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Journal of Ocular Pharmacology and... Apr 2023Losartan is an angiotensin II receptor blocker (ARB) that impedes transforming growth factor (TGF) beta signaling by inhibiting activation of signal transduction... (Review)
Review
Losartan is an angiotensin II receptor blocker (ARB) that impedes transforming growth factor (TGF) beta signaling by inhibiting activation of signal transduction molecule extracellular signal-regulated kinase (ERK). Studies supported the efficacy of topical losartan in decreasing scarring fibrosis after rabbit Descemetorhexis, alkali burn, and photorefractive keratectomy injuries, and in case reports of humans with scarring fibrosis after surgical complications. Clinical studies are needed to explore the efficacy and safety of topical losartan in the prevention and treatment of corneal scarring fibrosis, and other eye diseases and disorders where TGF beta has a role in pathophysiology. These include scarring fibrosis associated with corneal trauma, chemical burns, infections, surgical complications, and persistent epithelial defects, as well as conjunctival fibrotic diseases, such as ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Research is also needed to explore the efficacy and safety of topical losartan for hypothesized treatment of transforming growth factor beta-induced ()-related corneal dystrophies (Reis-Bu¨cklers corneal dystrophy, lattice corneal dystrophy type 1, and granular corneal dystrophies type 1 and type 2) where deposited mutant protein expression is modulated by TGF beta. Investigations could also explore the efficacy and safety of topical losartan treatments to reduce conjunctival bleb scarring and shunt encapsulation following glaucoma surgical procedures. Losartan and sustained release drug delivery devices could be efficacious in treating intraocular fibrotic diseases. Dosing suggestions and precautions that should be considered in trials of losartan are detailed. Losartan, as an adjuvant to current treatments, has the potential to augment pharmacological therapeutics for many ocular diseases and disorders where TGF beta plays a central role in pathophysiology.
Topics: Animals; Humans; Rabbits; Losartan; Cicatrix; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Corneal Dystrophies, Hereditary; Eye Diseases; Fibrosis; Transforming Growth Factor beta; Corneal Injuries
PubMed: 36877777
DOI: 10.1089/jop.2022.0174 -
Clinical Cancer Research : An Official... Feb 2022There is increasing recognition that progress in immuno-oncology could be accelerated by evaluating immune-based therapies in dogs with spontaneous cancers. Osteosarcoma...
Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment, and Combined With the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma.
PURPOSE
There is increasing recognition that progress in immuno-oncology could be accelerated by evaluating immune-based therapies in dogs with spontaneous cancers. Osteosarcoma (OS) is one tumor for which limited clinical benefit has been observed with the use of immune checkpoint inhibitors. We previously reported the angiotensin receptor blocker losartan suppressed metastasis in preclinical mouse models through blockade of CCL2-CCR2 monocyte recruitment. Here we leverage dogs with spontaneous OS to determine losartan's safety and pharmacokinetics associated with monocyte pharmacodynamic endpoints, and assess its antitumor activity, in combination with the kinase inhibitor toceranib.
PATIENTS AND METHODS
CCL2 expression, monocyte infiltration, and monocyte recruitment by human and canine OS tumors and cell lines were assessed by gene expression, ELISA, and transwell migration assays. Safety and efficacy of losartan-toceranib therapy were evaluated in 28 dogs with lung metastatic OS. Losartan PK and monocyte PD responses were assessed in three dose cohorts of dogs by chemotaxis, plasma CCL2, and multiplex cytokine assays, and RNA-seq of losartan-treated human peripheral blood mononuclear cells.
RESULTS
Human and canine OS cells secrete CCL2 and elicit monocyte migration, which is inhibited by losartan. Losartan PK/PD studies in dogs revealed that a 10-fold-higher dose than typical antihypertensive dosing was required for blockade of monocyte migration. Treatment with high-dose losartan and toceranib was well-tolerated and induced a clinical benefit rate of 50% in dogs with lung metastases.
