible for this study. Different admission variables were evaluated to predict the duration of ICP increase >20 mmHg in univariate and multivariate analyses. The association of the ICP course with SAH outcome parameters (risk of cerebral infarction, in-hospital mortali- ty, and unfavorable outcome at 6 months defined as modified Rankin scale >3) was adjusted for major outcome-relevant confounders.
RESULTS
Of 820 SAH patients, 378 individuals (46.1%) developed at least one ICP increase re- quiring conservative and/or surgical management after aneurysm treatment (mean duration: 1.76 days, range: 1 - 14 days). In the multivariable linear regression analysis, patients' age (unstand- ardized coefficient [UC]=-0.02, p <0.0001), World Federation of Neurosurgical Societies (WFNS) grade 4-5 at admission (UC=0.71, p <0.004), regular medication with the angiotensin- converting enzyme (ACE) inhibitors (UC=-0.61, p =0.01), and presence of intracerebral hemor- rhage (UC=0.59, p =0.002) were associated with the duration of ICP increase. In turn, patients with longer ICP elevations were at higher risk for cerebral infarction (adjusted odds ratio [aOR]=1.32 per-day-increase, p <0.0001), in-hospital mortality (aOR=1.30, p <0.0001) and un- favorable outcome (aOR=1.43, p <0.0001). SAH patients who underwent primary decompres- sive craniectomy (DC) showed shorter periods of ICP increase than patients with a secondary decompression (mean: 2.8 vs 4.9 days, p <0.0001).
CONCLUSION
The duration of ICP increase after aneurysm rupture is a strong outcome predictor and is related to younger age and higher initial severity of SAH. Further analysis of the factors impacting the course of ICP after SAH is essential for the optimization of ICP management and outcome improvement.
.PubMed: 38910272
DOI: 10.2174/0115672026312548240610104504 -
European Biophysics Journal : EBJ Jun 2024To find drugs against COVID-19, caused by the SARS-CoV-2, promising targets include the fusion of the viral spike with the human angiotensin-converting enzyme 2 (ACE2)...
Computational discovery of dual potential inhibitors of SARS-CoV-2 spike/ACE2 and M: 3D-pharmacophore, docking-based virtual screening, quantum mechanics and molecular dynamics.
To find drugs against COVID-19, caused by the SARS-CoV-2, promising targets include the fusion of the viral spike with the human angiotensin-converting enzyme 2 (ACE2) as well as the main protease (M). These proteins are responsible for viral entry and replication, respectively. We combined several state-of-the-art computational methods, including, protein-ligand interaction fingerprint, 3D-pharmacophores, molecular-docking, MM-GBSA, DFT, and MD simulations to explore two databases: ChEMBL and NANPDB to identify molecules that could both block spike/ACE2 fusion and inhibit M. A total of 1,690,649 compounds from the two databases were screened using the pharmacophore model obtained from PLIF analysis. Five recent complexes of M co-crystallized with different ligands were used to generate the pharmacophore model, allowing 4,829 compounds that passed this prefilter. These were then submitted to molecular docking against M. The 5% top-ranked docking hits from docking result having scores -8.32 kcal mol were selected and then docked against spike/ACE2. Only four compounds: ChEMBL244958, ChEMBL266531, ChEMBL3680003, and 1-methoxy-3-indolymethyl glucosinolate (4) displayed binding energies 8.21 kcal mol (for the native ligand) were considered as putative dual-target inhibitors. Furthermore, predictive ADMET, MM-GBSA and DFT/6-311G(d,p) were performed on these compounds and compared with those of well-known antivirals. DFT calculations showed that ChEMBL244958 and compound 4 had significant predicted reactivity values. Molecular dynamics simulations of the docked complexes were run for 100 ns and used to validate the stability docked poses and to confirm that these hits are putative dual binders of the spike/ACE2 and the M.
PubMed: 38907013
DOI: 10.1007/s00249-024-01713-z -
Comparative Biochemistry and... Jun 2024Sea cucumber is a valuable seafood product and autolysis is the main concern for the aquaculture industry. This study employed proteomics and transcriptomics to...
Sea cucumber is a valuable seafood product and autolysis is the main concern for the aquaculture industry. This study employed proteomics and transcriptomics to investigate the autolysis mechanism of sea cucumbers. The fresh sea cucumber was exposed to UV light to induce autolysis. The body wall samples were cut off to analyze by proteomics and transcriptomics. The angiotensin-converting enzyme (ACE) inhibitor of teprotide and the activator of imatinib were gastric gavage to live sea cucumbers, respectively, to identify the regulation target. Autolysis occurrence was evaluated by appearance, soluble peptide, and hydroxyproline content. Four gene-protein pairs were ACE, AJAP10923, Heme-binding protein 2-like, and Ficolin-2-like. Only the ACE protein and gene changed synchronously and a significant down-regulation of ACE occurred in the autolysis sea cucumbers. Teprotide led to a 1.58-fold increase in the TCA-soluble protein content and a 1.57-fold increase in hydroxyproline content. No significant differences were observed between imatinib-treated sea cucumbers and fresh ones regarding TCA-soluble protein content or hydroxyproline levels (P > 0.05). ACE inhibitor accelerated the autolysis of sea cucumber, but ACE activator inhibited the autolysis. Therefore, ACE can serve as a regulatory target for autolysis in sea cucumbers.
