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Eur J Clin Pharmacol (2006) 62:817–822DOI 10.1007/s00228-006-0176-1 Effects of amlodipine-atorvastatin combinationon inflammation markers and insulin sensitivityin normocholesterolemic obese hypertensive patients Roberto Fogari & Paola Preti & Annalisa Zoppi &Pierangelo Lazzari & Luca Corradi & Elena Fogari &Leonardina Ciccarelli & Giuseppe Derosa Received: 17 March 2006 / Accepted: 16 June 2006 / Published online: 2 August 2006 amlodipine) and HOMA-IR (2.86±0.4, p=0.0008 vs. place- Objective The objective of this study was to assess the effect bo and p=0.007 vs. amlodipine). The combination reduced of amlodipine-atorvastatin combination on plasma interleu- IL-6 (from 7.93±1.9 to 5.59±1.2 pg/mL, p=0.008 vs.
kin-6 (IL-6), tumor necrosis factor-α (TNF-α) and insulin placebo and p=0.007 vs. amlodipine) and TC (from 4.3± sensitivity in normocholesterolemic obese hypertensive 0.5 to 3.6±0.4 mmol/L, p=0.008 vs. placebo and vs.
amlodipine). HOMA-IR changes significantly correlated Materials and methods After a 4-week placebo wash- with TNF-α changes (r=0.38, p<0.05) during combination out period, 50 normocholesterolemic [total cholesterol but not during amlodipine monotherapy. In normocholester- (TC) <5.2 mmol/L], obese (BMI ≥30 kg/m2) hypertensive olemic, obese hypertensive patients, the amlodipine-ator- patients (DBP >90 and <105 mm Hg and SBP >140 and vastatin combination decreased inflammatory markers and <180 mm Hg) were randomly treated with amlodipine IR more than amlodipine monotherapy and produced a (10 mg) or with amlodipine (10 mg) plus atorvastatin (20 mg) according to a cross-over design; each treatmenthad a 12-week duration. At the end of the placebo and of Keywords Amlodipine . Atorvastatin . Insulin sensitivity .
each treatment period, blood pressure (BP), TNF-α, IL-6, insulin resistance (IR) by homeostasis model assessment ofIR index (HOMA-IR) and TC were evaluated.
Results Amlodipine monotherapy decreased both SBP (−17.1 mm Hg, p=0.008 vs. placebo) and DBP (−14.3 mmHg, p=0.008) as well as TNF-α (from 3.66±1.6 to 3.09± Population studies have shown that hypertension and 1.1 pg/ml, p=0.045) and HOMA-IR (from 4.58±0.7 to 3.88± obesity frequently coexist and their association increases 0.6, p=0.007). The amlodipine-atorvastatin combination cardiovascular risk [–]. Insulin resistance (IR) with produced a decrease in SBP (−22.5 mm Hg, p=0.0007 vs.
consequent hyperinsulinemia plays a pivotal role in the placebo, p=0.039 vs. amlodipine), DBP (−17.7 mm Hg, pathogenesis of obesity hypertension by directly affecting p=0.0007 vs. placebo; p=0.04 vs. amlodipine), TNF-α renal sodium excretion and, most importantly, by sympa- (2.59±0.9 pg/mL, p=0.007 vs. placebo and p=0.038 vs.
thetic nervous system stimulation [, Etiology of IR isstill unclear, although genetic and environmental factors areknown to be involved []. Adipose tissue, far from being aninert organ, synthesizes and secretes biologically active R. Fogari (*) P. Preti A. Zoppi P. Lazzari L. Corradi molecules, including leptin, adiponectin, resistin, plasmin- E. Fogari : L. Ciccarelli : G. DerosaDepartment of Internal Medicine and Therapeutics, ogen activator inhibitor-1 (PAI-1), tumor necrosis factor Clinica Medica II, IRCCS Policlinico S.Matteo, (TNF)-α and interleukin-6 (IL-6), that interact with each other and may affect cardiovascular risk factors [, α has been suggested to participate in IR in obese subjects [, ] by inhibiting tyrosine kinase activity and consequent phosphorylation of the insulin receptor [] and from the study were those with diabetes, angina, myocar- by decreasing expression of glucose transporters [].
