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W06.168 Effect of extended-release fluvastatin on serum lipids and paraoxonase activity
Workshops W6 Antiatherogenic functions of HDL analogues (NNRTI). Nevertheless, adverse effects at'e multiple and potentially life-ttu'eatening, including fat redistribution syn&'ome and hypel: lipidemia. This dyslipidemia shows an atherogenic profile: increased-LDL cholesterol, decreased-HDL-cholesterol and hypertriglyceridemia. Some studies have described that switching PI to a NNRTI could be of benefit to control these lipid changes, and therefore, to prevent future clinical implications. Efavfl'enz, a lipophylic NNRTI has been shown to improve this atherogenic profile in patients with HAART-related dyslipemia when the PI is withdrawn. We have observed that Efavfl'enz increases HDL-cholesterol when prescribed on substitution of a PI but also in na ve patients in a triglyceride-independent manner suggesting an implication of cholesteryl ester transfer protein (CETP) since this protein exchanges neutral lipids between lipoproteins and can be inhibited by lipophylic &'ugs. Hypothesis: Efavfl'enz improves lipoprotein profile by inhibiting CETE Methods and Patients: CETP activity was measut'ed by the CETP Activity-Assay-Kit, Medical & Biological-Laboratories Co., in 20 plasma samples of HIV-infected patients before Efavfl'enz administration and 48 weeks after continuous Efavfl'enz ~eatrnent. Results: No significant statistical differences were observed in CETP activity in plasma fi'om patients with or without efavfl'enz. Conclusion: CETP activity analyzed in plasma fi'om patients taking Efavfl'enz is not altered. Therefore, no significant inhibition of this protein occurs in vivo due to the presence of Efavfl'enz and it suggests the existence of an alternative HDL-raising mechanism associated with this ~eatment.
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EFFECT OF EXTENDED-RELEASE FLUVASTATIN ON SERUM LIPIDS AND PARAOXONASE ACTIVITY
G. Paragh, L. Illyes, E. Katona, M. Harangi, T. Kalmat', I. Seres. First
Department of Medicine, and University of Debrecen, Debrecen, St.Ferenc Hospital, Miskolc, Hungary New study data suggest that clinical outcome improve with mole aggressive LDL-C lowering. New formulations of fluvastatin extended-release prepat'ations, at'e achieving greater reductions in LDL-C levels. The HDL-associated pat'aoxonase (PON) activity may play an important role in the inhibition of LDL oxidation. Previous studies have demonstrated that serum pat'aoxonase activity was decreased in patients with hyperlipidemia and coronary heart disease. The aim of this study was to investigate the effect of extendedlelease fluvastatin (80 rag/day) on serum lipids and paraoxonase activity. 25 (11 males and 14 females) hyperlipidemic patients with Fredrickson type II.a hyperlipoproteinaemia (mean age: 59.56-4-9.01 yr, mean BMI: 28.33-4-3.58 kg/m 2) were enrolled. Serum lipids were measut'ed and serum PON activity was determined before and after 2 and 6 months of treatment. Liver enzymes (GOT, GPT, GGT) and kidney function were unchanged. Extended-release fluvastatin (XL) treatment significantly decreased serum cholesterol, LDL-C and apoB (p<0.0001) levels after 2 months, and with an additional significant (p<0.05) Cholesterin and LDL-C level 1eduction after 6 months therapy. There wele no significant changes in the triglyceride, HDL-C and ApoA1 levels. Serum pat'aoxonase activity (120.43-4-66.22; 132.11-4-75.65 U/l; p<0.001) was significantly increased after 2 month fluvastatin (XL) treatment and increased further (143.95-484.54 U/l) after 6 months of therapy. Fluvastatin XL 80 mg once daily was well tolerated and effectively managed plasma lipid profiles and improved antioxidant status by increasing serum pat'aoxonase activity in these patients. Acknowledgements: This study was supported by a grant fi'om ETF (503/2003), Hungary.
