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Circulation Aug 2022The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration.
METHODS
Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress.
RESULTS
Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m lower GFR compared with placebo-ramipril treatment (=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure-lowering effects (clinic systolic blood pressure lower by 4 mm Hg [=0.0112]; diastolic blood pressure lower by 3 mm Hg [=0.0032]) in conjunction with a 94.5 dynes × sex/cm lower total peripheral resistance (=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin.
CONCLUSIONS
Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT02632747.
Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Glomerular Filtration Rate; Glucose; Humans; Ramipril; Sodium; Sodium-Glucose Transporter 2
PubMed: 35862082
DOI: 10.1161/CIRCULATIONAHA.122.059150 -
International Journal of Medical... 2023For salt-sensitive hypertension (SSH), salt restriction and angiotensin-converting enzyme (ACE) inhibitors are essential treatments, but their effect on the function of...
For salt-sensitive hypertension (SSH), salt restriction and angiotensin-converting enzyme (ACE) inhibitors are essential treatments, but their effect on the function of resistance arteries is unclear. Here, we present an intravital study to detect the effect of salt restriction and ACE inhibitors on the function of the mesenteric small artery (MSA) in SSH. Dahl salt-sensitive rats were randomized into the following groups: ACE inhibitor gavage, salt restriction, ACE inhibitor combined with salt restriction, and high-salt diet. After a 12-week intervention, the mesenteric vessels maintained their perfusion , and the changes in the diameter and blood perfusion of the MSAs to norepinephrine (NE) and acetylcholine (ACh) were detected. Switching from a high-salt diet to a low-salt diet (i.e., salt restriction) attenuated the vasoconstriction of the MSAs to NE and promoted the vasodilatation to ACh, while ACE inhibitor improved the vasodilatation more obviously. Pathologically, changes in local ACE, AT1R, and eNOS expression were involved in these processes induced by a high-salt diet. Our study suggests that salt restriction and ACE inhibitor treatment improve high salt intake-induced MSA dysfunction in SSH, and salt restriction is a feasible and effective treatment. Our findings may provide a scientific basis for the treatment of hypertension.
Topics: Rats; Animals; Angiotensin-Converting Enzyme Inhibitors; Sodium Chloride, Dietary; Rats, Inbred Dahl; Hypertension; Sodium Chloride; Arteries; Blood Pressure
PubMed: 37082725
DOI: 10.7150/ijms.79741 -
SLAS Discovery : Advancing Life... Feb 2021Enzymes represent a significant proportion of the druggable genome and constitute a rich source of drug targets. Delivery of a successful program for developing a...
Enzymes represent a significant proportion of the druggable genome and constitute a rich source of drug targets. Delivery of a successful program for developing a modulator of enzyme activity requires an understanding of the enzyme's mechanism and the mode of interaction of compounds. This allows an understanding of how physiological conditions in disease-relevant cells will affect inhibitor potency. As a result, there is increasing interest in evaluating hit compounds from high-throughput screens to determine their mode of interaction with the target. This work revisits the common inhibition modalities and illustrates the impact of substrate concentration relative to K upon the pattern of changes in IC that are expected for increasing substrate concentration. It proposes a new, high-throughput approach for assessing mode of inhibition, incorporating analyses based on a minimal descriptive model, to deliver a workflow that allows rapid and earlier compound classification immediately after high-throughput screening.
Topics: Drug Discovery; Enzyme Activation; Enzyme Inhibitors; Enzymes; High-Throughput Screening Assays; Humans; Substrate Specificity; Workflow
PubMed: 33482076
DOI: 10.1177/2472555220983809 -
ACS Sensors Nov 2019Robust technology is required to underpin rapid point-of-care and in-field diagnostics to improve timely decision making across broad sectors. An attractive strategy...
Robust technology is required to underpin rapid point-of-care and in-field diagnostics to improve timely decision making across broad sectors. An attractive strategy combines target recognition and signal generating elements into an "active" enzyme-switch that directly transduces target-binding into a signal. However, approaches that are broadly applicable to diverse targets remain elusive. Here, an enzyme-inhibitor switch sensor was developed by insertion of non-immunoglobulin Affimer binding proteins, between TEM1-β-lactamase and its inhibitor protein, such that target binding disrupts the enzyme-inhibitor complex. Design principles for a successful switch architecture are illustrated by the rapid (min), simple (wash-free), and sensitive (pM) quantification of multimeric target analytes in biological samples (serum, plasma, leaf extracts), across three application areas. A therapeutic antibody (Herceptin), protein biomarker (human C-reactive protein), and plant virus (cow pea mosaic virus) were targeted, demonstrating assays for therapeutic drug monitoring, health diagnostics, and plant pathogen detection, respectively. Batch-to-batch reproducibility, shelf-life stability, and consistency with validated enzyme-linked immunosorbent assay analysis confirm that the principle of an Affimer-enzyme-inhibitor switch provides a platform for point-of-care and in-field diagnostics.