dial infarction or stroke within the past 6 months, liver or TNF-α can affect blood pressure by causing insulin kidney diseases, heart failure, secondary hypertension, resistance and hyperinsulinemia. Pro-inflammatory cytokine neurologic or psychiatric illness, smoking habits, co- interleukin-6, besides stimulating the liver to produce acute medication with corticosteroids or hormone replacement phase reactants, including C-reactive protein (CRP) and therapies, and known hypersensitivity to the drugs used in fibrinogen, both of which are related to hypertension, also the study, as well as those with conditions that may have takes an active part in the inflammation process [], caused metabolic alterations within the past year (pregnan- whose role in the development of atherosclerotic lesions is cy, abdominal surgery, weight gain or loss of more than 3 kg). The study protocol was approved by the local Ethical Optimal pharmacological treatment of obesity hyperten- Committee and written informed consent was obtained sion needs antihypertensive agents that at least do not from each participant at the time of enrollment.
exacerbate (and possibly improve) obesity-associated met- After an initial 4-week placebo period, patients fulfilling abolic disorders, beyond lowering BP levels. Dihydropyr- the inclusion criteria were randomly assigned to receive idine calcium-channel blockers (CCB) have been generally amlodipine (10 mg) or amlodipine (10 mg) plus atorvastatin reported to exert neutral or positive effects on insulin (20 mg) for 12 weeks according to a double-blind, cross- sensitivity []. In particular, the long-acting CCB over design. After each active treatment period there was a amlodipine has been found to improve insulin sensitivity 4-week wash-out placebo period. All treatments were in essential hypertensive patients with or without obesity administered once daily in the morning. Since the main –Besides, a study conducted by utilizing mice and objective of the study was to assess the potential advan- human peripheral blood mononuclear cell cultures indicated tages in terms of reduction of inflammatory markers and that amlodipine decreased TNF-α both in vivo and in vitro insulin resistance of adding a statin to antihypertensive conditions ]. A decreasing effect of amlodipine on TNF-α treatment in normocholesterolemic hypertensives who levels was also described in humans, although few data are primarily needed to have their BP lowered, we deemed it unethical to keep these patients without antihypertensive The 3-hydroxy-3-methylglutaryl-CoA reductase inhibi- therapy for 12 weeks. For this reason, a statin arm only was tors, so-called statins, have been shown to exert antiox- not included in the study design nor was a full matched idative and anti-inflammatory actions beyond their cholesterol-lowering effects [which may contribute No dietary advice was prescribed for the duration of the to the observed benefit in reducing cardiovascular events study. However, the nutritional habits of the patients were regardless of initial cholesterol concentrations ]. Thus recorded using a food-frequency questionnaire at the data from the Anglo-Scandinavian Cardiac Outcomes Trial beginning and at the end of each treatment period to verify (ASCOT) indicated a protective effect of statins in whether some of the participants have changed their habits.
hypertensive patients with normal cholesterol levels ].
At the end of the placebo wash-out and of each treatment Regarding the effects on inflammatory markers, statins period, office BP, BMI, plasma levels of TNF-α, IL-6, IR, have been found to decrease TNF-α and IL-6 levels as well TC, HDL-C, LDL-C and triglycerides (TG) were evaluated.
as IL-6-induced CRP and PAI-1 production in human All BP measurements were made with calibrated mercury manometers (Korotkoff I and V). Arm circumferences were With this background, the present study was undertaken measured to determine the appropriate cuff size. BP to evaluate the effects of combined therapy with the CCB was measured in the morning, before daily drug intake amlodipine and the statin atorvastatin on plasma TNF-α, (i.e., 24 h after dosing) and after the patient had been sitting IL-6, and insulin sensitivity in obese patients with hyper- for 10 min in a quiet room. Three separate measurements tension and normal total cholesterol levels.
were taken at least 2 min apart and the average of thesevalues was calculated.
