Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients.

Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells.

Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell-mediated tumor regression and postulated that antifibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1-induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8+ T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with blunted TGF-ß receptor signaling, reduced collagen deposition, and depletion of immunosuppressive fibroblasts.

The Angiotensin Antagonist Losartan Modulates Social Reward Motivation and Punishment Sensitivity via Modulating Midbrain-Striato-Frontal Circuits.

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that interactions between the dopamine (DA) and renin-angiotensin system (RAS) may modulate learning and reward-related processes. The present study therefore examined the behavioral and neural effects of the Angiotensin II type 1 receptor (AT1R) antagonist losartan on social reward and punishment processing in humans. A preregistered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay (SID) functional MRI (fMRI) paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of losartan (50 mg, n = 43, female = 17) or placebo (n = 44, female = 20). We evaluated reaction times (RTs) and emotional ratings as behavioral and activation and functional connectivity as neural outcomes. Relative to placebo, losartan modulated the reaction time and arousal differences between social punishment and social reward. On the neural level the losartan-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation. Losartan increased the reward-neutral difference in the ventral tegmental area (VTA) and attenuated VTA associated connectivity with the bilateral insula in response to punishment during the outcome phase. Thus, losartan modulated approach-avoidance motivation and emotional salience during social punishment versus social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.SIGNIFICANCE STATEMENT Social deficits and anhedonia characterize several mental disorders and have been linked to the midbrain-striato-frontal circuits of the brain. Based on initial findings from animal models we here combine the pharmacological blockade of the Angiotensin II type 1 receptor (AT1R) via losartan with functional MRI (fMRI) to demonstrate that AT1R blockade enhances the motivational salience of social rewards and attenuates the negative impact of social punishment via modulating the communication in the midbrain-striato-frontal circuits in humans. The findings demonstrate for the first time an important role of the AT1R in social reward processing in humans and render the AT1R as promising novel treatment target for social and motivational deficits in mental disorders.

Two-phase mechanism in the treatment of corneal stromal fibrosis with topical losartan.

Recent studies in rabbits and case reports in humans have demonstrated the efficacy of topical losartan in the treatment of corneal scarring fibrosis after a wide range of injuries, including chemical burns, infections, surgical complications, and some diseases. It is hypothesized that the effect of losartan on the fibrotic corneal stroma occurs through a two-phase process in which losartan first triggers the elimination of myofibroblasts by directing their apoptosis via inhibition of extracellular signal-regulated kinase (ERK)-mediated signal transduction, and possibly through signaling effects on the viability and development of corneal fibroblast and fibrocyte myofibroblast precursor cells. This first step likely occurs within a week or two in most corneas with fibrosis treated with topical losartan, but the medication must be continued for much longer until the epithelial basement membrane (EBM) is fully regenerated or new myofibroblasts will develop from precursor cells. Once the myofibroblasts are eliminated from the fibrotic stroma, corneal fibroblasts can migrate into the fibrotic tissue and reabsorb/reorganize the disordered extracellular matrix (ECM) previously produced by the myofibroblasts. This second stage is longer and more variable in different eyes of rabbits and humans, and accounts for most of the variability in the time it takes for the stromal opacity to be markedly reduced by topical losartan treatment. Eventually, keratocytes reemerge in the previously fibrotic stromal tissue to fine-tune the collagens and other ECM components and maintain the normal structure of the corneal stroma. The efficacy of losartan in the prevention and treatment of corneal fibrosis suggests that it acts as a surrogate for the EBM, by suppressing TGF beta-directed scarring of the wounded corneal stroma, until control over TGF beta action is re-established by a healed EBM, while also supporting regeneration of the EBM by allowing corneal fibroblasts to occupy the subepithelial stroma in the place of myofibroblasts.

Single nucleotide polymorphism (SNP) rs4291 of the angiotensin-converting enzyme (ACE) gene is associated with the response to losartan treatment in hypertensive patients.

