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GAMMA AGONIST TESAGLITAZAR BLOCKS PROGRESSION OF PRE-EXISTING ATHEROSCLEROSIS IN APOE*3LEIDEN.CETP TRANSGENIC MICE
Poster Sessions PO49 Therapeutic interventions – other PO49-773
EFFECTS OF TARANABANT, A NOVEL CANNABINOID 1 RECEPTOR (CB-1R) INVERSE AGONIST, ON WEIGHT REDUCTION IN OBESE PATIENTS OVER 12 WEEKS
R. Carr 1 , N. Erondu 2 , C. Gonzalez 3 , B. Gumbiner 4 , B. Musser 2 , K. Lu 2 , R. Capece 2 , S. Klein 5 , E. Ravussin 6 , J. Amatruda 2 , S. Heymsfield 2 . 1 Merck Sharp & Dohme A/S, Glostrup, Denmark; 2 Merck Research Laboratories, Rahway, NJ, USA; 3 Merck & Co., Inc., Whitehouse Station, NJ, USA; 4 Metabasis Therapeutica, Inc., La Jolla, CA, USA; 5 Washington University School of Medicine, St. Louis, MO, USA; 6 Pennington Biomedical Research Center, Baton Rouge, LA, USA
J.W. Van der Hoorn 1,2 , J.W. Jukema 2 , L.M. Havekes 1,2,3 , P.C. Rensen 3 , E. Lundholm 4 , G. Camejo 4 , H.M. Princen 1 . 1 BioSciences, TNO Quality of Life, Leiden, The Netherlands; 2 Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 3 General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; 4 R&D, AstraZeneca, Molndal, Sweden Background and aims: To evaluate the effect of the PPARα/γ agonist tesaglitazar (TESA) on the progression of pre-existing atherosclerotic lesions in APOE*3Leiden.CETP transgenic mice. Methods: E3L CETP mice were fed an atherogenic diet for 11 weeks to induce atherosclerosis, resulting in plasma cholesterol (TC) levels of about 20 mM. Thereafter, the cholesterol in the diet was reduced to obtain human-like TC levels. After 4 weeks TC levels were about 10mM and the mice were matched into 3 groups: a Baseline control group (BC), which was sacrificed, a regression control (RC) and a TESA-treated group, which were treated for 8 weeks and sacrificed thereafter to assess atherosclerosis development. Results: TESA reduced triglycerides by 71% (p<0.001), TC by 55% (p<0.001), mainly in the VLDL/LDL, and CETP mass by 42% (p=0.001) and increased HDL by 37% (p<0.01). In the BC group 136± 87*1000 µm2 lesion area per cross section was developed, of which 47± 23% were severe lesions. After 8 weeks the RC group showed lesion progression (210± 84*1000 µm2 and 69± 17% severe lesions; p<0.01), whereas TESA totally blocked further lesion development (140± 97*1000 µm2 ) and progression of severity (59±24%), and additionally stabilized the lesions, by increasing their collagen content (65± 9% vs 33± 11% in BC and 54± 10% in RC; p<0.01). Conclusions: Dual PPARα/γ agonism with TESA markedly reduced VLDL/LDL and increased HDL levels which may be the mechanism for the observed complete inhibition of progression and stabilization of pre-existing atherosclerotic lesions. PO49-776
Conclusions: Treatment with taranabant for 12 wks was generally well tolerated and led to significant weight loss in obese patients. PO49-774
PLATELET FUNCTION IN CORONARY ARTERY DISEASE: DEFINING RESPONSE TO ANTIPLATELETS
A. Gasparyan 1 , A. Blann 2 , T. Watson 2 , G. Lip 2 . 1 1st Department of Internal Medicine, Yerevan State Medical University, Armenia; 2 Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK Platelet aggregation plays a crucial role in coronary artery disease (CAD). Arachidonic acid (AA) and adenosine diphosphate (ADP) pathways are main sources of platelet activation. Issues of aspirin and clopidogrel resistance have emerged necessitating search for tests to diagnose and treat those who do not benefit from antiplatelet therapy. We aimed to define response to antiplatelets by AA and ADP induced platelet aggregometry and mean platelet volume (MPV). A total of 96 stable patients (aged 43-89; 68 males; 51 Caucasians, 28 South Asians, 17 Afro-Caribbeans) were recruited and divided into 4 groups: 1 – 29 with CAD with heart failure, on aspirin; 2 - 34 with CAD without heart failure, on aspirin; 3 – 21 with CAD without heart failure, after coronary angioplasty, on clopidogrel plus aspirin; 4 – 12 antiplatelet naïves without CAD. Aggregometry was performed in platelet-rich. MPV was measured in EDTA anticoagulated blood samples. Inhibition of platelet function was defined as aggregation with 0.5 mg/mL AA ≤20%, with 5 µmol/L ADP ≤70%, and MPV ≤8.1 fL. Lack of platelet function inhibition revealed in 41% in group 1, 50% 2, 10% - 3 and 58% in 4 by aggregometry, and in 38%, 56%, 38%, 50%, correspondingly, by MPV. The levels of aggregometry by 5 µmol/L ADP were correlated with MPV (r=0.26; p<0.05). Enhanced suppression of ADP induced aggregation and decrease of MPV was found in dual antiplatelet group. Aggregation with 5 µmol/L ADP and MPV are informative parameters for defining response to antiplatelets in CAD.
