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M.662 Effects of stearic acid (C18:0), oleic acid (C18:1) and linoleic acid (C18:2) on lipid and lipoprotein metabolism in humans
Miscellaneous ~60~
PHARMACODYNAMIC INTERACTION BETWEEN EZETIMIBE AND ROSUVASTATIN
T. Kosoglou, P. Statkevich, B. Yang, R. Suresh, Y. Zhu, S.E. Maxwell, R. Tiessen, D.L. Cutler. Schering-Plough Research Institute, Kenilworth,
USA; and Pharma Bio-Research Group B. V., Zuidlaren, The Netherlands B a c k g r o u n d : Ezetimibe (Zetia®/Ezetrol®; EZE)is a lipid-lowering drug
indicated for the treatment of hypercholesterolemia as monotherapy or as coadministration with HMG-CoA reductase inhibitors (statins). We evaluated the phal'macodynamic interaction between EZE and the new statin, rosuvastatin (Crestor®; ROS). M e t h o d s : In a randomized, evaluatol:blind, placebo-controlled, pal'allelgroup study 40 subjects (screening LDL-C_>3.36mmol/L) on a NCEP Step I diet were randomized to one of four treatments: ROS 10 mg + EZE 10 mg, ROS 10 rag, EZE 10 rag, or placebo administered orally Q AM × 14 days as inpatients in a Phase 1 Unit. Serum lipids were assessed predose (after an 8-hr fast) on Days 1 (Baseline), 7 and 14 by dfl'ect quantitative assay methods. Results: No serious AEs were reported. AEs were generally mild, nonspecific and similal" among treatments. There were no significant increases in clinical laboratory tests, particulal'ly those assessing muscle and liver function. EZE had no significant effect on ROS PK or vice versa. The mean (S.E.) % change fi'om baseline in serum lipids at endpoint were: Treatment
LDL-C
ROS i0rng + EZE i0rng (n=i2) ROS t0mg (n=12) EZE t0mg (n=8) PLACEBO (n=8)
Total-C
HDL-C
Conclusion: The coadministration
of EZE + ROS was well tolerated and significantly (p
•]
COMBINED DATA FROM LDL COMPOSITION AND S I Z E MEASUREMENT ARE COMPATIBLE WITH A DISCOID PARTICLE SHAPE
T. Teerlink, P.G. Scheffer, S.J.L. Bakker, R.J. Heine. Institute for
Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands B a c k g r o u n d : LDL size is usually reported as particle diameter, with the
implicit assumption that it is a spherical pal'ticle. On the other hand, data obtained by cryo-electron microscopy (cryo-EM) and mystallographic analysis suggest that LDL shape may be discoid, implying that two dimensions ale needed to describe its size, i.e. diameter and height. We have investigated LDL particle geometry by combining data on LDL lipid composition with size measul'ement. M e t h o d s : Mean LDL diameter of 160 samples was measul'ed by high performance gel-filtration chromatography (HPGC) and LDL particle volume was calculated fl'om its lipid composition. Results: Assuming a spherical shape, diameters calculated fl'om volume con'elated poorly with values obtained by HPGC (R2= 0.36). Assuming a discoid shape, pal'ticle height was calculated fl'om volume and HPGCdiameter. Diameter (20.9 4- 0.5 nm) and height (12.1 4- 0.8 nm) con'esponded closely to reported cryo-EM data. Diameter and height were not significantly related to each other (r = 0.14; P = 0.09) and accounted for 77% and 23% of the variation in particle volume, respectively. In multival'iate regression models, LDL core lipids were the main independent determinants of height (R2 = 0.83), whereas free cholesterol in the shell, which contributes only 5 9% to LDL mass, was the main detmlninant of diameter (R2 = 0.54). Conclusions: We conclude that combined data fi'om composition and size measul'ements are compatible with a discoid pal'ticle shape and propose a structural model for LDL in which flee cholesterol plays a major role in detellnining particle shape and diameter.
