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Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis.
Blanc, JF, Khemissa, F, Bronowicki, JP, Monterymard, C, Perarnau, JM, Bourgeois, V, Obled, S, Abdelghani, MB, Mabile-Archambeaud, I, Faroux, R, et al
Hepatology international. 2021;(1):93-104
Abstract
BACKGROUND AND AIMS There is limited data regarding the role for systemic treatment in patients with Hepatocellular Carcinoma with Child-Pugh B cirrhosis. METHODS PRODIGE 21 was a multicentric prospective non-comparative randomized trial. Patients were randomized to receive sorafenib (Arm A), pravastatin (Arm B), sorafenib-pravastatin (Arm C) combination, or best supportive care (Arm D). Primary endpoint was time to progression (TTP), secondary endpoints included safety and overall survival (OS). RESULTS 160 patients were randomized and 157 patients were included in the final analysis. 86% of patients were BCLC C and 55% had macrovascular invasion. The safety profiles of the drugs were as expected. Median TTP was 3.5, 2.8, 2.0 and 2.2 months in arms A, B, C and D, respectively, but analysis was limited by the number of patients deceased without radiological progression (59%). Median OS was similar between the four arms: 3.8 [95% CI: 2.4-6.5], 3.1 [95% CI: 1.9-4.3], 4.0 [95% CI: 3.2-5.5] and 3.5 months [95% CI: 2.2-5.4] in arms A, B, C and D, respectively. Median OS was 4.0 months [95% CI: 3.3-5.5] for patients treated with sorafenib, vs 2.9 months [95% CI: 2.2-3.9] for patients not treated with sorafenib. In patients with ALBI grade 1/2, median OS was 6.1 months [95% CI: 3.8-8.3] in patients treated with sorafenib vs 3.1 months [95% CI: 1.9-4.8] for patients not treated with sorafenib. CONCLUSION In the overall Child-Pugh B population, neither sorafenib nor pravastatin seemed to provide benefit. In the ALBI grade 1/2 sub-population, our trial suggests potential benefit of sorafenib. CLINICAL TRIAL REGISTRATION The study was referenced in clinicaltrials.gov (NCT01357486).
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Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML).
Advani, AS, Li, H, Michaelis, LC, Medeiros, BC, Liedtke, M, List, AF, O'Dwyer, K, Othus, M, Erba, HP, Appelbaum, FR
Leukemia research. 2018;:17-20
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Abstract
Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p = .062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.
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Statin Effects on Metabolic Profiles: Data From the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial).
Kofink, D, Eppinga, RN, van Gilst, WH, Bakker, SJL, Dullaart, RPF, van der Harst, P, Asselbergs, FW
Circulation. Cardiovascular genetics. 2017;(6)
Abstract
BACKGROUND Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance-based metabolomics platform. METHODS AND RESULTS We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low-density lipoprotein cholesterol (change in SD units [95% confidence interval]: -1.01 [-1.14, -0.88]), remnant cholesterol (change in SD units [95% confidence interval]: -1.03 [-1.17, -0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: -0.98 [-1.11, -0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios. CONCLUSIONS These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT03073018.
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Relationship between the G75A polymorphism in the apolipoprotein A1 (ApoA1) gene and the lipid regulatory effects of pravastatin in patients with hyperlipidemia.
Liu, TN, Wu, CT, He, F, Yuan, W, Li, SX, Li, HW, Yu, HY, Wu, M
Genetics and molecular research : GMR. 2016;(2)
Abstract
In this study, we investigated the relationship between the G75A polymorphism in the apolipoprotein A1 (ApoA1) gene and the lipid regulatory effect of pravastatin in patients with hyperlipidemia. A total of 179 patients were divided into two groups: the pravastatin (N = 97) and policosanol (N = 82) treatment groups. The total cholesterol (TC), triglyceride, low-density lipoprotein (LDL-c), high-density lipoprotein, ApoA, and ApoB concentrations in the serum were measured using an automatic biochemical analyzer before and after treatment for 12 weeks. The genotypes of the ApoA1 G75A SNP were detected by polymerase chain reaction-restriction fragment length polymorphism, and were subsequently statistically analyzed. Pravastatin treatment induced a significant decrease in the TC, LDL-c, and ApoB levels in patients expressing the ApoA1 AA+GA genotype (P < 0.05), and not in those expressing the GG genotype (P > 0.05). However, policosanol treatment induced a non-significant decrease in the serum TC levels (P > 0.05) and a significant decrease in the ApoB levels (P < 0.05), and did not induce a decrease in the LDL-c (P > 0.05) levels in patients with the AA+GA genotype. Policosanol also induced a significant decrease in the TC and LDL-c levels in patients with the GG genotype (P < 0.05). The various genotypes of the ApoA1 G75A SNP influence the efficacy of lipid regulation by pravastatin and policosanol in patients with hyperlipidemia.
