Combination Of Losartan Research Articles

Combination of Losartan and Platinum Nanoparticles with Photothermal Therapy Induces Immunogenic Cell Death Effective Against Neuroblastoma.

Photothermal therapy (PTT) is a promising therapeutic procedure with minimal side effects, which can not only kill tumor directly but also cause immunogenic cell death (ICD). However, most solid tumors, including neuroblastoma, are abundant in fibroblasts, which limit the penetration and delivery of nanoparticles. Losartan is an antihypertensive drug approved by the FDA, and it has been proved to have the effect of breaking down excessive ECM network. In this study, we investigated the application and potential mechanism of the combination of mesoporous platinum nanoparticles (MPNs) and losartan in the PTT of neuroblastoma by establishing neuroblastoma models in vitro and in vivo. Compared to the MPNs group without 808 nm laser irradiation, Neuro-2a cells pretreated with PTT and losartan showed lower survival rates, increased surface calreticulin, and higher release of HMGB1 and ATP. The group also exhibited the highest anti-tumor efficacy in vivo, with a tumor suppression ratio of approximately 80%. Meanwhile, we found that CD3+ T cells, CD4+ T cells and CD8+ T cells from the peripheral blood of experimental group mice were significantly higher than control groups, and CD8+PD-1+ cells were significantly lower than those in MPNs + Los group and Los + laser group. And the expression of PD-1 and α-SMA in Neuro-2a tumors tissue was reduced. Furthermore, losartan could reduce damage of liver function caused by MPNs and laser treatment. This study demonstrated that losartan-induced fibroblasts ablation increased the penetration of MPNs into tumors. Enhanced penetration allowed PTT to kill more tumor cells and synergistically activate immune cells, leading to ICD, indicating the great promise of the strategy for treating neuroblastoma in vivo.

Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report

BackgroundLipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1–27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness.Case presentationA 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels.ConclusionHerein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Abstract PO3-24-10: Losartan enhances the radiosensitivity of triple-negative breast cancer by reshaping the tumor immune microenvironment

Abstract Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, and the therapeutic options available for TNBC are limited. In addition to surgery and chemotherapy, radiotherapy (RT) is a primary treatment modality for TNBC. However, radio-resistance poses significant challenges to TNBC treatment. Prior research has shown that losartan, an angiotensin receptor blocker, can improve vessel perfusion and drug delivery, thereby enhancing the efficacy of chemotherapy or radiotherapy in cancer. However, in our study, we found that losartan could enhance the radiosensitivity of TNBC in immunocompetent mice model, but not in immunodeficient mice model and TNBC cells. It suggested that losartan might enhance the radiosensitivity of TNBC in an immune system dependent way. Previous studies had noted that tumor immune microenvironment (TIME) played an important role in radio-resistance. Therefore, we focused on the TIME in our further study. For immune cells, it had reported that the recruitment and activation of immunosuppressive cells such as M2 phenotype tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), could lead to the establishment of and immunosuppressive TIME and decreased the radiosensitivity. In this study, we found losartan facilitated the polarization of TAMs towards the M1 phenotype, and impeded the immunosuppressive function of MDSCs after RT in 4T1 TNBC mice model. Additionally, losartan also caused a significant increase of CD8+ T lymphocytes in the TIME, and also markedly enhanced the activity of infiltrated T cell. When the CD8+ T cells were eliminated by anti-CD8α antibody, the radiosensitization effect of losartan was significantly decreased. Therefore, T-cell mediated tumor suppression is essential for the radiosensitization caused by losartan in TNBC. For immune factors, we found that TNBC exhibited an increase in the expression of programmed death-ligand (PD-L1) and indoleamine-2,3-dioxygenase (IDO) upon exposure to irradiation, and the combination of losartan resulted in a significant reduction in their expression in vitro and in vivo. At the same time, the 4T1 TNBC transplantation tumors were significantly inhibited by losartan combined with PD-1 inhibitor after RT, which indicated that losartan might amplify the efficacy of radio-immunotherapy. Collectively, these findings suggest that losartan could reshape the TIME of TNBC through regulating immune cells (TAMs, MDCSs and CD8+ T cells) and immune factors (PD-L1 and IDO), which result in the enhancement of radiosensitivity of TNBC. In our investigation, losartan was innovatively found to increase the radiosensitivity of TNBC by reshaping the TIME rather than on the tumor stroma. As one of the most commonly prescribed drugs for hypertension, the safety and affordability of losartan have been extensively confirmed. In the future, losartan combined with radiotherapy might be a promising strategy for TNBC treatment. Citation Format: Cuiwei Liu, Xu Wang, Zihan Xia, Yuxi Ma, Yanxia Zhao. Losartan enhances the radiosensitivity of triple-negative breast cancer by reshaping the tumor immune microenvironment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-10.