Topics: Biosensing Techniques; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Humans; beta-Lactamases
PubMed: 31578863
DOI: 10.1021/acssensors.9b01574 -
Hypertension Research : Official... Jul 2022Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the possible roles of renin-angiotensin system (RAS) inhibitors in COVID-19 have been debated as... (Review)
Review
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the possible roles of renin-angiotensin system (RAS) inhibitors in COVID-19 have been debated as favorable, harmful, or neutral. Angiotensin-converting enzyme 2 (ACE2) not only is the entry route of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but also triggers a major mechanism of COVID-19 aggravation by promoting tissue RAS dysregulation, which induces a hyperinflammatory state in several organs, leading to lung injury, hematological alterations, and immunological dysregulation. ACE inhibitors and angiotensin II type-1 receptor blockers (ARBs) inhibit the detrimental hyperactivation of the RAS by SARS-CoV-2 and increase the expression of ACE2, which is a counter-regulator of the RAS. Several studies have investigated the beneficial profile of RAS inhibitors in COVID-19; however, this finding remains unclear. Further prospective studies are warranted to confirm the role of RAS inhibitors in COVID-19. In this review, we summarize the potential effects of RAS inhibitors that have come to light thus far and review the impact of RAS inhibitors on COVID-19.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; COVID-19; Humans; Peptidyl-Dipeptidase A; Renin-Angiotensin System; SARS-CoV-2
PubMed: 35581498
DOI: 10.1038/s41440-022-00922-3 -
Medical Science Monitor : International... Dec 2018BACKGROUND This study aimed to analyze the factors associated with the development of antibiotic-associated diarrhea (AAD) in critically ill patients receiving enzyme...
BACKGROUND This study aimed to analyze the factors associated with the development of antibiotic-associated diarrhea (AAD) in critically ill patients receiving enzyme inhibitor antibiotics. MATERIAL AND METHODS A retrospective study of patients with and without AAD admitted to the intensive care unit (ICU) of the First Teaching Hospital of Xi'an Jiaotong University from February 1, 2014, to January 31, 2016, was undertaken. Relevant clinical data underwent univariate or multivariate regression analysis. RESULTS Of 184 patients who received enzyme inhibitor antibiotic therapy, 70 patients (38.04%) developed AAD, with a mean duration of onset of 6.97±3.64 days. AAD was associated with the use of enzyme inhibitor antibiotic therapy alone (OR, 1.142; 95% CI, 1.038-1.256; P=0.007), and in combination with antifungal agents (OR, 2.449; 95% CI, 1.116-5.372; P=0.025), quinolones (OR, 5.219; 95% CI, 1.746-15.601; P=0.003), and oxazolidinones (OR 2.895; 95% CI, 1.183-7.083; P=0.020). The mean duration of ICU stay was significantly increased in patients with AAD (19.00±11.49 days vs. 9.60±6.76 days) (P<0.001). Mean duration of antibiotic therapy (14.09±8.82 days vs. 8.10±4.91 days) (P<0.001) and duration of enzyme inhibitor antibiotic therapy (9.26±5.06 days vs. 6.61±3.24 days) (P<0.001) were significantly increased in patients with AAD. CONCLUSIONS Duration of use of enzyme inhibitor antibiotic therapy and the combined use of antifungals, quinolones, and oxazolidinones increased the incidence and duration of AAD and increased the length of stay in ICU.