DUAL PPAR-ALPHA/GAMMA AGONIST TESAGLITAZAR BLOCKS PROGRESSION OF PRE-EXISTING ATHEROSCLEROSIS IN APOE*3LEIDEN.CETP TRANSGENIC MICE
LONG TERM TIROFIBAN INFUSION BEFORE PCI IN PATIENTS WITH ANGIOGRAPHICALLY MASSIVE INTRACORONARY THROMBUS
T. Timurkaynak, U. Arslan, S. Balcioglu, S.A. Kocaman, S. Turkoglu. Gazi University Medical School, Department of Cardiology, Ankara, Turkey Objective: To evaluate the impact of long term tirofiban infusion before percutaneous coronary intervention (PCI) on the angiographic results in the setting of visible intracoronary thrombus and compare it with the conventional PCI performed without tirofiban. Methods: Out of 2835 PCI, 156 (5.5%) patients with massive thrombus in whom PCI were applied, were included in this retrospective study. Out of these 156 patients, 82 (53%)had PCI in the presence of angiographically apparent thrombus without tirofiban and named as group A. However 74 (47%) received long term tirofiban infusion before PCI and were named as group B. Results: Although the baseline Thrombolysis In Myocardial Infarction (TIMI) 0-2 flow was not different between the groups, it is significantly lower in group B compared to group A after the PCI (8.1% vs 23.2%,p=0.015). The decrease in thrombus burden in group B after tirofiban infusion was also statistically significant compared to pre tirofiban levels (1.77±1.05 vs 3.42±0.76 respectively,p<0.001). Group B had better flow characteristics with a 91.9% TIMI 3 flow after PCI. Intervention was successful in the majority technically however no reflow was observed in 17 patients (20.7%) in group A and in 2 patients (2.7%) in group B (p<0.001). Major bleeding requiring transfusion was observed in both groups A (3 patients) and B (4 patients) due to gastrointestinal bleeding or access site hematomas (3.7%vs5.4%,NS). Conclusion: Pre PCI long term tirofiban infusion strategy in thrombus containing lesions seems to be a safe and feasible approach in avoiding “no re-flow” and dissolving the massive thrombus.
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey
POSTER SESSIONS
Objectives: Assess the short-term efficacy and safety/tolerability of taranabant. Methods: After a 2-wk single-blind placebo (Pbo) plus diet (500 kcal/d deficit) run-in period, patients (body mass index [BMI] >30 and <43 kg/m2 ) were randomized equally to one of 5 daily treatments for 12 wks: Pbo or taranabant (0.5, 2, 4, or 6 mg). Efficacy analyses were based on the all patients treated population using ANCOVA. Results: The study population included 533 patients (86% female) with a mean age, BMI, and BW of 42±10 yrs, 36±4 kg/m2 and 97±14 kg, respectively. Taranabant significantly reduced body weight (BW; primary) and waist circumferences (WC; secondary) compared to Pbo (Table). Taranabant was generally well tolerated; the most common AEs were gastrointestinal (GI)-related occurring in 40 (38.1%), 41 (38.7%), 48 (44.0%), 64 (61.0%), and 58 (53.7%) patients in the Pbo, taranabant 0.5, 2, 4, and 6 mg groups, respectively (p<0.001 Pbo through taranabant 4 mg). A total of 19 (18.1%), 22 (20.8%), 30 (27.5%), 33 (31.3%), and 30 (27.8%) psychiatric AEs were observed in the Pbo, taranabant 0.5, 2, 4, and 6 mg groups, respectively (p<0.050 Pbo through taranabant 4 mg). The GI and psychiatric AEs were generally mild in intensity.
