Tuesday September 30, 2003: Poster Session
166 Therapy
2P-0576 Pitavastatin inhibits atherosclerosis induced by chronic inhibition of nitric oxide synthesis in moderate hypercholesterolemic rabbits via inhibiting macrophage accumulation and macrophage foam cell formation
M. Kitahara1, T. Tamaki2, Y. Saito3.1Biological Research Laboratories, Nissan Chemical Industries Ltd., Saitama;2Tokyo Research Laboratories, Kowa Company Ltd.;3The Second Department of Internal Medicine, School of Medicine, Chiba University, Japan
Objective:To elucidate the effect of statin on atherosclerosis in moderate
hy-percholesterolemia and inflammatory responses in atherosclerosis, we studied the effect of pitavastatin on chronic nitric oxide synthase(NOS) inhibition-accelerated atherosclerosis in rabbits, monocyte-endothelial cell adhesion, macrophage foam cell formation and cholesterol efflux from macrophages.
Methods:After 1 week preconditioning with low dose L(w)-nitro
argi-nine methyl ester(L-NAME), rabbits were fed 0.2% cholesterol and 0.175% L-NAME containing diet and orally administered with pitavastatin(0.1 or 0.3 mg/kg/day) for 8 weeks. THP-1 cells and human umbilical vein endothelial cells(HUVEC) were treated with statins for 48 hrs, and THP-1 cells were loaded on HUVEC for 2 hrs. RAW264.7 cells were treated with statins for 26 hrs and incubated with acetylated LDL or oxidized LDL for 3 days and cholesterol ester was measured. In cholesterol efflux assay, RAW264.7 cells were labeled with14C-cholesterol and incubated with statins for 30 hrs.
Results:Pitavastatin suppressed the surface atherosclerotic lesion area of
the aorta and intimal thickening(intima/media ratio), RAM11 anti-macrophage antibody positive area and Oil red O stained area of the aortic arch. Pitavas-tatin potently inhibited cholesterol ester accumulation in RAW264.7 cells and THP-1 cell adhesion to HUVEC. These inhibitory effects of pitavastatin were attenuated by mevalonate. Atorvastatin suppressed cholesterol efflux from RAW264.7 cells but pitavastatin did not.
Conclusion:Pitavastatin suppressed chronic inhibition of NOS-accelerated
development of atherosclerosis with suppression of macrophage and lipid accumulation via inhibiting monocytes-endothelial cell adhesion and macro-phage foam cell formation in moderate hypercholesterolemic rabbits.
2P-0577 Effects of atorvastatin on plasma fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and serum homocysteine in patients with familial hypercholesterolaemia (FH) and non-familial hypercholesterolaemia (NFH)
T. Rahman, S. Muid, N.S. Osman, K. Yusoff, H. Nawawi.Faculty of Medicine, Universiti Kebangsaan Malaysia, Malaysia
Objective: To determine the effects of atorvastatin on plasma fibrinogen,
plasminogen activator inhibitor-1(PAI-1) and serum homocysteine (Hcys) levels in patients with Familial Hypercholesterolaemia(FH) and non-Familial Hypercholesterolaemia(NFH).
Materials and Methods:113 patients (47 FH and 66 NFH, 59 males,
54 females, mean±SD age=45.3±years) and 40 age and gender matched nor-molipaemic controls were recruited. FH patients were treated with 80mg/day atorvastatin (FHs) and NFH patients were either given 10mg/day atorvastatin (NFHs) or placebo (NFHp). Fasting blood samples were analysed for lipid pro-file, fibrinogen, PAI-1 and Hcys at baseline, 2 weeks, 3 months and 9 months.
Results:At baseline, the Hcys levels of FHs and NFHs were higher than
controls (mean D: 9.4±2.9 vs 10.5±3.6 vs 7.8±2.4µmol/L, p<0.05 and p<0.005 respectively). Baseline PAI-1 and fibrinogen levels were similar between all patients and controls. Compared to baseline, fibrinogen levels in-creased in FH patients at 3 months and 9 months (median[95%CI]: 1.4[0.3-4.0] vs 2.2[0.2-4.1] vs 2.5[0.7-6.5g/L], p<0.005), and in NFH patients at 9 months (1.6[0.4-3.9] vs 2.4[1.5-4.8g/L], p<0.005). There was no change in fibrinogen levels in the NFHp group. Compared to baseline, there was reduction in PAI-1 levels in FHs group at 2 weeks (40.4[11.8-106.9] vs 31.3[6.0-128.2ng/mL], p<0.05) and in NFHs at 9 months (49.2[17.3-108.5] vs 35.9[13.9-83.2ng/mL], p<0.05). Hcys levels were reduced in NFHs patients at 9 months compared to baseline (10.[4.8-24.1] vs 9.2[6.0-16.5µmol/L], p<0.05).
