Doses Of Losartan Research Articles

September 2021 at a glance: focus on biomarkers, sex differences and adherence to medical treatment.

Biomarkers represent useful tools in the management of patients with heart failure (HF). 1-3 Antigen carbohydrate 125 (CA125) is a novel marker of congestion, inflammation and right-sided HF. It emerged as an affordable and widely available tool for tailoring HF therapies and prognostic stratification, since high serum levels are associated with an increased risk of death and HF hospitalization.4 The role of cardiac troponin in HF is well-established.5 In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced), increasing levels of high-sensitivity cardiac troponin T (hs-cTnT) were associated with higher rates of comorbidities (i.e. diabetes and atrial fibrillation), more advanced New York Heart Association functional class, decreased renal function, higher concentrations of natriuretic peptides and worse clinical course. However, empagliflozin reduced the primary endpoint of cardiovascular death or HF hospitalization, regardless of baseline hs-cTnT levels,6 confirming the role of sodium–glucose co-transporter 2 (SGLT2) inhibitors as an essential treatment for patients with HF with reduced ejection fraction (HFrEF).7-9 Sex-based differences exist among patients with HF.10, 11 In the Effects of High-Dose versus Low-Dose Losartan on Clinical Outcomes in Patients with Heart Failure (HEAAL) trial, women appeared to respond similarly to low and high doses of losartan, whereas men had more benefits with high doses. However, women were older compared with men and more frequently presented severe symptoms and renal dysfunction.12 Sex differences were also investigated in the Patient-centered Care Transitions in Heart Failure: A Pragmatic Cluster Randomized (PACT-HF) study, enrolling 986 patients with the aim to test the effect of a patient-centred transitional care model. Such model improved discharge preparedness, transition quality, and the health-related quality of life both at 6 weeks and 6 months, with no differences between men and women. Women had a lower quality of life score at discharge, but experienced more benefits from treatment compared with men.13 Dietary interventions are related to HF incidence and outcome.14, 15 A meta-analysis, including 122 randomized controlled trials and 176 097 participants, summarized and confirmed the impact of nutritional and dietary interventions on HF-related outcomes. In particular, coenzyme Q10 was associated with lower all-cause mortality, whereas Mediterranean diet was related with a lower risk of developing HF.16 Ergoreflex is a cardiorespiratory reflex activated during physical effort. HF patients often develop skeletal myopathy,17 which is associated with increasing ergoreflex sensitivity and dyspnoea on effort. Exercise training represents a valuable strategy to reduce such sensitivity and increase exercise tolerance.18 Among the quality of life measures tested in the PARALLAX trial (a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure with mildly reduced and preserved ejection fraction), the Short Form Health Survey-36 physical functioning score was the most closely correlated with 6-min walk test (6MWT). A modest correlation was found between 6MWT and Kansas City Cardiomyopathy Questionnaire clinical summary score. Many factors were associated with worse values in both quality of life and exercise capacity (i.e. female sex, higher body mass index, higher levels of N-terminal pro-B-type natriuretic peptide and coronary artery disease).19 Adherence to guideline-directed medical therapy (GDMT) improves outcome in patients with HFrEF.20, 21 However, GDMT remains suboptimal in a large proportion of patients.22 A recent multinational observational study confirmed strong patterns of GDMT low-titration in HF patients. Target dose of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers, beta-blockers, and angiotensin receptor–neprilysin inhibitors, was achieved in 15%, 10%, 12%, and 30% of patients, respectively. An early discontinuation of therapy was frequently observed, with ACEi being the most withdrawn agent (55% at 12 months), followed by mineralocorticoid receptor antagonists (MRA) (40% at 12 months).23 Bhatt et al.24 evaluated the effects of both sacubitril/valsartan and enalapril on co-prescribed beta-blockers and MRA in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HH) trial. Sacubitril/valsartan did not influence beta-blocker treatment nor MRA initiation, but led to fewer MRA discontinuation compared to enalapril. The coronavirus disease 2019 (COVID-19) pandemic represented a great burden for the HF community.25-30 Management of heart transplant recipients require even tighter precautionary measures in this historical era.31 In a prospective single centre cohort study, including heart transplant recipients, short-term immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has been evaluated. Only 15% of patients displayed the presence of anti-spike IgG antibodies after the first dose, and a total of 49% responded to the full two-dose vaccine schedule. Older age and anti-metabolite-based immunosuppression were associated with lower immunogenicity.32

Dosing of losartan in men versus women with heart failure with reduced ejection fraction: the HEAAL trial.

In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit. The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66 years and 30% of patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high- vs. low-dose losartan for the composite outcome of all-cause death or all-cause hospitalization: 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women; interaction P= 0.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III/IV, and estimated glomerular filtration rate <60 mL/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe heart failure symptoms. Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g. kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders.

