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MAXIMUM LIPID-LOWERING THERAPY FOR FAMILIAL HYPERCHOLESTEROLEMIA: EFFICACY AND SAFETY WITH HIGH-DOSE STATIN, RESIN AND EZETIMIBE
Poster Sessions PO49 Therapeutic interventions – other PO49-765
DEVELOPMENT OF A RODENT MODEL RESPONSIVE TO MARKETED LIPID LOWERING DRUGS
J.M. Brusq, R. Guillard, M. Issandou. GSK biology department - Les Ulis France
PO49-766
EFFECT OF SHORT-TERM ADMINISTRATION OF CHOLESTYRAMINE AND CHENODEOXYCHOLIC ACID ON 7ALPHA-HYDROXY-4-CHOLESTEN-3-ONE CONCENTRATION
J. Kovar 1,2 , M. Lenicek 1,3 , L. Vitek 3 , J. Pitha 1,2 . 1 Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2 Centre for Cardiovascular Research, Prague, Czech Republic; 3 Institute of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic Background and aims: The concentration of 7alpha-hydroxy-4-cholesten3-one [C4] is assumed to be a measure of the activity of cholesterol 7alpha-hydroxylase [CYP7A1], the key enzyme of bile acid [BA] synthesis. To validate such an assumption, the concentration of C4 was measured in healthy volunteers after administration of two drugs known to affect the rate of BA synthesis. Methods: The three two-day experiments were conducted in 10 healthy men. On the first day, the fasting blood sample was obtained at 7 AM and the treatment with cholestyramine [Q] or chenodeoxycholic acid [CDCA] was started. No drug was administered in control experiment. On the second day, blood samples for determination of C4, cholesterol and BA were drawn in 90 min intervals for 15 hours from 7 AM till 10 PM. The order of experiments was randomized and they were carried out in three-week intervals. Results: Whereas the concentration of cholesterol was not affected by any treatment, fasting BA concentration rose on the second day and also 15hour area under curve [AUC] of BA was higher after treatment with CDCA. Cholestyramine administration had no effect on BA concentration. The fasting C4 concentration rose 3.7 times after Q and dropped to 30% after CDCA treatment. Similar changes were observed for AUC C4 (control: 313±137, Q: 1482±730, CDC: 87±50 ng*h/ml, p < 0.01). Similar results were obtained for C4/cholesterol ratio. Conclusions: The C4 concentration and C4/cholesterol ratio reflect expected changes of CYP7A1 activity. Supported by grant NR8987-3 from IGA MH CR.
CHANGES OF LABORATORY PARAMETERS DURING LONG-TERM EXTRACORPOREAL LDL-CHOLESTEROL ELIMINATION
M. Blaha 1 , M. Blazek 1 , V. Blaha 2 , C. Andrys 3 , J. Maly 1 , D. Sulkova 2 , D. Solichova 2 , E. Mistrik 2 . 1 IInd Internal Clinic, Faculty Hospital and Medical Faculty, Hradec Kralove, CZ; 2 Dpt. of Gerontology and Metabolism, Faculty Hospital and Medical Faculty, Hradec Kralove, CZ; 3 Institute of Immunology and Allergology, Faculty Hospital and Medical Faculty, Hradec Kralove, CZ Introduction: If the standard therapy (diet, medication) in patients with familial hypercholesterolemia (FH) failed, more aggressive measures such as LDL-apheresis are required. Changes in laboratory parameters (ionic disbalance or changes in other basic parameters of homeostasis) could be important, with side effects as the result. To verify what is the real situation is the aim of this study. Patients and methods: 9 patients (age:47±16,6 years, 6 homozygots and 3 heterozygots with long-term treatment for FH (7,2±2,96 years) were admitted to this study. Plasma obtained by continuous blood-cell separator Cobe-Spectra is then pumped into “the second stage” and run through an adsorber where defined pathogenetic elements are removed (LDL-cholesterol). Levels of biochemical and hematological parameters were measured and compared with the levels after further 100 days and, finally, after 600-800 days (mineralogram, glycemia, kreatinin, bilirubin, aminotransferases, uric acid, total cholesterol, LDL, HDL, Lp(a), TAG, Apo-A, B, parameters of blood count, t-PA, PAI-1, TP, albumin, plasma viscosity, thrombomodulin, vWf, and fibrinogen). Results: Significant decrease of target factors immediately after LDLapheresis was found (LDL, Lp(a), Apo-B). No statistically significant differences were found between laboratory parameters during the first 100 days after the therapy initiation and 600-800 days later. Side effects: 5,6%. Conclusion: The method is highly effective, it removes main pathogenetic agents in FH. The procedures are not accompanied by ionic disbalance or by significant undesirable hematological and biochemical changes; we observed minimum of side effects which are easily managed. Supported by the research task MH CZ NR/9103-4. PO49-768
