Glucose-lowering effect of colestimide is associated with baseline HbA1c in type 2 diabetic patients with hypercholesterolemia.

We previously reported that colestimide, an anion exchange resin, improved glycemic control in patients with type 2 diabetes. However, the factors associated with the decrease of HbA1c remain unclear. In present study, we retrospectively compared glycemic control between groups receiving colestimide (n=71), atorvastatin (n=99), pravastatin (n=85), and pitavastatin (n=95) until 3 months after the start of treatment. In the colestimide group, fasting plasma glucose decreased significantly from 169 ± 59 to 138 ± 29 mg/dL after 3 months (P<0.01), and glycated hemoglobin (HbA1c) declined from 8.1 ± 1.0% to 7.4 ± 0.8% (an 8% reduction, P<0.01). Fasting plasma glucose and HbA1c did not change in the pravastatin and pitavastatin groups. On the other hand, both parameters increased significantly in the atorvastatin group. Multivariate analysis revealed that baseline HbA1c was the main determinant of the decrease of HbA1c in the colestimide group while age, sex, BMI, and baseline lipid levels were not correlated with the effect of colestimide treatment. The decrease of HbA1c showed a positive correlation with baseline HbA1c (r=0.60, P<0.0001), and patients with a larger change of HbA1c (>8.4%) displayed a better response to colestimide. In conclusion, since patients with type 2 diabetes often have hyperlipidemia as well, colestimide therapy may have a clinically useful dual action in such patients. Baseline HbA1c has the most important independent influence on the glucose-lowering effect of colestimide.

Cost-effectiveness analysis of cholesterol-lowering therapies in Spain.

OBJECTIVE: To assess the cost efficacy of atorvastatin, simvastatin, lovastatin, fluvastatin, pravastatin, and colestyramine in the reduction of low-density lipoprotein-cholesterol (LDL-C) levels and the cost per patient to achieve the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) therapeutic objectives in Spain. METHOD: The following treatments were evaluated: atorvastatin, simvastatin, and pravastatin 10-40 mg/day; lovastatin and fluvastatin 20-80 mg/day; and colestyramine 12-24 g/day. The cost effectiveness of these treatments was evaluated, in terms of cost per percentage of LDL-C reduction, by comparing annual treatment costs versus the efficacy of LDL-C reduction. Treatment costs included medication costs (2003 wholesale prices), control measures, and the treatment of adverse affects. The efficacy of HMG-CoA reductase inhibitors (statins) was obtained from a meta-analysis of results obtained from clinical trials published between 1993 and 2003 that met the following criteria: monotherapy; >16 weeks of treatment; randomized allocation of individuals to the intervention and comparator groups; dietary treatment for > or =3 months before administration of medication; and double-blind measurement of outcomes. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of cholesterol-lowering treatments. RESULTS: Efficacy, in terms of percentage of LDL-C reduction, ranged from 10% for colestyramine 12 g/day to 49% for atorvastatin 40 mg/day. Total annual treatment costs ranged from euro 321 for fluvastatin 20 mg/day to euro 1151 for atorvastatin 40 mg/day. Cost-effectiveness ratios, in terms of cost per percentage of LDL-C reduced, were: euro 11-23 for atorvastatin; euro 12-21 for simvastatin; euro 14-22 for lovastatin; euro 15-24 for fluvastatin; euro 21-42 for pravastatin; and euro 35-46 for colestyramine. Atorvastatin 10 mg/day was the most cost-effective treatment, followed by simvastatin 10 mg/day, lovastatin 20 mg/day, and fluvastatin 20 mg/day. Atorvastatin was the most cost-effective treatment in the achievement of the NCEP ATP III LDL-C reduction objectives in patients with high (<100 mg/dL) and moderate (<130 mg/dL) risk of coronary heart disease (CHD), with a cost per patient of euro 747 and euro 405 per year, respectively. Fluvastatin was the most cost-effective treatment in the achievement of the NCEP ATPIII therapeutic objective in patients with low-risk of CHD (LDL-C <160 mg/dL), with a cost per patient of euro 321. CONCLUSION: Atorvastatin 10 mg/day was the most cost-effective cholesterol-lowering drug, followed by simvastatin 10 mg/day, lovastatin 20 mg/day, and fluvastatin 20 mg/day. The preferred statin should be atorvastatin in patients with moderate-to-high CHD risk and fluvastatin in patients with low risk for CHD.