Losartan protects against osteoarthritis by repressing the TGF-β1 signaling pathway via upregulation of PPARγ.

ObjectiveLosartan and activation of the peroxisome proliferator-activated receptor-γ (PPARγ) have been previously reported to alleviate the progression of osteoarthritis (OA). However, the nature of the interaction between losartan and PPARγ in OA remains elusive. Therefore, we aimed to investigate the mechanism of the regulation of PPARγ by losartan in the context of OA.MethodsClinical samples of OA patients were collected and the chondrocytes were further isolated, and used to construct OA chondrocyte model via induction with IL-1β. An OA mouse model was developed by the surgical destabilization of the medial meniscus (DMM). OA chondrocytes were treated with losartan, PPARγ siRNA and the PPAR-γ agonist GW1929 alone or in combination. Furthermore, the OA mice were treated with varying doses of losartan to determine the best mode of administration and treatment dose. Subsequently, the DMM mice were treated with losartan and GW9662. Expression of PPARγ, key proteins of the transforming growth factor-beta1 (TGF-β1) signaling pathway and the markers of OA degeneration were evaluated by the Western blot analysis, while effects on OA inflammatory factors were determined by ELISA.ResultsThe downregulation of PPARγ and the upregulation of TGF-β1 signaling pathway were detected in the OA cartilage tissues and chondrocytes. Losartan treatment or PPARγ activation contributes to reduced levels of IL-6, IL-1β, TNF-α, and COX-2, expression of TGF-β1, MMP-13, ADAMTS-4, ADAMTS-5, HtrA1, and iNOS, along with reduced Smad2 and Smad3 phosphorylation, but elevated PPARγ and Collagen II expression in vivo and in vitro. Additionally, the intraarticular injection of losartan into the knee joint proved to be the best mode of administration, and 10 ​mg/mL being the optimal treatment concentration.ConclusionOur results show that losartan could arrest the progression of OA by upregulating PPARγ expression and inactivating the TGF-β1 signaling pathway.The translational potential of this article: Our results provide a biological rationale for the use of losartan as a potential candidate for OA treatment.

Blood pressure-independent inhibition of Marfan aortic root widening by the angiotensin II receptor blocker valsartan.

Marfan syndrome (MFS) is a genetic disorder that results in accelerated aortic root widening and aneurysm. However, management of MFS patients with blood pressure (BP)‐lowering medications, such as angiotensin II (AngII) receptor blocker (ARB) losartan, continues to pose challenges due to their questionable efficacy at attenuating the rate of aortic root widening in patients. Herein we investigate the anti‐aortic root widening effects of a sub‐BP‐lowering dose valsartan, an ARB previously linked to non‐BP lowering anti‐remodeling effects. Despite absence of BP‐lowering effects, valsartan attenuated MFS aortic root widening by 75.9%, which was similar to a hypotensive dose of losartan (79.4%) when assessed by ultrasound echocardiography. Medial thickening, elastic fiber fragmentation, and phospho‐ERK signaling were also inhibited to a similar degree with both treatments. Valsartan and losartan decreased vascular contractility ex vivo between 60% and 80%, in a nitric oxide (NO)‐sensitive fashion. Valsartan increased acetylcholine (Ach)‐induced vessel relaxation and phospho‐eNOS levels in the aortic vessel supporting BP‐independent activation of protective endothelial function, which is critical to ARB‐mediated aortic root stability. This study supports the concept of achieving aortic root stability with valsartan in absence of BP‐lowering effects, which may help address efficacy and compliance issues with losartan‐based MFS patient management.

Angiotensin II receptor type 1 blockade improves hyporesponsiveness to vasopressors in septic shock

Sepsis activates the renin-angiotensin system and the production of angiotensin II, which has a key role in the regulation of blood pressure through AT1 receptors. However, excessive activation of AT1 receptor is associated with deleterious effects. We investigated the consequences of a differential blockade of AT1 receptor caused by two doses of losartan (0.25 mg/kg or 15 mg/kg, s.c), a selective AT1 receptor antagonist on sepsis outcome. These doses reduced the effect of angiotensin II in normal rats by 30% and >90% 8 h after administration, respectively, but only the higher dose maintained its inhibitory effect (~70%) 24 h after injection. Sepsis was induced by cecal ligation and puncture (CLP). Losartan was injected 2 h after CLP and parameters were evaluated 6 and 24 h after CLP. Septic rats developed hypotension and hyporesponsiveness to vasoconstrictors, an intense inflammatory process and increase in plasma markers of organ dysfunction. The lower dose of losartan improved the vasoconstrictive response to phenylephrine and angiotensin II, reduced lung myeloperoxidase and prevented leukopenia 24 h after CLP, but it did not reduce NOS-2 expression, plasma IL-6 levels or organ injury parameters of septic rats. On the other hand, the higher dose of losartan worsened the response to vasoconstrictors, potentiated the hypotension and increased further levels of creatine, urea and lactate in septic rats. Therefore, an early and partial blockade of AT1 receptor with a low dose of losartan may counteract sepsis-induced refractoriness to vasoconstrictors thus providing an opportunity to improve the outcome of this condition.

Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy

Previous trials have shown improved efficacy of neoadjuvant treatment when combined with angiotensin II receptor antagonist, losartan in patients with locally advanced pancreatic ductal adenocarcinoma (PDA). However, role of losartan is unknown in metastatic PDA. In this retrospective observational study, we examined the relationship between losartan use at time of diagnosis and continued through chemotherapy treatment with clinical outcomes in patients with metastatic PDA that received chemotherapy. We retrospectively evaluated 114 metastatic PDA patients treated at University of Kansas Cancer Center between January 2000 and November 2019. We compared overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) between patients using losartan at time of their cancer diagnosis and a control group of patients who were not on losartan. A subgroup analysis was performed based on patients who were on a 100 mg dose of losartan along with chemotherapy versus patients treated with chemotherapy (without losartan). Another subgroup analysis was performed based on chemotherapy regimen: Fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) versus Gemcitabine and Abraxane. No significant difference was found in OS (p=0.466) or PFS (p=0.919) in patients on losartan (median 274 day, 83 day) and control patients (median 279 day, 111 day). No significant difference was found in ORR (p=0.621) or in DCR (p=0.497). No significant difference was found in OS (p=0.771) or PFS (p=0.0604) in losartan patients (median 347 day, 350 day) and control patients (median 333 day, 101 day) treated with FOLFIRINOX. No significant difference was found in OS (p=0.916) or PFS (p=0.341) in losartan (median 312 day, 69 day) and control patients (median 221 day, 136 day) treated with Gemcitabine plus Abraxane. No significant difference was found in OS (p=0.727) or PFS (p=0.790) in 100 mg losartan patients (median 261 day, 84 day) and control (median 279 day, 111 day). Patients on losartan at time of diagnosis and continued through chemotherapy treatment had no significant difference in OS, PFS, ORR, DCR than control patients. Subgroup analysis of patients treated with FOLFIRINOX revealed a longer PFS with losartan than control but did not reach statistical significance, likely due to small sample size. Our findings should be validated in a larger cohort to confirm if the benefit of losartan and FOLFIRINOX seen in a neoadjuvant setting for locally advanced cancer also applies to metastatic cancer. This research adds to growing data on the efficacy of angiotensin receptor blocking drugs as adjunctive treatment in addition to chemotherapy in pancreatic cancer with specific focus on metastatic disease.

Reversion of cardiovascular remodelling in renovascular hypertensive 2K-1C rats by renin-angiotensin system inhibitors.

Evaluate whether the RAS dual blockade would induce additional beneficial effects on cardiovascular remodelling when compared to monotherapy in renal hypertensive two kidneys-one clip (2K-1C) rats. Hypertensive 2K-1C and normotensive (2K) rats were treated for 14days with submaximal doses of losartan (LOS), enalapril (ENA), losartan plus enalapril (LOS+ENA) or vehicle (water). Blood pressure and some parameters of cardiovascular remodelling were evaluated. Systolic blood pressure (SBP) was higher in 2K-1C (209±3mmHg, P<.05) than in 2K (113±1mmHg) rats. There was an additional effect in 2K-1C treated with LOS+ENA (153±9mmHg) on lowering SBP when compared to LOS (184±12mmHg) or ENA (177±9mmHg). None of the treatments had effect on SBP in 2K rats. In 2K-1C, cardiomyocyte hypertrophy was reduced by all treatments, although the cardiac hypertrophy indexes remained unchanged. 2K-1C aortas presented medial thickening that was partially reduced by the treatments. Intimal hyperplasia observed in 2K-1C (15.56±0.89µm vs 8.24±0.80µm) was reversed by ENA (9.52±0.45µm) or LOS+ENA (8.17±0.53µm). Collagen deposition was increased in 2K-1C hearts (1.77±0.16 vs 1.28±0.09) and aortas (8.1±0.6 vs 5.2±0.2). Treatment with LOS reduced (1.12±0.14%) and ENA (0.81±0.11%) or LOS+ENA (0.86±0.11%) additionally diminished collagen only in 2K-1C hearts. Submaximal doses of ACEi and/or ARB have inhibitory actions on cardiac remodelling and vascular hypertrophy not entirely dependent on their effects on blood pressure normalization in renovascular hypertensive rats. Combined therapy produced additional reduction in blood pressure than monotherapy despite a similar inhibition on cardiovascular remodelling.