Conclusion:There is a reduction in PAI-1 and Hcys levels but an
incre-ment in fibrinogen levels in atorvastatin treated FH and NFH patients, but not in the NFHp group. This suggests a reduction in prothrombotic state with atorvastatin treatment. However, the clinical significance of increment in fibrinogen levels remains to be established.
2P-0578 Combination of fluvastatin and fibrates: Effects of baseline triglycerides on changes in lipid profile
M. Farnier1, S. Dejager2, A.J. Troendle3, M. Bortoloni4.1Point Medical, Dijon, France;2Novartis East Hanover NJ;3Medpace, Cincinnati, OH; 4Novartis East Hanover, NJ, USA
The effect of baseline triglycerides (TG) on the changes in lipid and lipoprotein levels when treated with combination fluvastatin-fibrate therapy was assessed in a pooled analysis of 1018 patients with either mixed hyperlipidemia or primary hypercholesterolemia from 10 studies. For these patients, the mean dose of fluvastatin was 55.7 mg and the mean exposure was 37.7 weeks. Three fibrates were used: bezafibrate (n=493), fenofibrate (n=158) and gemfibrozil (n=367). Progressively greater reductions in TG were observed in patients with larger baseline TG levels (from 13.5% reduction in patients with baseline TG below 150 mg/dl to 40.9% reduction in patients with baseline TG greater than or equal to 400 mg/dl). On the opposite, larger reductions in LDL cholesterol were observed in patients with lower baseline TG levels, with the greatest percent reduction (34.7%) occurring in the subgroup of patients with baseline TG below 150 mg/dl. The greatest reduction (33.3%) in non-HDL cholesterol also occurred in patients with baseline TG below 150 mg/dl, but the range in reductions for non-HDL cholesterol across baseline TG subgroups was not as large as that observed for LDL cholesterol. There were no serious adverse events related to combined fluvastatin-fibrate therapy and only two patients had a creatine kinase level more than 10 times the upper limit of normal. Combination therapy with fluvastatin and a fibrate often results in an obvious improvement in all the lipid abnormalities that are present in combined hyperlipidemia.
2P-0579 Pleiotropic effects of fluvastatin on diabetic patients with hypercholesterolemia
H. Hayashi1, N. Kasahata1, H. Kawamitsu1, T. Amakawa1, E. Murakami2, G. Yoshino2.1Yokohama Red Cross Hospital, Yokohama;2Toho University, Japan
Objectives: Fluvastin has pleiotropic effects on atherosclerosis besides its
hypocholesterolemic action. The objectives of this study were to see pleiotropic effects of fluvastitin on diabetic patients and to observe several pleiotropic effects of fluvastatin simultaneously.
Methods:15 diabetic patients with hypercholesterolemia were treated with
20 mg/day of fluvastatin for 6 months. Various parameters measured were as follows: serum high-sensitive C-reactive protein (HS-CRP), urinary 8-iso-PGF2αexcretion, urinary 8-hydroxy-2-deoxyguanosine (8OHdG) excretion, serum VCAM-1, serum L-selectin, serum interleukin-18 (IL-18), and the size of LDL particles, which was expressed as the relative mobility of LDL in poly-acrylamide gel electrophoresis. Differences before and after the treatment were tested for significance by the Wilcoxon matched-pair, signed-rank sum test.
Results:Diabetic control did not change during the fluvastatin treatment.
Total cholesterol (240± 42 (mean±SD) vs 212 ±40 mg/dl, p<0.05) and LDL cholesterol (142±52 vs 101±26 mg/dl, p<0.01) significantly decreased while triglyceride and HDL cholesterol did not change. 8OHdG (9.6±4.1 vs 8.0±3.0 ng/mg creatinine, p<0.05), L-selectin (1032.1±
130.8 vs 958.6±164.2 ng/ml, p<0.01), and IL-18 (320.8±136.4 vs 258.6
±97.6 pg/ml, p<0.01) significantly decreased. Relative mobility of LDL significantly decreased from 0.398 ±0.035 to 0.370±0.045 (p<0.01), which means the size of LDL increased. The other parameters did not change significantly.
Conclusions:Pleiotropic effects of fluvastatin were exerted in diabetic
patients with hypercholesterolemia.
2P-0580 Anti-atherosclerotic effect of the novel acyl-CoA: cholesterol acyltransferase inhibitor, K-10191, on high cholesterol-fed rabbits
Y. Yoshinaka, H. Kobayashi, K. Kawamine, K. Shibuya, F. Sato.Kowa Company, Ltd., Tokyo, Japan
Objective: Acyl-CoA: cholesterol acyltransferase (ACAT) is considered to
be associated with the progression of atherosclerotic lesions and foamed macrophages formation. In this paper, we evaluated the effect of K-10191 histologically on the atherosclerotic legions induced by high cholesterol-diet in rabbits.
Methods:The atherosclerosis was induced by 1% cholesterol-diet for 8
weeks in NZW rabbits. Concurrently K-10191 (0.3 to 3 mg/kg, bid) was administered orally. On the next day of the final treatment, plasma lipids were
