Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Efficacy and safety of topical rosuvastatin & melatonin vs. placebo in patients with mild to moderate plaque psoriasis: A preliminary randomized double-blinded clinical trial.

BACKGROUND: Considering the pathogenesis of psoriasis and also the anti-oxidant, immunomodulatory, and anti-inflammatory properties of rosuvastatin and melatonin, the current clinical trial aimed to evaluate the efficacy of topical rosuvastatin and melatonin in patients with mild to moderate psoriasis. METHODS: The current randomized placebo-controlled clinical trial was conducted using a 3-arm parallel group included 77 adult patients (≥18 years old) with mild to moderate plaque psoriasis. Patients were randomized into a 1:1:1 ratio to one of three groups to receive one of the three interventions: melatonin cream, 5.0% (w/w), rosuvastatin cream, 5.0% (w/w), or placebo cream with a similar transparent appearance twice a day for 12 weeks. The primary outcome was severity of the disease using Psoriasis Area Severity Index (PASI). The secondary outcomes included the Dermatological Sum Score (DSS) to assess the erythema, scaling, and plaque elevation and the Dermatology Life Quality Index (DLQI). Photographs of the lesions were also taken at the baseline and at different periodic intervals thereafter. RESULTS: Among 77 randomized patients, 52 (mean (SD) age, 40.67 (10.85) years; 22 (42.30%) men) completed the study. A significant reduction of 45% (mean (SD) of 2.67 (0.98) to 1.74 (1.12)) and 70% (mean (SD) of 2.67 (0.98) to 1.31 (1.13)) in PASI score, and 46% (mean (SD) of 2.91(1.85) to 1.57 (1.11)) and 77% (mean (SD) of 2.91 (1.85) to 0.87 (0.67)) in DSS score on days 30 and 60 with rosuvastatin cream, 5% w/w (P < 0.001) compared with baseline was observed, respectively. Also a significant decrease of 35% (mean (SD) of 2.67 (0.98) to 1.74 (1.12)) and 51% (mean (SD) of 2.67 (0.98) to 1.31 (1.13)) in PASI score, and 40% (mean (SD) of 5.00 (1.58) to 3.00 (1.76))and 61% (mean (SD) of 5.00 (1.58) to 1.92 (1.71)) in DSS score on days 30 and 60 with melatonin cream, 5% w/w (P < 0.001) compared with baseline were observed, respectively. In each of the melatonin or rosuvastatin groups, DLQI improved significantly on days 30 (P < 0.0001) and 60 (P < 0.001) while the changes in the control group were not significant. CONCLUSION: The results of this clinical trial demonstrated that topical melatonin and rosuvastatin diminished the severity of mild to moderate plaque psoriasis with a satisfactory safety profile. Future clinical trials should assess both the long-term efficacy and safety of melatonin and rosuvastatin creams in larger study populations.

Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial.

Objectives: Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to ß-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers. Methods: In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication. Results: The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Treg) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339). Conclusions: We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.

Use of Statin and Target Low-density lipoprotein cholesterol attainment among post-ST elevation myocardial infarction patients in Shahid Gangalal National Heart Centre, Kathmandu, Nepal.

BACKGROUND: and objective: Lipid-lowering is an important intervention to reduce cardiovascular morbidity and mortality in the secondary prevention of STEMI. There is no study to analyze the use of statin and LDL-C treatment target attainment among STEMI patients in Nepal. This study aims to assess the use of statin and LDL-C treatment target attainment among STEMI patients. METHODS: It was a prospective observational single-center study conducted at the Shahid Gangalal National Heart Centre, Kathmandu, Nepal outpatient department. An outpatient department-based survey was conducted among STEMI patients who have lipid profile levels at the time of admission for STEMI and after 4-13 weeks of the index event. Lipid profile levels, diagnosis, and risk factors were collected during the outpatient follow-up. RESULTS: Our study included 280 post-STEMI patients; the mean age was 57.5±11.7 years with the majority being male. The mean duration of follow-up was 6.7 ± 0.1 weeks. Rosuvastatin was the preferred statin with 82.1%. The most common dose of statin used was Rosuvastatin 20mg (70%), followed by Atorvastatin 40mg (12.5%). LDL-C levels of <1.4mmol/l were achieved in 44.6% of cases and LDL levels of <1.8mmol/l in 71.8% of cases. In 36.8% of the study population, there was a greater than 50% decline in LDL-C levels. Diabetic patients (55.1% and 83.1%) only have the significant achievement of LDL goal of both <1.4mmol/l and <1.8mmol/l respectively, when compared to those without diabetes (44.9% and 16.9%). CONCLUSIONS: Most of the post-STEMI patients were treated with high doses of statins and achieved the target LDL-C levels.