•]
EFFECTS OF STEARIC ACID (C18:0), OLEIC ACID (C18:1) AND LINOLEIC ACID (C18:2) ON LIPID AND LIPOPROTEIN METABOLISM IN HUMANS
M. Thijssen, R. Mensink. Nutrition and Toxicology Research Institute Maastricht, Maastricht, The Netherlands Like for oleic and steal'ic acids, oleic and linoleic acids al'e thought to have
153
similal" effects on the serum lipoprotein profile. If true, then substituting these three C18 fatty acids for each other should result in similar serum lipid concentrations. To examine this in detail, 45 healthy, slightly hypercholesterolemic subjects (27 women and 18 men) were fed in random order three experimental diets during three periods of five weeks, interrupted by a washout period of at least one week. Dietal'y compositions were the same except for 7 en%, which was provided by stearic, oleic or linoleic acids, respectively. Experimental fats were incorporated into malgarines, bread and cake. Total fat intake was 37 en% fat and cholesterol intake less than 33 mg/MJ. At the end of weeks 4 and 5 of each period, serum lipid and lipoprotein concentrations were measul'ed and averaged. Serum LDL cholesterol was 3.794-0.92 mmol/L (mean 4- SD) on the high-stearic acid diet, 3.714-0.79 mmol/L on the high-oleic acid diet, and 3.664-0.91 mmol/L on the high-linoleic acid diet (P=0.137 for diet effects). For HDL cholesterol, these values were respectively 1.454-0.43, 1.464-0.45 and 1.464-0.44 mmol/L (P=0.866). Total cholesterol and triacylglycerol concentrations were also not significantly different between the diets. Concluding, out" results suggest that at realistic intakes differences between the effects of steal'ic, oleic and linoleic acids on the serum lipoprotein profile are small. (This study was financially supported by the Dutch Dah'y Foundation for Nutrition and Health/Dutch Dah'y Association)
•]
TG
-61.4(2. i) -49.4(i.8) -i8.4 (2. i) -i6.6 (5. i) -44.9 (2.4) -36.6 (2.8) -13.4(4.3) -16.1 (3.0) -16.8 (4.0) -18.8 (3.6) -13.4(5.7) -14.1 (6.7) -2.2 (7.2) -5.3 (4.8) -10.3(4.8) 2.7 (11.9)
Todorova
C A R D I O V A S C U L A R R I S K P R O F I L E S AND MORTALITY IN OLD AGE - A LONGITUDINAL APPROACH. THE BERLIN AGING STUDY (BASE)
H. Thomas, R. Nieczaj, E. Steinhagen-Thiessen, M. Borchelt. Geriatrics Research Group, Charit , Universitary Medicine, Berlin, Germany Cardiovasculal" disease is still the most prevalent risk factor causing prematul'e death and, hence, an important contributor towards selective mortality. This conclusion is based on research primarily on middle aged and "young old" persons (50 to 70 years). However, the evidence is less cleal" regal'ding advanced old age. Whether aging beyond the eighth and ninth decade is associated with the development of cal'diovasculal" disease due to specific vascular risk factors remains controversial. Longitudinal data of the Berlin Aging Study (BASE) were used (1) to analyze changes in individual risk profiles comprising family history of cat: diovasculal" events), lipid profiles (total cholesterol, HDL-, LDL-cholesterol, triglycerides, apolipoproteins), health conditions (diabetes, hypertension), and health habits (exercising, smoking, body weight) controlled for genetic factors (Apo-E-alleles, Lp(a)), and (2) to analyze the predictive value of these factors for mortality on the initial sample of N=516 individuals aged 70 to 103 years by multival'iate statistical methods. Preliminal'y multival'iate analyses on associations between changes in cardio-vascular risk profile status and mortality indicated that - even among persons beyond the age of 70 - male gender, development of diabetes and transition to enhanced LDL-levels significantly increases the risk of death within a period of 30 months. Since modified national and international guidelines for prevention of coronary heard disease have been established during the last yeal's - including new recommended treatment tal'gets for risk factors -, out" investigation focused on the validation of the former findings according to the new guidelines.