Combination of losartan with pirfenidone: a protective anti-fibrotic against pulmonary fibrosis induced by bleomycin in rats

Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some approaches such as combination therapy may be applicable for increasing therapeutic efficacy of PFD. Losartan (LOS), an angiotensin II receptor antagonist, could be a suitable candidate for combination therapy because of its stabilizing effect on the pulmonary function of IPF patients. Therefore, this study aimed to investigate the effects of LOS in combination with PFD on bleomycin (BLM)-induced lung fibrosis in rats. BLM-exposed rats were treated with LOS alone or in combination with PFD. The edema, pathological changes, level of transforming growth factor-β (TGF-β1), collagen content, and oxidative stress parameters were assessed in the lung tissues. Following BLM exposure, the inflammatory response, collagen levels, and antioxidant markers in rat lung tissues were significantly improved by PFD, and these effects were improved by combination with LOS. The findings of this in vivo study suggest that the combined administration of PFD and LOS may provide more potent protection against IPF than single therapy through boosting its anti-inflammatory, anti-fibrotic, and anti-oxidant effects. These results hold promise in developing a more effective therapeutic strategy for treating of lung fibrosis.

Role of angiotensin pathway and its target therapy to rescue from experimental cerebral malaria

Cerebral malaria (CM) induced by Plasmodium falciparum is a devastating neurological complication that may lead the patient to coma and death. This study aimed to protect Plasmodium-infected C57BL6 mice from CM by targeting the angiotensin II type 1 (AT1) receptor, which is considered the common connecting link between hypertension and CM. In CM, AT-1 mediates blood–brain barrier (BBB) damage through the overexpression of β-catenin. The AT-1-inhibiting drugs, such as irbesartan and losartan, were evaluated for the prevention of CM. The effectiveness of these drugs was determined by the down regulation of β-catenin, TCF, LEF, ICAM-1, and VCAM-1 in the drug-treated groups. The expression levels of VE-cadherin and vinculin, essential for the maintenance of BBB integrity, were found to be restored in the drug-treated groups. The pro-inflammatory cytokine levels were decreased, and the anti-inflammatory cytokine levels increased with the treatment. As a major highlight, the mean survival time of treated mice was found to be increased even in the absence of treatment with an anti-malarial agent. The combination of irbesartan or losartan with the anti-malarial agent α/β-arteether has contributed to an 80% cure rate, which is higher than the 60% cure rate observed with α/β-arteether alone treatment.

An angiotensin system inhibitor (losartan) potentiates antitumor efficacy of cisplatin in a murine model of non–small cell lung cancer

