MS356-SINGLE DOSE Pk-PD of DRL-17822, a Potent CETP Inhibitor-EAS-2010

78th EAS Congress

Atherosclerosis Supplements 11, no. 2 (2010) 109–222

Material and Methods: The research focused on 48 pregnant women (falowed during pregnancy and after childbirth in 5 time points), 15 sports players and 30 healthy individuals. As markers of prooxidative processes in HDL-lipoprotein fraction were determined concentrations of malondialdehide (MDA), lipid hydroperoxide (LOOH), advanced oxidation protein products ). The level of SH-groups was measured as (AOPP), superoxide anion (O×− 2 parameter of antioxidative processes. We folowed total paraoxonase activity in serum. Results: The levels of O×− , MDA, LOOH are significantly increased (P < 0.001), 2 but level of SH-groups is significantly decreased (P < 0.001) in subgroups of pregnant women compared to control group. The highest changes are in second trimester. In group of sports players concentration of MDA, LOOH, AOPP, SHgroups are significantly increased (P < 0.001) compared to control group. Conclusion: Our study has shown that pregnant women and professional sports players have increased levels of prooxidative parameters in HDL-lipoprotein fraction. Decreased concentration of SH groups in pregnant women and increased in sports players indicates to different antioxidative protection capability which is connected to changed paraoxonase activity. Keywords: Oxidative stress, changed physiological states MS353 THE COMPARATIVE STUDY OF COMMON CAROTID INTIMAMEDIA THICKNESS IN RUSSIAN AND GERMAN POPULATIONS I. Sobenin1,2 , V. Myasoedova1,2 , T. Kirichenko1,2 , O. Chuprakova2 , M. Bauer3 , R. Erbel3 , A. Orekhov2 . 1 Institute of General Pathology and Pathophysiology, 2 Institute for Atherosclerosis Research, Moscow, Russia, 3 University Duisburg-Essen, Essen, Germany Background: Carotid intima-media thickness (cIMT) is a surrogate marker for generalized atherosclerosis and a risk factor for the development of atherosclerotic diseases. Increased cIMT has become a target for detecting subclinical atherosclerosis. However, the decision on normal and high values of cIMT is highly dependent of the difference between populations and the methodology used for its measurement. Objective: We have compared the difference in cIMT distributions between population samples from Moscow (Russia) and Ruhr (Germany) regions. Patients and Methods: A subsample of 1740 participants of Heinz Nixdorf RECALL Study was compared to 1300 participants from Moscow, aged 45−75 and free from atherosclerotic diseases. High resolution ultrasonography of the distal centimeter of common carotid arteries was used for the measurement of cIMT, which was performed in the similar manner independently at both sites. Results: A striking difference in cIMT distributions between population samples was revealed, which accounted for 0.182 mm (95% CI 0.162–0.202) in men, and 0.191 (95% CI 0.178–0.205) in women, p < 0.001. For men in Moscow, 25th and 75th percentile values of cIMT were 0.770 and 0.960 mm, as compared to 0.600 and 0.780 mm in Ruhr (p < 0.001). In women, these values accounted for 0.718 and 0.790 mm in Moscow, as compared to 0.543 and 0.696 mm in Ruhr (p < 0.001). Conclusions: These findings demonstrate a geographical and socio-economic impact on the predisposition to atherosclerosis in different populations, as well as the role of cIMT for explanation of striking differences in cardiovascular morbidity and mortality between Russia and Germany. MS354 INFLUENCE OF PERIPHERAL ARTERIAL DISEASE ON LOWER EXTREMITY ARTERIAL STIFFNESS. THE CZECH POST-MONICA STUDY P. Wohlfahrt1 , D. Palous2 , M. Ingrischova3 , A. Krajcoviechova1 , J. Seidlerova4 , J. Bruthans1 , M. Galovcova1 , V. Adamkova1 , J. Filipovsky4 , R. Cifkova1 , The Czech post-MONICA Study Group. 1 Department of Preventive Cardiology, 2 Department of Radiology, Institute for Clinical and Experimental Medicine, 3 2nd Medical Department-Clinical Department of Cardiology and Angiology, 1st Medical Faculty, Charles University, Prague, 4 Center of Preventive Cardiology, 2nd Department of Internal Medicine, Charles University, Medical Faculty, Pilsen, Czech Republic Increased lower extremity arterial stiffness leads to decreased blood flow in popliteal artery, decreases transcutaneous oxygen tension and is closely associated with symptoms of lower limb peripheral arterial disease. The aim of the present study was to access association between ankle-brachial index (ABI) as a parameter of lower extremity atherosclerosis and lower extremity pulse wave velocity (ePWV) as a parameter of arterial stiffness. Methods: We included 884 patients from the Czech post-MONICA study (a randomly selected 1% representative population sample, mean age 54±13.5 years, 47% of men) with complete data on ABI and ePWV. ABI was measured using a handheld Doppler and ePWV using the validated Sphygmocor device. Results: Surprisingly ePWV increased with increasing ABI (r = 0.15, p < 0.001). Individuals with ABI below 0.9 had lower ePWV compared with subjects with normal (ABI 1−1.4) and high ABI (ABI>1.4) (8.1±1.9 vs. 9.8±1.8,