PO49-775
209
EFFECTS OF TARANABANT, A NOVEL CANNABINOID 1 RECEPTOR (CB-1R) INVERSE AGONIST, ON WEIGHT REDUCTION IN OBESE PATIENTS OVER 12 WEEKS
R. Carr 1 , N. Erondu 2 , C. Gonzalez 3 , B. Gumbiner 4 , B. Musser 2 , K. Lu 2 , R. Capece 2 , S. Klein 5 , E. Ravussin 6 , J. Amatruda 2 , S. Heymsfield 2 . 1 Merck Sharp & Dohme A/S, Glostrup, Denmark; 2 Merck Research Laboratories, Rahway, NJ, USA; 3 Merck & Co., Inc., Whitehouse Station, NJ, USA; 4 Metabasis Therapeutica, Inc., La Jolla, CA, USA; 5 Washington University School of Medicine, St. Louis, MO, USA; 6 Pennington Biomedical Research Center, Baton Rouge, LA, USA
J.W. Van der Hoorn 1,2 , J.W. Jukema 2 , L.M. Havekes 1,2,3 , P.C. Rensen 3 , E. Lundholm 4 , G. Camejo 4 , H.M. Princen 1 . 1 BioSciences, TNO Quality of Life, Leiden, The Netherlands; 2 Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 3 General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; 4 R&D, AstraZeneca, Molndal, Sweden Background and aims: To evaluate the effect of the PPARα/γ agonist tesaglitazar (TESA) on the progression of pre-existing atherosclerotic lesions in APOE*3Leiden.CETP transgenic mice. Methods: E3L CETP mice were fed an atherogenic diet for 11 weeks to induce atherosclerosis, resulting in plasma cholesterol (TC) levels of about 20 mM. Thereafter, the cholesterol in the diet was reduced to obtain human-like TC levels. After 4 weeks TC levels were about 10mM and the mice were matched into 3 groups: a Baseline control group (BC), which was sacrificed, a regression control (RC) and a TESA-treated group, which were treated for 8 weeks and sacrificed thereafter to assess atherosclerosis development. Results: TESA reduced triglycerides by 71% (p<0.001), TC by 55% (p<0.001), mainly in the VLDL/LDL, and CETP mass by 42% (p=0.001) and increased HDL by 37% (p<0.01). In the BC group 136± 87*1000 µm2 lesion area per cross section was developed, of which 47± 23% were severe lesions. After 8 weeks the RC group showed lesion progression (210± 84*1000 µm2 and 69± 17% severe lesions; p<0.01), whereas TESA totally blocked further lesion development (140± 97*1000 µm2 ) and progression of severity (59±24%), and additionally stabilized the lesions, by increasing their collagen content (65± 9% vs 33± 11% in BC and 54± 10% in RC; p<0.01). Conclusions: Dual PPARα/γ agonism with TESA markedly reduced VLDL/LDL and increased HDL levels which may be the mechanism for the observed complete inhibition of progression and stabilization of pre-existing atherosclerotic lesions. PO49-776
Conclusions: Treatment with taranabant for 12 wks was generally well tolerated and led to significant weight loss in obese patients. PO49-774
PLATELET FUNCTION IN CORONARY ARTERY DISEASE: DEFINING RESPONSE TO ANTIPLATELETS
A. Gasparyan 1 , A. Blann 2 , T. Watson 2 , G. Lip 2 . 1 1st Department of Internal Medicine, Yerevan State Medical University, Armenia; 2 Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK Platelet aggregation plays a crucial role in coronary artery disease (CAD). Arachidonic acid (AA) and adenosine diphosphate (ADP) pathways are main sources of platelet activation. Issues of aspirin and clopidogrel resistance have emerged necessitating search for tests to diagnose and treat those who do not benefit from antiplatelet therapy. We aimed to define response to antiplatelets by AA and ADP induced platelet aggregometry and mean platelet volume (MPV). A total of 96 stable patients (aged 43-89; 68 males; 51 Caucasians, 28 South Asians, 17 Afro-Caribbeans) were recruited and divided into 4 groups: 1 – 29 with CAD with heart failure, on aspirin; 2 - 34 with CAD without heart failure, on aspirin; 3 – 21 with CAD without heart failure, after coronary angioplasty, on clopidogrel plus aspirin; 4 – 12 antiplatelet naïves without CAD. Aggregometry was performed in platelet-rich. MPV was measured in EDTA anticoagulated blood samples. Inhibition of platelet function was defined as aggregation with 0.5 mg/mL AA ≤20%, with 5 µmol/L ADP ≤70%, and MPV ≤8.1 fL. Lack of platelet function inhibition revealed in 41% in group 1, 50% 2, 10% - 3 and 58% in 4 by aggregometry, and in 38%, 56%, 38%, 50%, correspondingly, by MPV. The levels of aggregometry by 5 µmol/L ADP were correlated with MPV (r=0.26; p<0.05). Enhanced suppression of ADP induced aggregation and decrease of MPV was found in dual antiplatelet group. Aggregation with 5 µmol/L ADP and MPV are informative parameters for defining response to antiplatelets in CAD.