PubMed: 38906042
DOI: 10.1016/j.cbd.2024.101274 -
Frontiers in Pharmacology 2024Antihypertensive drugs are used preventatively to lower the risk of cardiovascular disease events. Comparative effectiveness studies on angiotensin-converting enzyme...
INTRODUCTION
Antihypertensive drugs are used preventatively to lower the risk of cardiovascular disease events. Comparative effectiveness studies on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and thiazides have yielded inconsistent results and given little consideration to patient adherence. Using a longitudinal cohort and considering time-varying adherence and confounding factors, we aimed to estimate the real-world effectiveness of five major antihypertensive drug monotherapies in the primary prevention of cardiovascular events.
METHODS
Eligible patients for a retrospective inception cohort study were selected using information obtained from the University of Groningen IADB.nl pharmacy prescription database. Cohort 1 comprised adherent patients with a follow-up time exceeding 1 year, and cohort 2 comprised all patients independent of adherence. The exposures were ACEIs, ARBs, BBs, CCBs, and thiazides. The primary outcome was the time to the first prescription for an acute cardiac drug therapy (CDT) measured using valid drug proxies to identify the first major cardiovascular event. A per-protocol analytical approach was adopted with inverse probability of treatment weighted (IPTW), time-varying Cox regression analysis to obtain the hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS
In cohort 1 ( = 22,441), 1,294 patients (5.8%) were prescribed an acute CDT with an average follow-up time of 4.2 ± 2.8 years. Following IPTW, the hazard measures of ARBs and thiazides were lower than those of BBs (HRs: 0.79 and 0.80, respectively; 95% CIs: 0.64-0.97 and 0.69-0.94, respectively). Among drug-treated diabetic patients, the hazard measures were even lower, with HR point estimates of 0.43 (CI: 0.19-0.98) for ARBs and 0.32 (CI: 0.13-0.82) for thiazides. In cohort 2 ( = 33,427) and sensitivity analysis, the comparative effectiveness results for thiazides and BBs were similar to those for cohort 1.
CONCLUSION
The findings of this real-world analysis suggest that the incidence of CDT associated with long-term thiazide or ARB monotherapy is lower than the incidence of CDT with BBs, notably among high-risk patients. Incidences of CDT associated with ACEIs and CCBs were comparable relative to those associated with BBs.
PubMed: 38903996
DOI: 10.3389/fphar.2024.1357567 -
Journal of Cellular and Molecular... Jun 2024Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD... (Review)
Review
Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD neuropathology through modulation of oxidative stress, mitochondrial dysfunction and neuroinflammation. Therefore, modulation of brain RAS by angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may be effective in reducing the risk and PD neuropathology. It has been shown that all components including the peptides and enzymes of the RAS are present in the different brain areas. Brain RAS plays a critical role in the regulation of memory and cognitive function, and in the controlling of central blood pressure. However, exaggerated brain RAS is implicated in the pathogenesis of different neurodegenerative diseases including PD. Two well-known pathways of brain RAS are recognized including; the classical pathway which is mainly mediated by AngII/AT1R has detrimental effects. Conversely, the non-classical pathway which is mostly mediated by ACE2/Ang1-7/MASR and AngII/AT2R has beneficial effects against PD neuropathology. Exaggerated brain RAS affects the viability of dopaminergic neurons. However, the fundamental mechanism of brain RAS in PD neuropathology was not fully elucidated. Consequently, the purpose of this review is to disclose the mechanistic role of RAS in in the pathogenesis of PD. In addition, we try to revise how the ACEIs and ARBs can be developed for therapeutics in PD.
Topics: Renin-Angiotensin System; Humans; Parkinson Disease; Brain; Animals; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors
PubMed: 38899551
DOI: 10.1111/jcmm.18495 -
BMJ (Clinical Research Ed.) Jun 2024Resistant hypertension is defined as blood pressure that remains above the therapeutic goal despite concurrent use of at least three antihypertensive agents of different... (Review)
Review
Resistant hypertension is defined as blood pressure that remains above the therapeutic goal despite concurrent use of at least three antihypertensive agents of different classes, including a diuretic, with all agents administered at maximum or maximally tolerated doses. Resistant hypertension is also diagnosed if blood pressure control requires four or more antihypertensive drugs. Assessment requires the exclusion of apparent treatment resistant hypertension, which is most often the result of non-adherence to treatment. Resistant hypertension is associated with major cardiovascular events in the short and long term, including heart failure, ischemic heart disease, stroke, and renal failure. Guidelines from several professional organizations recommend lifestyle modification and antihypertensive drugs. Medications typically include an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, a calcium channel blocker, and a long acting thiazide-type/like diuretic; if a fourth drug is needed, evidence supports addition of a mineralocorticoid receptor antagonist. After a long pause since 2007 when the last antihypertensive class was approved, several novel agents are now under active development. Some of these may provide potent blood pressure lowering in broad groups of patients, such as aldosterone synthase inhibitors and dual endothelin receptor antagonists, whereas others may provide benefit by allowing treatment of resistant hypertension in special populations, such as non-steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease. Several device based approaches have been tested, with renal denervation being the best supported and only approved interventional device treatment for resistant hypertension.
Topics: Humans; Hypertension; Antihypertensive Agents; Drug Resistance; Drug Therapy, Combination; Calcium Channel Blockers; Blood Pressure
PubMed: 38897628
DOI: 10.1136/bmj-2023-079108