New models for describing outliers in meta-analysis.

An unobserved random effect is often used to describe the between-study variation that is apparent in meta-analysis datasets. A normally distributed random effect is conventionally used for this purpose. When outliers or other unusual estimates are included in the analysis, the use of alternative random effect distributions has previously been proposed. Instead of adopting the usual hierarchical approach to modelling between-study variation, and so directly modelling the study specific true underling effects, we propose two new marginal distributions for modelling heterogeneous datasets. These two distributions are suggested because numerical integration is not needed to evaluate the likelihood. This makes the computation required when fitting our models much more robust. The properties of the new distributions are described, and the methodology is exemplified by fitting models to four datasets. © 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons, Ltd.

A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease.

This prospective study evaluates the safety and efficacy of pravastatin for the treatment of chronic graft-versus-host disease (GVHD). We included 18 patients with refractory chronic GVHD. Oral pravastatin was started at 10 mg/day, and the dose was increased up to 40 mg/day in 4 weeks. This maximum dose was administered over 8 weeks. There were no severe adverse events caused by pravastatin. A clinical response was observed in the skin score in two patients, mouth score in five patients, eye score in two patients, liver score in three patients, platelet count score in one patient, and weight loss in two patients. The overall response rate was 28%. Immunophenotypic analyses showed that T-helper (Th)1 cells were dominant in all but one patient before treatment and that the Th1/Th2 ratio tended to be lower in the responders than in the nonresponders. A randomized controlled trial is warranted to evaluate the efficacy of pravastatin against chronic GVHD.

Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Pravastatin Multicenter Study Group II.

BACKGROUND: Treatment of severe hypercholesterolemia often requires high-dose therapy with a hydroxymethylglutaryl-coenzyme A reductase inhibitor alone or in combination with bile acid-binding resin. We evaluated the efficacy and safety of pravastatin, a new hydroxymethylglutaryl-coenzyme A reductase inhibitor with hydrophilic selectivity, alone and in combination with cholestyramine. METHODS: Pravastatin was studied at doses of 20 or 40 mg twice daily alone or 20 mg twice daily with cholestyramine, 12 g twice daily, vs placebo in a randomized, double-blind multicenter study of 311 patients for 8 weeks and in continued therapy through 24 weeks. RESULTS: After 8 weeks of therapy, pravastatin in a dosage of 20 mg twice daily reduced low-density lipoprotein cholesterol levels by 31%, whereas a dosage of 40 mg twice daily reduced low-density lipoprotein cholesterol levels by 38%. Cholestyramine, 24 g daily alone, reduced low-density lipoprotein cholesterol levels by 32%. Cholestyramine combined with 40 mg of pravastatin reduced the level by 51%. Pravastatin, 40 or 80 mg daily, reduced the triglyceride level by 13% to 19%, resin alone increased the triglyceride level by 21%, and no change was seen with combined therapy. High-density lipoprotein cholesterol levels increased by about 5% regardless of regimen. Similar effects were seen at 24 weeks. Symptoms reported were indistinguishable among placebo and pravastatin users and were less than with cholestyramine alone or cholestyramine in combination with pravastatin. Elevations of liver enzyme levels were small in all groups, indistinguishable between resin and pravastatin, and were highest when the two drugs were combined. Plasma creatine kinase levels did not increase in any treatment group. CONCLUSIONS: Pravastatin treatment of hypercholesterolemia is highly effective and well tolerated alone and in combination with bile acid-binding resin and shows no tendency to increase muscle enzyme levels.

Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials.

BACKGROUND: Previous overviews suggested that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), but not other lipid-lowering therapy (LLT), may reduce stroke incidence in coronary patients. OBJECTIVE: To investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: We searched the literature from 1966 to 2001 and then conducted a meta-analysis including randomized trials of primary and secondary coronary heart disease prevention, testing statins, nonstatin drugs, diet, or other interventions and providing data on stroke incidence. RESULTS: The meta-analysis (38 trials, 83 161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLT of 17% (P<.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary) or the type of LLT. The most substantial effects were obtained, however, with statins (RRR, 26%). Effect model analysis showed that treatment benefit appeared constant whatever the risk of stroke, suggesting that LLT may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol allowed clear separation between benefit (RRR>0) and no effect (RRR<0) of LLT on stroke incidence, with a cutoff for benefit of 232 mg/dL (6.0 mmol/L). CONCLUSION: Lipid-lowering therapy reduces stroke incidence in coronary patients, especially when total cholesterol level is lowered to less than 232 mg/dL (6.0 mmol/L), which explains the best results being obtained with statins.