Arterial hypertension is characterized by systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg and its treatment consists of the use of antihypertensive drugs, as losartan and hydrochlorothiazide. Blood pressure is regulated by angiotensin-converting enzyme (ACE) and polymorphisms in the ACE gene are associated to a greater predisposition to hypertension and response to treatment. The aim of this study was to evaluate the association of genetic polymorphisms of ACE rs4363, rs4291 and rs4335 and the response to antihypertensive drugs in hypertensive patients from Ouro Preto/MG, Brazil. A case-control study was carried out with 87 hypertensive patients being treated with losartan and 75 with hydrochlorothiazide, who answered a questionnaire and had blood samples collected. Biochemical analyzes were performed on serum using UV/Vis spectrophotometry and identification of ACE variants rs4363, rs4291 and rs4335 was performed by real-time PCR using the TaqMan® system. Univariate logistic regression test was performed to compare categorical data in STATA 13.0 software. The results showed that there was an influence of ACE polymorphisms on the response to losartan, demonstrating that AT or TT genotypes of rs4291 were more frequent in the group of controlled AH (54.9%), indicating that these individuals are 2.8 times more likely to of being controlled AH (95% CI 1.12-6.80, p. =0.026) compared to those with AA genotype. In contrast, no influence of ACE polymorphisms on the response to hydrochlorothiazide was observed. In conclusion, the presence of the T allele of the rs4291 variant was associated to controled blood pressure when losartan was used as an antihypertensive agent. These results show the importance of pharmacogenetic studies to detect genetic characteristics, enabling therapeutic individuality and reducing costs for the healthcare system.

Postoperative Angiotensin Receptor Blocker Use is Associated With Decreased Rates of Manipulation Under Anesthesia, Arthroscopic Lysis of Adhesions, and Prosthesis-Related Complications in Patients Undergoing Total Knee Arthroplasty.

BACKGROUND: The cellular mechanisms underlying excess scar tissue formation in arthrofibrosis following total knee arthroplasty (TKA) are well-described. Angiotensin receptor blockers (ARB), particularly losartan, is a commonly prescribed antihypertensive with demonstrated antifibrotic properties. This retrospective study aimed to assess the rates of 1- and 2-year postoperative complications in patients who filled prescriptions for ARBs during the 90 days after TKA. METHODS: Patients undergoing primary TKA were selected from a large national insurance database, and the impact of ARB use after TKA on complications was assessed. Of the 1,299,106 patients who underwent TKA, 82,065 had filled at least a 90-day prescription of losartan, valsartan, or olmesartan immediately following their TKA. The rates of manipulation under anesthesia (MUA), arthroscopic lysis of adhesions (LOA), aseptic loosening, periprosthetic fracture, and revision at 1 and 2 years following TKA were analyzed using multivariable logistic regressions to control for various comorbidities. RESULTS: ARB use was associated with decreased rates of MUA (odds ratio [OR] = 0.94, 95% confidence interval (CI), 0.90 to 0.99), arthroscopy/LOA (OR = 0.86, 95% CI, 0.77 to 0.95), aseptic loosening (OR = 0.71, 95% CI, 0.61 to 0.83), periprosthetic fracture (OR = 0.58, 95% CI, 0.46 to 0.71), and revision (OR = 0.79, 95% CI, 0.74 to 0.85) 2 years after TKA. CONCLUSIONS: ARB use throughout the 90 days after TKA is associated with a decreased risk of MUA, arthroscopy/LOA, aseptic loosening, periprosthetic fracture, and revision, demonstrating the potential protective abilities of ARBs. Prospective studies evaluating the use of ARBs in patients at risk for postoperative stiffness would be beneficial to further elucidate this association.

Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-ß1-42 (Aß1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aß1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

Tackling Losartan Contamination: The Promise of Peroxymonosulfate/Fe(II) Advanced Oxidation Processes.

