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Journal of the... 2021Excessive intake of fructose increases serum uric acid concentration. Hyperuricemia induces a negative effect on atherosclerosis and inflammation. Hyperuricemia is... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Excessive intake of fructose increases serum uric acid concentration. Hyperuricemia induces a negative effect on atherosclerosis and inflammation. Hyperuricemia is common in patients with arterial hypertension. Several antihypertensive drugs including diuretics increase serum uric acid concentration. In contrast, the angiotensin II receptor antagonist (ARB) losartan was found to lower serum uric acid though it may increase renal excretion while other ARBs showed mostly a neutral effect. In this study, effects of two AT1 receptor antagonists losartan and eprosartan on serum uric acid changes induced by oral fructose load were directly compared.
METHODS
The randomized, crossover, head-to-head comparative study comprised 16 ambulatory patients (mean age 64.5 ± 9.8 years). The patients fulfilled AHA/NHLBI 2005 criteria of metabolic syndrome. A daily single morning dose of each study drug (50 mg of losartan or 600 mg of eprosartan) was given during two 3-month periods in a random order separated by 2-week washout time. The oral fructose tolerance test (OFTT) was performed at baseline and after each two 3-onth treatment periods. Before and during OFTT, urine excretion of uric acid and creatinine was assessed in the first morning portion of urine. Blood samples for the measurement of serum uric acid and lipids were taken at baseline and 30, 60, and 120 minutes after oral intake of 75 g of fructose.
RESULTS
After 3-month treatment with eprosartan and losartan, both systolic and diastolic blood pressure decreased significantly and to a similar extent. After the treatment, serum uric acid and its baseline and postfructose urine excretion were unchanged. No significant changes of plasma lipids before and after OFTT were observed throughout the study.
CONCLUSIONS
The study showed that in patients with hypertension and metabolic syndrome, both losartan and eprosartan have a neutral effect on fasting and postfructose load serum uric acid concentration and its urinary excretion. This trial is registered with NCT04954560.
Topics: Acrylates; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Fructose; Humans; Hypertension; Imidazoles; Losartan; Metabolic Syndrome; Middle Aged; Thiophenes; Uric Acid
PubMed: 34527078
DOI: 10.1155/2021/2214978 -
International Journal of Molecular... Jun 2023Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal...
Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal diseases. For this reason, the study and application of this cell type is of great importance in the field of regenerative medicine. Hypertension is mainly regulated by the renin-angiotensin-aldosterone system (RAAS), with its main mediator being angiotensin II (ANG II). Elevated ANG II levels lead to a pro-fibrotic, inflammatory, and hypertrophic milieu that induces apoptosis in podocytes. The activation of RAAS is critical for the pathogenesis of podocyte injury; as such, to prevent podocyte damage, patients with hypertension are administered drugs that modulate RAAS signaling. A prime example is the orally active, non-peptide, selective angiotensin-II-type I receptor (AGTR1) blocker losartan. Here, we demonstrate that SIX2-positive urine-derived renal progenitor cells (UdRPCs) and their immortalized counterpart (UM51-hTERT) can be directly differentiated into mature podocytes. These podocytes show activation of RAAS after stimulation with ANG II, resulting in ANG II-dependent upregulation of the expression of the angiotensin-II-type I receptor, AGTR1, and the downregulated expression of the angiotensin-II-type II receptor 2 (AGTR2). The stimulation of podocytes with losartan counteracts ANG II-dependent changes, resulting in a dependent favoring of the specific receptor from AGTR1 to AGTR2. Transcriptome analysis revealed 94 losartan-induced genes associated with diverse biological processes and pathways such as vascular smooth muscle contraction, the oxytocin signaling pathway, renin secretion, and ECM-receptor interaction. Co-stimulation with losartan and ANG II induced the exclusive expression of 106 genes associated with DNA methylation or demethylation, cell differentiation, the developmental process, response to muscle stretch, and calcium ion transmembrane transport. These findings highlight the usefulness of UdRPC-derived podocytes in studying the RAAS pathway and nephrotoxicity in various kidney diseases.
Topics: Humans; Losartan; Angiotensin II; Podocytes; Gene Regulatory Networks; Receptor, Angiotensin, Type 1; Hypertension
PubMed: 37445727
DOI: 10.3390/ijms241310551 -
Osteoarthritis and Cartilage Apr 2023The aim of this study is to analyze the latest evidence on the effects of losartan or Ang II receptor antagonists on cartilage repair, with a focus on their clinical... (Review)
Review
OBJECTIVE
The aim of this study is to analyze the latest evidence on the effects of losartan or Ang II receptor antagonists on cartilage repair, with a focus on their clinical relevance.