Reduction of lipoprotein(a) by LDL-apheresis using a dextran sulfate cellulose column in patients with familial hypercholesterolemia.

Lipoprotein(a) (Lp(a)) was eliminated by LDL-apheresis using a dextran sulfate cellulose column in 3 homozygous and 10 heterozygous familial hypercholesterolemic patients. Immediately after LDL-apheresis by the LA-15 system (continuous LDL apheresis), there were significant reductions in Lp(a) concentrations (28.6 +/- 11.8 mg/dl (mean +/- S.E.) to 9.6 +/- 5.6 mg/dl (P < 0.01)), and in LDL-cholesterol concentrations (156 +/- 32 mg/dl to 48 +/- 18 mg/dl (P < 0.01)). Immediately following LDL-apheresis, Lp(a) and LDL-cholesterol were reduced by 67.4% +/- 11.6% and 68.3% +/- 11.8%, respectively. The removal of Lp(a) paralleled that of LDL-cholesterol. The reduced levels of Lp(a) nearly returned to baseline within 7 days. In 6 of the heterozygous FH patients the rates of recovery of LDL cholesterol and Lp(a) were calculated, according to Apstein's equation after discontinuing lipid altering drug treatment for 4 weeks. Mean constant k values of LDL cholesterol and Lp(a) were 0.354 (range: 0.136-0.752) and 0.427 (range 0.112-0.933), respectively. The average concentration during the 7 days following LDL-apheresis was calculated. Average reductions were 28% in LDL cholesterol and 18% in Lp(a). Pravastatin treatment, which continued for 4 weeks, significantly decreased LDL cholesterol (P < 0.01); however, before LDL-apheresis pravastatin treatment significantly increased Lp(a) levels (P < 0.05) in a small number (n = 6) of the FH patients, who had been regularly treated with LDL-apheresis. These results suggest that LDL-apheresis using the dextran sulfate cellulose column is an effective treatment to reduce levels of serum Lp(a) and LDL proportionally. This therapy may be of value in the prevention and regression of coronary artery disease in FH patients.

Intima-media thickness after cholesterol lowering in familial hypercholesterolemia. A three-year ultrasound study of common carotid and femoral arteries.

Patients with familial hypercholesterolemia (FH) (n = 53) were examined with B-mode ultrasound before and after 3 years of cholesterol-lowering therapy with pravastatin, cholestyramine, or a combination. The aim was to measure the progression rate of intima-media thickening during follow-up in the common carotid and common femoral arteries. Since for ethical reasons it was not possible to perform a randomized placebo controlled study in patients with FH, we chose to recruit an untreated control group with lower risk, matched for sex, age, height and weight, and with serum cholesterol below 6.5 mmol/l. At baseline, intima-media thickness was larger in the hypercholesterolemic group than in the control group in both the common carotid and common femoral arteries. The difference between the change over 3 years observed in the control group and the change observed in the hypercholesterolemic group was calculated and defined as 'net difference'. There was a -32% net difference in low density lipoprotein (LDL) in the hypercholesterolemic group during follow-up. The ultrasound investigation showed a concomitant net difference of -0.06 mm in mean carotid intima-media thickness (95% confidence interval, -0.11 to -0.01 mm) and of -0.09 mm in maximum carotid intima-media thickness (P < 0.05, 95% confidence interval, -0.16 to -0.01 mm), with no net change in lumen diameter. No decrease was recorded in common femoral intima-medial thickness. Seventeen of the patients with FH had a positive history of myocardial infarction (MI) and this subgroup had a significantly larger decrease in mean carotid intima-media thickness during follow-up than the subgroup of patients with a negative history of MI (P < 0.01). In conclusion, the results showed a reduction in common carotid intima-media thickness after long-term cholesterol-lowering therapy in patients with FH. This finding may indicate a beneficial effect on atherosclerosis development in these patients.

Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: in vitro and ex vivo studies.

Oxidized LDL, which has been discovered in vivo in areas of proximity to the atherosclerotic lesion, has been shown to enhance macrophage cholesterol accumulation. We studied the anti-oxidant potential of pravastatin, bezafibrate and cholestyramine in 18 patients with hypercholesterolemia. In addition, we examined the electrophoretic mobility and the uptake of LDL by macrophages before and after drug therapy. Pravastatin lowered plasma levels of LDL cholesterol by 57%, cholestyramine by 27% and bezafibrate by 25%. Pravastatin and bezafibrate also altered the composition of LDL as evidenced by the reduction of its cholesterol/apo B100 ratio. Pravastatin and bezafibrate reduced plasma triglyceride levels by 45% and 25%, respectively, whereas cholestyramine raised plasma triglyceride concentrations by 28%. LDL propensity for in vitro oxidation was analyzed following lipoprotein incubation with 10 microM copper ions and determination of LDL malondialdehyde (MDA), peroxides (PD) and conjugated dienes (CD) content. All drugs inhibited the susceptibility to in vitro oxidation of LDL isolated after drug therapy in comparison to LDL isolated before commencing drug therapy. Pravastatin reduced MDA content by 22%, PD by 18% and CD by 20%. Cholestyramine reduced LDL content of MDA by 41%, PD by 25% and CD by 63%. Bezafibrate reduced MDA by 41%, PD by 38% and CD by 45%. LDL vitamin E content was reduced after treatment with bezafibrate, pravastatin and cholestyramine by 49%, 36% and 8%, respectively. The electrophoretic mobility of LDL after all drug therapies was reduced in comparison to LDL obtained before therapy. Macrophage uptake of LDL assessed by either the cellular cholesterol esterification rate or by lipoprotein degradation was not affected by drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Low-density lipoprotein receptor genotype-dependent response to cholesterol lowering by combined pravastatin and cholestyramine in familial hypercholesterolemia.

We compared the effects of cholesterol-lowering therapy on 2 patient groups genetically defined as heterozygous for familial hypercholesterolemia (FH), 5 with a deletion of exon 15 (FH(Tonami-1)), and 7 with a point mutation at codon 664 (FH(Kanazawa-2)). There were significant differences in both serum and low-density lipoprotein cholesterol reductions between the 2 groups after combination therapy with pravastatin and cholestyramine, and the overall effect of genotype on serial changes in both was significant.

Pravastatin alone and in combination with low-dose cholestyramine in patients with primary hypercholesterolemia and coronary artery disease.

This randomized, open-label study compared the cost efficiency of low-dose pravastatin combined with low-dose cholestyramine with high-dose pravastatin monotherapy in 59 patients with moderate hypercholesterolemia and coronary disease. Both regimes were effective in improving lipid profiles in these patients; however, low-dose combination therapy enhanced achievement in therapeutic goals and cost efficiency.

Beneficial effects of pravastatin (+/-colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study).

Secondary prevention of coronary heart disease by antilipidemic therapy beginning at > or =3 months after an acute coronary syndrome is well documented. The impact, however, of immediate initiation of antilipidemic therapy on coronary stenoses and clinical outcome in patients with acute coronary syndrome is unknown. In our study, patients were randomized, on average, 6 days after an acute myocardial infarction and/or percutaneous transluminal coronary angioplasty secondary to unstable angina, to pravastatin (combined, when necessary, with cholestyramine and/or nicotinic acid) to achieve low-density lipoprotein cholesterol levels of < or =130 mg/dl (group A, n = 70). In controls (group B, n = 56), antilipidemic therapy was determined by family physicians. Quantitative coronary angiography was performed at inclusion, and at 6- and 24-month follow-up. The combined clinical end points were total mortality, cardiovascular death, nonfatal myocardial infarction, need for coronary intervention, stroke, and new onset of peripheral vascular disease. Minimal lumen diameter in group A increased by 0.05 +/- 0.20 mm after 6 months and 0.13 +/- 0.29 mm after 24 months, whereas it decreased by 0.08 +/- 0.20 mm and 0.18 +/- 0.27 mm, respectively, in group B (p = 0.004 at 6 months and p <0.001 at 24 months). After 2 years, 29 patients of 56 patients in group B, but only 16 of 70 patients in group A, experienced a clinical end point (p = 0.005; odds ratio 0.28, confidence intervals 0.13 to 0.6). We conclude that pravastatin-based therapy initiated immediately after an acute coronary syndrome is well tolerated and safe, lessens coronary atherosclerosis, and has a pronounced clinical benefit.