ObjectivePrevious studies have demonstrated synergistic antitumor effects of angiotensin system inhibition (ASI) combined with cisplatin therapy in pancreatic cancer. This study examines whether or not synergistic antitumor effects occur with combination ASI and cisplatin treatment in lung cancer, and whether or not ASI-induced changes in epithelial-mesenchymal transition play a role in the mechanism of this antitumor phenomenon. MethodsA set of lung cancer cell lines representing a spectrum of epithelial to mesenchymal phenotypes were identified and characterized. Response of epithelial-mesenchymal transition markers to losartan was characterized. Cell culture models of lung cancer were next treated with losartan, cisplatin, or combination of both. Markers of epithelial-mesenchymal transition or surrogates of other signaling pathways (AKT, Stat3, and programmed death-ligand), and cell viability were quantified. Findings were confirmed in both allogenic and syngeneic in vivo murine flank tumor models. ResultsLosartan treatment significantly increased E-cadherin and reduced vimentin in human lung cancer cell lines. Combination treatment with losartan and cisplatin enhanced epithelial markers, reduced mesenchymal markers, inhibited promesenchymal signaling mediators, and reduced cell viability. Findings were confirmed in vivo in a murine flank tumor model with transition from mesenchymal to epithelial phenotype and reduced tumor size following combination losartan and cisplatin treatment. ConclusionsCombination losartan and cisplatin treatment attenuates the epithelial-mesenchymal transition pathway and enhances the cytotoxic effect of chemotherapy with in vitro and in vivo models of non–small cell lung cancer. This study suggests an important role for ASI therapy in the treatment of lung cancer.

USE OF REPOURPOSED DRUGS LOSARTAN AND IVERMECTIN IN PATIENTS WITH CANCER FOR PREVENTION OF COVID-19 SERIOUS EVENTS DURING PANDEMIC. A randomized, double-blind, placebo-controlled phase II study.

Introduction: Cancer patients are at higher risk of COVID-19 severe complications and also demonstrated a lower antibodies conversion after vaccination. Therefore, therapeutic approaches after COVID-19 infection are needed in this population. Repurposing drugs has emerged as an appealing strategy during pandemic, and drugs such as angiotensin 2 antagonists and ivermectin may have a role against COVID-19. Objective: This trial evaluated losartan plus ivermectin aimed at decreasing the incidence of severe outcomes due to coronavirus infection among cancer patients. Methods: This was a randomized, double-blind, and placebo-controlled phase II study. Cancer patients with recent diagnosis of mild to moderate COVID-19 were randomized to receive 50 mg of losartan for 15 days plus a single dose of 12 mg of ivermectin or placebo. The primary endpoint was the incidence of severe complications, defined as a need for admission to the intensive care unit (ICU), need for mechanical ventilation (MV), or death. Secondary endpoints were safety and adherence. Results: Thirty-five patients were randomized to intervention arm and 34 to placebo arm. Seven (20%) patients in the losartan + ivermectin arm experienced severe outcomes versus 8 (23.5%) patients in the placebo arm (p = 1.00). No difference was observed in the need for intensive care unit (17.1% versus 17.6%; p = 1.00) or in the need for mechanical ventilation (17.1% versus 11.8%; p = 0.73). Four patients died in the losartan + ivermectin arm, while 3 in the placebo arm (11.4% versus 8.8%; p = 1.00). Severe adverse events and adherence were similar between groups. Conclusions and Relevance: The combination of losartan and ivermectin did not improve severe COVID-19 outcomes among cancer patients. This is the first study registered on ClinicalTrials.gov that evaluates active treatment for COVID-19 exclusively for cancer patients. and more studies should be performed for a more aggressive approach in this high-risk population.