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[Effect of pravastatine plus ezetimibe on carotid intima media thickness in patients with lupus erythematosus].
Vera-Lastra, OL, Olvera-Acevedo, A, Hernández, C, Medina, G, Carrillo-González, AL, Ángeles-Garay, U, Peralta-Amaro, AL, Jara, L
Revista medica del Instituto Mexicano del Seguro Social. 2015;:S74-9
Abstract
BACKGROUND Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis that can be assessed by the carotid intima media thickness (CIMT) measurement. A prompt hypolipidemic treatment should be a part of the integral management. The aim of this study is to determine the effect of therapy with pravastatin plus ezetimibe on the CIMT in SLE patients. METHODS Longitudinal, prospective, quasi-experimental trial. Out of 60 SLE patients in whom a carotid ultrasound was performed, we chose 22 with a CIMT>0.7 mm who were administered pravastatin plus ezetimibe during 6 months with determination of CIMT at the end of the study. We performed the following tests: total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, tryglicerides, C-reactive protein (CRP), liver function, muscle enzimes and glucose, basal and at the end of treatment. STATISTICAL ANALYSIS descriptive statistics and Wilcoxon test were used. RESULTS There were 22 women with an age of 42±6.3 years, average disease evolution 7.5±6.6 years, of whom, 18 concluded the study. Right basal CIMT was 0.829±0.1448 vs. final 0.688±0.1453, p<0.003; left CIMT was 0.820±0.1312 vs. 0.724±0.1348, p<0.004. TC 208 mg/dl vs 168 mg/dl, LDL-C 125 mg/dl vs. 72 mg/dl, p=0.0004. CRP 3.12 vs. 2.25 p=0.004. In 2 cases there were gastrointestinal, skin and muscle adverse effects. CONCLUSIONS Treatment with pravastatin plus ezetimibe decreases the CIMT with improvement in the concentration of total cholesterol, LDL-C and CRP levels with good toleration.
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The relationship between low-density lipoprotein cholesterol levels and the incidence of cardiovascular disease in high-risk patients treated with pravastatin: main results of the APPROACH-J study.
Daida, H, Teramoto, T, Kitagawa, Y, Matsushita, Y, Sugihara, M
International heart journal. 2014;(1):39-47
Abstract
This study aimed to evaluate the relationship between low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular disease (CVD) in high-risk patients with hypercholesterolemia without a history of CVD. Patients who were receiving or started treatment with pravastatin, were followed-up for 2 years. Patients were divided into quartiles according to on-treatment LDL-C. The maximum contrast method based on the Cox proportional hazards model was used to evaluate the relationship between achieved LDL-C and the incidence of CVD. Incidence of CVD was also compared according to whether a number of risk factor targets were achieved. A total 6,229 patients were enrolled, with 4,916 having reported LDL-C values. During the 2 years, 69 cases of CVD (6.7/1000 patient years), including 36 coronary artery disease (CAD) (3.5/1000 patient years) and 28 strokes (2.7/1000 patient years), occurred. The comparison of on-treatment LDL-C level quartiles suggested that the incidence of all CVD decreased linearly as the LDL-C levels decreased. Incidence of CAD showed a curvilinear relationship to LDL-C levels, suggesting some attenuation of risk below LDL-C of 119 mg/dL. The incidence of all CVD and CAD tended to be decreased as the number of achieved risk factor targets increased. In conclusion, through our observational study, it was shown that a linear relationship between the incidence of CVD and LDL-C was observed in high-risk hypercholesterolemic patients. The low incidence of CVD in the present study may be associated with multifactorial management of conventional risk factors including high LDL-C levels. However, prospective, randomized studies are needed to confirm these findings.
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Pravastatin reverses the membrane cholesterol reorganization induced by myocardial infarction within lipid rafts in CD14(+)/CD16(-) circulating monocytes.
Salvary, T, Gambert-Nicot, S, Brindisi, MC, Meneveau, N, Schiele, F, Séronde, MF, Lorgis, L, Zeller, M, Cottin, Y, Kantelip, JP, et al
Biochimica et biophysica acta. 2012;(9):1287-94
Abstract
Large numbers of monocytes are recruited in the infarcted myocardium. Their cell membranes contain cholesterol-rich microdomains called lipids rafts, which participate in numerous signaling cascades. In addition to its cholesterol-lowering effect, pravastatin has several pleiotropic effects and is widely used as secondary prevention treatment after myocardial infarction (MI). The aim of this study was to investigate the effects of pravastatin on the organization of cholesterol within monocyte membrane rafts from patients who had suffered myocardial infarction. Monocytes from healthy donors and acute MI patients were cultured with or without 4μM pravastatin. Lipid rafts were extracted by Lubrol WX, caveolae and flat rafts were separated using a modified sucrose gradient. Cholesterol level and caveolin-1 expression in lipid rafts were determined. In healthy donors, cholesterol was concentrated in flat rafts (63±3 vs 13±1%, p<0.001). While monocytes from MI patients presented similar cholesterol distribution in both caveolae and flat rafts. Cholesterol distribution was higher in flat rafts in healthy donors, compared to MI patients (63±3 vs 41±2%, p<0.001), with less distribution in caveolae (13±1 vs 34±2%, p<0.001). Pravastatin reversed the cholesterol distribution in MI patients cells between flat rafts (41±2 vs 66±3%, p<0.001) and caveolae (34±2 vs 18±1%, p<0.001). In conclusion, MI redistributes cholesterol from flat rafts to caveolae indicating monocyte membrane reorganization. In vitro pravastatin treatment restored basal conditions in MI monocytes, suggesting another effect of statins.