DESIGN
The PubMed, Embase, and Cochrane Library databases were searched up to November 12th 2021 to evaluate the effects of losartan or Ang II receptor antagonists on cartilage repair in in vitro studies and in vivo animal studies. Study design, sample characteristics, treatment type, duration, and outcomes were analyzed. The risk of bias and the quality of the eligible studies were assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES).
RESULTS
A total of 12 studies were included in this systematic review. Of the 12 eligible studies, two studies were in vitro human studies, three studies were in vitro animal studies, one study was an in vitro human and animal study, and six studies were in vivo animal studies. The risk bias and quality assessments were predominantly classified as moderate. Since meta-analysis was difficult due to differences in treatment type, dosage, route of administration, and method of outcome assessment among the eligible studies, qualitative evaluation was conducted for each study.
CONCLUSIONS
Both in vitro and in vivo studies provide evidence to demonstrate beneficial effects of Ang II receptor antagonists on osteoarthritis and cartilage defect models across animal species.
Topics: Animals; Humans; Angiotensin II Type 2 Receptor Blockers; Angiotensin Receptor Antagonists; Cartilage; Losartan; Osteoarthritis
PubMed: 36586717
DOI: 10.1016/j.joca.2022.11.014 -
European Review For Medical and... Oct 2015The effectiveness of chemotherapeutic agents is impaired by limited delivery of chemotherapeutic agents to the tumor cells. Improving drug penetration in tumor tissues...
OBJECTIVE
The effectiveness of chemotherapeutic agents is impaired by limited delivery of chemotherapeutic agents to the tumor cells. Improving drug penetration in tumor tissues is very important. We tested whether losartan, a selective antagonist against type 1 angiotensin II receptors (AT1R) with noted antifibrotic activity, can enhance the penetration and efficacy of doxorubicin.
MATERIALS AND METHODS
BALB/C mice, which implanted with CT26 tumor cells, were divided into four groups: control, doxorubicin alone, losartan alone and doxorubicin + losartan combination groups. At day 0, the losartan alone and doxorubicin + losartan combination groups received losartan; and at day 8, the doxorubicin alone and doxorubicin + losartan combination groups received doxorubicin i.v. Tumor growth and intratumoral distribution of doxorubicin were evaluated. The mechanism underlying the enhanced anti-tumor effect of the combination of doxorubicin and losartan was investigated by immunohistochemical analysis.
RESULTS
Treatment with losartan alone did not suppress tumor growth; In contrast, treatment with doxorubicin alone decreased tumor growth; losartan and doxorubicin were administered in combination, had a synergistic effect that the tumor growth was much more inhibited. The decreased proliferation as indicated by down-regulation of Ki67, and increased apoptosis as indicated by TUNEL and caspase-3 staining. The expression of tumor suppressor gene P53 increased in doxorubicin + losartan combination groups.
CONCLUSIONS
Losartan can increase the therapeutic effectiveness of doxorubicin, yielding more great antitumor benefit. This study provided a rationale for initiating clinical trials using losartan in combination with chemotherapeutic agents to increase their therapeutic effectiveness.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Doxorubicin; Losartan; Mice; Mice, Inbred BALB C; Neoplasms
PubMed: 26502868
DOI: No ID Found -
Clinical Interventions in Aging 2014Hypertension is common in Asian populations and is a major cause of cardiovascular diseases. The prevalence of hypertension is increasing in many Asian countries. The... (Review)
Review
Hypertension is common in Asian populations and is a major cause of cardiovascular diseases. The prevalence of hypertension is increasing in many Asian countries. The overall prevalence of hypertension in India and the People's Republic of China has been estimated to be 20.6% in men and 22.6% in women. However, the rates of detection, treatment, and control of hypertension remain low in Asia. This reflects a low level of literacy and education, as well as a low level of access to medical care. To overcome these obstacles, strategies targeted at education, promotion, and optimization of medical care, are crucial to achieve target blood pressure control. Angiotensin receptor blockers are one of the first-line treatments for essential hypertension because they confer better cardiovascular outcomes. Losartan has been widely evaluated for the management of hypertension. Although some studies suggested that the blood pressure-lowering effect of losartan is perhaps lower than for other angiotensin receptor blockers, losartan has been demonstrated to be beneficial in terms of renal protection in patients with diabetes, heart failure resulting from either systolic or diastolic dysfunction, and diuretic-induced hyperuricemia. However, most of these data were obtained from Caucasian populations. The efficacy and safety of losartan in Asian populations may be different because of genetic and ethnic variations. Therefore, the efficacy and safety of losartan in Asian patients with hypertension warrant further study.
