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Levocetirizine and montelukast in the COVID-19 treatment paradigm.
May, BC, Gallivan, KH
International immunopharmacology. 2022;:108412
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Abstract
Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of 'Long COVID,' thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March - November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed. Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.
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High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.
Omote, K, Yokota, I, Nagai, T, Sakuma, I, Nakagawa, Y, Kamiya, K, Iwata, H, Miyauchi, K, Ozaki, Y, Hibi, K, et al
Journal of atherosclerosis and thrombosis. 2022;(1):50-68
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Abstract
AIM: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) <120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.
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The Efficacy and Safety of Anlotinib in Neoadjuvant Treatment of Locally Advanced Thyroid Cancer: A Single-Arm Phase II Clinical Trial.
Huang, NS, Wei, WJ, Xiang, J, Chen, JY, Guan, Q, Lu, ZW, Ma, B, Sun, GH, Wang, YL, Ji, QH, et al
Thyroid : official journal of the American Thyroid Association. 2021;(12):1808-1813
Abstract
Background: Surgery is the primary treatment for locally advanced thyroid cancer. For some cases, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. Anlotinib is a multitarget tyrosine kinase inhibitor, which demonstrated antitumor activity in radioiodine-refractory differentiated thyroid cancer and medullary thyroid cancer. We aimed to evaluate the efficacy and safety of anlotinib in locally advanced thyroid cancer in the neoadjuvant setting. Methods: This single-arm phase II study investigated the efficacy and safety of anlotinib (12 mg orally daily, 2 weeks on/1 week off) for 2-6 cycles in patients with locally advanced thyroid cancer in the neoadjuvant setting. The key eligibility criteria included age 14-80 years old; locally advanced thyroid cancer that would benefit from surgery, and at least one measurable lesion. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were enrolled and received an average of 3.5 cycles of anlotinib treatment. The ORR of anlotinib was 76.9% (95% confidence interval: 46.2-95.0%). The R0/R1 resection rate in the intent-to-treat population was 61.5% and in the per-protocol population was 72.7%. The median time to response was 61.5 days, and the disease control rate at 18 weeks was 92.3%. No patients had blood transfusion or tracheotomy. Most adverse events (AEs) were grade 1 or 2 and tended to discontinue when neoadjuvant treatment ceased. Common AEs of all grades were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), thyrotropin increase (53.8%), cholesterol elevation (53.8%), and hand-foot syndrome (38.5%). Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment and the majority of patients achieved R0/R1 resection. AEs were consistent with the known anlotinib AE profile. These results suggest that anlotinib neoadjuvant treatment represents a new option for locally advanced thyroid cancer. Clinical Trial Registration Number: NCT04309136.
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The leukotriene receptor antagonist montelukast in the treatment of non-alcoholic steatohepatitis: A proof-of-concept, randomized, double-blind, placebo-controlled trial.
Abdallah, MS, Eldeen, AH, Tantawy, SS, Mostafa, TM
European journal of pharmacology. 2021;:174295
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with fat accumulation in the liver which can progress into non-alcoholic steatohepatitis (NASH). There is no specific treatment strategy for NASH. In this context, this study aimed at evaluating the efficacy and safety of montelukast in the treatment of patients with NASH. In this randomized double-blind placebo-controlled study, 52 overweight/obese patients with NASH were randomized into group 1 (n = 26) which received montelukast 10 mg tablets once daily and group 2 (n = 26) which received placebo tablets once daily for 12 weeks. The fibro-scan was used to assess liver stiffness as a primary outcome at baseline and 12 weeks post-treatment. Furthermore, patients were assessed for biochemical analysis of liver aminotransferases, metabolic parameters, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), liver fibrosis biomarkers including hyaluronic acid (HA) and transforming growth factor beta-1 (TGF-β1). Beck depression inventory questionnaire was used to report depressive symptoms. Data were statistically analyzed by paired and unpaired student's t-test, and Chi-square test. A total number of 44 patients completed the study. The two groups were statistically similar at baseline. After treatment and as compared to baseline data and placebo, montelukast showed a statistically significant improvement in liver stiffness, liver enzymes, metabolic parameters (except LDL-C), TNF-α, 8-OHdG, and liver fibrosis biomarkers (HA and TGF-β1). Furthermore, montelukast was well tolerated and didn't provoke depression. In this proof-of-concept study, treatment with montelukast may represent a promising therapeutic strategy for patients with non-alcoholic steatohepatitis secondary to its efficacy and safety. Clinicaltrial.gov ID: NCT04080947.
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Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.
Finn, RS, Kudo, M, Cheng, AL, Wyrwicz, L, Ngan, RKC, Blanc, JF, Baron, AD, Vogel, A, Ikeda, M, Piscaglia, F, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(17):4848-4858
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Abstract
PURPOSE In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. EXPERIMENTAL DESIGN Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. RESULTS Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; P = 0.0253). CONCLUSIONS Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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Montelukast's ability to fight COVID-19 infection.
Bozek, A, Winterstein, J
The Journal of asthma : official journal of the Association for the Care of Asthma. 2021;(10):1348-1349
Abstract
Montelukast can be effective in the treatment of SARS-CoV-2 infection.
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Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy.