Body weight was measured in the fasting state with the subjects wearing only light clothes and without shoes andBMI was calculated as weight in kg/m2.
The study population was selected according to the For evaluation of TNF-α, IL-6, and IR blood samples following inclusion criteria: outpatients of both sexes with were always drawn in the morning, between 08.00 and obesity (BMI ≥30 kg/m2), never treated, mild to moderate 09.00 hours, after an overnight fast. The blood samples were hypertension (DBP >90 and <105 mm Hg and SBP >140 vortexed and centrifuged immediately at 4°C for 20 min at and <180 mm Hg after a 4-week placebo period) and 300 rpm and plasma samples were stored at −80°C until normal TC levels (TC<5.2 mmol/L). Subjects excluded TNF-α and IL-6 levels were measured with commercial to 3.88±0.6, −15.3%, p=0.007 vs. placebo) while it did not enzyme linked immunosorbent assay (ELISA) kits. IR was modify IL-6 (from 7.93±1.9 to 7.67±1.9 pg/mL, −3.3%, evaluated using the homeostasis model assessment of p=0.097 vs. amlodipine) and lipid profile [TC, from 4.3±0.5 insulin resistance index (HOMA-IR), defined as fasting to 4.2±0.5 mmol/L, −2.3%, p=0.10 vs. amlodipine; HDL-C, glucose (mmol/L) × fasting insulin (μU/mL) divided by from 0.43±0.05 to 0.42±0.05 mmol/L, −2.3%, p=0.114 vs.
22.5 [which has been shown to correlate well with IR amlodipine; LDL-C, from 3.6±0.4 to 3.5±0.4 mmol/L, evaluated using the clamp technique ]. Blood glucose −2.8%, p=0.10 vs. amlodipine; and Tg, from 1.2±0.4 to was measured by the glucose oxidase method and plasma 1.1±0.3 mmol/L, −8.3%, p=0.085 vs. amlodipine]. The insulin levels were determined by radioimmunoassay ].
amlodipine/atorvastatin combination produced a greater TC and TG were determined by the enzymatic method of reduction in TNF-α (2.59±0.9 pg/mL, −28.4%, p=0.007 the Chemetron Company (Frankfurt, Germany). HDL-C vs. placebo and p=0.038 vs. amlodipine monotherapy) and was determined by the enzymatic method of Roschlau [ HOMA-IR (2.86±0.4, −36.8%, p=0.0008 vs. placebo and after LDL and VLDL precipitation with polyethylene p=0.007 vs. amlodipine) and significantly reduced also IL-6 glycol 6000 by the method of Viikari ]. The LDL-C (from 7.93±1.9 to 5.59±1.2 pg/mL, −29.5%, p=0.008 vs.
was calculated by the formula of Friedewald et al. [At placebo and p=0.007 vs. amlodipine), TC (from 4.3±0.5 to each visit, all adverse drug reactions spontaneously 3.6±0.4 mmol/L, −16.7%, p=0.008 vs. placebo and vs.
reported by the patients or elicited on indirect questioning amlodipine), LDL-C (from 3.6±0.4 to 2.9±0.3 mmol/L, of the patients were recorded. Treatment compliance was p=0.008 vs. placebo and 0.007 vs. amlodipine) and TG assessed by counting the tablets remaining at each visit.
levels (from 1.2±0.4 to 0.8±0.2 mmol/L, p=0.040 vs.
Data are expressed as means±SD. Statistical analysis of placebo and p=0.041 vs. amlodipine), while increased the results was performed by repeated measures analysis of HDL-C (from 0.43±0.05 to 0.46±0.06 mmol/L, p=0.038 variance (ANOVA) for the cross-over design followed by vs. placebo and p=0.039 vs. amlodipine). BMI was the Bonferroni correction. Values of p<0.05 were consid- unchanged during treatment with both amlodipine and ered to indicate statistical significance. To verify the basic amlodipine/atorvastatin combination.
of the cross-over design [the possibility of a carry-over Correlation analysis showed no relationship between the or sequence effect was also investigated using the crossover changes in HOMA-IR, TNF-α, and IL-6 and the BP and TC changes under both treatments. HOMA-IR changeswere significantly correlated with TNF-α changes (r=0.38,p<0.05) during combination treatment but not during No serious adverse event was reported during the trial.