Impacts of ABCG2 loss of function variant (p. Gln141Lys, c.421 C > A, rs2231142) on lipid levels and statin efficiency: a systematic review and meta-analysis.

BACKGROUND: The latest evidence indicates that ATP-binding cassette superfamily G member 2 (ABCG2) is critical in regulating lipid metabolism and mediating statin or cholesterol efflux. This study investigates whether the function variant loss within ABCG2 (rs2231142) impacts lipid levels and statin efficiency. METHODS: PubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until November 18, 2023. RESULTS: Fifteen studies (34,150 individuals) were included in the analysis. The A allele [Glu141Lys amino acid substitution was formed by a transversion from cytosine (C) to adenine (A)] of rs2231142 was linked to lower levels of high-density lipoprotein cholesterol (HDL-C), and higher levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). In addition, the A allele of rs2231142 substantially increased the lipid-lowering efficiency of rosuvastatin in Asian individuals with dyslipidemia. Subgroup analysis indicated that the impacts of rs2231142 on lipid levels and statin response were primarily in Asian individuals. CONCLUSIONS: The ABCG2 rs2231142 loss of function variant significantly impacts lipid levels and statin efficiency. Preventive use of rosuvastatin may prevent the onset of coronary artery disease (CAD) in Asian individuals with dyslipidemia.

Clinical Analysis and in Vitro Correlation of BCRP-Mediated Drug-Drug Interaction in the Gastrointestinal Tract.

Breast cancer resistance protein (BCRP) is a drug efflux transporter expressed on the epithelial cells of the small intestine and on the lateral membrane of the bile duct in the liver; and is involved in the efflux of substrate drugs into the gastrointestinal lumen and secretion into bile. Recently, the area under the plasma concentration-time curve (AUC) of rosuvastatin (ROS), a BCRP substrate drug, has been reported to be increased by BCRP inhibitors, and BCRP-mediated drug-drug interaction (DDI) has attracted attention. In this study, we performed a ROS uptake study using human colon cancer-derived Caco-2 cells and confirmed that BCRP inhibitors significantly increased the intracellular accumulation of ROS. The correlation between the cell to medium (C/M) ratio of ROS obtained by the in vitro study and the absorption rate constant (ka) ratio obtained by clinical analysis was examined, and a significant positive correlation was observed. Therefore, it is suggested that the in vitro study using Caco-2 cells could be used to quantitatively estimate BCRP-mediated DDI with ROS in the gastrointestinal tract.

Comparative effects of pravastatin and rosuvastatin on carbohydrate metabolism in an experimental diabetic rat model.

Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins on liver enzymes related to carbohydrate metabolism have not been fully studied. Therefore, we aimed to compare the effects of the statin derivatives, pravastatin, and rosuvastatin, on carbohydrate metabolism in an experimental diabetic rat model. Female Wistar albino rats were used and diabetes was induced by intraperitoneal injection of streptozotocin. Thereafter, 10 and 20 mg kg-1 day-1 doses of both pravastatin and rosuvastatin were administered by oral gavage to the diabetic rats for 8 weeks. At the end of the experiment, body masses, the levels of fasting blood glucose, serum insulin, insulin resistance (HOMA-IR), liver glycogen, and liver enzymes related to carbohydrate metabolism were measured. Both doses of pravastatin significantly in creased the body mass in diabetic rats, however, rosuvastatin, especially at the dose of 20 mg kg-1 day-1 reduced the body mass signi ficantly. Pravastatin, especially at a dose of 20 mg kg-1 day-1, caused significant increases in liver glycogen synthase and glucose 6-phosphate dehydrogenase levels but significant decreases in the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase. Hence, pravastatin partially ameliorated the adverse changes in liver enzymes caused by diabetes and, especially at the dose of 20 mg kg-1 day-1, reduced the fasting blood glucose level and increased the liver glycogen content. However, rosuvastatin, especially at the dose of 20 mg kg-1 day-1, significantly reduced the liver glycogen synthase and pyruvate kinase levels, but increased the glycogen phosphorylase level in diabetic rats. Rosuvastatin, 20 mg kg-1 day-1 dose, caused significant decreases in the body mass and the liver glycogen content of diabetic rats. It can be concluded that pravastatin, especially at the dose of 20 mg kg-1 day-1 is more effective in ameliorating the negative effects of diabetes by modulating carbohydrate metabolism.

Medium-intensity statin with ezetimibe versus high-intensity statin in acute ischemic cerebrovascular disease (MESIA): A randomized clinical trial.

BACKGROUND: High-risk stroke patients are recommended to receive high-intensity statin therapy to reduce the risk of stroke recurrence. However, doubling the dosage of statin drugs did not increase the achievement rate of LDL-C target or provide additional clinical benefits, but significantly increased the risk of adverse reactions. Statins and ezetimibe work through different mechanisms and the combined use of statins and ezetimibe significantly improves outcomes with comparable safety profiles. We tested the hypothesis that moderate-intensity statin with ezetimibe may offer advantages over the conventional high-intensity statin regimen in terms of efficacy and safety. METHODS: We conducted a randomized controlled trial. Eligible participants were aged 18 years or older with acute ischemic cerebrovascular disease. We randomly assigned (1:1) participants within the acute phase of ischemic stroke, i.e., within 1 week after the onset of mild ischemic stroke (NIHSS score ≤ 5), within 1 month for severe cases (NIHSS score ≥ 16), and within 2 weeks for the rest, as well as patients with TIA within 1 week of symptom onset, to receive either moderate-intensity statin with ezetimibe (either 10-20 mg atorvastatin calcium tablets plus a 10 mg ezetimibe tablet, or 5-10 mg rosuvastatin calcium tablets once per day plus a 10 mg ezetimibe tablet once per day) or high-intensity statin (40 mg atorvastatin calcium tablets or 20 mg rosuvastatin calcium tablets once per day) for 3 months. Randomization was performed using a random number table method. The primary efficacy outcome was the level and achievement rate of LDL-C after 3 months of treatment, specifically LDL-C ≤ 1.8 mmol/L or a reduction in LDL-C ≥ 50 %. The secondary outcome was the incidence of new stroke or transient ischemic attack (TIA) within 3 months. The safety outcome was liver and renal function tests, and the occurrence of statin-related muscle events within 3 months. FINDINGS: This trial took place between March 15, 2022, and March 7, 2023. Among 382 patients screened, 150 patients were randomly assigned to receive either medium-intensity statins with ezetimibe (n = 75) or high-intensity statins (n = 75). Median age was 60.0 years (IQR 52.75-70.25); 49 (36.6 %) were women and 85 (63.4 %) were men. The target achievement of LDL-C at 3 months occurred in 62 (89.86 %) of 69 patients in the medium-intensity statin with ezetimibe group and 46 (70.77 %) of 65 patients in the high-intensity statin group (P=0.005, OR=0.273, 95 % CI: 0.106, 0.705). The reduction magnitude of LDL-C in moderate-intensity statin with ezetimibe group was significantly higher (-56.540 % vs -47.995 %, P=0.001). Moderate-intensity statin with ezetimibe group showing a trend of a greater reduction in LDL-C absolute value than high-intensity statin group but without statistical significance (-1.77±0.90 vs -1.50±0.89, P=0.077). New AIS or TIA within 3 months, liver and renal function tests, and the occurrence of statin-related muscle events within 3 months were also statistically insignificant. Multivariate logistic regression analysis showed that both gender and lipid-lowering regimen as independent risk factors influencing the rate of LDL-C achievement in individuals diagnosed with acute ischemic cerebrovascular disease, but only lipid-lowering regimen had predictive value. INTERPRETATION: Compared to guideline-recommended high-intensity statin therapy, moderate-intensity statin with ezetimibe further improved the achievement rate of LDL-C in patients with acute ischemic cerebrovascular disease, with a higher reduction magnitude in LDL-C. In terms of safety, there was no significant difference between the two regimens, suggesting that moderate-intensity statin with ezetimibe can also be considered as an initial treatment option for patients with acute ischemic cerebrovascular disease.