Losartan, an angiotensin II receptor antagonist frequently detected in wastewater effluents, poses considerable risks to both aquatic ecosystems and human health. Seeking to address this challenge, advanced oxidation processes (AOPs) emerge as robust methodologies for the efficient elimination of such contaminants. In this study, the degradation of Losartan was investigated in the presence of activated peroxymonosulfate (PMS), leveraging ferrous iron as a catalyst to enhance the oxidation process. Utilizing advanced analytical techniques such as NMR and mass spectrometry, nine distinct byproducts were characterized. Notably, seven of these byproducts were identified for the first time, providing novel insights into the degradation pathway of Losartan. The study delved into the kinetics of the degradation process, assessing the degradation efficiency attained when employing the catalyst alone versus when using it in combination with PMS. The results revealed that Losartan degradation reached a significant level of 64%, underscoring the efficacy of PMS/Fe(II) AOP techniques as promising strategies for the removal of Losartan from water systems. This research not only enriches our understanding of pollutant degradation mechanisms, but also paves the way for the development of sustainable water treatment technologies, specifically targeting the removal of pharmaceutical contaminants from aquatic environments.

Development of Losartan Orally Disintegrating Tablets by Direct Compression: a Cost-Effective Approach to Improve Paediatric Patient's Compliance.

The development of suitable dosage forms is essential for an effective pharmacological treatment in children. Orally disintegrating tablets (ODTs) are attractive dosage forms that avoid swallowing problems, ensure dosage accuracy and are easy to administer as they disintegrate in the oral cavity. This study aimed to develop ODTs containing losartan potassium (LP) for the treatment of arterial hypertension in children. The ODTs, produced by the cost-effective manufacturing process of direct compression, consisted of a mixture of diluent, superdisintegrant, glidant and lubricant. Five superdisintegrants (croscarmellose sodium, two grades of crospovidone, sodium starch glycolate and pregelatinized starch) were tested (at two concentrations), and combined with three diluents (mannitol, lactose and sorbitol). Thus, thirty formulations were evaluated based on disintegration time, hardness and friability. Two formulations, exhibiting the best results concerning disintegration time (< 30 s), hardness and friability (≤ 1.0%), were selected as the most promising ones for further evaluation. These ODTs presented favourable drug-excipient compatibility, tabletability and flow properties. The in vitro dissolution studies demonstrated 'very rapid' drug release. Preliminary stability studies highlighted the requirement of a protective packaging. All quality properties retained appropriate results after 12 months of storage in airtight containers. In conclusion, the ODTs were successfully developed and characterised, suggesting a potential means to accomplish a final prototype that enables an improvement in childhood arterial hypertension treatment.

Angiotensin II receptor type 1 blockade regulates Klotho expression to induce TSC2-deficient cell death.

Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle-like "LAM" cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear. Here, we report that TSC2-deficient cells are sensitive to the blockade of angiotensin II receptor type 1 (Agtr1). We show that treatment of these cells with the AGTR1 inhibitor losartan or silencing of the Agtr1 gene leads to increased cell death in vitro and attenuates tumor progression in vivo. Notably, we found the effect of Agtr1 blockade is specific to TSC2-deficient cells. Mechanistically, we demonstrate that cell death induced by Agtr1 inhibition is mediated by an increased expression of Klotho. In TSC2-deficient cells, we showed overexpression of Klotho or treatment with recombinant (soluble) Klotho mirrored the cytocidal effect of angiotensin blockade. Furthermore, Klotho treatment decreased the phosphorylation of AKT, potentially leading to this cytocidal effect. Conversely, silencing of Klotho rescued TSC2-deficient cells from cell death induced by Agtr1 inhibition. Therefore, we conclude that Agtr1 and Klotho are important for TSC2-deficient cell survival. These findings further illuminate the role of the RAS in LAM and the potential of targeting Agtr1 inhibition in TSC2-deficient cells.

In Situ Tumor Vaccine for Lymph Nodes Delivery and Cancer Therapy Based on Small Size Nanoadjuvant.

