-
Hypertension (Dallas, Tex. : 1979) Dec 2019Losartan was the ninth most prescribed drug in the United States in 2016, and several other angiotensin-II receptor blockers (ARBs) are widely prescribed. Since July... (Review)
Review
Losartan was the ninth most prescribed drug in the United States in 2016, and several other angiotensin-II receptor blockers (ARBs) are widely prescribed. Since July 2018, >2 dozen specific ARB products have been recalled owing to the presence of potentially carcinogenic nitrosamine impurities in selected lots. As is the case with all U.S. drug recalls, the ARB recalls have been voluntary on the part of the companies involved. In April 2019, the Food and Drug Administration categorized marketed ARB products with respect to nitrosamine impurities: (1) not present, (2) to be determined with no prior lots removed from the market (TBD), or (3) to be determined in the context of prior lots having been removed from the market (TBD*). The data were structured as hundreds of rows of products. Owing to the complexity of these data, more than a year into the recalls, it remains difficult for clinicians to understand which ARB products are free of impurities.
Topics: Angiotensin Receptor Antagonists; Antihypertensive Agents; Carcinogens; Drug Recalls; Drug Utilization; Female; Humans; Hypertension; Losartan; Male; United States; United States Food and Drug Administration
PubMed: 31630573
DOI: 10.1161/HYPERTENSIONAHA.119.13955 -
BMJ Open Apr 2023To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first...
OBJECTIVES
To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first Angiotensin-Receptor-Blocker (ARB) (valsartan) was recalled.
DESIGN
Retrospective cohort study.
SETTING
USA, Canadian administrative healthcare data, Danish National Prescription Registry and UK primary care electronic health records.
PARTICIPANTS
Patients aged 18 years and older between January 2014 and December 2020.
INTERVENTION
Valsartan, losartan and irbesartan.
MAIN OUTCOME
Monthly percentages of individual ARB episodes, new users and switches to another ARB, ACE inhibitors (ACEI) or calcium channel blockers containing products.
RESULTS
We identified 10.8, 3.2, 1.8 and 1.2 million ARB users in the USA, UK, Canada and Denmark, respectively. Overall proportions of valsartan, losartan and irbesartan use were 18.4%, 67.9% and 5.2% in the USA; 3.1%, 48.3% and 10.2% in the UK, 16.3%, 11.4% and 18.3% in Canada, 1%, 93.5% and 0.6% in Denmark. In July 2018, we observed an immediate steep decline in the proportion of valsartan use in the USA and Canada. A similar trend was observed in Denmark; however, the decline was only minimal. We observed no change in trends of ARB use in the UK. Accompanying the valsartan decline was an increase in switching to other ARBs in the USA, Canada and Denmark. There was a small increase in switching to ACEI relative to the valsartan-to-other-ARBs switch. We also observed increased switching from other affected ARBs, losartan and irbesartan, to other ARBs throughout 2019, in the USA and Canada, although the usage trends in the USA remained unchanged.
CONCLUSION
The first recall notice for valsartan resulted in substantial decline in usage due to increased switching to other ARBs. Subsequent notices for losartan and irbesartan were also associated with increased switching around the time of the recall, however, overall usage trends remained unchanged.
Topics: Humans; Losartan; Irbesartan; Valsartan; Angiotensin Receptor Antagonists; Retrospective Studies; Cohort Studies; Hypertension; Tetrazoles; Biphenyl Compounds; Angiotensin-Converting Enzyme Inhibitors; Canada; Denmark; United Kingdom
PubMed: 37068898
DOI: 10.1136/bmjopen-2022-070985 -
Journal of Cardiology Jul 2023Serum uric acid (SUA) is activated in catabolic, hypoxic, and inflammatory conditions characteristic of heart failure (HF) and is a source of reactive oxygen species.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Serum uric acid (SUA) is activated in catabolic, hypoxic, and inflammatory conditions characteristic of heart failure (HF) and is a source of reactive oxygen species. Losartan is unique among other angiotensin receptor blockers in reducing SUA.