Development of a highly sensitive and green first-derivative synchronous fluorescence spectroscopic method for the simultaneous quantification of telmisartan and rosuvastatin: Greenness metric assessment and application to a pharmacokinetic study in rats.

Hypertension and hyperlipidemia frequently coexist and are correlated with elevated cardiovascular adverse outcomes. Fixed dose combination tablets containing antihypertensive and antihyperlipidemic drugs have the potential to improve patient compliance. Telmisartan and rosuvastatin fixed dose combination tablet has been recently formulated. This study provided the first fluorescence spectroscopic method for simultaneously quantifying telmisartan and rosuvastatin in tablet dosage form and plasma. The native fluorescence spectra of telmisartan and rosuvastatin completely overlapped, making direct measurement unachievable. However, through the implementation of synchronous fluorescence measurements of telmisartan and rosuvastatin at a Δλ = 60, distinct narrow bands were observed at 358 nm and 375 nm, respectively. Regrettably, the challenge of overlapping remained unresolved. Nevertheless, by converting these synchronous spectra into first-order spectra, the problem of overlapping was completely resolved. This conversion also allowed for the selective quantification of telmisartan and rosuvastatin at 374 nm and 358 nm, respectively. The validity of this method was confirmed in accordance with ICH guidelines, yielding satisfactory results in terms of the validation characteristics. The method demonstrated linear relationships between the response and the studied drugs concentrations in working range of 50-1000 ng/mL for telmisartan and 100-2000 ng/mL for rosuvastatin. The described methodology was applied for the pharmacokinetic study of telmisartan and rosuvastatin in rat plasma after a single oral dose of 4 mg/kg telmisartan and 50 mg/kg rosuvastatin. Pharmacokinetic analyses revealed a moderate drug-drug interaction between the two drugs, which was not considered to be clinically significant. Moreover, the described method was assessed in terms of sensitivity and environmental sustainability against three previously documented methods. The comparison effectively underscores the supremacy of the proposed technique over the documented techniques.

In-lab synthesized turn-off fluorescence sensor for estimation of Gemigliptin and Rosuvastatin polypill appraised by Spider diagram, AGREE and whiteness metrics.