Tumor vaccine is a promising cancer treatment modality, however, the convenient antigens loading in vivo and efficient delivery of vaccines to lymph nodes (LNs) still remain a formidable challenge. Herein, an in situ nanovaccine strategy targeting LNs to induce powerful antitumor immune responses by converting the primary tumor into whole-cell antigens and then delivering these antigens and nanoadjuvants simultaneously to LNs is proposed. The in situ nanovaccine is based on a hydrogel system, which loaded with doxorubicin (DOX) and nanoadjuvant CpG-P-ss-M. The gel system exhibits ROS-responsive release of DOX and CpG-P-ss-M, generating abundant in situ storage of whole-cell tumor antigens. CpG-P-ss-M adsorbs tumor antigens through the positive surface charge and achieves charge reversal, forming small-sized and negatively charged tumor vaccines in situ, which are then primed to LNs. Eventually, the tumor vaccine promotes antigens uptake by dendritic cells (DCs), maturation of DCs, and proliferation of T cells. Moreover, the vaccine combined with anti-CTLA4 antibody and losartan inhibits tumor growth by 50%, significantly increasing the percentage of splenic cytotoxic T cells (CTLs), and generating tumor-specific immune responses. Overall, the treatment effectively inhibits primary tumor growth and induces tumor-specific immune response. This study provides a scalable strategy for in situ tumor vaccination.

The effects of losartan or angiotensin II receptor antagonists on cartilage: a systematic 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.

High- Versus Low-dose Losartan and Serum Potassium: An Analysis From HEAAL.

BACKGROUND: Patients with heart failure (HF) experience frequent alterations of serum potassium. Despite the high risk of events associated with hypokalemia, hyperkalemia is feared by clinicians and often leads to interruption or discontinuation of renin-angiotensin-aldosterone system inhibitors. Data on serum potassium of patients treated with different doses of renin-angiotensin-aldosterone system inhibitors are scarce. METHODS AND RESULTS: The effects of high-dose vs low-dose losartan on clinical outcomes in patients with heart failure (HEAAL) trial randomized 3834 patients with HFrEF intolerant to angiotensin-converting enzyme inhibitors to losartan 150 mg/d (high dose) vs 50 mg/d (low dose). We studied the associations of serum potassium (baseline and time updated) with study outcomes and the effect of the randomized treatment on serum potassium. Patients with higher baseline potassium were older, had diabetes, poorer renal function, and used mineralocorticoid receptor antagonists more frequently. In time-updated models, hyperkalemia (>5.0 or ≥5.5 mmol/L) was not associated with cardiovascular death or the composite of cardiovascular death or HF hospitalization. Hypokalemia (serum potassium of ≤3.5 mmol/L, in particular) was associated with a higher risk of the composite of cardiovascular death or HF hospitalization (hazard ratio [HR] 1.58, 95% confidence interval [CI] 1.19-2.08), all-cause death (HR 1.68, 95% CI 1.26-2.24), and sudden cardiac death or resuscitated cardiac arrest (HR 1.74, 95% CI 1.11-2.73). High-dose losartan decreased the risk of hypokalemia (HR 0.77, 95% CI 0.63-0.92) and increased the risk of hyperkalemia (HR 1.21, 95% CI 1.05-1.39). High-dose losartan decreased the composite of cardiovascular death or HF hospitalizations consistently across the full spectrum of serum potassium at baseline (interaction P = .85). CONCLUSIONS: In patients with HF with reduced ejection fraction intolerant to angiotensin-converting enzyme inhibitors and treated with either high- or low-dose losartan, incident hypokalemia had a stronger association with poor outcomes than incident hyperkalemia. High-dose losartan reduced the incidence of hypokalemia, and its benefits were maintained across the full spectrum of serum potassium.

Mechanisms underlying the blood pressure-lowering effects of empagliflozin, losartan and their combination in people with type 2 diabetes: A secondary analysis of a randomized crossover trial.

