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2P-0615 Rosuvastatin is a potent hepatoselective inhibitor of sterol synthesis in human cells in vitro
Tuesday September 30, 2003: Poster Session Therapy who had 1 AE or more were the same (57%) in both RSV 10-40 mg (n=453) and placebo groups (n=382). In fixed-dose controlled trials, RSV 10-40 mg showed an AE profile similar to those for atorvastatin 10-80 mg, simvastatin 10-80 mg and pravastatin 10-40 mg. Clinically significant ALT increases occurred in <0.1% of patients receiving RSV 10-40 mg. In all controlled and uncontrolled trials, AEs attributed to RSV 1-80 mg (n=7316) were generally mild and transient: myalgia, ALT or AST increased, CK increased, asthenia, nausea, abdominal pain and constipation. In all controlled and uncontrolled trials plus ongoing trials, treatment-related myopathy (muscle symptoms plus CK increases >10 × ULN) occurred in ≤0.03% of patients in the RSV 10-40 mg group. Occurrence of proteinuria at RSV doses up to 40 mg was comparable to that seen with other statins and was not predictive of acute or progressive renal disease. No deaths in the program were attributed to RSV and no rhabdomyolysis occurred in patients receiving RSV 10-40 mg. At doses from 10-40 mg, rosuvastatin was well tolerated and its safety profile compared favorably with other marketed statins investigated in a large clinical trial program. 2P-0614
How does the time to treatment effect the long term prognosis of patients with acute myocardial infarction treated with PCI ?
S. Simek, M. Aschermann, J. Horak, V. Reznicek, L. Golan, J. Humhal, J.C. Lubanda. 1st School of Medicine, General Faculty Hospital, II. Interni Klinika VFN, Prague, Czech Republic
2P-0615
Rosuvastatin is a potent hepatoselective inhibitor of sterol synthesis in human cells in vitro
L.H. Cohen, R.E.W. Van Leeuwen, G.C.F. Van Thiel. TNO Prevention and Health, Gaubius Laboratory, Netherlands The ability of statins to inhibit HMG-CoA reductase within cells is dependent on the affinity for the enzyme and their ability to enter cells. We investigated the potency of 4 statins on the inhibition of cholesterol synthesis in human primary cells: hepatocytes, skeletal myoblasts, vascular smooth muscle cells (VSMC) and human umbilical vein endothelial cells (HUVEC). The IC50 for inhibition was determined by incorporation of [14 C]-acetate into sterols; the effect on cell proliferation and apoptosis was also measured for simvastatin and rosuvastatin. In hepatocytes the order of potency was rosuva >>atorva = simva > prava. All statins were more potent in hepatocytes compared to non-hepatic cells but the degree of selectivity varied considerably. However, in non-hepatic cells, the order of potency was the same as the order of lipophilicity, with lipophilic statins having the highest potency due to a higher rate of passive diffusion into cells. In contrast, in hepatocytes, which possess liver-specific organic
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
-0.3 ± 0.1
1.1 ± 0.0
1.6 ± 0.1
-0.8 ± 0.1
0.018 28 81 39
0.94 4.5 7.0 8.9
2.5 4.0 1.9 0.5
9.0 7000 2800 3800
anion transporter proteins with known affinity for statins, the hydrophilic compounds enter cells more rapidly with an overall potency being highest for rosuvastatin, a relatively hydrophilic molecule with greater enzyme affinity than pravastatin. Cytoskeletal changes and apoptosis in VSMC were seen only at high concentrations and long exposure of simvastatin and rosuvastatin, and were reversed by mevalonate co-incubation. Concomitant decreases in the activation of prenylated proteins Rac1 and Rho-A were detected, indicating a role for depletion of important regulatory isoprenoid intermediates. Thus rosuvastatin displays optimised features for liver-directed potency and lipid-lowering efficacy, with low potential for adverse extrahepatic cellular effects. 2P-0616
The effect of hormone replacement therapy on cardiovascular performance