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HDL DOES NOT INHIBIT MCP-1 SECRETION BY ENDOTHELIAL CELLS, IN RESPONSE TO INCUBATION WITH TNF¢~
D. Hine, M. Mackness, P. Dun'ington, B. Mackness. University of
Manchester, Manchester, United Kingdom Objective: To determine whether the HDL associated protein Apolipoprorein AI (Apo AI) attenuates the secretion of Monocyte Chemoattractant Protein 1 (MCP-1) by the endothelial cell line EA.hy 926 in response to Turnout" Necrosis Factor c~(TNF-c0. Methods: Endothelial cells were incubated with up to 4001xg/ml Apo AI o1" the equivalent amount of HDL associated Apo AI for 17hrs. Cells were washed and then incubated for a fut'ther 24 hrs in the presence of TNF-c~. Secretion of MCP-1 into cell medium was measut'ed by a commercially available ELISA.
Hammami
39
Results: l:h'e-incubation with Apo AI resulted in a significant 30% declease in the secretion of MCP-1 after 4hrs (p = 0.034). l:h'e-incubation with HDL did not reduce MCP-1 secretion. Conclusion: Purified Apo AI is able to attenuate secretion of MCP-1 by endothelial cells. HDL with equivalent concentrations of Apo AI did not affect MCP- 1 secretion.
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STUDY OF FACTORS INFLUENCING THE DECREASED PARAOXONASE ACTIVITY WITH AGING
I. Seres, G. Paragh, E. Deschene, T. Fulop, A. Khalil. First Department of Medicine, University of Debrecen, Debrecen; Centre de Recherche Sur leViellissement-IUGS, University of Sherbrooke, Sherbrooke, Hungary Paraoxonase (PON1) is principally complexed to HDL and is responsible, at least in pat't, for its antioxidant properties. PON1 activity decreases in several pathologies associated with atherosclerosis. The aim of this study was to investigate the PON1 activity and factors influencing its activity as a function of age. One hundred and twenty nine healthy subjects aged between 22 and 89 yeat's were recruited for the study. We found that serum PON1 activity significantly decreased with age (r = -0.38, p < 0.0001) while its at'ylesterase activity as well as its concentration in the serum did not change significantly. HDL concentrations remained unchanged with age, however, Apo A1 concentration showed a slight negative but significant con'elation with age (r = - 0.19, p <0.027). Moleover, the total cholesterol concentration was positively and significantly con'elated with age (r = 0.40, p < 0.001). Thus, our results suggest that the decrease in PON1 activity can not be explained by the decrease in Apo A1 concentrations with age. HDL fi'om elderly subjects was more susceptible to oxidation than HDL fi'om young subjects measut'ed by higher lipid peroxidation rate. Thus, the decrease in PON1 activity may contribute to this increased susceptibility of HDL to oxidation with aging. Altogether our results suggest that the decrease in PON1 activity may be related to the development of oxidative stress conditions with aging and the increased HDL susceptibility to oxidation in elderly subjects. Acknowledgements: This study was supported by a grant fi'om ETT (503/2003), Hungat'y
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ASSOCIATION BETWEEN CHOLESTERYL ESTER TRANSFER PROTEIN ACTIVITY AND CORONARY ARTERY DISEASE COMPLICATION IN TUNISIAN PATIENTS WITH TYPE 2 DIABETES
M. Hammami, R. Chaaba, S. Hammami, N. Attia, S. Mahjoub, M. Smaoui, K. Ben Hamd, M. Ben Fat'hat. Faculty of Medicine, C H U Monastir,
Monastir, Tunisie CETP plays an important role in leverse cholesterol transfer. The CETP gene was considered as a candidate gene in coronary artery disease (CAD) in type 2 diabetic patients. Patients: 98 controls, 73 patients with CAD and 87 without CAD at'e included.Only 19 patients fi'om those with one at'tery disease and 15 fi'om those with two o1"three artery disease didn't have angioplasty. Method: CETP activity was defined as the amount of radiolabeled cholesteryl ester (CE) transferred fi'om exogenous HDL to exogenous apo B containing lipoproteins and expressed in nmol of CE transferred/ml of plasma/2hout's. Results: The CETP activity was higher in type 2 diabetic patients than in controls, but there was no diffelence between those with CAD and those without CAD (44,29-4-25,15 vs 53.46-4-26.7 vs 55.44-4-27.02 for controls, type 2 diabetic with CAD and type 2 diabetic without CAD respectively; p = 0.02). Also patients without CAD have higher C-HDL concentration than those with CAD (0.94 -4-0.3 vs 0.76-4-0.2 retool/l; p <0.001). Out" results showed that CETP activity is higher in patients having 2 o1"3 at'tery disease than in those with one at'tery disease only (p = 0.025). Whereas there is no difference in C-HDL concentration. Also, if we take into consideration angioplasty, the CETP activity in patients with two or three artery disease and no angioplasty was more higher than those having angioplasty (p = 0.013). Conclusion: CETP activity was associated with coronat'y at'tery disease and its complications.
