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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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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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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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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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Pravastatin decreases blood pressure in hypertensive and hypercholesterolemic patients receiving antihypertensive treatment.
Kawano, H, Yano, K
Circulation journal : official journal of the Japanese Circulation Society. 2006;(9):1116-21
Abstract
BACKGROUND Previous studies have suggested that the lipid-lowering agents, statins, may help reduce blood pressure (BP). The goal of the present study was to characterize the effect of pravastatin on BP in hypercholesterolemic and hypertensive patients already receiving antihypertensive drugs. METHODS AND RESULTS Eighty-two patients with hypercholesterolemia were retrospectively studied before and after 3 months of treatment with pravastatin. Forty-four patients had hypertension (HT group) and were receiving antihypertensive treatment, while the remaining 38 patients were normotensive (NT group). Patients in the HT group were further subdivided into those with uncontrolled or controlled BP. Pravastatin treatment significantly reduced systolic BP (SBP) in the HT group (134+/-16 to 130+/-13 mmHg, p<0.005) but not in the NT group (124+/-10 to 123+/-9 mmHg, p=0.52), despite the fact that treatment significantly reduced low-density lipoprotein cholesterol in both groups (HT group 178+/-27 to 132+/-17 mg/dl, p<0.0001; NT group 169+/-27 to 125+/-21 mg/dl, p<0.0001). Further, pravastatin significantly decreased SBP in the uncontrolled BP group (148+/-7 to 138+/-12 mmHg, p<0.005) but not in the controlled BP group (122+/-10 to 123+/-9 mmHg, p=0.72). CONCLUSION Concomitant use of statins and antihypertensive drugs could result in improved BP control in hypertensive patients with hypercholesterolemia.
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Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial.
Ridker, PM, Morrow, DA, Rose, LM, Rifai, N, Cannon, CP, Braunwald, E
Journal of the American College of Cardiology. 2005;(10):1644-8
Abstract
OBJECTIVES The aim of this research was to compare relative efficacy of different statin regimens in achieving the dual goals of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) reduction. BACKGROUND While secondary prevention guidelines for statin therapy suggest lowering LDL-C levels <70 mg/dl, we have recently shown that clinical outcomes are improved when CRP levels are also lowered <2 mg/l. METHODS We addressed the relative efficacy of pravastatin 40 mg and atorvastatin 80 mg daily to reduce LDL-C and CRP among 3,745 acute coronary syndrome patients. RESULTS A total of 1,018 participants (27.1%) achieved the dual goals of LDL-C <70 mg/dl and CRP <2 mg/l. After adjustment for age, gender, smoking, diabetes, hypertension, obesity, and HDL-C, these individuals had a 28% lower risk of recurrent myocardial infarction or vascular death (relative risk = 0.72; 95% confidence interval 0.52 to 0.99). Of those who achieved dual goals, 80.6% received atorvastatin 80 mg, while 19.4% received pravastatin 40 mg (p < 0.001). Only 11% allocated pravastatin and 44% allocated atorvastatin achieved the goals of LDL-C <70 mg/dl and CRP <2 mg/l, and only 5.8% allocated pravastatin 40 mg and 26.1% allocated atorvastatin 80 mg reached the even lower goals of LDL-C <70 mg/dl and CRP <1 mg/l. The correlation coefficient for CRP measured at 30 days and at end of study was 0.61 (p < 0.001), a value almost identical to that for LDL-C over the same follow-up period (r = 0.62, p < 0.001). CONCLUSIONS While atorvastatin 80 mg was superior to pravastatin 40 mg in terms of achieving the dual goals of aggressive LDL-C and CRP reduction, neither agent brought the majority of patients below thresholds needed to maximize patient benefit.
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A comparative crossover study of the effects of fluvastatin and pravastatin (FP-COS) on circulating autoantibodies to oxidized LDL in patients with hypercholesterolemia.