M. Düzenli, K. Özdemir, A. Sökmen, M. Tokaç, A. Soylu, M. Yazýcý, B. Altunkeser. Selcuk University School of Medicine, Selcuk, Turkey Objective: Recent studies demonstrated that hormone replacement therapy (HRT) had no place at preventing from cardiovascular diseases. However, the effect of HRT on cardiovascular functions hasn’t been investigated widely. In this study, it is aimed to investigate the short term effects of HRT on cardiovascular functions in healthy postmenopausal women. Methods: Thirty-seven patients given HRT were taken as study group and 32 patients with qualifications similar to study group were taken as control group. Treadmill exercise test and standard echocardiography were performed to every patient. Concurrently, by using pulsed wave tissue Doppler, systolic and diastolic time intervals were measured and myocardial performance index was calculated. After three months, the same processes were repeated, and then baseline and 3 month values were compared. Results: Exercise duration (p<0.001) and METS (p<0.001) value were detected to increase significantly after 3 months in HRT taking group. Although myocardial performance index (MPI) values decreased after 3 months in HRT taking group, this result was not statistically significant. There was no statistically significant change at LV segmental Sm, mean Sm, and tricuspid Sm levels of the tissue Doppler parameters after 3 months in both groups. As mean LV Em increased in HRT group, Am level decreased and Em/Am ratio increased. Nevertheless these changes couldn’t reach to a statistically significance. Conclusion: We detected improvement in cardiac response to exercise by using HRT. MPI reduction indicating improvement in cardiac functions didn’t reach to statistically significance. Long term, wide spectrum randomized studies are needed to expose whether this improvement trend will be significant or not. 2P-0617
Pleiotropic effects after a 3-day treatment with the lipid lowering drugs in patients with coronary artery disease
M. Celinska-Lowenhoff, A. Undas, T. Domagala, T. Iwaniec, A. Szczeklik. Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland The present study aimed to evaluate the short-term effect of these agents on blood coagulation and inflammatory markers in hypercholesterolemic patients with coronary artery disease (CAD). In a randomized, double-blind study, patients with documented stable angina and cholesterol LDL > 3.4 mmol/L were assigned to a 3-day treatment with either simvastatin [Merck Sharp and Dohme] (40 mg/d) or fenofibrate micronised [Fournier Laboratoires] (160 mg/d). Before and after a 3-day treatment, C-reactive protein (CRP), interleukin-6 (IL-6) and thrombin-antithrombin complexes (TAT) were measured in the venous blood; TAT levels were also determined twice in the blood collected every 30 seconds from the standardized skin incisions. In 24 patients treated with simvastatin or fenofibrate, cholesterol LDL decreased already after 3 doses of both agents. Simultaneously, thrombin generation, as evidenced by plasma TAT concentrations, was slightly attenuated as early as
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
Aims: The benefit of thrombolysis in patients with acute myocardial infarction (AMI) strongly depends on the time from onset of AMI to the initiation of treatment (TT). For AMI patients treated with PCI this time seems to be less important. The aim of this study was to assess the influence of TT of AMI with PCI on short and long term prognosis. Methods: We followed 339 consecutive AMI patients treated with PCI in one centre. Patients were divided to five groups according to TT. Results: TT < 90 min was achieved in 10.5; 91-210 min in 31; 211-330 min in 21; 331-690 min in 22; >691 min in 15.5% of patients. Ischemic time in the groups was <2h; 2-4h; 4-6h; 6-12h; >12h. The 30d mortality was 5.7%, 2.9%, 11.1%, 10.8%, 11.3% in the groups respectively, showing no signif. differences. However the higher rate of TIMI 3 flow was achieved in patients with TT shorter than 3.5 h compared to patients treated later (93.6% vs. 83.9%, p=0.007). The lower 30d mortality (3.6% vs. 11.1%, p=0.012), lower 3y mortality (8.6% vs. 19.1%, p=0.003), lover frequency of heart failure during hospitalisation (11.4% vs. 28.1%, p<0.001) as well as lower maximal level of released kreatinkinase (32+29 vs. 44+39 µkat/l, p=0.005) was observed in patients treated within 3.5 h from symptoms onset compared to patients treated later. Conclusion: The success rate of primary PCI to achieve normal flow in infarct related artery is high, but decreases when TT is longer than 3.5 h. The short and long term mortality as well as heart failure incidence is lowest when the intervention was started within 3.5 h from AMI onset. Initiation of intervention after 3.5 h resulted in significant mortality increase, but further delay of treatment had minimal impact on patients prognosis. Great effort needs to be paid to start the primary PTCA within 3.5 h from AMI onset in as many patients as possible. Sponsored by LN00B107.