Association of losartan use with outcomes in metastatic pancreatic cancer patients treated with chemotherapy.

e16738 Background: A phase II trial has shown improved efficacy of neoadjuvant therapy when combined with losartan (by remodeling desmoplasia) in locally advanced pancreatic ductal adenocarcinoma (PDA). However, role of losartan is unknown in metastatic PDA. We examined the relationship between the use of the angiotensin II receptor antagonist, losartan, at time of diagnosis with clinical outcomes in metastatic PDA pts that received chemo. Methods: We retrospectively evaluated 114 metastatic PDA pts treated at our center between Jan 2000 and Nov 2019. We compared OS, PFS, objective response rate (ORR), and disease control rate (DCR) between pts using losartan at time of cancer diagnosis and a control group of pts not on losartan. A subanalysis was performed based on losartan dose: 100mg dose versus control pts. and based on chemo: FOLFIRINOX or gemcitabine+abraxane. Results: Table shows baseline demographics. No significant difference was found in OS [p = 0.455] or PFS [p = 0.919] in pts on losartan (median 274d, 83d) vs control (median 279d, 111d) [p = 0.466]. No significant difference was found in ORR [p = 0.621] or in DCR [p = 0.497]. No significant difference was found in OS [p = 0.771] or PFS [p = 0.064] in losartan pts (median 347d, 350d) vs control (median 333d, 101d) treated with FOLFIRINOX. No significant difference was found in OS [p = 0.916] or PFS [p = 0.341] in losartan (median 312d, 69d) vs control (median 221d, 136d) [p = 0.916] treated with gemcitabine+abraxane. No significant difference was found in OS [p = 0.727] or PFS [p = 0.790] in 100mg losartan pts (median 261d, 84d) vs control (median 279d, 111d). Conclusions: Pts on losartan at time of diagnosis had no significant difference in OS, PFS, ORR, DCR than control pts. However, a subanalysis of pts treated with FOLFIRINOX revealed a longer PFS with losartan than control but did not meet statistical significance, likely due to small sample size. To confirm if the benefit of losartan + FOLFIRINOX seen in neoadjuvant setting for locally advanced cancer also applies to metastatic cancer, our findings need to be validated in a larger cohort. [Table: see text]

Potential pharmacodynamic and pharmacokinetic interactions of Nigella Sativa and Trigonella Foenum-graecum with losartan in L-NAME induced hypertensive rats.

The objective of this investigation was to study whether Nigella Sativa and Trigonella Foenum-graecum, could modulate the losartan pharmacodynamic (PD) and pharmacokinetic (PK) in experimental L-NAME induced hypertensive rats. For in vivo study, the systolic blood pressure (SBP) of rats was measured by the “tail-cuff system” after the treatment of rats with herb alone and herb + losartan in hypertensive rats. The SBP of rats treated with L-NAME + losartan also recorded. For the PK study, blood samples were obtained for up to 12 h to determine the concentrations of the drug, and various PK parameters were calculated. The data displayed that the SBP was significantly (p < 0.05) decreased in the rats when administered with L-NAME + N. Sativa or L-NAME + T. Foenum-graecum in contrast to the rats administered with L-NAME alone. A more prominent decline (p < 0.05) in SBP was detected in rats administered with L-NAME + N. Sativa + losartan and L-NAME + T. Foenum-graecum + losartan. In a PK study, higher losartan Cmax and AUC0-t were noted in rats treated with N. Sativa + losartan and T. Foenum-graecum + losartan, although the difference was not significant in contrast to the control group. This study proposed that the interaction between N. Sativa & losartan and T. Foenum-graecum & losartan could take place on concurrent administration; consequently, the dose of losartan may need to be accustomed when they are utilized simultaneously.

Adherence to guideline-directed medical therapy among left ventricular systolic dysfunction patients in Shahid Gangalal National Heart Centre, Kathmandu, Nepal

Background and Aims: Heart Failure (HF) with reduced Ejection Fraction (HFrEF) is defined as the clinical diagnosis of HF and left ventricular ejection fraction (LVEF) ≤ 40%, also referred to as systolic HF. Guideline-directed medical therapy (GDMT) has shown to reduce mortality for HFrEF. We aim to evaluate adherence to GDMT treatment in our outpatients.&#x0D; Methods: It was a cross-sectional observational study. All patients who attended the Department of preventive medicine and cardiac rehabilitation for medical counseling from October 2016 to May 2018 and have already completed 3 months of follow up for HF were included in this study. Performa was designed to collect patient information which included; age, gender, NYHA functional class, LVEF, systolic and diastolic blood pressure, pulse rate, creatinine, potassium and drugs with doses were recorded.&#x0D; Results: Among the 451 patients, ninety-nine (65.6%) were male and 52 (34.4%) were female. The mean age was 56.2±4.2 years. Most of the patients were in NYHA class II 114 (75.5%) and in Sinus rhythm 119 (79.4%). Mean LVEF was 26.6±6.1%. Dilated Cardiomyopathy was the most common clinical diagnosis in 76 (50.3%). Diuretic, Angiotensin-converting enzyme inhibitor (ACEI)/Angitensin receptor blocker (AB), Aldosterone Antagonist, β-blocker and digoxin were prescribed in 151 (100%), 140 (93.3%), 127 (84.1%), 114 (75.4%) and 46 (30.4%) patients respectively. The mean dose of furosemide, Enalapril, Losartan, carvedilol, bisoprolol and metoprolol succinate was 45.3mg, 4.0mg, 33.2mg, 33.6mg, 18.8mg, 3.0mg, and 27.5mg was respectively.&#x0D; Conclusion: Our center's adherence to GDMT in HFrEF patients is comparable to international studies. We still need more effort to re-emphasize the importance of GDMT by focusing on the optimization of drug doses during out-patient visits.