Topics: Adult; Antihypertensive Agents; Asia; Asian People; Blood Pressure; Female; Humans; Hypertension; Losartan; Male; Middle Aged
PubMed: 24672231
DOI: 10.2147/CIA.S39780 -
Drug Design, Development and Therapy 2020A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Comparison of Pharmacokinetics of a Fixed-Dose Combination of Amlodipine/Losartan/Rosuvastatin with Concomitant Administration of Amlodipine/Losartan and Rosuvastatin in Healthy Volunteers.
BACKGROUND
A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet.
SUBJECTS AND METHODS
A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUC) and the maximum plasma concentration (C) were calculated. Safety was monitored throughout the study.
RESULTS
The GMR (90% CI) values of AUC and C were 0.9946 (0.9663-1.0238) and 0.9690 (0.9379-1.0011) for amlodipine, 0.9855 (0.9422-1.0308) and 0.9178 (0.8349-1.0089) for losartan, 0.9814 (0.9501-1.0136) and 0.9756 (0.9313-1.0219) for EXP3174, and 0.9448 (0.8995-0.9923) and 0.9609 (0.8799-1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment.
CONCLUSION
We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.
Topics: Administration, Oral; Adult; Amlodipine; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Combinations; Drug Compounding; Healthy Volunteers; Humans; Losartan; Male; Middle Aged; Rosuvastatin Calcium; Tablets
PubMed: 32109991
DOI: 10.2147/DDDT.S233014 -
Advanced Science (Weinheim,... Oct 2022Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and...
Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is applied as a tumor stroma modulator and developed into a nanosystem. A series of lipophilic losartan prodrugs are constructed by esterification of the hydroxyl group on losartan to fatty acids. Based on the self-assembly ability and hydrodynamic diameter, the losartan-linoleic acid conjugate is selected for further investigation. To improve the stability in vivo, nanoassemblies are refined with PEGylation to form losartan nanoblocker (Los NB), and administered via intravenous injection for experiments. On murine models of pancreatic cancer, Los NB shows a greater ability to remodel the tumor microenvironment than free losartan, including stromal depletion, vessel perfusion increase, and hypoxia relief. Furthermore, Los NB pretreatment remarkably enhances the accumulation and penetration of 7-ethyl-10-hydroxycamptothecin (SN38)-loaded nanodrugs (SN38 NPs) in tumor tissues. Expectedly, overall therapeutic efficacy of SN38 NPs is significantly enhanced after Los NB pretreatment. Since losartan is one of the most commonly used antihypertension agents, this study may provide a potential for clinical transformation in stroma-rich PDAC treatment.
Topics: Animals; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Fatty Acids; Irinotecan; Linoleic Acids; Losartan; Mice; Nanoparticles; Pancreatic Neoplasms; Perfusion; Prodrugs; Tumor Microenvironment
PubMed: 36026578
DOI: 10.1002/advs.202201931 -
Current Medicinal Chemistry 2009The renin-angiotensin system (RAS) plays an important role in the homeostasis of the cardiovascular system and in the development of cardiovascular diseases. An abnormal... (Review)
Review
The renin-angiotensin system (RAS) plays an important role in the homeostasis of the cardiovascular system and in the development of cardiovascular diseases. An abnormal expression or over activation of the local RAS in the heart and vasculature system is one of the most common mechanisms in pathophysiological processes in cardiovascular diseases. This also provides a basis for medical prevention and treatments using chemical approaches. Losartan is a selective nonpeptite antagonist against type 1 angiotensin II receptors (AT1R), and has been applied in medical treatments of a variety of cardiovascular diseases, including essential hypertension. This article reviews direct and indirect cardiovascular effects of losartan on the heart and blood vessels. It summarizes the chemical basis of AT1R for the action site of losartan,focuses on the mechanisms underlying the action of losartan involved in both the heart and vasculature, and reviews the information that may be helpful in the development of new chemical candidates or approaches in the war against cardiovascular diseases.