AIM: To study the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, the angiotensin receptor blocker (ARB) losartan, and their combination on blood pressure, while studying the mechanisms potentially involved. METHODS: A total of 24 people with type 2 diabetes (T2D) (age: 66 ± 6 years; body mass index: 31.0 ± 3 kg/m2 ; estimated glomerular filtration rate: 90 ml/min/1.73m2 ) received a 1-week treatment with empagliflozin 10 mg once daily, losartan 50 mg once daily, their combination, and placebo, in a randomized double-blind crossover design, with 4-week washout periods in between. Blood pressure, arterial stiffness, autonomic nervous system activity and plasma volume, extracellular fluid and serum albumin were assessed. RESULTS: Versus placebo (139 mmHg), empagliflozin reduced systolic blood pressure (SBP) by 8 mmHg (P = .001), losartan by 12 mmHg (P = .001) and empagliflozin + losartan by 15 mmHg (P < .001). Combination therapy had a larger SBP-lowering effect versus empagliflozin monotherapy (-7 [95% CI -12; -2] mmHg) and numerically larger effects versus losartan monotherapy (-3 [-8; 2] mmHg). Empagliflozin reduced sympathetic nervous system (SNS) activity, arterial stiffness and extracellular fluid, while increasing serum albumin. Losartan reduced SNS activity and arterial stiffness. Combination therapy induced volume contraction variables, together with a reduction in SNS activity and arterial stiffness. CONCLUSION: In people with T2D, SGLT2 inhibition in combination with an ARB had a larger blood pressure-lowering effect versus placebo than either of the drugs alone. Our data further suggest that the mechanisms underlying these blood pressure reductions at least partially differ between these agents.

Angiotensin receptor blockers might be protective against hepatic steatosis after liver transplantation.

BACKGROUND: Hepatic steatosis is an increasing complication in liver transplant recipients. Currently, there is no pharmacologic therapy for treatment of hepatic steatosis after liver transplantation. The aim of this study was to determine the association between use of angiotensin receptor blockers (ARB) and hepatic steatosis in liver transplant recipients. METHODS: We conducted a case-control analysis on data from Shiraz Liver Transplant Registry. Liver transplant recipients with and without hepatic steatosis were compared for risk factors including use of ARB. RESULTS: A total of 103 liver transplant recipients were included in the study. Thirty five patients treated with ARB and 68 patients (66%) did not receive these medications. In univariate analysis, ARB use (P = 0.002), serum triglyceride (P = 0.006), weight after liver transplantation (P = 0.011) and etiology of liver disease (P = 0.008) were associated with hepatic steatosis after liver transplantation. In multivariate regression analysis, ARB use was associated with lower likelihood of hepatic steatosis in liver transplant recipients (OR = 0.303, 95% CI: 0.117-0.784; P = 0.014). Mean duration of ARB use (P = 0.024) and mean cumulative daily dose of ARB (P = 0.015) were significantly lower in patients with hepatic steatosis. CONCLUSION: Our study showed that ARB use was associated with reduced incidence of hepatic steatosis in liver transplant recipients.

Is losartan a promising agent for the treatment of type 1 diabetes-induced testicular germ cell apoptosis in rats?

BACKGROUND: Diabetes mellitus (DM) is common metabolic disease that poses a major risk to public health and fertility. Previous studies indicate that DM may cause male infertility by triggering oxidative stress and germ cell apoptosis in the testis. Due to the undesirable effects of known antidiabetic drugs, scientists have begun to investigate the use of alternative drugs to control infertility complications observed in men. In this context, present study aimed to investigate the possible antiapoptotic effect of losartan against DM-induced testicular germ cell apoptosis. METHODS AND RESULTS: Expreimental DM model was induced by intraperitoneal injection of streptozocin (STZ, 55 mg/kg) to 28 rats, which were then randomly assigned to 4 groups; 1 mL saline solution was given to DM + saline group by oral gavage, 5 mg/kg/day oral losartan was given to DM + low-dose losartan, 20 mg/kg/day oral losartan was given to DM + mid-dose losartan and, 80 mg/kg/day oral losartan was given to DM + high-dose losartan group for 4 weeks. Bax, Bcl-2 and cleaved-Caspase 3 immunoexpression, terminal-deoxynucleotidyl transferase dutp nick end labeling (TUNEL), Annexin-V and Real Time PCR analyses performed to evaluate antiapoptotic effects of losartan on diabetic rats' testis. In addition, biochemical analyzes carried out to evaluate change in oxidative stress. CONCLUSION: The results showed that losartan may have dose-related antiapoptotic effects on rats' testis via decreasing oxidative stress.