Losartan: A Pharmacotherapy in Cardiovascular Disease

Background: A recently published article confirmed that in 2019, around 523 million people suffered from cardiovascular disease (including 18.6 million deaths) worldwide. Losartan, a drug, was patented 35 years ago and approved for medical use in the United States in 1995 (28 years ago). As an effective treatment for hypertension, losartan blocks the interaction of angiotensin II with its receptor by inhibiting the renin-angiotensin system. Objective: This article aims to review the available literature and recent studies demonstrating the efficacy, safety, mechanism of action and drug-drug interactions of losartan in cardiovascular disease. Methods: This is a focused literature review with the keywords relevant to the terms performed in PubMed, Scopus and Web of Science through May 28, 2023, according to the PRISMA guidelines. Based on the PICO standard format, fifty-two relevant in-depth consequent guide approaches and evidence-based choices were selected associated with a knowledgeable collection of current, high-quality manuscripts. Results: After oral administration, time to reach maximum concentration is about 1-2 hours. With a 78% binding to protein, it has a bioavailability of 25-35%. Losartan is not removed by hemodialysis. For the full effect to occur, it may take up to 6 weeks. The drug is mainly prescribed for patients with high blood pressure, diabetic nephropathy, hypertension and left ventricular hypertrophy. The publication reported higher drug exposures and adverse reactions in women than men with antihypertensive medications. Losartan could improve changes in gut microbiota that might be associated with hypertension. In the high-risk group of renal transplant recipients with arterial hypertension, research reported well-controlled blood pressure with losartan monotherapy. Conclusion: In addition to the major losartan interactions with captopril, enalapril, lisinopril, and lithium, there are moderate interactions with aspirin, pregabalin, alprazolam, amitriptyline, baclofen, betamethasone, buspirone. Muscle cramps, respiratory infection, cough, hyperkalemia, anemia and stuffy nose are the main reported side effects. As polypharmacy could hide pharmacokinetics interaction due to cytochrome P450, therefore, the combination of losartan with drugs such as phenobarbital, rifampin or fluconazole needs vigilant attention regarding therapeutic drug monitoring.

Marfan’s Syndrome and associated pathologies: An integrative systematic review of randomised controlled trials

Background Marfan’s syndrome (MFS) is an autosomal dominant hereditary connective tissue disorder associated with numerous skeletal, ocular, cardiovascular, and respiratory pathologies which advance with age. Following multiple system involvement of body, the clinical presentation and management of MFS with associated pathologies are an area of cautious focus. Therefore, this review focused on highlighting various management options that are currently being supported for the MFS patients. Methodology The search methodology involved randomized controlled trials (RCTs) published between 2018 to 2022 from PubMed and Google Scholar databases. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) were followed for reviewing the data extracted following the inclusion and exclusion criteria using the keywords “Marfan’s Syndrome”, “Irbesartan”, “Aortic Dilatation”, “Atenolol”, and “Lens Subluxation.” Results A total of eight articles were reviewed for the preferred distribution of population and the management options followed in the studies consisting of medical, psychological, and surgical interventions. Also, the associated pathologies related to MFS patients were analysed and found to have significant impact on health-related quality of life of MFS patients. Conclusions The review concluded that a combination of drugs atenolol, a β-blocker, and losartan which is an angiotensin receptor blocker, is beneficial in case of aortic root dilatation and higher aortic root stiffness. Additionally, ADRB1 testing may determine patients that are more likely to respond therapeutically to atenolol in comparison to losartan. Cionni modified capsular tension rings (MCTR) have been acknowledged as an effective device for delivering good capsular bag stabilization in cases of lens subluxation in MFS patients.

Phloretin as an add-on therapy to losartan attenuates diabetes-induced AKI in rats: A potential therapeutic approach targeting TLR4-induced inflammation

AimTargeting Toll-like receptor 4 (TLR4) and Angiotensin II type 1 receptor (AT1R) could provide renoprotection during acute kidney injury (AKI) mainly by regulating inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Phloretin (TLR4 inhibitor) as an add-on therapy to losartan (AT1R inhibitor) could provide more therapeutic benefits against AKI under diabetic condition. We aimed to study the effect of phloretin as an add-on therapy to losartan against AKI under diabetic condition. Main methodsTo mimic diabetic AKI condition, bilateral ischemia-reperfusion injury (BIRI) was done in diabetic male Wistar rats, and sodium azide treatment was given to high glucose NRK52E cells to mimic hypoxia-reperfusion injury. In diabetic rats, phloretin (50 mg/kg/per os (p.o.)) and losartan (10 mg/kg/p.o.) treatment was given for 4 days and 1 h prior to surgery while in NRK52E cells, both drugs (phloretin 50 μM and losartan 10 μM) were given 24 h prior to the hypoxia condition. The in vivo and in vitro samples were further used for different experiments. Key findingsTreatment with phloretin and losartan decreased diabetic and AKI biomarkers such as plasma creatinine, blood urea nitrogen (BUN), and kidney injury molecular 1 (KIM1). Moreover, a combination of phloretin and losartan significantly preserved ΔΨm and kidney morphology potentially by inhibiting TLR4-associated inflammation and AT1R-associated mitochondrial dysfunction, thereby oxidative stress. SignificanceCombination therapy of phloretin and losartan was more effective than monotherapies. Both drugs target TLR4/MyD88/NF-κB pathway and reduce inflammation and mitochondrial dysfunction in AKI under diabetic condition.

