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Profiles of Drug Substances,... 2015Losartan (Cozaar™) is an angiotensin II receptor antagonist with antihypertensive activity. It is used in the management of hypertension and heart failure.... (Review)
Review
Losartan (Cozaar™) is an angiotensin II receptor antagonist with antihypertensive activity. It is used in the management of hypertension and heart failure. Nomenclature, formulae, elemental analysis, and appearance of the drug are included in this review. The uses, applications, and the variety of synthetic pathways of this drug are outlined. Physical characteristics including: ionization constant, solubility, X-ray powder diffraction pattern, thermal methods of analysis, UV spectrum, IR spectrum, mass spectrum with fragmentation patterns, and NMR (1H and 13C) spectra of losartan together with the corresponding figures and/or tables are all produced. This profile also includes the monograph of British Pharmacopoeia, together with several reported analytical methods including: spectrophotometric, electrochemical, chromatographic, and capillary electrophoretic methods. The stability, the pharmacokinetic behavior and the pharmacology of the drug are also provided.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Chemistry, Pharmaceutical; Drug Stability; Humans; Hypertension; Losartan; Molecular Structure; Technology, Pharmaceutical
PubMed: 26051686
DOI: 10.1016/bs.podrm.2015.02.003 -
Clinical Pharmacokinetics 2005Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching... (Review)
Review
Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching maximum concentrations 1-2 hours post-administration. After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite. E 3174 is 10- to 40-fold more potent than its parent compound and its estimated terminal half-life ranges from 6 to 9 hours. The pharmacokinetics of losartan and E 3174 are linear, dose-proportional and do not substantially change with repetitive administration. The recommended dosage of losartan 50 mg/day can be administered without regard to food. There are no clinically significant effects of age, sex or race on the pharmacokinetics of losartan, and no dosage adjustment is necessary in patients with mild hepatic impairment or various degrees of renal insufficiency. Losartan, or its E 3174 metabolite, is not removed during haemodialysis. The major metabolic pathway for losartan is by the cytochrome P450 (CYP) 3A4, 2C9 and 2C10 isoenzymes. Overall, losartan has a favorable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between this drug and a range of inhibitors and stimulators of the CYP450 system. Losartan does not have a drug-drug interaction with hydrochlorothiazide, warfarin or digoxin. Losartan should be avoided in pregnancy, as is the case with all other angiotensin-receptor antagonists. When given in the second and third trimester of pregnancy, losartan is often associated with serious fetal toxicity. Losartan is a competitive antagonist that causes a parallel rightward shift of the concentration-contractile response curve to angiotensin-II, while E 3174 is a noncompetitive "insurmountable" antagonist of angiotensin-II. The maximum recommended daily dose of losartan is 100mg, which can be given as a once-daily dose or by splitting the same total daily dose into two doses. Losartan reduces blood pressure comparably to other angiotensin-receptor antagonists. Losartan has been extensively studied relative to end-organ protection, with studies having been conducted in diabetic nephropathy, heart failure, post-myocardial infarction and hypertensive patients with left ventricular hypertrophy. The results of these studies have been sufficiently positive to support a more widespread use of angiotensin-receptor antagonists in the setting of various end-organ diseases. Losartan, like other angiotensin-receptor antagonists, is devoid of significant adverse effects.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Diabetic Nephropathies; Humans; Hypertension; Losartan; Prodrugs; Stroke
PubMed: 16029066
DOI: 10.2165/00003088-200544080-00003 -
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 -
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 -
Revista de Medicina de La Universidad... 1997
Review
Topics: Abnormalities, Drug-Induced; Adult; Aged; Angiotensin II; Antihypertensive Agents; Clinical Trials as Topic; Drug Interactions; Female; Hemodynamics; Humans; Hypertension; Inactivation, Metabolic; Infant, Newborn; Kidney; Losartan; Male; Myocardial Contraction; Natriuresis; Pregnancy; Safety
PubMed: 10420926
DOI: No ID Found -
Journal of Clinical Gastroenterology 2002Losartan, an angiotensin II receptor antagonist, is widely used for the treatment of hypertension. Clinical experience with this drug has demonstrated that it is safe.... (Review)
Review
Losartan, an angiotensin II receptor antagonist, is widely used for the treatment of hypertension. Clinical experience with this drug has demonstrated that it is safe. Losartan-induced hepatic toxicity is extremely rare. We report a case of severe hepatic toxicity and fibrosis caused by losartan use, and we review four previously reported cases. Drug-induced hepatic injury may be seen during the treatment of hypertension by losartan and the clinician should be aware of this toxicity, especially during the initial phase of treatment.
Topics: Antihypertensive Agents; Biopsy; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Liver Cirrhosis; Losartan; Middle Aged
PubMed: 11960076
DOI: 10.1097/00004836-200205000-00022 -
Molecules (Basel, Switzerland) Apr 2022Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic...
Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) could improve its pharmacological profile. Thus, its molecular interactions are studied using a combination of Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR) and Molecular Dynamics (MD). First, its complexation is shown through Differential Scanning Calorimetry as lyophilization provided distinct thermal properties in comparison to the mixture. The complexation is further proved by utilizing the chemical shift changes in the complexation and T1 values. Furthermore, the reversible favorable complexation was shown by MD calculations. Such physical chemical properties provide evidence that this formulation must be further explored through biological experiments.
Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antihypertensive Agents; Calorimetry, Differential Scanning; Freeze Drying; Humans; Hypromellose Derivatives; Losartan; Solubility
PubMed: 35458617
DOI: 10.3390/molecules27082421 -
Biomedicine & Pharmacotherapy =... May 2022The genesis and development of renal fibrosis involve a variety of pathways closely related to inflammation, cytokines, oxidative stress and metabolic abnormalities....
The genesis and development of renal fibrosis involve a variety of pathways closely related to inflammation, cytokines, oxidative stress and metabolic abnormalities. Renal fibrosis is the result of a complex combination of a variety of lesions. Epithelial-mesenchymal transdifferentiation (EMT) of renal tubular epithelial cells is considered the key to renal fibrosis. Losartan is a typical Angiotensin II (ANG II) receptor antagonist and relaxes blood vessels. In this study, we investigated the effects of losartan on Unilateral Ureteral Obstruction (UUO) model mice by studying the changes in the TGF-β/Smad and metabolomics. Male C57BL/6 J mice were intervened with the UUO model and given losartan (10, 20, 30 mg/kg/d) for 28 consecutive days. The results showed that losartan could reduce UUO-induced abnormal serum metabolic spectrum and renal function. It could also improve renal tubular-interstitial injury and fibrosis by reducing tubulointerstitial dilation and collagen deposition. In addition, losartan promoted the expression of Smurf2 and Smurf1, i.e., Smad7 and E3 ubiquitin-linked enzymes, in the nucleus to degrade the type I receptor of TGF-β1 (TβR-I) and P-Smad2/3 to inhibit renal tubular epithelial cells EMT. In summary, these findings indicated that losartan could regulate the TGF-β/Smad and metabolic pathway in UUO model mice through ubiquitination to reduce renal fibrosis.
Topics: Animals; Fibrosis; Kidney; Kidney Diseases; Losartan; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ureteral Obstruction
PubMed: 36068784
DOI: 10.1016/j.biopha.2022.112931 -
Science Translational Medicine Jul 2021Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME)...
Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) increasing oxygen delivery and enhancing efficacy of radiation therapy. In preparation to translate these exciting findings into the clinic, we used patient samples and data and demonstrated that IL-6/STAT3 signaling inversely associated with hearing function, that elevated production of tumor-derived IL-6 was associated with reduced viability of cochlear sensory cells and neurons in ex vivo organotypic cochlear cultures, and that patients receiving angiotensin receptor blockers have no progression in VS-induced hearing loss compared with patients on other or no antihypertensives based on a retrospective analysis of patients with VS and hypertension. Our study provides the rationale and critical data for a prospective clinical trial of losartan in patients with VS.
Topics: Animals; Hearing Loss; Humans; Losartan; Mice; Neurilemmoma; Neurofibromatosis 2; Prospective Studies; Retrospective Studies; Rodentia; Treatment Outcome; Tumor Microenvironment
PubMed: 34261799
DOI: 10.1126/scitranslmed.abd4816 -
Expert Review of Cardiovascular Therapy Jul 2004Diabetic nephropathy has become the single most important cause of end-stage renal disease in the USA, Europe and Japan. The earliest marker of incipient diabetic... (Review)
Review
Diabetic nephropathy has become the single most important cause of end-stage renal disease in the USA, Europe and Japan. The earliest marker of incipient diabetic nephropathy is the transition of normoalbuminuria to microalbuminuria at an albumin excretion rate of 20 microg/min. Human studies in patients both with and without diabetic kidney diseases have shown that the severity of baseline proteinuria is an important predictor of the rate of loss of renal function. Moreover, the reduction in protein excretion rate when patients with nephropathies are being treated with antihypertensive agents predicts the efficacy of subsequent renoprotection. Experimental and clinical observations provide the rationale for targeting the renin-angiotensin system as a renoprotective approach in diabetic and nondiabetic proteinuric nephropathies. Losartan (Cozaar, Merck Sharpe and Dohme) is a potent, orally active and highly specific angiotensin-type 1 receptor blocker. In addition to its antihypertensive efficacy, losartan decreases the left ventricular mass index in patients with hypertension, left ventricular end-diastolic and end-systolic volume in subjects with heart failure and prevents cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction. Short-term studies in Type 1 diabetic patients with overt nephropathy have demonstrated that losartan and angiotensin-converting enzyme inhibitors have similar beneficial effects on albumin excretion rate, blood pressure and renal hemodynamics. Losartan also lowered albumin excretion rate in microalbuminuric patients with Type 2 diabetes mellitus. Moreover, the large multicenter Reduction of End points in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial has shown that blockade of angiotensin-type 1 receptor with losartan is superior to conventional antihypertensive therapy in slowing the progression of overt Type 2 diabetic nephropathy. Together, data from clinical trials demonstrate the beneficial effect of angiotensin-type 1 receptor blockers, including losartan, in the primary and secondary prevention of renal disease progression in diabetic patients. Nevertheless, it can be expected that the positive results achieved so far with this class of drugs may be further implemented by including angiotensin-type 1 receptor antagonists as a part of the multidrug approach that may hold more promise for the future of renoprotection in diabetic patients with chronic nephropathy.
Topics: Angiotensin II Type 1 Receptor Blockers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Kidney Failure, Chronic; Losartan
PubMed: 15225108
DOI: 10.1586/14779072.2.4.473