Zhang, B, Noda, K, Matsunaga, A, Kumagai, K, Saku, K
Journal of atherosclerosis and thrombosis. 2005;(1):41-7
Abstract
This study compared the effects of fluvastatin and pravastatin on the in vivo oxidation of LDL in a crossover design to evaluate whether or not it is justified to switch between the two statins with regard to serum levels of lipids, lipoproteins, and apolipoproteins (apo), and circulating autoantibodies to oxidized LDL (OxLDL-Ab). Patients with hypercholesterolemia (n = 46) were randomly assigned into groups who received fluvastatin (20 mg/d) or pravastatin (10 mg/d). After 3 months, they were crossed to receive the other statin for another 3 months. Circulating levels of OxLDL-Ab were measured by an OxLDL IgG ELISA test. Fluvastatin and pravastatin similarly decreased serum levels of total cholesterol (TC), LDL-C, and apo B, and increased HDL(2)-C levels. After crossover to the other statin, these lipid parameters were not further changed by either statin. Before crossover, circulating levels of OxLDL-Ab were decreased in patients with fluvastatin treatment, but not in those with pravastatin treatment. After switching from the other statin, both fluvastatin and pravastatin further decreased OxLDL-Ab levels. In conclusion, fluvastatin at 20 mg/d and pravastatin at 10 mg/d are similar with regard to their efficacy in decreasing TC, LDL-C, and apo B levels and increasing HDL(2)-C levels. Fluvastatin lowered circulating levels of OxLDL-Ab, and these effects continued after switching to pravastatin.
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Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using three-dimensional integrated backscatter intravascular ultrasound.
Kawasaki, M, Sano, K, Okubo, M, Yokoyama, H, Ito, Y, Murata, I, Tsuchiya, K, Minatoguchi, S, Zhou, X, Fujita, H, et al
Journal of the American College of Cardiology. 2005;(12):1946-53
Abstract
OBJECTIVES The purpose of the present study was twofold: 1) to evaluate the usefulness of three-dimensional (3D) integrated backscatter (IB) intravascular ultrasound (IVUS) for quantitative tissue characterization of coronary plaques; and 2) to use this imaging technique to determine if six months of statin therapy alters the tissue characteristics of coronary plaques. BACKGROUND Three-dimensional IVUS techniques for quantitative tissue characterization of plaque composition have not been developed. METHODS Radiofrequency (RF) signals were obtained using an IVUS system with a 40-MHz catheter. The IB values of the RF signal were calculated and color-coded. The 3D reconstruction of the color-coded map was performed by computer software. A total of 18 IB IVUS images were captured at an interval of 1 mm in each plaque. A total of 52 patients with hyperlipidemia were randomized to treatment with pravastatin (20 mg/day, n = 17), atorvastatin (20 mg/day, n = 18), or diet (n = 17) for six months. The tissue characteristics of arterial plaque in each patient (one arterial segment per patient) were analyzed with 3D IB IVUS before and after treatment. RESULTS Significant increases of fibrous volume (pravastatin: 25.4 +/- 6.5% to 28.1 +/- 6.1%; atorvastatin: 26.2 +/- 5.7% to 30.1 +/- 5.5%) and mixed lesion volume (atorvastatin: 25.5 +/- 6.6% to 28.7 +/- 5.1%) and a reduction of lipid volume (pravastatin: 25.5 +/- 5.7% to 21.9 +/- 5.3%; atorvastatin: 26.5 +/- 5.2% to 19.9 +/- 5.5%) were observed after statin therapy. CONCLUSIONS Statin therapy reduced the lipid component in patients with stable angina without reducing the degree of stenosis. Three-dimensional IB IVUS offers the potential for quantitative volumetric tissue characterization of coronary atherosclerosis.
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Biomarkers of inflammation and progression of chronic kidney disease.