Multitarget, multiagent PLGA nanoparticles for simultaneous tumor eradication and TME remodeling in a melanoma mouse model

Despite the fact that chemoimmunotherapy has emerged as a key component in the era of cancer immunotherapy, it is challenged by the complex tumor microenvironment (TME) that is jam-packed with cellular and non-cellular immunosuppressive components. The aim of this study was to design a nanoparticulate system capable of sufficiently accumulating in the tumor and spleen to mediate local and systemic immune responses, respectively. The study also aimed to remodel the immunosuppressive TME. For such reasons, multi-functional polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were engineered to simultaneously eradicate the cancer cells, silence the tumor-associated fibroblasts (TAFs), and re-educate the tumor-associated macrophages (TAMs) using doxorubicin, losartan, and metformin, respectively. These agents were also selected for their ability to tip the balance of the splenic immune cells towards immunostimulatory phenotypes. To establish TAM and TAF cultures, normal macrophages and fibroblasts were incubated with B16F10 melanoma cell (Mel)-derived secretome. Drug-loaded PLGA NPs were prepared, characterized, and tested in the target cell types. Organ distribution of fluorescein-loaded PLGA NPs was evaluated in a mouse model of melanoma. Finally, the local and systemic effects of different combination therapy programs were portrayed. The in vitro studies showed that the drug-loaded PLGA NPs could significantly ablate the immunosuppressive nature of Mel and skew TAMs and TAFs towards more favorable phenotypes. While in vivo, PLGA NPs were proven to exhibit long blood circulation time and to localize preferentially in the tumor and the spleen. The combination of either metformin or losartan with doxorubicin was superior to the monotherapy, both locally and systemically. However, the three-agent combo produced detrimental effects in the form of compromised well-being, immune depletion, and metastasis. These findings indicate the potential of TME remodeling as means to prime the tumors for successful chemoimmunotherapy. In addition, they shed light on the importance of the careful use of combination therapies and the necessity of employing dose-reduction strategies.Graphical D-NPs doxorubicin-loaded NPs, M-NPs metformin-loaded NPs, L-NPs losartan-loaded NPs, TAMs tumor-associated macrophages, TAFs tumor-associated fibroblasts, PD-L1 programmed death ligand 1, TNF-α tumor necrosis factor alpha, TGF-β transforming growth factor beta, CD206/40/86 cluster of differentiation 206/40/86, α-SMA alpha-smooth muscle actin, MMPs matrix metalloproteases

Combination losartan with hyaluronic acid modified diethyldithiocarbamate loaded hollow copper sulfide nanoparticles for the treatment of breast cancer and metastasis

The application of photothermal therapy (PTT) is greatly limited by the low accumulation of photothermal agents, uneven photothermal distribution, and heat endurance of cancer cells. Worse still, despite PTT enhances immunogenicity, the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death (ICD) induction and poor infiltration of immune cells. To solve the above problems of PTT, we developed hyaluronic acid (HA) modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate (DDTC) to construct a breast tumor targeting and near infrared (NIR) photo-responsive drug delivery system (D-HCuS@HA), which further combined with losartan to improve the accumulation and penetration in the tumor site. Upon irradiation, D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)2 to eliminate heat endurance tumor cells, thereby enhancing anti-tumor effect and inducing effective ICD. Moreover, the combination with losartan could remodel the tumor microenvironment, allowing more T cells to infiltrate into the tumor, and significantly inhibiting the occurrence and development of metastatic tumors. In vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan, which provides a new paradigm for anti-tumor and anti-metastases.

A Randomized, Multicenter, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of a Quadruple Combination of Amlodipine, Losartan, Rosuvastatin, and Ezetimibe in Patients with Concomitant Essential Hypertension and Dyslipidemia.