The effects of lipid lowering on diabetic retinopathy.

The effect of lipid lowering on hard exudates was determined in six consecutive patients with insulin-dependent diabetes mellitus. Diet and hypolipidemic drug therapy including the use of pravastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase, were used to treat patients for one year. The total cholesterol concentration decreased from a mean baseline value of 231 mg/dl to a treatment mean value of 165 mg/dl. The mean low-density lipoprotein cholesterol concentration decreased from 157 mg/dl to 93 mg/dl. Masked grading of fundus photographs indicated an improvement in hard exudates in all six patients and a decrease in microaneurysms in four patients. Visual acuity improved in one patient and did not change (one line or less change) in five patients. No remarkable side effects resulting from treatment were observed. Our pilot study suggests that aggressive therapy of diabetic patients with hyperlipidemia may have a beneficial effect on background retinopathy.

Four years' treatment efficacy of patients with severe hyperlipidemia. Lipid lowering drugs versus LDL-apheresis.

A total of 47 patients suffering from heterozygous hyperlipidemia were treated with LDL-apheresis (24 patients, aged 49.5 +/- 11.5 years), diet and/or lipid-lowering drugs or with diet and lipid-lowering drugs only (23 patients, aged 48.0 +/- 11.9 years). After treatment periods of 44.4 +/- 14.3 (apheresis group) and 33.5 +/- 15.9 (drug group) months, respectively, the ensuing results revealed significant differences (p < 0.0001): total cholesterol decreased from 10.4 to 5.5 vs 9.9 to 8.7 mmol/l, LDL from 7.4 to 3.9 vs 6.6 to 5.2 mmol/l, triglycerides from 5.8 to 3.7 vs 4.8 to 4.1 mmol/l and the LDL/HDL-ratio decreased from 7.1 to 3.4 vs 6.7 to 5.8. In the apheresis group one patient died from myocardial infarction vs one non-fatal myocardial infarction and the manifestation of coronary heart disease in three cases in the drug group. There were no severe side-effects in either group. All patients in the apheresis group experienced an increased clinical performance. On the other hand physological well-being of these patients was lower than that of the drug group (scores 42.3 +/- 8.9 vs 50.2 +/- 9.9, p < 0.002). The present trial suggests that a continuing reduction in serum lipid concentrations may lower in a dose dependent manner the risk of development and progression of coronary heart disease. With respect to clinical and laboratory results, LDL-apheresis seems safe and appears to be the most effective therapy.

[Clinical evaluation of a selective inhibitor of cholesterol synthesis: pravastatin]. / Valutazione clinica di un inibitore selettivo della sintesi del colesterolo: la pravastatina.

The recent introduction in clinical practice of a new class of drugs able to reduce the endogenous synthesis of cholesterol has undoubtedly made a noteworthy contribution to the treatment of hypercholesterolaemia which, as is well known, is one of the greatest risk factors in the natural history of atherosclerotic disease and of its cardiovascular complications. A last generation drug belonging to this family is pravastatin which differs from the other substances inhibiting the activity of the key enzyme of cholesterol metabolism, HMGCaA reductase, because of certain features of the molecule, such as hydrophilia and the fact it is already pharmacologically active at the moment of oral administration. Pravastatin, which is probably a special category of HMGCoA reductase inhibitor, has shown, in numerous experimental studies and controlled clinical trials, a notable effectiveness in reducing in a highly selective fashion the synthesis of cholesterol in the liver cells and consequently the number of cholesterol-rich lipoproteins in the systemic circulation, without also determining significant biologically negative side-effects.

Treatment of familial hypercholesterolaemia. United Kingdom lipid clinics study of pravastatin and cholestyramine.