Gemigliptin-Rosuvastatin single-pill combination is a promising therapeutic tool in the effective control of hyperglycemia and hypercholesterolemia. Organic sensors with high quantum yields have profoundly significant applications in the pharmaceutical industry, such as routine quality control of marketed formulations. Herein, the fluorescence sensor, 2-Morpholino-4,6-dimethyl nicotinonitrile 3, (λex; 226 nm, λem; 406 nm), was synthesized with a fluorescence quantum yield of 56.86% and fully characterized in our laboratory. This sensor showed high efficiency for the determination of Gemigliptin (GEM) and Rosuvastatin (RSV) traces through their stoichiometric interactions and simultaneously fractionated by selective solvation. The interaction between the stated analytes and sensor 3 was a quenching effect. Various experimental parameters and the turn-off mechanism were addressed. The adopted approach fulfilled the ICH validation criteria and showed linear satisfactory ranges, 0.2-2 and 0.1-1 µg/mL for GEM and RSV, respectively with nano-limits of detection less than 30 ng/mL for both analytes. The synthesized sensor has been successfully applied for GEM and RSV co-assessment in their synthetic polypill with excellent % recoveries of 98.83 ± 0.86 and 100.19 ± 0.64, respectively. No statistically significant difference between the results of the proposed and reported spectrophotometric methods in terms of the F- and t-tests. Ecological and whiteness appraisals of the proposed study were conducted via three novel approaches: the Greenness Index via Spider Diagram, the Analytical Greenness Metric, and the Red-Green-Blue 12 model. The aforementioned metrics proved the superiority of the adopted approach over the previously published one regarding eco-friendliness and sustainability. Our devised fluorimetric turn-off sensing method showed high sensitivity, selectivity, feasibility, and rapidity with minimal cost and environmental burden over other sophisticated techniques, making it reliable in quality control labs.

Clinical Evaluation of the Effect of Encorafenib on Bupropion, Rosuvastatin, and Coproporphyrin I and Considerations for Statin Coadministration.

BACKGROUND AND OBJECTIVES: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI. METHODS: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods. RESULTS: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib. CONCLUSION: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.

Increasing the efficiency of hypolipidemic therapy with the combined use of quercetin in patients with non-alcoholic fatty liver disease on the background of the metabolic syndrome.

The article analyzes the results of a set of biochemical indicators in the course of treatment with the combined use of rosuvastatin with quercetin in patients with metabolic syndrome (MS) combined with non-alcoholic fatty liver disease. Changes in blood biochemical parameters have been identified and presented with MS, essential for revealing generalbiological mechanisms development and interrelationship between the components of MS and non-alcoholic fatty liver. The effect of an increase in free cholesterol and triglycerides and activation of freeradical oxidation of lipids followed by theaccumulation of oxidative stress products was noted. In the course of long-term hypolipidemic therapy (90 days), 86 patients with non-alcoholic fatty liver disease on the background of metabolic syndrome were previously divided into 2 groups: a comparison group (45 patients), who weretreated with basic therapy - only rosuvastatin, the main group (41 patients) received quercetin together with rosuvastatin -40 mg 3 times a day, clinical and laboratory-instrumental examinations were carried out. On the 90th day of treatment, positive results in the functional state of the liver and lipid spectrum of the blood wereregistered in all patients. A more significant advantage of the therapeutic combination of rosuvastatin with quercetin was proved. The inclusion of quercetin contributed to reducing the intensity of oxidative stress and enhancing antioxidant protection activity, resultingin a decrease in apoptosis of hepatocytes (cytokeratin-18 level was 1.27 times decreased). The studies have shown the feasibility of combined use of quercetin with rosuvastatin for the prevention of the development and progression of metabolic disorders associated with non-alcoholic fatty liver disease.

Efficacy and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe in patients with dyslipidemia and hypertension: A randomized, double-blind, multicenter, therapeutic confirmatory, phase III clinical trial.

This study aimed to compare and evaluate the efficacy of the blood pressure (BP) control and cholesterol-lowering effects and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe versus rosuvastatin and ezetimibe double therapy or telmisartan single therapy in dyslipidemia patients with hypertension. After a wash-out/therapeutic lifestyle change period of ≥4 weeks, a total of 100 eligible patients were randomized and received one of three treatments for 8 weeks: (1) telmisartan 80 mg/rosuvastatin 20 mg/ezetimibe 10 mg (TRE), (2) rosuvastatin 20 mg/ezetimibe 10 mg (RE), or (3) telmisartan 80 mg (T). The primary endpoint was the efficacy evaluation of TRE by comparing changes in mean sitting systolic blood pressure (msSBP) and mean percentage change in low-density lipoprotein-C (LDL-C) from baseline after 8 weeks of treatment. The least square (LS) mean (SE) changes in msSBP at 8 weeks compared with baseline were -23.02 (3.04) versus -7.18 (3.09) mmHg in the TRE and RE groups, respectively (p < .0001), and -25.80 (2.74) versus -14.92 (2.65) mmHg in the TRE and T groups, respectively (p = .0005). The percentage changes in the mean (SD) LDL-C at 8 weeks compared with baseline were -54.97% (3.49%) versus -0.17% (3.23%) in the TRE and T groups, respectively (p < .0001). No serious adverse events occurred, and no statistically significant differences in the incidence of overall AEs and adverse drug reactions occurred among the three groups. TRE therapy significantly decreased msSBP and LDL-C compared to RE or T therapy with comparable safety and tolerability profiles.