OBJECTIVES
To study the patient characteristics and outcome associations by SUA levels, as well as the effect of high- vs. low-dose losartan on SUA levels in HF.
METHODS
HEAAL was a double-blind trial, comparing the effect of two doses of losartan 150 (high dose) vs. 50 (low dose) mg/day among 3834 patients with symptomatic HF, a left ventricular ejection fraction≤40 %, and known intolerance to angiotensin-converting enzyme inhibitors. In the present study, we studied the associations of SUA with outcomes and the effect of high- vs. low-dose losartan on SUA levels, incident hyperuricemia, and gout.
RESULTS
Patients with higher SUA had more comorbidities, worse renal function, were more symptomatic, used diuretics more frequently, and were 1.5- to 2-fold more likely to experience HF hospitalizations and cardiovascular death. The benefit of high-dose losartan to improve HF outcomes was not influenced by baseline SUA levels (interaction p > 0.1). Compared with low-dose, high-dose losartan reduced SUA by -0.27 (-0.34 to -0.21) mg/dL, p < 0.001. The incidence of hyperuricemia was reduced with high-dose losartan, but the incidence of gout was not.
CONCLUSIONS
In HEAAL, hyperuricemia was associated with worse outcomes. High-dose losartan reduced SUA and hyperuricemia more than low-dose and the cardiovascular benefits of high-dose losartan were not modified by SUA levels.
Topics: Humans; Losartan; Uric Acid; Hyperuricemia; Stroke Volume; Ventricular Function, Left; Heart Failure
PubMed: 37030532
DOI: 10.1016/j.jjcc.2023.04.005 -
Pediatric Nephrology (Berlin, Germany) Oct 2021Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and enalapril had comparable effects on proteinuria in children.
METHODS
We conducted a post hoc analysis of results from a prospective trial in which the proteinuria-reducing effects of losartan and enalapril were compared. We have now evaluated (a) the effects of these medications on SUA in 248 children with proteinuria and (b) the correlation between changes in SUA and eGFR.
RESULTS
SUA levels after 36 months were found to be increased when compared to baseline in both losartan and enalapril groups. The mean change in SUA from baseline was significantly different at 12 months between 23 hypertensive patients randomised to losartan (3.69% decrease [95% CI 11.31%, 3.93%]) and 24 randomised to enalapril (12.57% increase [95% CI 3.72%, 21.41%]), p = 0.007. This significant difference remained after 24, 30 and 36 months but was observed in the entire group of 248 patients only at 12 months. There was a statistically significant negative correlation between changes in SUA and changes in eGFR at each time point over 36 months.
CONCLUSIONS
Losartan may have long-term beneficial effects on SUA and eGFR in children with proteinuria.
Topics: Adult; Antihypertensive Agents; Child; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Losartan; Prospective Studies; Proteinuria; Uric Acid
PubMed: 33881639
DOI: 10.1007/s00467-021-05045-4 -
Journal of Clinical Hypertension... Oct 2023Serum urate is a risk factor for hypertension and gout. The DASH diet and losartan independently lower blood pressure (BP); however, their effects on serum urate are... (Randomized Controlled Trial)
Randomized Controlled Trial
Serum urate is a risk factor for hypertension and gout. The DASH diet and losartan independently lower blood pressure (BP); however, their effects on serum urate are understudied. We performed a post-hoc analysis of the DASH-losartan trial, which randomized participants with hypertension in parallel fashion to the DASH diet or a standard American diet (control) and in crossover fashion to 4-week losartan or placebo. Serum urate was measured at baseline and after each 4-week period. Diets were designed to maintain weight constant. We examined the effects of DASH (vs control) and/or losartan (vs placebo) on serum urate, overall and among those with baseline serum urate ≥6 mg/dL, using generalized estimating equations. Of 55 participants (mean age 52 years, 58% women, 64% Black), mean (±SD) baseline ambulatory SBP/DBP was 146±12/91±9 and mean (±SD) serum urate was 5.2±1.2 mg/dL. The DASH diet did not significantly reduce urate levels overall (mean difference -0.05 mg/dL; 95%CI: -0.39, 0.28), but did decrease levels among participants with baseline hyperuricemia (-0.33 mg/dL; 95%CI: -0.87, 0.21; P-interaction=0.007 across hyperuricemia groups). Losartan significantly decreased serum urate (-0.23 mg/dL; 95%CI: -0.40, -0.05) with greater effects on serum urate among adults <60 years old versus adults ≥60 years old (-0.33 mg/dL vs 0.16 mg/dL, P interaction = 0.003). In summary, the DASH diet significantly decreased serum urate among participants with higher urate at baseline, while losartan significantly reduced serum urate, especially among younger adults. Future research should examine the effects of these interventions in patients with hyperuricemia or gout.