•]
LDL SUBCLASSES DISTRIBUTION IN DIFFERENT ETHNIC GROUPS IN MACEDONA
B. Todorova, S. Alabakovska, D. Labudovic, K. Tosheska. Dep. of Medical
Biochemistry, Skopje, Macedonia Changes in low-density lipoprotein (LDL) subclasses distribution towal'd smaller pal'ticles have been associated with premature coronal'y artery disease. In this study we have examined LDL subclass distribution and phenotype as well as LDL size in 440 healthy subjects, 345 Macedonians and 95 Albanians. LDL subclass sepal'ation was performed using polyacrylamide gradient (3-31%) gel electrophoresis method. Foul" major LDL subclasses (LDL1 to LDL4) were detected in different individuals. In 19% of the subjects only one LDL subclass was dominant. However, most subjects had polydispersion of LDL subclasses. In 61% a second subclass and in 20% more than two subclasses were detected. One of the subclasses was always dominant in each subject. In 88,5% of the Macedonians, lalge LDL1 and LDL2 subclasses were dominant and they belong to phenotype A, whereas in 11,5% small LDL3 and LDL4 were dominant - phenotype B. In Albanian subjects, 68% belonged to phenotype A and 38% belonged to phenotype B. There was significant difference
74th EAS Congress, 17-20 April 2004, Seville, Spain
PHARMACODYNAMIC INTERACTION BETWEEN EZETIMIBE AND ROSUVASTATIN
T. Kosoglou, P. Statkevich, B. Yang, R. Suresh, Y. Zhu, S.E. Maxwell, R. Tiessen, D.L. Cutler. Schering-Plough Research Institute, Kenilworth,
USA; and Pharma Bio-Research Group B. V., Zuidlaren, The Netherlands B a c k g r o u n d : Ezetimibe (Zetia®/Ezetrol®; EZE)is a lipid-lowering drug
indicated for the treatment of hypercholesterolemia as monotherapy or as coadministration with HMG-CoA reductase inhibitors (statins). We evaluated the phal'macodynamic interaction between EZE and the new statin, rosuvastatin (Crestor®; ROS). M e t h o d s : In a randomized, evaluatol:blind, placebo-controlled, pal'allelgroup study 40 subjects (screening LDL-C_>3.36mmol/L) on a NCEP Step I diet were randomized to one of four treatments: ROS 10 mg + EZE 10 mg, ROS 10 rag, EZE 10 rag, or placebo administered orally Q AM × 14 days as inpatients in a Phase 1 Unit. Serum lipids were assessed predose (after an 8-hr fast) on Days 1 (Baseline), 7 and 14 by dfl'ect quantitative assay methods. Results: No serious AEs were reported. AEs were generally mild, nonspecific and similal" among treatments. There were no significant increases in clinical laboratory tests, particulal'ly those assessing muscle and liver function. EZE had no significant effect on ROS PK or vice versa. The mean (S.E.) % change fi'om baseline in serum lipids at endpoint were: Treatment
LDL-C
ROS i0rng + EZE i0rng (n=i2) ROS t0mg (n=12) EZE t0mg (n=8) PLACEBO (n=8)
Total-C
HDL-C
Conclusion: The coadministration
of EZE + ROS was well tolerated and significantly (p
•]
COMBINED DATA FROM LDL COMPOSITION AND S I Z E MEASUREMENT ARE COMPATIBLE WITH A DISCOID PARTICLE SHAPE
T. Teerlink, P.G. Scheffer, S.J.L. Bakker, R.J. Heine. Institute for
Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands B a c k g r o u n d : LDL size is usually reported as particle diameter, with the
implicit assumption that it is a spherical pal'ticle. On the other hand, data obtained by cryo-electron microscopy (cryo-EM) and mystallographic analysis suggest that LDL shape may be discoid, implying that two dimensions ale needed to describe its size, i.e. diameter and height. We have investigated LDL particle geometry by combining data on LDL lipid composition with size measul'ement. M e t h o d s : Mean LDL diameter of 160 samples was measul'ed by high performance gel-filtration chromatography (HPGC) and LDL particle volume was calculated fl'om its lipid composition. Results: Assuming a spherical shape, diameters calculated fl'om volume con'elated poorly with values obtained by HPGC (R2= 0.36). Assuming a discoid shape, pal'ticle height was calculated fl'om volume and HPGCdiameter. Diameter (20.9 4- 0.5 nm) and height (12.1 4- 0.8 nm) con'esponded closely to reported cryo-EM data. Diameter and height were not significantly related to each other (r = 0.14; P = 0.09) and accounted for 77% and 23% of the variation in particle volume, respectively. In multival'iate regression models, LDL core lipids were the main independent determinants of height (R2 = 0.83), whereas free cholesterol in the shell, which contributes only 5 9% to LDL mass, was the main detmlninant of diameter (R2 = 0.54). Conclusions: We conclude that combined data fi'om composition and size measul'ements are compatible with a discoid pal'ticle shape and propose a structural model for LDL in which flee cholesterol plays a major role in detellnining particle shape and diameter.