Rosuvastatin as a Supplemental Treatment for the Clinical Symptoms of Nephropathia Epidemica: A Pilot Clinical Study.

Nephropathis epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS), is an acute zoonotic disease endemic in the Republic of Tatarstan. This study aimed to assess the impact of rosuvastatin on the clinical and laboratory results of NE. A total of 61 NE patients and 30 controls were included in this study; 22 NE patients and 7 controls received a daily dose of rosuvastatin (10 mg) for ten consecutive days. Serum samples were collected on days 1, 5, and 10 after admission to the hospital. These samples were analyzed to determine the levels of lipids, cytokines, and kidney toxicity markers. Our findings indicate that rosuvastatin reduced the duration of the second wave of fever and alleviated back pain and headache symptoms. Additionally, low-density lipoprotein cholesterol (LDL-C) serum levels were significantly decreased on days 5 and 10 upon rosuvastatin treatment. Furthermore, rosuvastatin decreased the levels of cytokines in the serum, particularly proinflammatory cytokines IL-1ß and IL-8. NE patients had significantly altered levels of the kidney toxicity markers albumin and osteopontin. The data from our study provide evidence supporting the therapeutic potential of rosuvastatin in NE cases.

Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation.

BACKGROUND: Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown. METHODS: We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery. RESULTS: We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis. CONCLUSIONS: Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG.

Rosuvastatin and diosmetin inhibited the HSP70/TLR4 /NF-κB p65/NLRP3 signaling pathways and switched macrophage to M2 phenotype in a rat model of acute kidney injury induced by cisplatin.

Numerous efforts to manage acute kidney injury (AKI) were unsuccessful because its pathophysiology is still poorly understood. Thus, our research hotspot was to explore the possible renoprotective effects of rosuvastatin (Ros) and diosmetin (D) on macrophage polarization and the role of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signaling in cis-induced AKI and study the activity of D against uropathogenic bacteria. Fifty-four albino male rats were randomized into 9 groups equally: Control, Ros, D20, D40, untreated Cis, and Cis groups cotreated with Ros, D20, D40 and Ros+D40 for 10 days. Our results indicated that Ros and D, in a dose-dependent manner, markedly restored body weight, systolic blood pressure, and renal histological architecture besides significantly upregulated SOD levels, expression of anti-inflammatory CD163 macrophages, arginase1levels, IL-10 levels,STAT3 and PCNA immunoreactivity. Also, they significantly downregulated renal index, serum urea, serum creatinine, serum cystatin c, inflammatory biomarkers (C reactive protein, IL1ß & TNF-α), MDA levels, HSP70/TLR4/MyD88/NF-κB p65/NLRP3 expressions, proinflammatory CD68 macrophages and caspase-3 immunoreactivity, resulting in a reversal of cis-induced renal damage. These findings were further confirmed by molecular docking that showed the binding affinity of Ros and D towards TLR4 and NLRP3. Furthermore, D had antibacterial action with a minimum inhibitory concentration ranging from 128 to 256 µg/mL and caused a delay in the growth of the tested isolates, and negatively affected the membrane integrity. In conclusion, Ros and D had antioxidant, anti-inflammatory and antiapoptotic properties and switched macrophage from proinflammatory CD68 to anti-inflammatory CD163. Additionally, the targeting of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signals are effective therapeutic strategy in AKI.