Topics: Angiotensin II Type 1 Receptor Blockers; Cardiovascular Diseases; Coronary Vessels; Heart; Losartan
PubMed: 19747137
DOI: 10.2174/092986709789178046 -
Journal of Clinical Hypertension... Nov 2021Various single-pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real-world evidence regarding...
Clinical effectiveness and safety of amlodipine/losartan-based single-pill combination therapy in patients with hypertension: Findings from real-world, multicenter observational databases.
Various single-pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real-world evidence regarding the effectiveness of these SPCs for hypertension. This study evaluated the real-world clinical efficacy and safety of amlodipine/losartan-based SPC therapies in patients with hypertension in a real-world setting. A total of 15 538 patients treated with amlodipine/losartan-based SPCs [amlodipine + losartan (AL), amlodipine + losartan + rosuvastatin (ALR), and amlodipine + losartan + chlorthalidone (ALC)] were selected from the database of three tertiary hospitals in Korea. The efficacy endpoints were target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) achievement rates. Safety was evaluated based on laboratory parameters. Drug adherence was defined as the proportion of medication days covered (PDC). The target BP attainment rate was above 90% and was similar among the three groups. Although many patients in the AL and ALC groups took statins, the target LDL-C attainment rate was significantly higher in the ALR group than in the AL and ALC groups. Safety endpoints were not significantly different among the groups, except serum uric acid level and incidence rate of new-onset hyperuricemia, which were significantly lower in the AL and ALR groups than in the ALC group. The PDC was > 90% in all groups. In the real-world hypertensive patients, amlodipine/losartan-based SPC therapy demonstrated good target BP achievement rates. Especially, rosuvastatin-combination SPC showed better target LDL-C goal achievement rate compared to the other SPCs. All three amlodipine/losartan-based SPC had excellent drug adherence.
Topics: Amlodipine; Antihypertensive Agents; Humans; Hypertension; Losartan; Treatment Outcome; Uric Acid
PubMed: 34714968
DOI: 10.1111/jch.14380 -
Drug Design, Development and Therapy 2019After a trauma, exuberant tissue healing with fibrosis of the joint capsule can lead to posttraumatic joint stiffness (PTJS). Losartan and atorvastatin have both shown...
BACKGROUND
After a trauma, exuberant tissue healing with fibrosis of the joint capsule can lead to posttraumatic joint stiffness (PTJS). Losartan and atorvastatin have both shown their antifibrotic effects in different organ systems.
OBJECTIVE
The purpose of this study was the evaluation of the influence of losartan and atorvastatin on the early development of joint contracture. In addition to joint angles, the change in myofibroblast numbers and the distribution of bone sialoprotein (BSP) were assessed.
STUDY DESIGN AND METHODS
In this randomized and blinded experimental study with 24 rats, losartan and atorvastatin were compared to a placebo. After an initial joint injury, rat knees were immobilized with a Kirschner wire. Rats received either losartan, atorvastatin or a placebo orally daily. After 14 days, joint angle measurements and histological assessments were performed.
RESULTS
Losartan increased the length of the inferior joint capsule. Joint angle and other capsule length measurements did not reveal significant differences between both drugs and the placebo. At cellular level both losartan and atorvastatin reduced the total number of myofibroblasts (losartan: 191±77, atorvastatin: 98±58, placebo: 319±113 per counting field, <0.01) and the percentage area of myofibroblasts (losartan: 2.8±1.8% [<0.05], atorvastatin: 2.5±1.7% [<0.01], vs control [6.4±4%], respectively). BSP was detectable in equivalent amounts in the joint capsules of all groups with only a trend toward a reduction of the BSP-stained area by atorvastatin.
CONCLUSION
Both atorvastatin and losartan reduced the number of myofibroblasts in the posterior knee joint capsule of rat knees 2 weeks after trauma and losartan increased the length of the inferior joint capsule. However, these changes at the cellular level did not translate an increase in range of motion of the rats´ knee joints during early contracture development.
Topics: Animals; Atorvastatin; Disease Models, Animal; Fibrosis; Joint Capsule; Knee Injuries; Knee Joint; Losartan; Male; Rats; Rats, Sprague-Dawley
PubMed: 31440039
DOI: 10.2147/DDDT.S204135