Topics: Humans; Adult; Female; Middle Aged; Male; Hypertension; Losartan; Uric Acid; Hyperuricemia; Dietary Approaches To Stop Hypertension; Gout
PubMed: 37695134
DOI: 10.1111/jch.14721 -
Annals of Translational Medicine Nov 2022Diffuse pulmonary vein stenosis (PVS) is an intractable congenital heart disease for which the underlying mechanism remains unclear. In this study, we investigated the...
BACKGROUND
Diffuse pulmonary vein stenosis (PVS) is an intractable congenital heart disease for which the underlying mechanism remains unclear. In this study, we investigated the effect of losartan and the role of the Hippo pathway in PVS.
METHODS
A total of 19 neonatal piglets were divided into 3 groups: a sham group (n=7), a banded group (n=6) with the left upper pulmonary vein and common trunk of both lower pulmonary veins banded, and a losartan group (n=6) with losartan treatment (1 mg/kg/d) after the banding operation. After 8 weeks, the piglets underwent hemodynamic measurement and harvesting. The upstream pulmonary veins were collected for histological staining and molecular biological analysis. Losartan and/or angiotensin II (stepwise concentrations from 0.1 to 100 µmol/L) were added to a human umbilical vein endothelial cell culture to investigate the potential mechanism .
RESULTS
The modified model demonstrated the main characteristics of patients with PVS, including pulmonary hypertension and intimal hyperplasia in the upstream veins. Upregulation of yes-associated protein (YAP) and angiotensin II type 1 receptor was observed in the neointima (P<0.01). Losartan treatment improved the pathological changes in piglets and decreased YAP expression in the neointima (P<0.01). In vitro, losartan suppressed angiotensin II-induced cell proliferation by inhibiting dephosphorylation and nuclear translocation of YAP in human umbilical vein endothelial cells (P<0.05).
CONCLUSIONS
Losartan treatment ameliorates intimal hyperplasia and inhibits YAP activation. The activation of the Hippo-YAP pathway is involved in the vasculopathy of progressive PVS. These findings may contribute to the development of new approaches for treating PVS.
PubMed: 36467357
DOI: 10.21037/atm-22-2621 -
Journal of Pharmacy & Pharmaceutical... 2021SARS-CoV-2 infection is associated with substantial mortality and high morbidity. This study tested the effect of angiotensin II type I receptor blocker, losartan, on...
PURPOSE
SARS-CoV-2 infection is associated with substantial mortality and high morbidity. This study tested the effect of angiotensin II type I receptor blocker, losartan, on SARS-CoV-2 replication and inhibition of the papain-like protease of the virus.