Angiotensin II-Type I Receptor Antagonism Does Not Influence the Chemoreceptor Reflex or Hypoxia-Induced Central Sleep Apnea in Men.

Components of the renin-angiotensin system (RAS) situated within the carotid body or central nervous system may promote hypoxia-induced chemoreceptor reflex sensitization or central sleep apnea (CSA). We determined if losartan, an angiotensin-II type-I receptor (AT1R) antagonist, would attenuate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia, and consequently CSA severity. In a double-blind, randomized, placebo-controlled, crossover protocol, 14 men (age: 25 ± 2 years; BMI: 24.6 ± 1.1 kg/m2; means ± SEM) ingested 3 doses of either losartan (50 mg) or placebo every 8 h. Chemoreceptor reflex sensitivity was assessed during hypoxic and hyperoxic hypercapnic ventilatory response (HCVR) tests and during six-20s hypoxic apneas before and after 8 h of sleep in normobaric hypoxia (FIO2 = 0.135). Loop gain was assessed from a ventilatory control model fitted to the ventilatory pattern of CSA recorded during polysomnography. Prior to nocturnal hypoxia, losartan had no effect on either the hyperoxic (losartan: 3.6 ± 1.1, placebo: 4.0 ± 0.6 l/min/mmHg; P = 0.9) or hypoxic HCVR (losartan: 5.3 ± 1.4, placebo: 5.7 ± 0.68 l/min/mmHg; P = 1.0). Likewise, losartan did not influence either the hyperoxic (losartan: 4.2 ± 1.3, placebo: 3.8 ± 1.1 l/min/mmHg; P = 0.5) or hypoxic HCVR (losartan: 6.6 ± 1.8, placebo: 6.3 ± 1.5 l/min/mmHg; P = 0.9) after nocturnal hypoxia. Cardiorespiratory responses to apnea and participants’ apnea hypopnea indexes during placebo and losartan were similar (73 ± 15 vs. 75 ± 14 events/h; P = 0.9). Loop gain, which correlated with CSA severity (r = 0.94, P < 0.001), was similar between treatments. In summary, in young healthy men, hypoxia-induced CSA severity is strongly associated with loop gain, but the AT1R does not modulate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia.

The effects of combined treatment of losartan and ramipril on hypertension and related complications

Polypharmacy has been an important strategy for the management of hypertension. The aim of this study was to investigate the effect of combined treatment of losartan with ramipril on hypertension, myocardial infarction and vascular remodeling in disease animal models. In 8-telemetered spontaneous hypertensive rats (SHRs) orally treated with various doses of drugs or vehicle by cross-over protocol, systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were measured. The infarct size was measured in rats subjected to 30 min occlusion of the left anterior descending coronary artery (LAD) followed by 150 min reperfusion in myocardial ischemia/reperfusion (MI/R) rats injected drugs or vehicle once through femoral vein 15 min before inducing ischemia. The neointima formation and DNA synthesis in intima and media layer of the blood vessels were measured in cuff-induced vascular injury mice orally treated with drugs for 2 weeks. As compared with single treatment, the combination therapy of both drugs significantly decreased SBP and MAP without significant reflex tachycardia. The combined treatment of both drugs significantly increased the expression of endothelial nitric oxide synthase (eNOS) in coronary arterial tissues including area at occlusion. The combination therapy significantly decreased the thickness of vascular media layer and the number of bromodeoxyuridine (BrdU)-positive cells in both intima and media. The present data suggest that the combination therapy with fixed doses of losartan and ramipril may exert greater BP-lowering effects with protection against myocardial infarction and vascular remodeling.

Angiotensin involvement in trauma processing-exploring candidate neurocognitive mechanisms of preventing post-traumatic stress symptoms.