CONCLUSIONS
Losartan inhibits the CCL2-CCR2 axis, and in combination with toceranib, exerts significant biological activity in dogs with metastatic osteosarcoma, supporting evaluation of this drug combination in patients with pediatric osteosarcoma. See related commentary by Weiss et al., p. 571.
Topics: Animals; Bone Neoplasms; Dog Diseases; Dogs; Humans; Leukocytes, Mononuclear; Losartan; Mice; Monocytes; Osteosarcoma
PubMed: 34580111
DOI: 10.1158/1078-0432.CCR-21-2105 -
Translational Vision Science &... Jul 2022To evaluate the efficacy of losartan and prednisolone acetate in inhibiting corneal scarring fibrosis after alkali burn injury in rabbits.
PURPOSE
To evaluate the efficacy of losartan and prednisolone acetate in inhibiting corneal scarring fibrosis after alkali burn injury in rabbits.
METHODS
Sixteen New Zealand White rabbits were included. Alkali injuries were produced using 1N sodium hydroxide on a 5-mm diameter Whatman #1 filter paper for 1 minute. Four corneas in each group were treated six times per day for 1 month with 50 µL of (1) 0.8 mg/mL losartan in balanced salt solution (BSS), (2) 1% prednisolone acetate, (3) combined 0.8 mg/mL losartan and 1% prednisolone acetate, or (4) BSS. Area of opacity and total opacity were analyzed in standardized slit-lamp photos with ImageJ. Corneas in both groups were cryofixed in Optimal cutting temperature (OCT) compound at 1 month after surgery, and immunohistochemistry was performed for alpha-smooth muscle actin (α-SMA) and keratocan or transforming growth factor β1 and collagen type IV with ImageJ quantitation.
RESULTS
Combined topical losartan and prednisolone acetate significantly decreased slit-lamp opacity area and intensity, as well as decreased stromal myofibroblast α-SMA area and intensity of staining per section and confined myofibroblasts to only the posterior stroma with repopulation of the anterior and mid-stroma with keratocan-positive keratocytes after 1 month of treatment. Corneal fibroblasts produced collagen type IV not associated with basement membranes, and this production was decreased by topical losartan.
CONCLUSIONS
Combined topical losartan and prednisolone acetate decreased myofibroblast-associated fibrosis after corneal alkali burns that produced full-thickness injury, including corneal endothelial damage. Increased dosages and duration of treatment may further decrease scarring fibrosis.
TRANSLATIONAL RELEVANCE
Topical losartan and prednisolone acetate decrease myofibroblast-mediated scarring fibrosis after corneal injury.
Topics: Adrenal Cortex Hormones; Alkalies; Animals; Burns, Chemical; Cicatrix; Collagen Type IV; Corneal Diseases; Corneal Injuries; Fibrosis; Losartan; Myofibroblasts; Rabbits
PubMed: 35819289
DOI: 10.1167/tvst.11.7.9 -
Cells Nov 2021Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease after diabetes. For years, hypertensive kidney disease has been focused on the... (Review)
Review
Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease after diabetes. For years, hypertensive kidney disease has been focused on the afferent arterioles and glomeruli damage and the involvement of the renin angiotensin system (RAS). Nonetheless, in recent years, novel evidence has demonstrated that persistent high blood pressure injures tubular cells, leading to epithelial-mesenchymal transition (EMT) and tubulointerstitial fibrosis. Injury primarily determined at the glomerular level by hypertension causes changes in post-glomerular peritubular capillaries that in turn induce endothelial damage and hypoxia. Microvasculature dysfunction, by inducing hypoxic environment, triggers inflammation, EMT with epithelial cells dedifferentiation and fibrosis. Hypertensive kidney disease also includes podocyte effacement and loss, leading to disruption of the filtration barrier. This review highlights the molecular mechanisms and histologic aspects involved in the pathophysiology of hypertensive kidney disease incorporating knowledge about EMT and tubulointerstitial fibrosis. The role of the Hsp70 chaperone on the angiotensin II-induced EMT after angiotensin II type 1 receptor (ATR) blockage, as a possible molecular target for therapeutic strategy against hypertensive renal damage is discussed.