Few data are available regarding the efficacy and safety of a single-pill combination (SPC) consisting of four medications in patients with concomitant hypertension and dyslipidemia. We aimed to determine the efficacy and tolerability of a fixed-dose SPC consisting of 5 mg amlodipine, 100 mg losartan, 20 mg rosuvastatin, and 10 mg ezetimibe (A/L/R/E) in patients with concomitant hypertension and dyslipidemia. This was a 14-week, randomized, multicenter, double-blind, placebo-controlled, phase III clinical trial. In total, 145 patients were randomized to receive A/L/R/E, A/L, or L/R/E. The primary endpoints were the average change in the low-density lipoprotein cholesterol (LDL-C) level in the A/L/R/E and A/L groups and the sitting systolic blood pressure (sitSBP) in the A/L/R/E and L/R/E groups. The numbers of patients with adverse drug reactions (ADRs) were compared as safety variables. The average percentage change in the LDL-C level as the least squares mean (LSM) from the baseline LDL-C level at the end of the 8-week treatment was -59.0% in the A/L/R/E group and 0.2% in the A/L group (LSM difference -59.2, 95% confidence interval [CI] -68.1 to -50.4; p<0.0001). The average change in the sitSBP as the LSM was -15.8 mmHg in the A/L/R/E group and -4.7 mmHg in the L/R/E group (LSM difference -11.1, 95% CI -16.8 to -5.4; p=0.0002). No ADRs occurred in the A/L/R/E group. A/L/R/E as an SPC could be an effective treatment for patients with hypertension and dyslipidemia without significant safety issues. NCT04074551 (registered 30 August 2019).

Losartan in Combination With Bone Marrow Stimulation Showed Synergistic Effects on Load to Failure and Tendon Matrix Organization in a Rabbit Model

To investigate the effects of combining bone marrow stimulation (BMS) with oral losartan to block transforming growth factor β1 (TGF-β1) on biomechanical repair strength in a rabbit chronic injury model. Forty rabbits were randomly allocated into 4 groups (10 in each group). The supraspinatus tendon was detached and left alone for 6 weeks to establish a rabbit chronic injury model and was then repaired in a surgical procedure using a transosseous, linked, crossing repair construct. The animals were divided into the following groups: control group (group C), surgical repair only; BMS group (group B), surgical repair with BMS of the tuberosity; losartan group (group L), surgical repair plus oral losartan (TGF-β1 blocker) for 8 weeks; and BMS-plus-losartan group (group BL), surgical repair plus BMS plus oral losartan for 8 weeks. At 8 weeks after repair, biomechanical and histologic evaluations were performed. The biomechanical testing results showed significantly higher ultimate load to failure in group BL than in group B (P= .029) but not compared with group C or group L. A 2× 2 analysis-of-variance model found that the effect of losartan on ultimate load significantly depended on whether BMS was performed (interaction term F1,28= 5.78, P= .018). No difference was found between the other groups. No difference in stiffness was found between any groups. On histologic assessment, groups B, L, and BL showed improved tendon morphology and an organized type I collagen matrix with less type III collagen compared with group C. Group BL showed the most highly organized tendon matrix with more type I collagen and less type III collagen, which indicates less fibrosis. Similar results were found at the bone-tendon interface. Rotator cuff repair combined with oral losartan and BMS of the greater tuberosity showed improved pullout strength and a highly organized tendon matrix in this rabbit chronic injury model. Tendon healing or scarring is accompanied by the formation of fibrosis, which has been shown to result in compromised biomechanical properties, and is therefore a potential limiting factor in healing after rotator cuff repair. TGF-β1 expression has been shown to play an important role in the formation of fibrosis. Recent studies focusing on muscle healing and cartilage repair have found that the downregulation of TGF-β1 by losartan intake can reduce fibrosis and improve tissue regeneration in animal models.

Co-administration of metformin and/or glibenclamide with losartan reverse NG-nitro-l-arginine-methyl ester-streptozotocin-induced hypertensive diabetes and haemodynamic sequelae in rats.