Abe, M, Ozaki, Y, Takahashi, H, Ishii, M, Masunaga, N, Ismail, TF, Iimuro, S, Fujita, R, Iwata, H, Sakuma, I, et al
American heart journal. 2021;:89-100
Abstract
BACKGROUND It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction. METHODS The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model. RESULTS The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30). CONCLUSION Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.
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Forty-eight weeks of statin therapy for type 2 diabetes mellitus patients with lower extremity atherosclerotic disease: Comparison of the effects of pitavastatin and atorvastatin on lower femoral total plaque areas.
Zhou, X, Wu, L, Chen, Y, Xiao, H, Huang, X, Li, Y, Xiao, H, Cao, X
Journal of diabetes investigation. 2021;(7):1278-1286
Abstract
AIMS/INTRODUCTION Type 2 diabetes mellitus is correlated with systemic atherosclerosis. Statin therapies have been proved to reduce low-density lipoprotein cholesterol (LDL-C) level, protecting type 2 diabetes mellitus patients from cardiovascular events. Recently, more interest has been focused on the regression of lower extremity atherosclerotic disease (LEAD) for the potential prevention of amputation. However, the effects of pitavastatin and atorvastatin on LEAD in type 2 diabetes mellitus patients have not been directly compared. MATERIALS AND METHODS This study compared the effects of pitavastatin and atorvastatin on femoral total plaque areas (FTPA), and lipids and glucose metabolism in type 2 diabetes mellitus patients with elevated LDL-C level and LEAD. Type 2 diabetes mellitus patients with LDL-C level >2.6 mmol/L and LEAD were randomly assigned to receive either pitavastatin 2 mg/day or atorvastatin 10 mg/day for 48 weeks. FTPA were measured at baseline and the end of the study. Levels of glucose and lipids profile were measured periodically. The efficacy was evaluated in 63 patients. RESULTS The percentage change in FTPA measurements was similar between the pitavastatin group and atorvastatin group (-17.79 ± 21.27% vs -14.34 ± 16.33%), as were the changes in LDL-C (-44.0 ± 18.0% vs -40.3 ± 18.2%) and triglyceride (17.6 ± 20.0% vs 16.2 ± 17.0%). However, the level of high-density lipoprotein cholesterol was significantly higher in the pitavastatin group compared with the atorvastatin group after 48 weeks of treatment (12.9 ± 10.3% vs 7.2 ± 11.7%, P < 0.05). There were no significant differences between groups for the measurements of glucose metabolism. CONCLUSION In type 2 diabetes mellitus patients with elevated LDL-C level and LEAD, 48 weeks of treatment with either pitavastatin or atorvastatin was associated with significant regression of FTPA. Pitavastatin treatment resulted in a significantly higher high-density lipoprotein cholesterol level compared with atorvastatin treatment.
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LTA4H rs2660845 association with montelukast response in early and late-onset asthma.
Maroteau, C, Espuela-Ortiz, A, Herrera-Luis, E, Srinivasan, S, Carr, F, Tavendale, R, Wilson, K, Hernandez-Pacheco, N, Chalmers, JD, Turner, S, et al
PloS one. 2021;(9):e0257396
Abstract
Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04-8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61-4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.
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[18F]-FDG-PET/CT Correlates With the Response of Radiorefractory Thyroid Cancer to Lenvatinib and Patient Survival.
Valerio, L, Guidoccio, F, Giani, C, Tardelli, E, Puccini, G, Puleo, L, Minaldi, E, Boni, G, Elisei, R, Volterrani, D
The Journal of clinical endocrinology and metabolism. 2021;(8):2355-2366
Abstract
CONTEXT 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography ([18F]-FDG-PET/CT)-positive metastatic lesions in radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) have a poor prognosis and lenvatinib represents the best therapy. OBJECTIVE We investigated the role of [18F]-FDG-PET/CT in the evaluation of metabolic response and prediction of the outcome of RAI-R DTC patients treated with lenvatinib. METHODS Patients (n = 33) with progressive metastatic RAI-R DTC who were treated with lenvatinib were investigated at baseline and during follow-up with biochemical (thyroglobulin and thyroglobulin antibodies), morphological (whole-body CT scan) and metabolic ([18F]-FDG-PET/CT) evaluation. RESULTS Nineteen (57.6%) patients showed the greatest metabolic response at the first [18F]-FDG-PET/CT scan, performed after 4 weeks of lenvatinib, while 5/33 (15.1%) patients had this response later. Moreover, 66.7% of patients had both a metabolic response at the first [18F]-FDG-PET/CT scan and a morphological response at the first CT scan. We observed a correlation between the metabolic response at [18F]-FDG-PET/CT scan performed after 4 weeks of treatment and the biochemical response at the same time in 60.6% of patients. The median overall survival (OS) was significantly longer in patients with either a metabolic response at last [18F]-FDG-PET/CT (40.00 vs 8.98 months) or a morphological response at last CT scan (37.22 vs 9.53 months) than in those without response. Moreover, the OS was longer in patients with a metabolic response at [18F]-FDG-PET/CT performed after 4 weeks of treatment (36.53 vs 11.28 months). CONCLUSIONS Our data show that [18F]-FDG-PET/CT can early predict the response to lenvatinib and correlates with the OS of RAI-R DTC patients treated with this drug.