Topics: Adult; Aged; Anti-Bacterial Agents; Antifungal Agents; China; Critical Illness; Diarrhea; Enzyme Inhibitors; Female; Humans; Incidence; Intensive Care Units; Male; Middle Aged; Oxazolidinones; Quinolones; Retrospective Studies
PubMed: 30512009
DOI: 10.12659/MSM.913739 -
International Journal of Environmental... Nov 2022Both lisinopril and enalapril are angiotensin-converting enzyme (ACE) drugs and widely used in the treatment of hypertension. Enalapril does not cross the blood-brain... (Randomized Controlled Trial)
Randomized Controlled Trial
Both lisinopril and enalapril are angiotensin-converting enzyme (ACE) drugs and widely used in the treatment of hypertension. Enalapril does not cross the blood-brain barrier, but lisinopril is centrally active. Our goal was to find out if there was a link between the actual concentration of ACE inhibitors and cognition and if there was a detectable difference between the two types of ACE inhibitors. Asymptomatic, non-treated patients were diagnosed by screening and the hypertension was confirmed by ambulatory blood pressure monitoring (ABPM). A battery of cognitive tests was used to assess the impact of randomly assigning participants to receive either lisinopril or enalapril. All neurocognitive functions were measured, especially the most affected by conditions of compromised perfusion pressures, such as hypertension, which are attention and executive functions. The lisinopril concentration showed a significant inverse correlation with mosaic test (coeff. = -0.5779) and seemed to have a significant negative effect on perceptual motor skills (coeff. = -0.5779), complex attention (coeff. = -0.5104) and learning (coeff. = -0.5202). Compared with enalapril, lisinopril is less successful in improving the components of cognitive functions.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure Monitoring, Ambulatory; Cognition; Enalapril; Hypertension; Lisinopril
PubMed: 36361252
DOI: 10.3390/ijerph192114375 -
Protein Science : a Publication of the... Oct 2018The worldwide trend of limiting the use of antibiotic growth promoters (AGPs) in animal production creates challenges for the animal feed industry, thus necessitating... (Review)
Review
The worldwide trend of limiting the use of antibiotic growth promoters (AGPs) in animal production creates challenges for the animal feed industry, thus necessitating the development of effective non-antibiotic alternatives to improve animal performance. Increasing evidence has shown that the growth-promoting effect of AGPs is highly correlated with the reduced activity of bile salt hydrolase (BSH, EC 3.5.1.24), an intestinal bacteria-producing enzyme that has a negative impact on host fat digestion and energy harvest. Therefore, BSH inhibitors may become novel, attractive alternatives to AGPs. Detailed knowledge of BSH substrate preferences and the wealth of structural data on BSHs provide a solid foundation for rationally tailored BSH inhibitor design. This review focuses on the relationship between structure and function of BSHs based on the crystal structure, kinetic data, molecular docking and comparative structural analyses. The molecular basis for BSH substrate recognition is also discussed. Finally, recent advances and future prospectives in the development of potent, safe, and cost-effective BSH inhibitors are described.
Topics: Amidohydrolases; Animals; Enzyme Inhibitors; Humans; Molecular Structure
PubMed: 30098054
DOI: 10.1002/pro.3484 -
Experimental Physiology Aug 2021What is the central question of this study? We questioned whether an angiotensin-converting enzyme (ACE) inhibitor prevents skeletal muscle fibrosis in diabetic mice....
NEW FINDINGS
What is the central question of this study? We questioned whether an angiotensin-converting enzyme (ACE) inhibitor prevents skeletal muscle fibrosis in diabetic mice. What is the main finding and its importance? Administration of ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after induction of diabetes by streptozotocin. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes.
ABSTRACT
Fibrosis is characterized by the excessive production and accumulation of extracellular matrix components, including collagen. Although the extracellular matrix is an essential component of skeletal muscle, fibrosis can have negative effects on muscle function. Skeletal muscle fibrosis was shown to be increased in spontaneously hypertensive rats and to be prevented by an angiotensin-converting enzyme (ACE) inhibitor, an antihypertensive drug, in dystrophic mice or a mouse model of myocardial infarction. In this study, we therefore analysed whether (1) there is increased skeletal muscle fibrosis in streptozotocin (STZ)-induced diabetic mice, and (2) a preventive effect on skeletal muscle fibrosis by administration of an ACE inhibitor. Skeletal muscle fibrosis was significantly increased in STZ-induced diabetic mice compared with control mice from 2 to 14 days post-STZ. The ACE inhibitor prevented both skeletal muscle fibrosis and the reduction in muscle function in STZ-treated mice. Our study demonstrated that administration of an ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after onset of diabetes. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Future studies are required to clarify whether skeletal muscle fibrosis is also linked directly to physical activity.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Fibrosis; Mice; Muscle, Skeletal; Rats
PubMed: 33998079
DOI: 10.1113/EP089375 -
Molecules (Basel, Switzerland) Nov 2019In this review, a general introduction to fragment-based drug design and the underlying concepts is given. General considerations and methodologies ranging from library... (Review)
Review
In this review, a general introduction to fragment-based drug design and the underlying concepts is given. General considerations and methodologies ranging from library selection/construction over biophysical screening and evaluation methods to in-depth hit qualification and subsequent optimization strategies are discussed. These principles can be generally applied to most classes of drug targets. The examples given for fragment growing, merging, and linking strategies at the end of the review are set in the fields of enzyme-inhibitor design and macromolecule-macromolecule interaction inhibition. Building upon the foundation of fragment-based drug discovery (FBDD) and its methodologies, we also highlight a few new trends in FBDD.
Topics: Drug Design; Drug Discovery; Enzyme Inhibitors; Humans; Macromolecular Substances
PubMed: 31779114
DOI: 10.3390/molecules24234309