Topics: Animals; Epithelial-Mesenchymal Transition; HSP70 Heat-Shock Proteins; Humans; Hypertension, Renal; Kidney; Losartan; Nephritis; Protective Agents
PubMed: 34831368
DOI: 10.3390/cells10113146 -
American Family Physician Nov 2020Drugs are being prescribed with more frequency and in higher quantities. A serious adverse drug event from prescribed medications constitutes 2.4% to 16.2% of all...
Drugs are being prescribed with more frequency and in higher quantities. A serious adverse drug event from prescribed medications constitutes 2.4% to 16.2% of all hospital admissions. Many of the adverse drug events present intraorally or periorally in isolation or as a clinical symptom of a systemic effect. Clinical recognition and treatment of adverse drug events are important to increase patient adherence, manage drug therapy, or detect early signs of potentially serious outcomes. Oral manifestations of commonly prescribed medications include gingival enlargement, oral hyperpigmentation, oral hypersensitivity reaction, medication-related osteonecrosis, xerostomia, and other oral or perioral conditions. To prevent dose-dependent adverse drug reactions, physicians should prescribe medications judiciously using the lowest effective dose with minimal duration. Alternatively, for oral hypersensitivity reactions that are not dose dependent, quick recognition of clinical symptoms associated with time-dependent drug onset can allow for immediate discontinuation of the medication without discontinuation of other medications. Physicians can manage oral adverse drug events in the office through oral hygiene instructions for gingival enlargement, medication discontinuation for oral pigmentation, and prescription of higher fluoride toothpastes for xerostomia.
Topics: Albuterol; Amlodipine; Anticonvulsants; Antihypertensive Agents; Atorvastatin; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bronchodilator Agents; Deprescriptions; Drug Hypersensitivity; Fluorides; Gingival Overgrowth; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperpigmentation; Hypoglycemic Agents; Lisinopril; Losartan; Metformin; Metoprolol; Mouth Diseases; Omeprazole; Oral Hygiene; Proton Pump Inhibitors; Simvastatin; Thyroxine; Toothpastes; Xerostomia
PubMed: 33179891
DOI: No ID Found -
Cancer Cell Jun 2020Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher...
Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher in liver metastases than in primary colorectal tumors. Highly activated metastasis-associated fibroblasts increase tissue stiffness, which enhances angiogenesis and anti-angiogenic therapy resistance. Drugs targeting the renin-angiotensin system, normally prescribed to treat hypertension, inhibit fibroblast contraction and extracellular matrix deposition, thereby reducing liver metastases stiffening and increasing the anti-angiogenic effects of bevacizumab. Patients treated with bevacizumab showed prolonged survival when concomitantly treated with renin-angiotensin inhibitors, highlighting the importance of modulating the mechanical microenvironment for therapeutic regimens.
Topics: Angiogenesis Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Bevacizumab; Cancer-Associated Fibroblasts; Captopril; Colorectal Neoplasms; Drug Synergism; Humans; Liver Neoplasms; Losartan; Lung Neoplasms; Neovascularization, Pathologic; Renin-Angiotensin System; Tumor Microenvironment
PubMed: 32516590
DOI: 10.1016/j.ccell.2020.05.005 -
American Journal of Cardiovascular... Jul 2023Few data are available regarding the efficacy and safety of a single-pill combination (SPC) consisting of four medications in patients with concomitant hypertension and... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
BACKGROUND
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.
OBJECTIVE
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
A/L/R/E as an SPC could be an effective treatment for patients with hypertension and dyslipidemia without significant safety issues.
CLINICAL TRIALS REGISTRATION
NCT04074551 (registered 30 August 2019).
Topics: Humans; Losartan; Rosuvastatin Calcium; Antihypertensive Agents; Ezetimibe; Cholesterol, LDL; Blood Pressure; Amlodipine; Hypertension; Essential Hypertension; Dyslipidemias; Double-Blind Method; Treatment Outcome
PubMed: 37395974
DOI: 10.1007/s40256-023-00590-9