•]
EFFECTS OF STEARIC ACID (C18:0), OLEIC ACID (C18:1) AND LINOLEIC ACID (C18:2) ON LIPID AND LIPOPROTEIN METABOLISM IN HUMANS
M. Thijssen, R. Mensink. Nutrition and Toxicology Research Institute Maastricht, Maastricht, The Netherlands Like for oleic and steal'ic acids, oleic and linoleic acids al'e thought to have
153
similal" effects on the serum lipoprotein profile. If true, then substituting these three C18 fatty acids for each other should result in similar serum lipid concentrations. To examine this in detail, 45 healthy, slightly hypercholesterolemic subjects (27 women and 18 men) were fed in random order three experimental diets during three periods of five weeks, interrupted by a washout period of at least one week. Dietal'y compositions were the same except for 7 en%, which was provided by stearic, oleic or linoleic acids, respectively. Experimental fats were incorporated into malgarines, bread and cake. Total fat intake was 37 en% fat and cholesterol intake less than 33 mg/MJ. At the end of weeks 4 and 5 of each period, serum lipid and lipoprotein concentrations were measul'ed and averaged. Serum LDL cholesterol was 3.794-0.92 mmol/L (mean 4- SD) on the high-stearic acid diet, 3.714-0.79 mmol/L on the high-oleic acid diet, and 3.664-0.91 mmol/L on the high-linoleic acid diet (P=0.137 for diet effects). For HDL cholesterol, these values were respectively 1.454-0.43, 1.464-0.45 and 1.464-0.44 mmol/L (P=0.866). Total cholesterol and triacylglycerol concentrations were also not significantly different between the diets. Concluding, out" results suggest that at realistic intakes differences between the effects of steal'ic, oleic and linoleic acids on the serum lipoprotein profile are small. (This study was financially supported by the Dutch Dah'y Foundation for Nutrition and Health/Dutch Dah'y Association)
•]
TG
-61.4(2. i) -49.4(i.8) -i8.4 (2. i) -i6.6 (5. i) -44.9 (2.4) -36.6 (2.8) -13.4(4.3) -16.1 (3.0) -16.8 (4.0) -18.8 (3.6) -13.4(5.7) -14.1 (6.7) -2.2 (7.2) -5.3 (4.8) -10.3(4.8) 2.7 (11.9)
Todorova
C A R D I O V A S C U L A R R I S K P R O F I L E S AND MORTALITY IN OLD AGE - A LONGITUDINAL APPROACH. THE BERLIN AGING STUDY (BASE)
H. Thomas, R. Nieczaj, E. Steinhagen-Thiessen, M. Borchelt. Geriatrics Research Group, Charit , Universitary Medicine, Berlin, Germany Cardiovasculal" disease is still the most prevalent risk factor causing prematul'e death and, hence, an important contributor towards selective mortality. This conclusion is based on research primarily on middle aged and "young old" persons (50 to 70 years). However, the evidence is less cleal" regal'ding advanced old age. Whether aging beyond the eighth and ninth decade is associated with the development of cal'diovasculal" disease due to specific vascular risk factors remains controversial. Longitudinal data of the Berlin Aging Study (BASE) were used (1) to analyze changes in individual risk profiles comprising family history of cat: diovasculal" events), lipid profiles (total cholesterol, HDL-, LDL-cholesterol, triglycerides, apolipoproteins), health conditions (diabetes, hypertension), and health habits (exercising, smoking, body weight) controlled for genetic factors (Apo-E-alleles, Lp(a)), and (2) to analyze the predictive value of these factors for mortality on the initial sample of N=516 individuals aged 70 to 103 years by multival'iate statistical methods. Preliminal'y multival'iate analyses on associations between changes in cardio-vascular risk profile status and mortality indicated that - even among persons beyond the age of 70 - male gender, development of diabetes and transition to enhanced LDL-levels significantly increases the risk of death within a period of 30 months. Since modified national and international guidelines for prevention of coronary heard disease have been established during the last yeal's - including new recommended treatment tal'gets for risk factors -, out" investigation focused on the validation of the former findings according to the new guidelines.
•]
LDL SUBCLASSES DISTRIBUTION IN DIFFERENT ETHNIC GROUPS IN MACEDONA
B. Todorova, S. Alabakovska, D. Labudovic, K. Tosheska. Dep. of Medical
Biochemistry, Skopje, Macedonia Changes in low-density lipoprotein (LDL) subclasses distribution towal'd smaller pal'ticles have been associated with premature coronal'y artery disease. In this study we have examined LDL subclass distribution and phenotype as well as LDL size in 440 healthy subjects, 345 Macedonians and 95 Albanians. LDL subclass sepal'ation was performed using polyacrylamide gradient (3-31%) gel electrophoresis method. Foul" major LDL subclasses (LDL1 to LDL4) were detected in different individuals. In 19% of the subjects only one LDL subclass was dominant. However, most subjects had polydispersion of LDL subclasses. In 61% a second subclass and in 20% more than two subclasses were detected. One of the subclasses was always dominant in each subject. In 88,5% of the Macedonians, lalge LDL1 and LDL2 subclasses were dominant and they belong to phenotype A, whereas in 11,5% small LDL3 and LDL4 were dominant - phenotype B. In Albanian subjects, 68% belonged to phenotype A and 38% belonged to phenotype B. There was significant difference
74th EAS Congress, 17-20 April 2004, Seville, Spain