METHODS
The dose-dependent inhibitory effect of losartan, in concentrations from 1μM to 100μM as determined by quantitative cell analysis combining fluorescence microscopy, image processing, and cellular measurements (Cellomics analysis) on SARS-CoV-2 replication was investigated in Vero E6 cells. The impact of losartan on deubiquitination and deISGylation of SARS-CoV-2 papain-like protease (PLpro) were also evaluated. Results: Losartan reduced PLpro cleavage of tetraUbiquitin to diUbiquitin. It was less effective in inhibiting PLpro's cleavage of ISG15-AMC than Ubiquitin-AMC. To determine if losartan inhibited SARS-CoV-2 replication, losartan treatment of SARS-CoV-2 infected Vero E6 was examined. Losartan treatment one hour prior to SARS-CoV-2 infection reduced levels of SARS-CoV-2 nuclear protein, an indicator of virus replication, by 80% and treatment one-hour post-infection decreased viral replication by 70%.
CONCLUSION
Losartan was not an effective inhibitor of deubiquitinase or deISGylase activity of the PLpro but affected the SARS-CoV-2 replication of Vero E6 cells in vitro. As losartan has a favorable safety profile and is currently available it has features necessary for efficacious drug repurposing and treatment of COVID-19.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antiviral Agents; Chlorocebus aethiops; Computational Biology; Coronavirus Papain-Like Proteases; Deubiquitinating Enzymes; Losartan; SARS-CoV-2; Ubiquitin; Vero Cells; Virus Replication; COVID-19 Drug Treatment
PubMed: 34319871
DOI: 10.18433/jpps31931 -
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 -
Chemical Science Aug 2022The development of chemoselective C(sp)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective,...
The development of chemoselective C(sp)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective, iridium(iii)-bipyridonate-catalyzed hydrogen(H)/deuterium(D) isotope exchange of alcohols using deuterium oxide (DO) as the primary deuterium source. This method enables the direct, chemoselective deuteration of primary and secondary alcohols under basic or neutral conditions without being affected by coordinative functional groups such as imidazole and tetrazole. Successful substrates for deuterium labelling include the pharmaceuticals losartan potassium, rapidosept, guaifenesin, and diprophylline. The deuterated losartan potassium shows higher stability towards the metabolism by CYP2C9 than the protiated analogue. Kinetic and DFT studies indicate that the direct deuteration proceeds through dehydrogenation of alcohol to the carbonyl intermediate, conversion of [Ir-H] to [Ir-D] with DO, and deuteration of the carbonyl intermediate to give the α-deuterated product.
PubMed: 35975159
DOI: 10.1039/d2sc01805e -
Molecules (Basel, Switzerland) Apr 2022Axitinib is one of the most potent inhibitors of the vascular endothelial growth factor (VEGF) receptor and shows strong antitumor activity toward various malignant...
Axitinib is one of the most potent inhibitors of the vascular endothelial growth factor (VEGF) receptor and shows strong antitumor activity toward various malignant tumors. However, its severe side effects affect the quality of life and prognosis of patients. Losartan, which functions as a typical angiotensin receptor blocker, controls the average arterial pressure of patients with essential hypertension and protects against hypertension-related secondary diseases, including proteinuria and cardiovascular injury. To explore the effects of losartan on side effects caused by axitinib and its antitumor activity, several animal experiments were conducted. This study first analyzed and explored the effect of losartan on the amelioration of side effects in Wistar rats caused by axitinib. The results showed that the systolic blood pressure of Wistar rats was significantly increased by about 30 mmHg in 7 days of axitinib treatment, while the combination of losartan significantly reduced the blood pressure rise caused by axitinib. The Miles experimental model and mouse xenograft tumor model were further used to evaluate the effect of losartan on the antitumor effect of axitinib. The result clearly demonstrated that losartan has no significant influence on axitinib-related low vascular permeability and antitumor activity. In summary, our results showed that the combination of axitinib and losartan significantly reduced the side effects and maintained the antitumor effects of axitinib. This study provides information for overcoming VEGF receptor inhibitor-related side effects.
Topics: Angiogenesis Inhibitors; Animals; Axitinib; Blood Pressure; Humans; Hypertension; Losartan; Mice; Quality of Life; Rats; Rats, Wistar; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A
PubMed: 35566115
DOI: 10.3390/molecules27092764