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Antihypertensive and antihyperglycemic effects of combinations of losartan with metformin and/or glibenclamide in desoxycorticosterone acetate and streptozotocin-induced hypertensive diabetic rats

BackgroundHypertension is a medical condition that often comorbidly exist in patients with type II diabetes. Therefore, it is very important to manage both conditions simultaneously to mitigate the complications and mortality connected with this comorbidity. Hence, this study investigated the antihypertensive and antihyperglycemic effects of combinations of losartan (LOS) with metformin (MET) and/or glibenclamide (GLB) in hypertensive diabetic rats. Hypertensive diabetic state was induced with desoxycorticosterone acetate (DOCA) and streptozotocin (STZ) in adult Wistar rats. The rats were divided into 5 groups (n = 5): control group (group 1), hypertensive diabetic (HD) control (group 2), treatment groups receiving LOS + MET (group 3), LOS + GLB (group 4), and LOS + MET + GLB (group 5). Group 1 comprised healthy rats while groups 2–5 were HD rats. The rats were treated orally once daily for 8 weeks. Fasted blood glucose (FBS) level, haemodynamic parameters, and some biochemical indices were thereafter assessed.ResultsFBS level and blood pressure measurements were significantly (P < 0.05) increased following induction by DOCA/STZ. The drug treatment combinations, particularly combination of LOS + MET + GLB, significantly (P < 0.05) reduced the induced hyperglycemia and remarkably decreased systolic blood pressure and heart rate. There was significant (P < 0.05) reduction in raised lactate dehydrogenase and creatinine kinase levels by all drug treatment combinations except LOS + GLB.ConclusionsOur findings suggest that LOS combinations with MET and/or GLB exhibited significant antidiabetic and antihypertensive effects against DOCA/STZ-induced hypertensive diabetic state in rats.

Combination of losartan and puerarin induced pharmacokinetic interaction in hypertension rats enhances the antihypertensive effect of losartan

The co-administration of losartan and puerarin in hypertension rat models was investigated aiming to evaluate their interaction and potential mechanism. Hypertension rat models were established with N (omega)-nitro-L-arginine methyl ester and the pharmacokinetics and antihypertensive effect of losartan were analyzed in normal and hypertension rats. In vitro, the metabolic stability of losartan was evaluated in rat liver microsomes, and the effect of puerarin on the activity of CYP2C9 and 3A4 was assessed in human liver microsomes. Puerarin significantly changed the pharmacokinetic profiling of losartan in hypertension rats, with the behaviour of increasing AUC, AUMC, Cmax, and prolonged t1/2. The antihypertensive effect of losartan was enhanced by the co-administration of puerarin, which reduced the systolic blood pressure and diastolic blood pressure below normal levels. In vitro, puerarin significantly improved the metabolic stability of losartan with a reduced intrinsic clearance rate. Puerarin also showed significant inhibitory effects on the activity of CYP2C9 and 3A4 with the IC50 of 17.15 and 7.69 μM, respectively. Losartan co-administered with puerarin increased the system exposure and metabolic stability of losartan and enhanced its antihypertensive effect. The inhibition of CYP2C9 and 3A4 by puerarin was the potential mechanism mediating their interaction.

Modulating the tumor microenvironment improves antitumor effect of anti-PD-L1 mAb in breast cancer.