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Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: results of a phase IIb dose-ranging study.
Ballantyne, CM, Miller, M, Niesor, EJ, Burgess, T, Kallend, D, Stein, EA
American heart journal. 2012;(3):515-21, 521.e1-3
Abstract
BACKGROUND Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. METHODS Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. RESULTS Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5'-triphosphate-binding cassette A1- and scavenger receptor type BI-mediated cholesterol efflux increased. CONCLUSIONS Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.
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Coronary plaque regression and lifestyle modification in patients treated with pravastatin. - Assessment mainly by daily aerobic exercise and an increase in the serum level of high-density lipoprotein cholesterol -.
Tani, S, Nagao, K, Anazawa, T, Kawamata, H, Furuya, S, Takahashi, H, Iida, K, Matsumoto, M, Washio, T, Kumabe, N, et al
Circulation journal : official journal of the Japanese Circulation Society. 2010;(5):954-61
Abstract
BACKGROUND The purpose of this study was to explore the effect of lifestyle modification, mainly daily aerobic exercise, on coronary atherosclerosis in patients with coronary artery disease (CAD). METHODS AND RESULTS A 6-month prospective observational study was conducted with 84 CAD patients receiving pravastatin treatment in order to evaluate the relationship between lifestyle modification, in particular aerobic exercise, and plaque volume as assessed by intravascular ultrasound (IVUS). Lifestyle during the study period was assessed by the-lifestyle modification score. A significant decrease in plaque volume by 12.9% was observed after 6 months of pravastatin therapy (P<0.0001 vs baseline). The change in plaque volume correlated with the change in the serum level of high-density lipoprotein cholesterol (HDL-C) (r=-0.549, P<0.0001), non-HDL-C (r=0.248, P=0.03), low-density lipoprotein cholesterol/HDL-C (r=0.505, P<0.0001), apolipoprotein (apo) A-1 (r=-0.335, P=0.007) and apoB/apoA-1 (r=0.335, P=0.007), and lifestyle modification score (r=-0.616, P<0.0001). There was a clear positive correlation between a change in the serum HDL-C level and lifestyle modification score. Multivariate regression analysis revealed that the increase in serum HDL-C level and lifestyle modification score were independent predictors of coronary plaque regression. CONCLUSIONS An appropriate combination of statin therapy and lifestyle modification, in particular, physical activity, may result in coronary plaque regression. This combined treatment strategy, inducing an increase of the serum HDL-C, may contribute to coronary plaque regression.
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Association of leukocyte subtype counts with coronary atherosclerotic regression following pravastatin treatment.
Tani, S, Nagao, K, Anazawa, T, Kawamata, H, Furuya, S, Takahashi, H, Iida, K, Matsumoto, M, Washio, T, Kumabe, N, et al
The American journal of cardiology. 2009;(4):464-9
Abstract
The purpose of this study was to clarify the relation between differential leukocyte counts and inhibition of the development of coronary atherosclerosis in patients with coronary artery disease. A 6-month prospective study was conducted in 84 patients treated with pravastatin. Plaque volume, as assessed by volumetric analysis using intravascular ultrasound, decreased significantly by 12.6% (p <0.0001 vs baseline) after treatment; furthermore, a corresponding decrease of total leukocyte count (8.9%, p <0.01 vs baseline) was seen. Change in plaque volume was correlated with changes in monocyte (r = 0.35, p = 0.002) and lymphocyte (r = 0.25, p = 0.03) counts but not with changes in neutrophil, eosinophil, or basophil counts. In a multivariate regression analysis with changes in serum lipids, traditional risk factors, and medications as covariates, the decrease in monocyte count was identified as an independent predictor of coronary plaque regression (beta coefficient 0.313, 95% confidence interval 0.089 to 0.353, p = 0.0014). No correlation was found between change in monocyte count and changes in any other lipid levels. This study demonstrated that monocyte count was the only leukocyte type significantly and independently associated with coronary atherosclerotic regression, even after adjustment for changes in any lipid levels. In conclusion, the decrease in monocyte count as a nonlipid-lowering effect of statins may be used as a novel marker of coronary atherosclerotic regression.