[Economic evaluation of a fixed-dose combination (acetylsalicylic acid and rosuvastatin) in the cardiovascular context]. / Valutazione farmacoeconomica di una combinazione a dose fissa (acido acetilsalicilico e rosuvastatina) in ambito cardiovascolare.

BACKGROUND: Cardiovascular diseases pose a significant challenge to the society and healthcare systems, with serious implications in terms of mortality and healthcare expenditure. The treatment of cardiovascular diseases, based on acetylsalicylic acid combined with statins in multi-pill regimens, is characterized by a lower adherence rate among patients compared to the single-pill combination. A potential solution lies in single-pill formulations, drugs that combine two or more active ingredients at a fixed dosage within the same dosage unit. METHODS: In order to assess the potential pharmacoeconomic impact of single-pill treatment, a budget impact model (BIM) was developed, considering the combination of 100 mg acetylsalicylic acid and 5 mg, 10 mg, or 20 mg rosuvastatin. RESULTS: The use of the single pill, according to the selected scenario, could result in savings in Italy compared to the use of multi-pill at 100%, ranging from € 951 201 in the case of using both single and multi-pill at 50%, to € 1 902 402 in the case of using the single pill exclusively. Sensitivity analysis confirmed the robustness of the results. CONCLUSIONS: The developed BIM allows observing the potential savings that single-pill treatment could generate, linked both to an increase in adherence rates and the consequent improvement in clinical outcomes for patients, as well as the lower cost of medications. The use of single pills represents a promising solution to enhance patient adherence and reduce costs in the management of cardiovascular diseases in Italy.

Lipid lowering therapy: implications of recent clinical trials.

Recent lipid lowering therapy trials have provided important insights on certain agents while also continuing to expand our understanding of atherosclerotic cardiovascular disease (ASCVD) risk. Findings from current trials include the impact of statin therapy on ASCVD among populations with HIV, the benefit of lowering low-density lipoprotein cholesterol with bempedoic acid among patients considered statin intolerant, the safety and efficacy of inclisiran over a 4-year period, another failed attempt for fibrates to reduce ASCVD risk, which omega-3 fatty to utilize for lowering cardiovascular events, 'n-of-1' trials evaluating statin intolerance, and how low-dose rosuvastatin compared with commonly utilized supplements for lowering lipid parameters. Such data help inform so clinicians can optimize lipid lowering therapy and improve ASCVD outcomes.

Uptake of Fluorescein via a pH-Dependent Monocarboxylate Transporter by Human Kidney 2 (HK-2) Cells.

Herein, we investigated whether a fluorescent probe for an organic anion transporter (OAT), fluorescein (FLS), could be accumulated by human kidney 2 (HK-2) cells derived from human kidney proximal tubular epithelia. HK-2 cells took up FLS in a pH-dependent and concentration-dependent manner. FLS accumulation by HK-2 cells was inhibited by monocarboxylic acids, ibuprofen, rosuvastatin, and indoleacetic acid but not by typical substrates for OATs. A typical protonophore, carbonyl cyanide p-trichloromethoxyphenylhydrazone completely abolished FLS accumulation by HK-2 cells. The FLS efflux process from the preloaded HK-2 cells exhibited substantial trans-stimulation by the excess amount of extracellular FLS transport inhibitable monocarboxylate compounds such as 2,4-dichloro phenoxyacetic acid, fluvastatin, ibuprofen, indoleacetic acid, salicylic acid and rosuvastatin, indicating that the FLS transporter can recognize and accumulate them into the cells in a pH-dependent manner. The involvement of the FLS transporter in the reabsorption of monocarboxylic compounds was indicated by demonstrating that the pH-dependent FLS uptake is inhibited by various monocarboxylates in rabbit renal brush border membrane vesicles. pH-dependent FLS uptake was trans-stimulated by the inhibitable monocarboxylates. Collectively, the present data indicate that the pH-dependent transporters expressed in HK-2 cells are involved in the reabsorption of monocarboxylates from the urinary fluid into the tubular epithelia.