74th EAS Congress, 17-20 April 2004, Seville, Spain
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EFFECT OF EXTENDED-RELEASE FLUVASTATIN ON SERUM LIPIDS AND PARAOXONASE ACTIVITY
G. Paragh, L. Illyes, E. Katona, M. Harangi, T. Kalmat', I. Seres. First
Department of Medicine, and University of Debrecen, Debrecen, St.Ferenc Hospital, Miskolc, Hungary New study data suggest that clinical outcome improve with mole aggressive LDL-C lowering. New formulations of fluvastatin extended-release prepat'ations, at'e achieving greater reductions in LDL-C levels. The HDL-associated pat'aoxonase (PON) activity may play an important role in the inhibition of LDL oxidation. Previous studies have demonstrated that serum pat'aoxonase activity was decreased in patients with hyperlipidemia and coronary heart disease. The aim of this study was to investigate the effect of extendedlelease fluvastatin (80 rag/day) on serum lipids and paraoxonase activity. 25 (11 males and 14 females) hyperlipidemic patients with Fredrickson type II.a hyperlipoproteinaemia (mean age: 59.56-4-9.01 yr, mean BMI: 28.33-4-3.58 kg/m 2) were enrolled. Serum lipids were measut'ed and serum PON activity was determined before and after 2 and 6 months of treatment. Liver enzymes (GOT, GPT, GGT) and kidney function were unchanged. Extended-release fluvastatin (XL) treatment significantly decreased serum cholesterol, LDL-C and apoB (p<0.0001) levels after 2 months, and with an additional significant (p<0.05) Cholesterin and LDL-C level 1eduction after 6 months therapy. There wele no significant changes in the triglyceride, HDL-C and ApoA1 levels. Serum pat'aoxonase activity (120.43-4-66.22; 132.11-4-75.65 U/l; p<0.001) was significantly increased after 2 month fluvastatin (XL) treatment and increased further (143.95-484.54 U/l) after 6 months of therapy. Fluvastatin XL 80 mg once daily was well tolerated and effectively managed plasma lipid profiles and improved antioxidant status by increasing serum pat'aoxonase activity in these patients. Acknowledgements: This study was supported by a grant fi'om ETF (503/2003), Hungary.
~
HDL DOES NOT INHIBIT MCP-1 SECRETION BY ENDOTHELIAL CELLS, IN RESPONSE TO INCUBATION WITH TNF¢~
D. Hine, M. Mackness, P. Dun'ington, B. Mackness. University of
Manchester, Manchester, United Kingdom Objective: To determine whether the HDL associated protein Apolipoprorein AI (Apo AI) attenuates the secretion of Monocyte Chemoattractant Protein 1 (MCP-1) by the endothelial cell line EA.hy 926 in response to Turnout" Necrosis Factor c~(TNF-c0. Methods: Endothelial cells were incubated with up to 4001xg/ml Apo AI o1" the equivalent amount of HDL associated Apo AI for 17hrs. Cells were washed and then incubated for a fut'ther 24 hrs in the presence of TNF-c~. Secretion of MCP-1 into cell medium was measut'ed by a commercially available ELISA.