Fifty patients (24 males and 26 females), aged 39–65 years Six patients complained of ankle oedema, and only one were enrolled in the study and two withdrew after patient was removed from the study due to this side-effect; randomization; one due to change in her food intake habits one reported headache and one gastric discomfort during while the other refused to go on with the study due to sideeffects (ankle oedema). The main demographic and clinical Table 1 Demographic and clinical characteristics of the study characteristics are reported in Table and the main results of the 48 patients who completed the study are reported in As expected, amlodipine monotherapy was significantly effective in decreasing both systolic BP (−17.1 mm Hg, p=0.008 vs. placebo) and DBP mean values (−14.3 mm Hg, p=0.008 vs. placebo). The BP normalization (BP<140/90) was achieved in 25 patients. Interestingly, amlodipine/ atorvastatin combination produced a significantly greater reduction in both SBP (−22.5 mm Hg, p=0.007 vs. placebo, p=0.039 vs. amlodipine) and DBP (−17.6 mm Hg, p=0.007 vs. placebo, p=0.040 vs. amlodipine) than amlodipine alone; the BP normalization (BP<140/90) was achieved in Amlodipine monotherapy significantly decreased plasma BMI body mass index; SBP systolic blood pressure; DBP diastolic TNF-α levels (from 3.66±1.6 to 3.09±1.1 pg/mL, −15.6%, blood pressure; HOMA-IR insulin resistance index; LDL low- p=0.045 vs. placebo) as well as HOMA-IR (from 4.58±0.7 density lipoprotein; HDL high-density lipoprotein Table 2 Effects of treatment with placebo, amlodipine, and amlodipine/atorvastatin combination on systolic blood pressure (SBP), diastolic bloodpressure (DBP), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), andtriglycerides (Tg) Data are means±SD*=p<0.05 vs. placebo; **=p<0.01 vs. placebo; ***=p<0.001 vs. placebo; +=p<0.05 vs. amlodipine; ++=p<0.01 vs. amlodipine. Detailed values the first week of the combination therapy. Based on induced CRP production directly in the hepatocytes via counting the remaining tablets at each visit, 89% of the inhibition of protein geranylgeranylation and consequent prescribed tablets were taken during amlodipine monother-apy and 88% during combination therapy, indicating good The results of this study showed that in obese patients with hypertension and normal TC levels the amlodipine/atorvas- Amlodipine
Amlodipine-
tatin combination reduced the plasma inflammatory Atorvastatin
markers TNF-α and IL-6 and IR more than amlodipine monotherapy and also produced a greater decrease in BP In agreement with some previous observations , ], in the present study amlodipine monotherapy, besides its well-known antihypertensive effect, was effective in signif- icantly reducing TNF-α levels and improving HOMA-IR,while it did not influence IL-6 values. The effect on TNF-α has been related to the capability of amlodipine to Amlodipine
Amlodipine-
scavenger free radicals and to increase vascular Atorvastatin
prostacyclin production [two actions that are known to suppress TNF-α action or production [TNF-α is known to contribute to IR in obese subjects and its reduction may result in improved insulin sensitivity –In this study, however, the lack of correlation between TNF-α andHOMA-IR changes suggests that the observed amelioration in insulin sensitivity during amlodipine monotherapy was atleast in part independent from its effect on TNF-α.
Treatment with the amlodipine/atorvastatin combination Amlodipine
Amlodipine-
produced a greater reduction in TNF-α and HOMA-IR and Atorvastatin
also significantly decreased IL-6 values, possibly due to the * = p < 0.05 vs placebo; ** = p < 0.01 vs placebo; *** = p < 0.001 vs placebo specific action of the statin added to that of the CCB.