Lipophilicity (Log D at pH 7.4) Mean IC50 (nM) Hepatocytes VSMC Skeletal myoblasts HUVEC
175
How does the time to treatment effect the long term prognosis of patients with acute myocardial infarction treated with PCI ?
S. Simek, M. Aschermann, J. Horak, V. Reznicek, L. Golan, J. Humhal, J.C. Lubanda. 1st School of Medicine, General Faculty Hospital, II. Interni Klinika VFN, Prague, Czech Republic
2P-0615
Rosuvastatin is a potent hepatoselective inhibitor of sterol synthesis in human cells in vitro
L.H. Cohen, R.E.W. Van Leeuwen, G.C.F. Van Thiel. TNO Prevention and Health, Gaubius Laboratory, Netherlands The ability of statins to inhibit HMG-CoA reductase within cells is dependent on the affinity for the enzyme and their ability to enter cells. We investigated the potency of 4 statins on the inhibition of cholesterol synthesis in human primary cells: hepatocytes, skeletal myoblasts, vascular smooth muscle cells (VSMC) and human umbilical vein endothelial cells (HUVEC). The IC50 for inhibition was determined by incorporation of [14 C]-acetate into sterols; the effect on cell proliferation and apoptosis was also measured for simvastatin and rosuvastatin. In hepatocytes the order of potency was rosuva >>atorva = simva > prava. All statins were more potent in hepatocytes compared to non-hepatic cells but the degree of selectivity varied considerably. However, in non-hepatic cells, the order of potency was the same as the order of lipophilicity, with lipophilic statins having the highest potency due to a higher rate of passive diffusion into cells. In contrast, in hepatocytes, which possess liver-specific organic
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
-0.3 ± 0.1
1.1 ± 0.0
1.6 ± 0.1
-0.8 ± 0.1
0.018 28 81 39
0.94 4.5 7.0 8.9
2.5 4.0 1.9 0.5
9.0 7000 2800 3800
anion transporter proteins with known affinity for statins, the hydrophilic compounds enter cells more rapidly with an overall potency being highest for rosuvastatin, a relatively hydrophilic molecule with greater enzyme affinity than pravastatin. Cytoskeletal changes and apoptosis in VSMC were seen only at high concentrations and long exposure of simvastatin and rosuvastatin, and were reversed by mevalonate co-incubation. Concomitant decreases in the activation of prenylated proteins Rac1 and Rho-A were detected, indicating a role for depletion of important regulatory isoprenoid intermediates. Thus rosuvastatin displays optimised features for liver-directed potency and lipid-lowering efficacy, with low potential for adverse extrahepatic cellular effects. 2P-0616
The effect of hormone replacement therapy on cardiovascular performance
M. Düzenli, K. Özdemir, A. Sökmen, M. Tokaç, A. Soylu, M. Yazýcý, B. Altunkeser. Selcuk University School of Medicine, Selcuk, Turkey Objective: Recent studies demonstrated that hormone replacement therapy (HRT) had no place at preventing from cardiovascular diseases. However, the effect of HRT on cardiovascular functions hasn’t been investigated widely. In this study, it is aimed to investigate the short term effects of HRT on cardiovascular functions in healthy postmenopausal women. Methods: Thirty-seven patients given HRT were taken as study group and 32 patients with qualifications similar to study group were taken as control group. Treadmill exercise test and standard echocardiography were performed to every patient. Concurrently, by using pulsed wave tissue Doppler, systolic and diastolic time intervals were measured and myocardial performance index was calculated. After three months, the same processes were repeated, and then baseline and 3 month values were compared. Results: Exercise duration (p<0.001) and METS (p<0.001) value were detected to increase significantly after 3 months in HRT taking group. Although myocardial performance index (MPI) values decreased after 3 months in HRT taking group, this result was not statistically