MAXIMUM LIPID-LOWERING THERAPY FOR FAMILIAL HYPERCHOLESTEROLEMIA: EFFICACY AND SAFETY WITH HIGH-DOSE STATIN, RESIN AND EZETIMIBE
A. Nohara 1 , T. Noguchi 1 , H. Tada 2 , M. Mori 2 , M. Tsuchida 2 , M. Takata 2 , M. Kawashiri 2 , A. Inazu 2 , J. Kobayashi 1 , M. Yamagishi 2 , H. Mabuchi 1 . 1 Department of Lipidology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; 2 Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by LDL receptor gene mutation. FH patients suffer premature coronary disease because of high LDL-C, and intensive LDL-C lowering therapy is required even in primary prevention to improve their prognosis with full consciousness of possible adverse effects. We evaluated the safety and efficacy of clinically available maximally intensive therapy in FH patients. Methods and results: Eleven FH patients (M/F=6/5) with established CAD were enrolled. [Mean age 62±7 yrs, TC 380±69, TG 133± 49, HDL-C 43±11, LDL-C 299±71 in basal (Mean ± SD; mg/dl.)] Atorvasatin 40mg with resin (n=5) or rosuvastatin 20mg with resin (n=9; 3 were overlapped with atorvastatin group) achieved -42% reduction in TC and -53% in LDL-C, and +18% increase in HDL-C. AST and ALT slightly but significantly increased +27% in each, and CPK increased +28%, but most of them were within normal limit. Ezetimibe was additionally prescribed to high dose statin and resin in 3 patients, and LDL-C was reduced -10% furthermore without hepatic and muscle enzyme elevation. Even with these intensive therapy, LDL-C goal (<100mg/dl) were achieved only in 1 patient. Conclusion: These results suggests the efficacy, safety and limitation of intensive oral medication available in Japan. Further therapeutics should be considered if needed.
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey
POSTER SESSIONS
Background and aims: Statins represent the major class of hypolipidemic drugs. Ezetimibe, a new LDL cholesterol-lowering therapy acting through inhibition of cholesterol absorption is mainly prescribed in combination with statins. The objective of this combination is to reach the National Cholesterol Education Program’s goal (NCEP/ATPIII guidelines) and to limit potential side effects observed with high doses of statins. Clearly, the discovery of new drugs that could be developed in combination with statins is still of interest. This requires convenient, robust and validated rodent models, knowing that the main drawback of animal models of dyslipidemia is their lack of response to statins regarding LDL cholesterol lowering. Here, we describe the effects of Atorvastatin and Ezetimibe in a CETP transgenic model. Methods: CETP transgenic mice were fed with a lipid/cholate –rich diet for 8 weeks. Dyslipidemic mice were then orally treated for 11 days with Atorvastatin (0.5 mg/kg/day) or Ezetimibe (5 mg/kg/day). Results: Upon diet, CETP Tg mice displayed a humanized LDLchol/HDLchol ratio (2.5 compared to 0.2 in chow fed C57Bl6 mice). Alteration of the LDL/HDL ratio was due to an increase in the LDL cholesterol fraction and a parallel decrease in the HDL fraction. Dyslipidemic mice treated with Atorvastatin or Ezetimibe, showed a 32 and 41% decrease in LDL cholesterol, respectively. As expected, the decrease in LDL cholesterol levels was accompanied by an increase in hepatic LDL receptor expression. Conclusions: These results suggest that this rodent model could be useful for validation and evaluation of new lipid lowering agents.