Introduction: Immune checkpoint inhibitors (ICIs) have provided noteworthy benefits in multiple cancer patients. However, the efficacy of monotherapy of ICIs was very limited. In this study, we endeavored to explore whether losartan can modulate the solid tumor microenvironment (TME) and improve the therapeutic efficacy of anti-PD-L1 mAb in 4T1 mouse breast tumor model and the underlying mechanism. Methods: The tumor-bearing mice were treated with control agents, losartan, anti-PD-L1 mAb or the dual agents. The blood and tumor tissues were respectively used for ELISA and immunohistochemical analysis. CD8-depletion and lung metastatic experiments were performed. Results: Compared to control group, losartan inhibited the expression of alpha-smooth muscle actin (α-SMA), deposition of collagen I in the tumor tissues. The concentration of transforming growth factor-β1 (TGF-β1) in the serum was low in the losartan treated group. Although losartan alone was ineffective, the combination of losartan and anti-PD-L1 mAb elicited dramatic antitumor effect. Immunohistochemical analysis revealed that there were more intra-tumoral infiltration of CD8+ T cells and increased granzyme B production in the combination therapy group. In addition, the size of spleen was smaller in the combination therapy group, compared to monotherapy. The CD8-depleting Abs abrogated the antitumor efficacy of losartan and anti-PD-L1 mAb in vivo. The combination of losartan and anti-PD-L1 mAb significantly inhibited 4T1 tumor cells lung metastatic in vivo. Conclusion: Our results indicated that losartan can modulate the tumor microenvironment, and improve the efficacy of anti-PD-L1 mAb.

Losartan enhances the suppressive effect of pirfenidone on the bleomycin-induced epithelial-mesenchymal transition and oxidative stress in A549 cell line.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. Despite the promising anti-fibrotic effect, the toleration of pirfenidone (PFD) by the patients in full dose is low. Combination therapy is a method for enhancing the therapeutic efficiency of PFD and decreasing its dose. Therefore, the present study evaluated the effect of a combination of losartan (LOS) and PFD on oxidative stress parameters and the epithelial-mesenchymal transition (EMT) process induced by bleomycin (BLM) in human lung adenocarcinoma A549 cells. The non-toxic concentrations of BLM, LOS, and PFD were assessed by the MTT assay. Malondialdehyde (MDA) and anti-oxidant enzyme activity including catalase (CAT) and superoxide dismutase (SOD) were assessed after co-treatment. Migration and western blot assays were used to evaluate EMT in BLM-exposed A549 after single or combined treatments. The combination treatment exhibited a remarkable decrease in cellular migration compared with both single and BLM-exposed groups. Furthermore, the combination treatment significantly improved cellular anti-oxidant markers compared with the BLM-treated group. Moreover, combined therapy markedly increased epithelial markers while decreasing mesenchymal markers. This in vitro study revealed that the combination of PFD with LOS might be more protective in pulmonary fibrosis (PF) than single therapy because of its greater efficacy in regulating the EMT process and oxidative stress. The current results might offer a promising therapeutic strategy for the future clinical therapy of lung fibrosis.

Pentosan polysulfate exerts anti-inflammatory effect and halts albuminuria progression in diabetic nephropathy: Role of combined losartan.

Pentosan polysulfate sodium (PPS) is a polysulfated glycosaminoglycan approved for the treatment of interstitial cystitis. It also showed renoprotective effects in chronic kidney injury models, for example, 5/6 nephrectomy and diabetic nephropathy (DN). In the present study, we addressed to evaluate the therapeutic value of PPS in DN of rats in combination with losartan (LSR). Sixty male Sprague-Dawley rats were randomly divided into six groups: control group, untreated diabetic groups (8 and 16 weeks after diabetes induction by streptozotocin "STZ", 60 mg/kg, intraperitoneal [I.P.]), LSR-treated diabetic group (10mg/kg/day, P.O.), PPS-treated diabetic group (25 mg/kg/day, P.O.), and combination-treated diabetic group. Drug treatment was started 8 weeks after induction of diabetes and continued for a further 8 weeks. Renal functions, albuminuria, renal IL-6, oxidative stress, and renal histopathology were evaluated. STZ-treated diabetic rats developed progressive albuminuria, renal dysfunction, and significant glomerular change 16 weeks after induction of diabetes. Administration of PPS, alone or in combination with LSR, showed some beneficial effects on DN evolution and significantly decreased renal inflammation as detected by IL-6 level. The best beneficial effect on DN evolution was obtained by PPS sole therapy based on albuminuria evaluation and renal histopathology. However, the combination of PPS and LSR did not show additive benefits. This study reported that the renoprotection of PPS in the setting of DN is evident by exerting anti-inflammatory and antioxidant effects, but this effect could be masked when combined with an angiotensin receptor blocker.