significant. There was no statistically significant change at LV segmental Sm, mean Sm, and tricuspid Sm levels of the tissue Doppler parameters after 3 months in both groups. As mean LV Em increased in HRT group, Am level decreased and Em/Am ratio increased. Nevertheless these changes couldn’t reach to a statistically significance. Conclusion: We detected improvement in cardiac response to exercise by using HRT. MPI reduction indicating improvement in cardiac functions didn’t reach to statistically significance. Long term, wide spectrum randomized studies are needed to expose whether this improvement trend will be significant or not. 2P-0617
Pleiotropic effects after a 3-day treatment with the lipid lowering drugs in patients with coronary artery disease
M. Celinska-Lowenhoff, A. Undas, T. Domagala, T. Iwaniec, A. Szczeklik. Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland The present study aimed to evaluate the short-term effect of these agents on blood coagulation and inflammatory markers in hypercholesterolemic patients with coronary artery disease (CAD). In a randomized, double-blind study, patients with documented stable angina and cholesterol LDL > 3.4 mmol/L were assigned to a 3-day treatment with either simvastatin [Merck Sharp and Dohme] (40 mg/d) or fenofibrate micronised [Fournier Laboratoires] (160 mg/d). Before and after a 3-day treatment, C-reactive protein (CRP), interleukin-6 (IL-6) and thrombin-antithrombin complexes (TAT) were measured in the venous blood; TAT levels were also determined twice in the blood collected every 30 seconds from the standardized skin incisions. In 24 patients treated with simvastatin or fenofibrate, cholesterol LDL decreased already after 3 doses of both agents. Simultaneously, thrombin generation, as evidenced by plasma TAT concentrations, was slightly attenuated as early as
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
Aims: The benefit of thrombolysis in patients with acute myocardial infarction (AMI) strongly depends on the time from onset of AMI to the initiation of treatment (TT). For AMI patients treated with PCI this time seems to be less important. The aim of this study was to assess the influence of TT of AMI with PCI on short and long term prognosis. Methods: We followed 339 consecutive AMI patients treated with PCI in one centre. Patients were divided to five groups according to TT. Results: TT < 90 min was achieved in 10.5; 91-210 min in 31; 211-330 min in 21; 331-690 min in 22; >691 min in 15.5% of patients. Ischemic time in the groups was <2h; 2-4h; 4-6h; 6-12h; >12h. The 30d mortality was 5.7%, 2.9%, 11.1%, 10.8%, 11.3% in the groups respectively, showing no signif. differences. However the higher rate of TIMI 3 flow was achieved in patients with TT shorter than 3.5 h compared to patients treated later (93.6% vs. 83.9%, p=0.007). The lower 30d mortality (3.6% vs. 11.1%, p=0.012), lower 3y mortality (8.6% vs. 19.1%, p=0.003), lover frequency of heart failure during hospitalisation (11.4% vs. 28.1%, p<0.001) as well as lower maximal level of released kreatinkinase (32+29 vs. 44+39 µkat/l, p=0.005) was observed in patients treated within 3.5 h from symptoms onset compared to patients treated later. Conclusion: The success rate of primary PCI to achieve normal flow in infarct related artery is high, but decreases when TT is longer than 3.5 h. The short and long term mortality as well as heart failure incidence is lowest when the intervention was started within 3.5 h from AMI onset. Initiation of intervention after 3.5 h resulted in significant mortality increase, but further delay of treatment had minimal impact on patients prognosis. Great effort needs to be paid to start the primary PTCA within 3.5 h from AMI onset in as many patients as possible. Sponsored by LN00B107.
Lipophilicity (Log D at pH 7.4) Mean IC50 (nM) Hepatocytes VSMC Skeletal myoblasts HUVEC
175