PO49-767
207
DEVELOPMENT OF A RODENT MODEL RESPONSIVE TO MARKETED LIPID LOWERING DRUGS
J.M. Brusq, R. Guillard, M. Issandou. GSK biology department - Les Ulis France
PO49-766
EFFECT OF SHORT-TERM ADMINISTRATION OF CHOLESTYRAMINE AND CHENODEOXYCHOLIC ACID ON 7ALPHA-HYDROXY-4-CHOLESTEN-3-ONE CONCENTRATION
J. Kovar 1,2 , M. Lenicek 1,3 , L. Vitek 3 , J. Pitha 1,2 . 1 Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2 Centre for Cardiovascular Research, Prague, Czech Republic; 3 Institute of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic Background and aims: The concentration of 7alpha-hydroxy-4-cholesten3-one [C4] is assumed to be a measure of the activity of cholesterol 7alpha-hydroxylase [CYP7A1], the key enzyme of bile acid [BA] synthesis. To validate such an assumption, the concentration of C4 was measured in healthy volunteers after administration of two drugs known to affect the rate of BA synthesis. Methods: The three two-day experiments were conducted in 10 healthy men. On the first day, the fasting blood sample was obtained at 7 AM and the treatment with cholestyramine [Q] or chenodeoxycholic acid [CDCA] was started. No drug was administered in control experiment. On the second day, blood samples for determination of C4, cholesterol and BA were drawn in 90 min intervals for 15 hours from 7 AM till 10 PM. The order of experiments was randomized and they were carried out in three-week intervals. Results: Whereas the concentration of cholesterol was not affected by any treatment, fasting BA concentration rose on the second day and also 15hour area under curve [AUC] of BA was higher after treatment with CDCA. Cholestyramine administration had no effect on BA concentration. The fasting C4 concentration rose 3.7 times after Q and dropped to 30% after CDCA treatment. Similar changes were observed for AUC C4 (control: 313±137, Q: 1482±730, CDC: 87±50 ng*h/ml, p < 0.01). Similar results were obtained for C4/cholesterol ratio. Conclusions: The C4 concentration and C4/cholesterol ratio reflect expected changes of CYP7A1 activity. Supported by grant NR8987-3 from IGA MH CR.
CHANGES OF LABORATORY PARAMETERS DURING LONG-TERM EXTRACORPOREAL LDL-CHOLESTEROL ELIMINATION
M. Blaha 1 , M. Blazek 1 , V. Blaha 2 , C. Andrys 3 , J. Maly 1 , D. Sulkova 2 , D. Solichova 2 , E. Mistrik 2 . 1 IInd Internal Clinic, Faculty Hospital and Medical Faculty, Hradec Kralove, CZ; 2 Dpt. of Gerontology and Metabolism, Faculty Hospital and Medical Faculty, Hradec Kralove, CZ; 3 Institute of Immunology and Allergology, Faculty Hospital and Medical Faculty, Hradec Kralove, CZ Introduction: If the standard therapy (diet, medication) in patients with familial hypercholesterolemia (FH) failed, more aggressive measures such as LDL-apheresis are required. Changes in laboratory parameters (ionic disbalance or changes in other basic parameters of homeostasis) could be important, with side effects as the result. To verify what is the real situation is the aim of this study. Patients and methods: 9 patients (age:47±16,6 years, 6 homozygots and 3 heterozygots with long-term treatment for FH (7,2±2,96 years) were admitted to this study. Plasma obtained by continuous blood-cell separator Cobe-Spectra is then pumped into “the second stage” and run through an adsorber where defined pathogenetic elements are removed (LDL-cholesterol). Levels of biochemical and hematological parameters were measured and compared with the levels after further 100 days and, finally, after 600-800 days (mineralogram, glycemia, kreatinin, bilirubin, aminotransferases, uric acid, total cholesterol, LDL, HDL, Lp(a), TAG, Apo-A, B, parameters of blood count, t-PA, PAI-1, TP, albumin, plasma viscosity, thrombomodulin, vWf, and fibrinogen). Results: Significant decrease of target factors immediately after LDLapheresis was found (LDL, Lp(a), Apo-B). No statistically significant differences were found between laboratory parameters during the first 100 days after the therapy initiation and 600-800 days later. Side effects: 5,6%. Conclusion: The method is highly effective, it removes main pathogenetic agents in FH. The procedures are not accompanied by ionic disbalance or by significant undesirable hematological and biochemical changes; we observed minimum of side effects which are easily managed. Supported by the research task MH CZ NR/9103-4. PO49-768