The angiotensin-II antagonist losartan is a promising candidate that has enhanced extinction in a post-traumatic stress disorder (PTSD) animal model and was related to reducing PTSD symptom development in humans. Here, we investigate the neurocognitive mechanisms underlying these results, testing the effect of losartan on data-driven and contextual processing of traumatic material, mechanisms proposed to be relevant for PTSD development. In a double-blind between-subject design, 40 healthy participants were randomised to a single oral dose of losartan (50 mg) or placebo, 1 h before being exposed to distressing films as a trauma analogue while heart rate (HR) was measured. Peritraumatic processing was investigated using blurry picture stimuli from the films, which transformed into clear images. Data-driven processing was measured by the level of blurriness at which contents were recognised. Contextual processing was measured as the amount of context information retrieved when describing the pictures' contents. Negative-matched control images were used to test perceptual processing of peripheral trauma-cues. Post-traumatic stress symptoms were assessed via self-report questionnaires after analogue trauma and an intrusion diary completed over 4 days following the experiment. Compared to placebo, losartan facilitated contextual processing and enhanced detail perception in the negative-match pictures. During the films, the losartan group recorded lower HR and higher HR variability, reflecting lower autonomic stress responses. We discuss potential mechanisms of losartan in preventing PTSD symptomatology, including the role of reduced arousal and increased contextual processing during trauma exposure, as well as increased threat-safety differentiation when encountering peripheral trauma-cues in the aftermaths of traumatic events.

Mid-dose losartan mitigates diabetes-induced hepatic damage by regulating iNOS, eNOS, VEGF, and NF-κB expressions

Background/aimLosartan, an antihypertensive drug, is highly preferred in patients with diabetes mellitus (DM) and hypertension because of its retarding effect on diabetic nephropathy. In this study, we investigated the potential therapeutic effect of different doses of losartan on hepatic damage in a streptozotocin (STZ, 50 mg/kg)-induced DM model in rats.Materials and methodsIn this study, five different groups were formed: control, DM, low-dose losartan (5 mg/kg), mid-dose losartan (20 mg/kg), and high-dose losartan (80 mg/kg). Liver tissues of experimental groups were evaluated immunohistochemically for TUNEL, iNOS, eNOS, VEGF, and NF-κB pathways. In addition to immunohistochemical analysis, analyses of SOD and MDA, which are oxidative stress markers, were also performed and the results were evaluated together.ResultsWhen biochemical and immunohistochemical findings were evaluated together, it was found that the results obtained from the mid-dose losartan group were closer to those of the control than the other groups.ConclusionThis study indicated that mid-dose losartan administration may have a therapeutic effect by inhibiting apoptosis and regulating iNOS, eNOS, VEGF, and NF-κB protein expressions in DM-induced hepatic damage.

Evaluation of potential herbal-drug interactions of a standardized propolis extract (EPP-AF®) using an in vivo cocktail approach

Ethnopharmacological relevancePropolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. Aim of the studyThe main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. Materials and methodsSubtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. ResultsAfter exposure to EPP-AF®, it was observed decrease in the AUC0−∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80–1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80–1.25. ConclusionsIn conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.

The Impact of a Dedicated Heart Failure (HF) Clinic on Hospitalization Rates, Hospitalization Costs, and Left Ventricular Ejection Fraction (LVEF) in Systolic Heart Failure Patients