+ = p < 0.05 vs amlodipine; ++ = p < 0.01 vs amlodipine Previous studies have demonstrated that statins reduce the Fig. 1 Mean values of plasma levels of tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), and insulin resistance index (HOMA- expression of TNF-α and other pro-inflammatory cytokines IR) at the end of the placebo wash-out and after 12-week treatment levels in circulating monocytes as well as in adipocytes with amlodipine monotherapy or with amlodipine/atorvastatin , , ]. There is also evidence that statins reduce IL-6- reduction of transcription factor STAT3 phosphorylation 2. Stamler R (1978) Weight and blood pressure. Findings in ]. Statins also decreased IL-6-induced expression of hypertension screening of 1 million Americans. JAMA 240:1607–1610 PAI-1 in HepG2 cells, highly differentiated human hepato- 3. Aneja A, El-Atat F, McFarlane SI, Sowers JR (2004) Hypertension ma-derived cells used as in vitro models of acute-phase and obesity. Recent Prog Horm Res 59:169–205 response Such anti-inflammatory effects of statins seem 4. Reaven GM, Lithell H, Landsberg L (1996) Hypertension and to be independent from their cholesterol-lowering effect.
associated metabolic abnormalities - the role of insulin resistanceand the sympathetic nervous system. N Engl J Med 334:374–381 Indeed, in the present study no significant correlation was 5. Nishina M, Kikichi T, Yamazaki H, Kameda K, Hiura M, found between the changes in TNF-α and IL-6 levels and Uchiyama M (2003) Relationship among systolic blood pressure, the reduction in TC produced by the amlodipine/atorvastatin serum insulin and leptin and visceral fat accumulation in obese combination. A positive correlation was observed between 6. DeFronzo RA, Ferrannini E (1991) Insulin resistance. A multi- TNF-α and HOMA-IR changes during combination therapy, faceted syndrome responsible for NIDDM, obesity, hypertension, which suggests that the amelioration in insulin sensitivity dyslipidemia and atherosclerotic cardiovascular disease. Diabetes observed with amlodipine/atorvastatin combination may be mainly due to the greater reduction in TNF-α levels.
7. Schuldner AR, Yang R, Gong DW (2001) Resistin, obesity and insulin resistance: the emerging role of the adipocyte as an Many factors, like BMI and BP, might affect IR in obese endocrine organ. N Engl J Med 345:1345–1346 hypertensive patients. In the present study, however, BMI 8. Sowers JR (2003) Obesity as a cardiovascular risk factor. Am J remained unchanged during treatment with both regimens, while changes in BP did not correlate with changes in 9. Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A (1993) Tumor necrosis factor-α suppresses insulin-induced tyrosine HOMA-IR, possibly excluding the direct effect of decrease phosphorylation of insulin receptor and its substrates. J Biol The results of this study also showed that combining 10. Hotamisligil GS, Spiegelman BM (1996) TNF-α and the insulin amlodipine with atorvastatin significantly improved BP resistance of obesity. In: LeRoith D, Taylor SI, Olefsky JM (eds)Diabetes mellitus: a fundamental and clinical text. Lippincott- control. This finding, which is in agreement with previous observations by us and other authors [], confirms the 11. Hotamisligil GS, Budavari A, Murray D, Spiegelman BM (1994) positive interaction between statins and CCB also in Reduced tyrosine kinase activity of the insulin receptor in obesity- hypertensive subjects with normal TC. Such a synergism diabetes. Central role of tumor necrosis factor-α. J Clin Invest94:1543–1549 in lowering BP could be due to a direct hypotensive effect 12. Stephens JM, Lee J, Pilch PF (1997) Tumor necrosis factor-α of statins, possibly related to an improvement of endothe- induced insulin resistance in 3T3-L1 adipocytes is accompanied lium-mediated vasodilation ] and/or to the capability of by a loss of insulin receptor substrate-1 and GLUT4 expression statins to improve the sensibility of the vascular wall to the without a loss of insulin receptor mediated signal transduction.