MAXIMUM LIPID-LOWERING THERAPY FOR FAMILIAL HYPERCHOLESTEROLEMIA: EFFICACY AND SAFETY WITH HIGH-DOSE STATIN, RESIN AND EZETIMIBE
A. Nohara 1 , T. Noguchi 1 , H. Tada 2 , M. Mori 2 , M. Tsuchida 2 , M. Takata 2 , M. Kawashiri 2 , A. Inazu 2 , J. Kobayashi 1 , M. Yamagishi 2 , H. Mabuchi 1 . 1 Department of Lipidology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; 2 Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by LDL receptor gene mutation. FH patients suffer premature coronary disease because of high LDL-C, and intensive LDL-C lowering therapy is required even in primary prevention to improve their prognosis with full consciousness of possible adverse effects. We evaluated the safety and efficacy of clinically available maximally intensive therapy in FH patients. Methods and results: Eleven FH patients (M/F=6/5) with established CAD were enrolled. [Mean age 62±7 yrs, TC 380±69, TG 133± 49, HDL-C 43±11, LDL-C 299±71 in basal (Mean ± SD; mg/dl.)] Atorvasatin 40mg with resin (n=5) or rosuvastatin 20mg with resin (n=9; 3 were overlapped with atorvastatin group) achieved -42% reduction in TC and -53% in LDL-C, and +18% increase in HDL-C. AST and ALT slightly but significantly increased +27% in each, and CPK increased +28%, but most of them were within normal limit. Ezetimibe was additionally prescribed to high dose statin and resin in 3 patients, and LDL-C was reduced -10% furthermore without hepatic and muscle enzyme elevation. Even with these intensive therapy, LDL-C goal (<100mg/dl) were achieved only in 1 patient. Conclusion: These results suggests the efficacy, safety and limitation of intensive oral medication available in Japan. Further therapeutics should be considered if needed.
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey
POSTER SESSIONS
Background and aims: Statins represent the major class of hypolipidemic drugs. Ezetimibe, a new LDL cholesterol-lowering therapy acting through inhibition of cholesterol absorption is mainly prescribed in combination with statins. The objective of this combination is to reach the National Cholesterol Education Program’s goal (NCEP/ATPIII guidelines) and to limit potential side effects observed with high doses of statins. Clearly, the discovery of new drugs that could be developed in combination with statins is still of interest. This requires convenient, robust and validated rodent models, knowing that the main drawback of animal models of dyslipidemia is their lack of response to statins regarding LDL cholesterol lowering. Here, we describe the effects of Atorvastatin and Ezetimibe in a CETP transgenic model. Methods: CETP transgenic mice were fed with a lipid/cholate –rich diet for 8 weeks. Dyslipidemic mice were then orally treated for 11 days with Atorvastatin (0.5 mg/kg/day) or Ezetimibe (5 mg/kg/day). Results: Upon diet, CETP Tg mice displayed a humanized LDLchol/HDLchol ratio (2.5 compared to 0.2 in chow fed C57Bl6 mice). Alteration of the LDL/HDL ratio was due to an increase in the LDL cholesterol fraction and a parallel decrease in the HDL fraction. Dyslipidemic mice treated with Atorvastatin or Ezetimibe, showed a 32 and 41% decrease in LDL cholesterol, respectively. As expected, the decrease in LDL cholesterol levels was accompanied by an increase in hepatic LDL receptor expression. Conclusions: These results suggest that this rodent model could be useful for validation and evaluation of new lipid lowering agents.
PO49-767
207