IntroductionHeart failure with reduced ejection fraction (HFrEF) is one of the most costly conditions with high morbidity and mortality. There is still paucity of data for cost-effective outpatient heart failure (HF) management. In an effort to prevent hospital admissions and morbidity, the focus has shifted toward effective outpatient care of these complex patients. Southwest Medical Associates Cardiology instituted a HF clinic in 2015, a collaboration of cardiologists with expertise in Advanced Heart Failure/Transplant, nurse practitioners, and nurse case managers. Each team member sees patients for routine medication uptitrations and as needed for hospital follow-ups. The team provides patients with extensive education regarding disease management, reinforces compliance, and closely monitors clinical status.HypothesisThe authors sought to determine the impact of a dedicated HF clinic on hospitalization rates, hospitalization costs, and left ventricular ejection fraction (LVEF). The authors wanted to determine if goals of guideline directed medical therapy (GDMT) optimization were met.MethodsData was collected on a cohort of 412 HFrEF patients who have been enrolled in the program for at least six months since 2016. Comparisons were made between six months before enrollment and six months after.ResultsHospitalization rates dropped from 0.61% to 0.29% (p=<.00001). Hospitalization costs decreased from $1035 to $828 (p=0.177). Average LVEF increased from 28% to 37% (p=.00001).Average lisinopril and losartan doses were unchanged. Lisinopril usage increased from 24.9% to 35.6% (p=.00084). Losartan usage increased from 6.1% to 19.2% (p=<.00001). Average carvedilol dose increased from 13 mg to 17 mg BID (p=0.001362). Metoprolol succinate dose increased from 50 mg to 108 mg daily. (p=0.000118). Carvedilol use increased from 11% to 46.2% (p=<.00001). Metoprolol use increased from 3.4% to 20.6% (p=< .00001). Spironolactone use increased from 15.7% to 29.2% (p=0.01208).ConclusionsHaving a dedicated HF clinic led to significant reductions in HF hospitalizations and cost and a modest increase in average LVEF in 412 patients after six months. Usage of ACEis, ARBS, BBs, and spironolactone showed statistically significant increases after enrollment. Future studies may be undertaken to determine the impact of extending the clinic enrollment for more than 6 months with emphasis on hospitalization rates, changes in BNP, LVEF improvement, and cost, as well as increased dosing/utilization of GDMT. Heart failure with reduced ejection fraction (HFrEF) is one of the most costly conditions with high morbidity and mortality. There is still paucity of data for cost-effective outpatient heart failure (HF) management. In an effort to prevent hospital admissions and morbidity, the focus has shifted toward effective outpatient care of these complex patients. Southwest Medical Associates Cardiology instituted a HF clinic in 2015, a collaboration of cardiologists with expertise in Advanced Heart Failure/Transplant, nurse practitioners, and nurse case managers. Each team member sees patients for routine medication uptitrations and as needed for hospital follow-ups. The team provides patients with extensive education regarding disease management, reinforces compliance, and closely monitors clinical status. The authors sought to determine the impact of a dedicated HF clinic on hospitalization rates, hospitalization costs, and left ventricular ejection fraction (LVEF). The authors wanted to determine if goals of guideline directed medical therapy (GDMT) optimization were met. Data was collected on a cohort of 412 HFrEF patients who have been enrolled in the program for at least six months since 2016. Comparisons were made between six months before enrollment and six months after. Hospitalization rates dropped from 0.61% to 0.29% (p=<.00001). Hospitalization costs decreased from $1035 to $828 (p=0.177). Average LVEF increased from 28% to 37% (p=.00001). Average lisinopril and losartan doses were unchanged. Lisinopril usage increased from 24.9% to 35.6% (p=.00084). Losartan usage increased from 6.1% to 19.2% (p=<.00001). Average carvedilol dose increased from 13 mg to 17 mg BID (p=0.001362). Metoprolol succinate dose increased from 50 mg to 108 mg daily. (p=0.000118). Carvedilol use increased from 11% to 46.2% (p=<.00001). Metoprolol use increased from 3.4% to 20.6% (p=< .00001). Spironolactone use increased from 15.7% to 29.2% (p=0.01208). Having a dedicated HF clinic led to significant reductions in HF hospitalizations and cost and a modest increase in average LVEF in 412 patients after six months. Usage of ACEis, ARBS, BBs, and spironolactone showed statistically significant increases after enrollment. Future studies may be undertaken to determine the impact of extending the clinic enrollment for more than 6 months with emphasis on hospitalization rates, changes in BNP, LVEF improvement, and cost, as well as increased dosing/utilization of GDMT.

Improvement of Cartilage Repair With Biologically Regulated Marrow Stimulation by Blocking TGF-β1 in A Rabbit Osteochondral Defect Model

Objectives: Application of growth factors for cartilage injury has been considered in recent studies; however, the effect of blocking detrimental growth factors for cartilage injury has not been well described. It is known that transforming growth factor beta 1 (TGF-β1) is overproduced in osteoarthritic joints. It has been reported that angiotensin II-induced activation of TGF-β1-pSmad2/3 signaling, which can result in fibrosis, can be inhibited by losartan (an FDA-approved hypertension drug). Although bone marrow stimulation (BMS) is often the first choice for clinical treatment of cartilage injuries, fibrocartilage, not pure hyaline cartilage, has been reported after BMS surgery. Our lab has shown that blocking TGF-β1 with losartan can decrease fibrosis in muscle injury models. We hypothesized that blocking TGF-β1 would improve cartilage healing in a rabbit osteochondral defect injury model via decreasing the amount of fibrocartilage formation, and increase hyaline-like cartilage formation, thus enhancing BMS-mediated cartilage repair. Methods: An osteochondral defect (diameter: 5 mm, depth: 2 mm) was made in the patellar groove of 48 New Zealand White rabbits. The rabbits were divided into 3 groups (N=8/group/time point) randomly: a control group (defect only), a BMS group (osteochondral defect + BMS), and a losartan-treated group (osteochondral defect + BMS + losartan). For the rabbits in the losartan-treated group, 10mg/kg/day dose of losartan was administrated orally from the day after surgery through the day of euthanasia. Rabbits were sacrificed 6 weeks and 12 weeks post-operatively, respectively. Macroscopic appearance, microcomputed tomography (microCT), histological assessment, and gene expression were evaluated. Results: The losartan-treated group scored highest in the International Cartilage Repair Society (ICRS) macroscopic assessment. MicroCT showed healing of the bony defect in the losartan-treated group, in comparison to no healing in the control group and partial healing in the BMS group. Histologically, results obtained using the Modified O’Driscoll ICRS grading system yielded significantly superior scores in the losartan-treated group compared to both the control group and the BMS group (12 weeks, mean [SD], control: 30.1 [3.6], BMS: 35.0 [3.7], losartan-treated: 41.4 [4.7]; p&lt; 0.001 compared to control group, p= 0.012 compared to BMS group, respectively). TGF-β1 signaling and TGF-β activated kinase-1 were suppressed in the fat pad tissues. Conclusion: Biologically regulated BMS by blocking TGF-β1 (oral intake of losartan) provided superior cartilage repair via decreasing fibrocartilage formation and resulting in hyaline-like cartilage, compared to outcomes from BMS only. FDA-approved blocking growth factor drugs will be a new frontier of biologically regulated BMS, which will be easily translatable into clinical settings as an off-label use. [Figure: see text]