J Biol Chem 272:971–976 13. Yudkin JS, Stehouwer CDA, Emeis JJ, Coppack SW (1999) Amlodipine-atorvastatin combination was generally well C-reactive protein in healthy subjects: association with obesity, tolerated and treatment compliance was good. Availability of insulin resistance and endothelial dysfunction. A potential role for the fixed-combination of the two drugs could possibly further cytokines originating from adipose tissue? Arterioscler ThrombVasc Biol 19:972–978 improve patients’ compliance especially in the long term.
14. Rattazzi M, Puato M, Faggin E, Bertipaglia B, Zambon A, Pauletto P (2003) C-reactive protein and interleukin-6 in vasculardisease: culprits or passive bystanders. J Hypertens 21:1787–1803 15. Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1142 The results of this study provide evidence that the 16. Trost BN, Weidmann P (1987) Effects of calcium antagonists on glucose homeostasis and serum lipids in non-diabetic and diabetic amlodipine-atorvastatin combination may be a treatment subjects: a review. J Hypertens 5(Suppl.):S81–S104 of choice in obese patients with hypertension also in the 17. Hedner T, Samuelsson O, Lindholm L (1991) Effects of presence of normal TC levels due to its ability to decrease antihypertensive therapy on glucose tolerance; focus on calcium inflammatory markers, improve insulin sensitivity, and antagonists. J Intern Med Suppl 735:101–111 18. Goyal RK (1999) Hyperinsulinemia and insulin resistance in afford greater BP control. Potential clinical benefits hypertension: differential effects of antihypertensive agents. Clin conferred by these properties in terms of cardiovascular prevention need further clinical studies.
19. Harano Y, Kageyama A, Hirose J, Asakura Y, Yokota T, Ikebuchi M et al (1995) Improvement of insulin sensitivity for glucosemetabolism with the long-acting Ca-channel blocker amlodipinein essential hypertensive subjects. Metabolism 44:315–319 20. Ueshiba H, Tsuboi K, Miyachi Y (2001) Effects of amlodipine on serum levels of adrenal androgens and insulin in hypertensive men 1. Kannel WB, Brand N, Skinner J, Dawber T, McNamara P (1967) with obesity. Horm Metab Res 33:167–169 The relation of adiposity to blood pressure and development of 21. Ersoy C, Imamoglu S, Budak F, Tuncel E, Erturk E, Oral B (2004) hypertension. The Framingham Study. Ann Intern Med 67:48–59 Effect of amlodipine on insulin resistance and tumor necrosis factor-α levels in hypertensive obese type 2 diabetic patients.
35. Viikari J (1976) Precipitation of plasma lipoproteins by PEG-6000 and its evaluation with electrophoresis and ultracentrifugation.