DUAL PPAR-ALPHA/GAMMA AGONIST TESAGLITAZAR BLOCKS PROGRESSION OF PRE-EXISTING ATHEROSCLEROSIS IN APOE*3LEIDEN.CETP TRANSGENIC MICE
LONG TERM TIROFIBAN INFUSION BEFORE PCI IN PATIENTS WITH ANGIOGRAPHICALLY MASSIVE INTRACORONARY THROMBUS
T. Timurkaynak, U. Arslan, S. Balcioglu, S.A. Kocaman, S. Turkoglu. Gazi University Medical School, Department of Cardiology, Ankara, Turkey Objective: To evaluate the impact of long term tirofiban infusion before percutaneous coronary intervention (PCI) on the angiographic results in the setting of visible intracoronary thrombus and compare it with the conventional PCI performed without tirofiban. Methods: Out of 2835 PCI, 156 (5.5%) patients with massive thrombus in whom PCI were applied, were included in this retrospective study. Out of these 156 patients, 82 (53%)had PCI in the presence of angiographically apparent thrombus without tirofiban and named as group A. However 74 (47%) received long term tirofiban infusion before PCI and were named as group B. Results: Although the baseline Thrombolysis In Myocardial Infarction (TIMI) 0-2 flow was not different between the groups, it is significantly lower in group B compared to group A after the PCI (8.1% vs 23.2%,p=0.015). The decrease in thrombus burden in group B after tirofiban infusion was also statistically significant compared to pre tirofiban levels (1.77±1.05 vs 3.42±0.76 respectively,p<0.001). Group B had better flow characteristics with a 91.9% TIMI 3 flow after PCI. Intervention was successful in the majority technically however no reflow was observed in 17 patients (20.7%) in group A and in 2 patients (2.7%) in group B (p<0.001). Major bleeding requiring transfusion was observed in both groups A (3 patients) and B (4 patients) due to gastrointestinal bleeding or access site hematomas (3.7%vs5.4%,NS). Conclusion: Pre PCI long term tirofiban infusion strategy in thrombus containing lesions seems to be a safe and feasible approach in avoiding “no re-flow” and dissolving the massive thrombus.
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey
POSTER SESSIONS
Objectives: Assess the short-term efficacy and safety/tolerability of taranabant. Methods: After a 2-wk single-blind placebo (Pbo) plus diet (500 kcal/d deficit) run-in period, patients (body mass index [BMI] >30 and <43 kg/m2 ) were randomized equally to one of 5 daily treatments for 12 wks: Pbo or taranabant (0.5, 2, 4, or 6 mg). Efficacy analyses were based on the all patients treated population using ANCOVA. Results: The study population included 533 patients (86% female) with a mean age, BMI, and BW of 42±10 yrs, 36±4 kg/m2 and 97±14 kg, respectively. Taranabant significantly reduced body weight (BW; primary) and waist circumferences (WC; secondary) compared to Pbo (Table). Taranabant was generally well tolerated; the most common AEs were gastrointestinal (GI)-related occurring in 40 (38.1%), 41 (38.7%), 48 (44.0%), 64 (61.0%), and 58 (53.7%) patients in the Pbo, taranabant 0.5, 2, 4, and 6 mg groups, respectively (p<0.001 Pbo through taranabant 4 mg). A total of 19 (18.1%), 22 (20.8%), 30 (27.5%), 33 (31.3%), and 30 (27.8%) psychiatric AEs were observed in the Pbo, taranabant 0.5, 2, 4, and 6 mg groups, respectively (p<0.050 Pbo through taranabant 4 mg). The GI and psychiatric AEs were generally mild in intensity.
PO49-775
209