Microextraction by packed sorbent of N-nitrosamines from Losartan tablets using a high-throughput robot platform followed by liquid chromatography-tandem mass spectrometry.

The development of a fast, cost-effective, and efficient microextraction by packed sorbent setup was achieved by combining affordable laboratory-repackable devices of microextraction with a high-throughput cartesian robot. This setup was evaluated for the development of an analytical method to determine N-nitrosamines in losartan tablets. N-nitrosamines pose a significant concern in the pharmaceutical market due to their carcinogenic risk, necessitating their control and quantification in pharmaceutical products. The parameters influencing the performance of this sample preparation for N-nitrosamines were investigated through both univariate and multivariate experiments. Microextractions were performed using just 5.0 mg of carboxylic acid-modified polystyrene divinylbenzene copolymer as the extraction phase. Under the optimized conditions, the automated setup enabled the simultaneous treatment of six samples in less than 20 min, providing reliable analytical confidence for the proposed application. The analytical performance of the automated high-throughput microextraction by the packed sorbent method was evaluated using a matrix-matching calibration. Quantification was performed using ultra-high-performance liquid chromatography-tandem mass spectrometry with chemical ionization at atmospheric pressure. The method exhibited limits of detection as low as 50 ng/g, good linearity, and satisfactory intra-day (1.38-18.76) and inter-day (2.66-20.08) precision. Additionally, the method showed accuracy ranging from 80% to 136% for these impurities in pharmaceutical formulations.

Clinical Trial of Losartan for Pulmonary Emphysema: Pulmonary Trials Cooperative Losartan Effects on Emphysema Progression Clinical Trial.

Rationale: There are no pharmacologic agents that modify emphysema progression in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of losartan, an angiotensin receptor blocker, to reduce emphysema progression. Methods: The trial was a multicenter, randomized, placebo-controlled trial conducted between May 2017 and January 2021. Eligible participants were aged ⩾40 years, had moderate to severe airflow obstruction, ⩾10 pack-years of smoking, mild-moderate emphysema on high-resolution computed tomography, and no medical indication for or intolerance of angiotensin receptor blockers. Treatment with losartan 100 mg daily or matching placebo (1:1) was randomly assigned. The primary outcome was emphysema progression on high-resolution computed tomography over 48 weeks. Secondary outcomes included the St George's Respiratory Questionnaire, the modified Medical Research Council dyspnea scale, the COPD Assessment Test, and the Physical Function-Short Form 20a. Measurements and Main Results: A total of 220 participants were enrolled; 58% were men, 19% were African American, and 24% were current smokers. The medians (interquartile ranges) for age were 65 (61-73) years and 48 (36-59) for percent predicted FEV1 after bronchodilator use. The mean (95% confidence interval) percentage emphysema progression was 1.35% (0.67-2.03) in the losartan group versus 0.66% (0.09-1.23) in the placebo group (P = NS). Conclusions: Losartan did not prevent emphysema progression in people with COPD with mild-moderate emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT02696564).

Simultaneous quantification of losartan potassium and its active metabolite, EXP3174, in rabbit plasma by validated HPLC-PDA.

Herein, we report a novel, accurate and cost-effective validated analytical method for the quantification of losartan potassium and its active metabolite, EXP 3174, in rabbit plasma by reversed-phase high-performance liquid chromatography. Valsartan was used as an internal standard. The method was validated as per International Conference on Harmonization guidelines. The analytes were extracted in rabbit plasma using liquid-liquid extraction technique and analyzed at 247 nm after separation through a reverse-phase C18 column. The isocratic mobile phase used is a mixture of acetonitrile, water and glacial acetic acid in the ratio of 60:40:1 v/v/v maintained at pH 3.4. All calibration curves showed a good linear relationship (r > 0.995) within the test range. Precision was evaluated by intra- and interday tests with RSDs <1.91% and accuracy showed validated recoveries of 86.20-101.11%. Based on our results, the developed method features good quantification parameters and can serve as an effective quality control method for the standardization of drugs.

Unveiling Angiotensin II and Losartan-Induced Gene Regulatory Networks Using Human Urine-Derived Podocytes.

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.