22. Fukuzawa M, Satoh J, Ohta S, Takahashi K, Miyaguchi S, Qiang X et al (2000) Modulation of tumor necrosis factor-α production 36. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of with antihypertensive drugs. Immunopharmacology 48:65–74 the concentration of low-density lipoprotein cholesterol in 23. Wolfrum S, Jensen KS, Liao JK (2003) Endothelium-dependent plasma without use of preparative ultracentrifuge. Clin Chem effects of statins. Arterioscler Thromb Vasc Biol 23:729–736 24. Bonnie KY, Rader DJ (2005) The effects of statin therapy on 37. Senn SJ (1993) Cross-over trials in clinical research. Wiley, New plasma markers of inflammation in patients without vascular 38. Tulenko TN, Laury-Kleintop L, Walter MF, Mason RP (1997) 25. Heart Protection Study Collaborative Group: MRC/BHF Heart Cholesterol, calcium and atherosclerosis: is there a role for Protection Study of cholesterol lowering with simvastatin in calcium channel blockers in atheroprotection? Int J Cardiol 62 20,536 high-risk individuals: a randomized, placebo-controlled 39. Pirich C, Schmidt P, Fitscha P, Wytek R, O’grady J, Sinzinger H 26. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M (1994) Influence of calcium antagonists on platelet function and et al (2003) Prevention of coronary and stroke events with vascular prostacyclin production. Blood Pressure 3(Suppl 1):75–80 atorvastatin in hypertensive patients who have average or lower 40. Chaudri G, Clark IA (1989) Reactive oxygen species facilitate the than average cholesterol concentrations in the Anglo-Scandinavian in vitro and in vivo lipopolysaccaride-induced release of tumor Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a necrosis factor. J Immunol 143:1290–1294 multicenter randomised controlled trial. Lancet 361:1149–1158 41. Eisenhut T, Shina B, Grottrup-Wolfers E, Semmler J, Siess W, 27. Yu Y, Ohmori K, Chen Y, Sato C, Kiyomoto H, Shinomiya K et al Endres S (1993) Prostacyclin analogs suppress the synthesis of (2004) Effects of pravastatin on progression of glucose intolerance tumor necrosis factor-α in LPS-stimulated human peripheral and cardiovascular remodelling in type II diabetes model. J Am blood mononuclear cells. Immunopharmacology 26:259–264 42. Grip O, Janciauskiene S, Lindgren S (2000) Pravastatin down- 28. Luo Y, Jang D, Wen D, Yang J, Li L (2004) Changes in serum regulates inflammatory mediators in human monocytes in vitro.
interleukin-6 and high sensitivity C-reactive protein levels in patients with acute coronary syndrome and their responses to 43. Rezaie-Majd A, Maca T, Bucek RA et al (2002) Simvastatin reduces expression of cytokines interleukin-6, interleukin-8 and 29. Arnaud C, Burger F, Steffens S, Veillard NR, Nguyen TH, Trono D, monocyte chemoattractant protein-1 in circulating monocytes Mach F (2005) Statins reduce interleukin-6 induced C-reactive from hypercholesterolemic patients. Arterioscl Thromb Vasc Biol protein in human hepatocytes. New evidence for direct anti- inflammatory effects of statins. Arterioscl Thromb Biol 25: 44. Borghi C, Dormi A, Veronesi M, Immordino V, Ambrosioni E (2002) Use of lipid-lowering drugs and blood pressure 30. Dong J, Fujii S, Li H, Nakabayashi H, Sakai M, Nishi S et al control in patients with arterial hypertension. J Clin Hypertens (2005) Interleukin-6 and mevastatin regulate plasminogen activa- tor inhibitor-1 through CCAAT/Enhancer-binding protein-δ.
45. Fogari R, Derosa G, Lazzari P, Zoppi A, Fogari E, Rinaldi A, Arterioscer Thromb Vasc Biol 25:1078–1084 Mugellini A (2004) Effect of amlodipine-atorvastatin combination 31. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, on fibrinolysis in hypertensive hypercholesterolemic patients with Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose 46. Fogari R, Derosa G, Destro M, Corradi L, Rinaldi A, Pasotti C, and insulin concentrations in man. Diabetologia 28:412–419 Mugellini A (2005) Effect of manidipine-simvastatin combina- 32. Lansang MC, Williams GH, Carrol J (2001) Correlation between tion on fibrinolysis, adhesion molecules and C-reactive protein the glucose clamp technique and the homeostasis model assess- in hypertensive hypercholesterolemic patients. AJH 18:171A ment in hypertension. Am J Hypertens 14:51–53 33. Heding LG (1972) Determination of total serum insulin (IRI) in 47. Ferrier KE, Muhlmann MH, Baguet JP, Cameron JD, Jennings insulin-treated diabetic patients. Diabetologia 8:260–266 GL, Dart AM, Kingwell BA (2002) Intensive cholesterol 34. Roschlau P (1974) Enzymatische bestimmung des gesamtchole- reduction lowers blood pressure and large-artery stiffness in sterin in serum. Z Klin Chem Klin Biochem 12:403 isolated systolic hypertension. J Am Coll Cardiol 39:1020–1025

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