Tonelli, M, Sacks, F, Pfeffer, M, Jhangri, GS, Curhan, G, ,
Kidney international. 2005;(1):237-45
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Abstract
BACKGROUND Chronic kidney disease is associated with higher levels of inflammatory biomarkers. Statins have anti-inflammatory properties and may attenuate loss of kidney function. Although inflammation may mediate progressive renal injury, the relation between statin use, markers of inflammation, and the rate of kidney function loss has not been elucidated. We examined the association between pravastatin use, levels of C-reactive protein (CRP), soluble tumor necrosis factor receptor II (sTNFrii), and the rate of kidney function loss. METHODS We performed a post hoc analysis of data from a randomized placebo controlled trial of pravastatin 40 mg daily in people with previous myocardial infarction. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease Study (MDRD) GFR equation. We studied 687 subjects with chronic kidney disease (GFR < 60 mL/min/1.73 m(2)) who did not experience a cardiovascular event during follow-up. Multivariate linear regression was used to study the relation between baseline CRP and sTNFrii and the rate of kidney function loss in mL/min/1.73 m(2)/year. Cross-product interaction terms were used to determine if these relations varied with pravastatin use. RESULTS Median baseline GFR was 54.5 mL/min/1.73 m(2) (interquartile range 49.7, 57.8) and median duration of follow-up was 58 months. Higher baseline CRP level was independently associated with more rapid kidney function loss (highest tertile 0.6 mL/min/1.73 m(2) per year faster than lowest tertile) (P= 0.001). A similar independent relation was observed between tertile of sTNFrii and rate of kidney function loss (highest tertile 0.5 mL/min/1.73 m(2) per year faster than lowest tertile) (P= 0.006). Subjects with both CRP and sTNFrii in the highest tertile ("inflamed" status) appeared to derive more renal benefit from pravastatin than those without (P for interaction 0.047). In these 108 subjects, renal function loss in pravastatin recipients was 0.8 mL/min/1.73 m(2)/year slower than placebo (95% CI 0 to 1.5 mL/min/1.73 m(2)/year slower) (P= 0.039). CONCLUSION Higher CRP and sTNFrii are independently associated with faster rates of kidney function loss in chronic kidney disease. Pravastatin appears to prevent loss of kidney function to a greater extent in individuals with greater evidence of inflammation, although this was of borderline significance. These data suggest that inflammation may mediate the loss of kidney function among subjects with chronic kidney disease and concomitant coronary disease.
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The effect of pravastatin on intima media thickness of the carotid artery in patients with normal cholesterol.
Reid, JA, Wolsley, C, Lau, LL, Hannon, RJ, Lee, B, Young, IS, Soong, CV
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2005;(5):464-8
Abstract
OBJECTIVE Carotid intima media thickness (IMT) is a good indicator of the severity of atherosclerotic disease. Statins have been found to reduce carotid IMT in patients with hypercholesterolaemia. The aim of this study was to investigate if pravastatin is effective in reducing IMT in normocholesterolaemic patients with carotid artery disease. METHODS Patients with carotid artery stenosis and normal cholesterol levels who were not on a statin, were recruited. Patients were randomised to receive pravastatin or placebo daily. Serum concentration of cholesterol and IMT of common carotid arteries were measured before randomisation and at 3 monthly intervals thereafter, for 9 months. IMT was analysed to give the mean of a standardised 2 cm of the common carotid artery (CCA). Results are expressed as median (IQR) and comparison made using the Wilcoxon signed ranks test. RESULTS Fifty-four patients were examined. Twenty-eight patients were randomised to active treatment. There was no difference in demographic details and co-morbid states between the two groups. A significant reduction in cholesterol concentration was observed from 3 months in patients randomised to the pravastatin group [5.14(4.72-5.88) vs. 4.11(3.44-5.33), p < 0.05], while there was also a significant decrease in combined IMT form 6 months [1.53(1.36-1.87) vs. 1.41 (1.33-1.78), p < 0.05]. CONCLUSIONS The results demonstrate that pravastatin reduces intima media thickness of the common carotid artery in normocholesterolaemic patients with moderate carotid stenosis.