Hammami
39
Results: l:h'e-incubation with Apo AI resulted in a significant 30% declease in the secretion of MCP-1 after 4hrs (p = 0.034). l:h'e-incubation with HDL did not reduce MCP-1 secretion. Conclusion: Purified Apo AI is able to attenuate secretion of MCP-1 by endothelial cells. HDL with equivalent concentrations of Apo AI did not affect MCP- 1 secretion.
iiiiiii iiiiiiiiiiiiiiii
iiiiii..".O.'iiiiiiiiiiiiiiii ~
STUDY OF FACTORS INFLUENCING THE DECREASED PARAOXONASE ACTIVITY WITH AGING
I. Seres, G. Paragh, E. Deschene, T. Fulop, A. Khalil. First Department of Medicine, University of Debrecen, Debrecen; Centre de Recherche Sur leViellissement-IUGS, University of Sherbrooke, Sherbrooke, Hungary Paraoxonase (PON1) is principally complexed to HDL and is responsible, at least in pat't, for its antioxidant properties. PON1 activity decreases in several pathologies associated with atherosclerosis. The aim of this study was to investigate the PON1 activity and factors influencing its activity as a function of age. One hundred and twenty nine healthy subjects aged between 22 and 89 yeat's were recruited for the study. We found that serum PON1 activity significantly decreased with age (r = -0.38, p < 0.0001) while its at'ylesterase activity as well as its concentration in the serum did not change significantly. HDL concentrations remained unchanged with age, however, Apo A1 concentration showed a slight negative but significant con'elation with age (r = - 0.19, p <0.027). Moleover, the total cholesterol concentration was positively and significantly con'elated with age (r = 0.40, p < 0.001). Thus, our results suggest that the decrease in PON1 activity can not be explained by the decrease in Apo A1 concentrations with age. HDL fi'om elderly subjects was more susceptible to oxidation than HDL fi'om young subjects measut'ed by higher lipid peroxidation rate. Thus, the decrease in PON1 activity may contribute to this increased susceptibility of HDL to oxidation with aging. Altogether our results suggest that the decrease in PON1 activity may be related to the development of oxidative stress conditions with aging and the increased HDL susceptibility to oxidation in elderly subjects. Acknowledgements: This study was supported by a grant fi'om ETT (503/2003), Hungat'y
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ASSOCIATION BETWEEN CHOLESTERYL ESTER TRANSFER PROTEIN ACTIVITY AND CORONARY ARTERY DISEASE COMPLICATION IN TUNISIAN PATIENTS WITH TYPE 2 DIABETES
M. Hammami, R. Chaaba, S. Hammami, N. Attia, S. Mahjoub, M. Smaoui, K. Ben Hamd, M. Ben Fat'hat. Faculty of Medicine, C H U Monastir,
Monastir, Tunisie CETP plays an important role in leverse cholesterol transfer. The CETP gene was considered as a candidate gene in coronary artery disease (CAD) in type 2 diabetic patients. Patients: 98 controls, 73 patients with CAD and 87 without CAD at'e included.Only 19 patients fi'om those with one at'tery disease and 15 fi'om those with two o1"three artery disease didn't have angioplasty. Method: CETP activity was defined as the amount of radiolabeled cholesteryl ester (CE) transferred fi'om exogenous HDL to exogenous apo B containing lipoproteins and expressed in nmol of CE transferred/ml of plasma/2hout's. Results: The CETP activity was higher in type 2 diabetic patients than in controls, but there was no diffelence between those with CAD and those without CAD (44,29-4-25,15 vs 53.46-4-26.7 vs 55.44-4-27.02 for controls, type 2 diabetic with CAD and type 2 diabetic without CAD respectively; p = 0.02). Also patients without CAD have higher C-HDL concentration than those with CAD (0.94 -4-0.3 vs 0.76-4-0.2 retool/l; p <0.001). Out" results showed that CETP activity is higher in patients having 2 o1"3 at'tery disease than in those with one at'tery disease only (p = 0.025). Whereas there is no difference in C-HDL concentration. Also, if we take into consideration angioplasty, the CETP activity in patients with two or three artery disease and no angioplasty was more higher than those having angioplasty (p = 0.013). Conclusion: CETP activity was associated with coronat'y at'tery disease and its complications.
74th EAS Congress, 17-20 April 2004, Seville, Spain
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