OBJECTIVE: To compare the efficacy and safety of cholestyramine, an anion exchange resin, and pravastatin, a new hydrophilic specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in the treatment of heterozygous familial hypercholesterolaemia. DESIGN: Double blind, double dummy, placebo controlled study with three parallel groups. SETTING: Six specialist lipid clinics in the United Kingdom. PATIENTS: 128 patients aged 18-70 with heterozygous familial hypercholesterolaemia diagnosed on strict biochemical and clinical findings. MAIN OUTCOME MEASURES: Total plasma cholesterol, triglyceride, and lipoprotein subfractions and biochemical and haematological safety parameters. RESULTS: Pravastatin (40 mg/day) led to a 25% reduction in total plasma cholesterol concentration and a reduction in low density lipoprotein cholesterol concentration of 30%. Cholestyramine (24 g/day) led to similar reductions in concentrations of total cholesterol (23%) and low density lipoprotein cholesterol (31%). No consistent changes occurred in high density lipoprotein cholesterol values with either compound. Plasma triglyceride concentrations showed a small rise (18%) on resin therapy. No serious adverse drug reactions occurred during the study. CONCLUSIONS: Pravastatin seems to be a highly effective, well tolerated drug for severe hypercholesterolaemia. Patients chosen for this study were recruited on the basis that they could tolerate a full dose of cholestyramine, and in this situation cholestyramine was also highly effective in lowering plasma low density lipoprotein cholesterol concentrations.

Cholesterol-lowering drugs. Some drugs with demonstrated efficacy but different benefits in primary and secondary prevention.

(1) In primary prevention trials, pravastatin and lovastatin prevented myocardial infarction and had a positive risk-benefit ratio in men with LDL-cholesterol values exceeding 4.5 mmol/l (1.7 g/l). Cholestyramine and gemfibrozil also prevented myocardial infarction in men with more severe hypercholesterolaemia; while clofibrate had a negative risk-benefit ratio in patients with moderate hypercholesterolaemia. These treatments have not been assessed for primary prevention in women or in patients aged over 70. (2) In trials involving patients with coronary heart disease, pravastatin and simvastatin both reduced the risk of myocardial infarction and/or mortality in patients of both sexes with LDL-cholesterol values above 3.2 mmol/l (1.2 g/l). Gemfibrozil also reduced the risk of myocardial infarction but not mortality, while clofibrate and bezafibrate had no preventive effect.

Liposomal pravastatin inhibits tumor growth by targeting cancer-related inflammation.

The chronic inflammatory environment of tumors is a target for novel antitumor therapeutic strategies. Besides cholesterol lowering effects, statins have been studied for their anti-inflammatory and immunomodulatory properties. These pleiotropic effects result mainly from the altered post-translational modification of GTP-binding proteins which regulate many intracellular pathways involved in cell growth and survival. Although pre-clinical studies suggest that statins may be effective anticancer agents required doses that are 100 to 500 fold higher than those needed to lower cholesterol levels. Furthermore, in view of their wide-ranging effects on cellular metabolism, target site-specific delivery is preferred. In this study, we investigated tumor-specific delivery of pravastatin using small long-circulating liposomes. In vitro studies on the effects of (liposomal) pravastatin on viability and proliferation of tumor cells, endothelial cells and macrophages revealed that the latter were the most sensitive cell type towards (liposomal) pravastatin treatment. In vivo, liposome-encapsulated pravastatin (5mg/kg) inhibited murine B16F10-melanoma growth over 70% as compared to free pravastatin, which was ineffective. As expected, treatments did not influence serum cholesterol levels within the time frame of the study. At 48 h post-injection, 3 µg of pravastatin could still be recovered from the tumors of liposomal pravastatin treated mice, whereas pravastatin could not be detected in tumors of the free drug treated mice (i.e. < 20 ng). In contrast to the free drug, liposomal pravastatin treatment effectively inhibited the production of several pro-inflammatory/pro-angiogenic mediators involved in inflammation and angiogenesis, out of a range of a panel of 24 proteins studied. Furthermore, liposomal pravastatin treatment increased MHC class I protein expression in the tumor tissue whereas free drug showed no effect. Taken together, targeted delivery of statins can improve their tumor growth inhibiting activity by increasing local drug concentration and direct modulation of macrophage function. The antitumor activity seems to result primarily from a local inhibition of tumor inflammation and stimulation of antitumor immune response.