Losartan and isoproterenol promote alterations in the local renin-angiotensin system of rat salivary glands.

Renin-angiotensin system (RAS) systemically or locally collaborates with tissue homeostasis, growth and development, which has been extensively studied for its pharmacological implications. This study was primarily aimed at finding and characterizing local RAS in rat parotid, sublingual and submandibular glands. It was also hypothesized that vasoactive drugs could affect the expression of RAS targets, as well as saliva flow and its composition. Therefore, another objective of this study was to compare the effects of losartan (angiotensin II receptor blocker) and isoproterenol (β-adrenergic receptor agonist). Forty-one Wistar rats were divided into three groups and administered a daily intraperitoneal dose of saline, losartan or isoproterenol solutions for one week. The following RAS targets were studied using qPCR: renin (REN), angiotensinogen (AGT), angiotensin converting enzyme (ACE), ACE-2, elastase-2 (ELA-2), AT1-a and MAS receptors, using RPL-13 as a reference gene. Morphology of glands was analyzed by immunohistochemistry using REN, ACE, ACE-2, AT1, AT2 and MAS antibodies. The volume and total protein content of saliva were measured. Our results revealed that ACE, ACE-2, AT1-a, AT2 and MAS receptors were expressed in all salivary gland samples, but REN and ELA-2 were absent. Losartan decreased mRNA expression of RAS targets in parotid (MAS) and submandibular glands (ACE and both AT receptors), without affecting morphological alterations, and significantly decreased saliva and total protein secretions. Isoproterenol treatment affected gene expression profiles in parotid (ACE, ACE-2, AT1-a, MAS, AGT), and submandibular (ACE, AT2, AGT) glands, thus promoting acinar hypertrophy in serous acini, without significant changes in salivary flow or total protein content. These drugs affected mainly acini, followed by duct systems and myoepithelial cells, whereas blood vessels were not affected. In conclusion, there is a local RAS in major rat salivary glands and losartan, an angiotensin II receptor blocker, affected not only the RAS-target gene expression but also decreased salivary flow and total protein content.

EFFECT OF LOSARTAN ON HEMOSTATIC PROFILE IN RATS

Ace inhibitors like ramipril have been shown to affect coagulation profile in rats. This study was carried out to find the interactions between aspirin and losartan on coagulation profile. Three doses of losartan and its combination with aspirin were tested for their effect on hemostatic profile in albino Wistar rats. The findings of the study suggest that there is a possibility of interaction between aspirin and losartan when used together in patients.

Novel therapeutic potential of angiotensin receptor 1 blockade in a rat model of diabetes-associated depression parallels altered BDNF signalling

Aims/hypothesisDiabetes is a worldwide epidemic linked with diverse diseases of the nervous system, including depression. A few studies suggested a connection between renin–angiotensin–aldosterone system blockers and reduced depressive symptoms, although underlying mechanisms are unclear. Here we investigated the antidepressant effect and the mechanisms of action of the angiotensin receptor 1 blocker (ARB) losartan in an experiential model of diabetes-associated depression.MethodsExperimental diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated for 2 weeks with a non-pressor oral dose of losartan (20 mg/kg). In protocol 1, cerebrovascular perfusion and glial activation were evaluated by single-photon emission computed tomography–MRI and immunohistochemistry. In protocol 2, behaviour studies were performed (forced swim test and open field test). Hippocampal proinflammatory response and brain-derived neurotrophic factor (BDNF) signalling were also assessed.ResultsHere, we show that diabetic rats exhibit depression-like behaviour, which can be therapeutically reversed by losartan. This action of losartan occurs via changes in diabetes-induced neuroinflammatory responses rather than altered cerebral perfusion. We also show that as a part of its protective effect losartan restores BDNF production in astrocytes and facilitates BDNF–tropomyosin receptor kinase B–cAMP response element-binding protein signalling in the diabetic brain.Conclusions/interpretationWe identified a novel effect of losartan in the nervous system that may be implemented to alleviate symptoms of diabetes-associated depression. These findings explore a new therapeutic horizon for ARBs as possible antidepressants and suggest that BDNF could be a target of future drug development in diabetes-induced complications.