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p < 0.05; 8.1±1.9 vs. 10.6±1.3, p < 0.005). Individuals with ABI over 1.4 had significantly increased ePWV compared with low ABI (10.6±1.3 vs. 8.1±1.9, p < 0.005) and normal ABI groups (10.6±1.3 vs. 9.8±1.8, p < 0.05). These associations remained significant after adjustments for traditional cardiovascular risk factors. Conclusion: Lower extremity pulse wave velocity in patients with peripheral arterial disease is artificially decreased probably due to blood pressure decrease and waveform changes behind significant stenosis. Subjects with incompressible arteries (ABI>1.4) have significantly increased ePWV. MS355 IS C-REACTIVE PROTEIN A BETTER PREDICTOR OF RECURRENT CAROTID DISEASE FOLLOWING CAROTID ENDARTERECTOMY THAN ESTABLISHED RISK FACTORS FOR ATHEROCLEROSIS? I. Lusic1 , V. Radoni´c2 , S. Pavelin1 , I. Bilic1 . 1 Neurology, 2 Vascular Surgery, University Hospital Centre and Medical Faculty, Split, Croatia Background: To identify possible relation between established and novel risk factors for atherosclerosis (gender, age, diabetes mellitus, hypertension, smoking and C-reactive protein) and possibility of carotid restenosis following carotid endarterectomy (CEA). Material and Methods: A prospective study of 193 consecutive patients, admitted electively for carotid endarterectomy during 68 months, was conducted. 131 patients had symptomatic and 62 asymptomatic carotid disease. An attempt was made to follow-up on all operated arteries with duplex sonography at 2 month, 6 months, 12 months, and 24 months postoperatively. The correlation of previously mentioned variables (gender, age, diabetes mellitus, hypertension, smoking and average values of C-reactive protein) with progressive or recurrent disease was determined by chi-square analysis and analysis of variance. Results: Of all 193 examined patients 29 demonstrated increasing degree of artery stenosis, while recurrent artery stenosis of >69% was diagnosed in 11 patients. Age, gender, hypertension, and diabetes did not play a significant role in the presence of progressive (or recurrent) disease, while active smokers and patients with preoperative and average C-reactive protein (CRP) levels over 3.0 mg/L had a greater propensity to develop progression (or recurrence) of carotid disease. Conclusion: Increased levels of CRP in serum may be a better predictor of carotid restenosis after CEA than are cholesterol levels and other established risk factors for vascular − except active smoking. MS356 SINGLE DOSE PHARMACODYNAMICS AND PHARMACOKINETICS OF DRL-17822, A POTENT CETP INHIBITOR, IN HEALTHY SUBJECTS S. Hasham, T. Mangapathiraju, S. Vittal, A. Bapat, M. Rao, S. Sai, A. Shanavas, K. Allenby, R. Kumar. Dr. Reddy’s Laboratories Ltd., Hyderabad, India Introduction: The inverse correlation between low HDL-C and cardiovascular risk has encouraged the development of cholesteryl ester transfer protein (CETP) inhibitors to raise HDL-C. DRL-17822 is an orally active potent small molecule CETP inhibitor. In preclinical models, DRL-17822 significantly increased HDL-C levels and was well tolerated with no observed effects on blood pressure or heart rate. Objectives: DRL-17822 was evaluated for its pharmacodynamics and pharmacokinetics in a single ascending dose study in normal healthy subjects. Methods: Seven groups of 6 subjects each were randomized to receive a single dose of either placebo or DRL-17822 (5, 25, 100, 300, 600, 800 and 1000 mg) under fasted state. Plasma CETP activity and concentrations of DRL-17822 were measured. Results: DRL-17822 was well tolerated at all doses. DRL-17822 was gradually absorbed with maximum plasma concentrations being attained at 5 to 6 h postdose; tmax was dose independent. There was a dose related increase in plasma exposure of DRL-17822 as well as plasma CETP inhibition from 25 to 600 mg. Plasma CETP inhibition became apparent as early as 2 hrs post dose and maximal inhibition was observed at 6 hrs. At tmax mean plasma CETP inhibition of 24, 32, 64, 92, 100, 100 and 96% compared to baseline was observed at 5, 25, 100, 300, 600, 800 and 1000 mg respectively. The CETP activity showed a trend towards returning to baseline activity by 24 h post dose. Conclusions: DRL-17822 was well tolerated with favorable pharmacokinetics and dose dependent CETP inhibition in normal healthy subjects. MS357 IRBESARTAN REDUCES PLATELET ACTIVATION IN HYPERTENSIVE-HYPERCHOLESTEROLEMIC HAMSTER N. Alexandru, A. Georgescu, D. Popov, E. Andrei, E. Dragan, M. Simionescu. Institute of Cellular Biology and Pathology ‘Nicolae Simionescu’, Bucharest, Romania Altered platelet function and enhanced oxidative stress have been reported both in hypertension and in hypercholesterolemia. Among the proatherogenic agents, angiotensin II plays a considerable role in the development of atherosclerosis.