Effects of D-003, a Mixture of Sugarcane Wax Acids, on Platelet Aggregation in Hypercholesterolemic Patients

Abstract

Increased platelet aggregation contributes to vascular risk. D-003, a mixture of high molecular weight sugarcane wax acids, has shown antiplatelet effects in experimental models and healthy volunteers. This randomised, double-blinded, placebo-controlled study investigated the effects of titrated doses of D-003 (5-20 mg/d) on platelet aggregation in hypercholesterolemic patients. After a 4-week baseline phase, 56 patients were randomised to D-003 5 mg/d or placebo. The doses were doubled every 15 days if arachidonic acid (AA)-induced platelet aggregation was not inhibited at least by 15%.AA (0.75 and 1.5 mmol/L) and collagen (1 µg/mL)-induced platelet aggregation, laboratory and physical safety indicators were assessed at baseline and every 15 days thereafter, when adverse events (AE) were also reported. No significant change of platelet aggregation was found in the placebo group. After 15, 30 and 45 on therapy, D-003 reduced platelet aggregation induced with both AA 0.75 mmol/L (18.1%, 19.0% and 30.3%, respectively) and AA 1.5 mmol/L (17.0%, 16.3% and 22.5%, respectively), and also collagen-induced platelet aggregation (26.6%, 20.8% and 29.4%) (p < 0.01 at days 15 and 30 versus placebo, p < 0.0001 at study completion). The mean inhibition of platelet aggregation with D-003 at day 15, at which all patients had received the lowest dose, was over 15%. Nineteen out of 28 D-003 randomised patients (67.9%) required dose titration to achieve such goal. At trial completion, the mean estimated dose was 11.6 mg/d. D-003 lowered low-density lipoprotein (22.0%), total cholesterol (14.7%) and raised high-density lipoprotein-cholesterol (10.9%) (p < 0.0001 versus placebo). Six patients (2 placebo, 4 D-003) withdrew from the trial, none due to AE. D-003 did not modify the safety indicators with respect to placebo. Four patients (2 placebo, 2 D-003-treated) reported AE: pruritus and increased blood pressure (2 placebo) and rash and polyphagia (2 D-003). In conclusion, D-003 (5-20 mg/d) given as doses titrated every 15 days (5-20 mg/d) inhibited AA- and collagen-induced platelet aggregation in hypercholesterolemic patients and was well tolerated.

Key words

Antiplatelet drugs - D-003, effect on platelet aggregation, hypercholesterolemic patients - Platelet aggregation - Sugarcane wax acids

• References

• 1 Murray CJL, Lόpez AD. Alternate projections of mortality and disability by cause 1990-2020. Global Burden disease Study. Lancet. 1997; 349: 1498-1504
• 2 Falk E, Fernández-Ortiz A. Role of thrombosis in atherosclerosis and its complications. Am J Cardiol. 1995; 75: 1B-7B
• 3 Steinberg D. Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia. J Lipid Res. 2005; 46: 2037-2051
• 4 Wilson JM, Ferguson JJ. Platelet-endothelial interactions in atherothrombotic disease: therapeutic implications. Clin Cardiol. 1999; 23: 687-698
• 5 Willoughby S, Holmes A, Loscalzo J. Platelets and cardiovascular disease. Eur J Cardiovasc Nurs. 2002; 1: 273-288
• 6 Wu K. Recent advances in hemostatic risk factors and cardiovascular diseases. Fibrinolysis & Proteolysis. 1997; 11 ((Suppl 1)) 31-34
• 7 Fowkes FGR, Housley E, Riemersma RA. Smoking, lipids, glucose intolerance and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am. J. Epidemiol. 1992; 135: 331-340
• 8 Lowe GDO, Fowkes FGR, Dawes J. Blood viscosity, fibrinogen and activation of coagulation and leucocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation. 1993; 87: 1915-1920
• 9 Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein (a) and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001; 285: 2481-2485
• 10 Antiplatelet Trialists’ Collaboration: Collaborative overview of randomized trials of antiplatelet therapy-I: Prevention of death myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. Brit. Med. J. 1994; 308: 81-106
• 11 Wood D: European and American recommendations for coronary heart disease prevention Eur Heart J. 1998 19 (Suppl A):A12–A19.
• 12 Schafer A. Antiplatelet therapy. Am J Med. 1996; 101: 199-209
• 13 Awiry EH, Loscalzo J. Aspirin. Circulation. 2000; 101: 1206-1208
• 14 Hassan M, Amonkar M. Aspirin for primary and secondary prophylaxis of cardiovascular disease. Curr Ther Res. 2001; 62: 676-690
• 15 Patrono C, Coller B, Dalen JE Fitzgerald GA, Fuster V, Gent M et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2001; 119: 39S-63S
• 16 Clagett GP, Sobel M, Jackson MR, Lip GYH, Tangelder M, Verhaeghe R. Antithrombotic therapy in peripheral arterial occlusive disease. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004; 126: 609S-626S
• 17 Hiatt WR, Krantz MJ. Master class series in peripheral arterial disease. Antiplatelet therapy for peripheral arterial disease and claudication. Vasc Med. 2006; 11: 55-60
• 18 Mas R. D-003: A new substance with promising lipid modifying and pleiotropic effects for atherosclerosis management. Drug Future. 2004; 29: 773-786
• 19 Molina V, Arruzazabala ML, Carbajal D, Mas R, Valdés S. Antiplatelet and Antithrombotic effects of D003. Pharmacol Res. 2000; 42: 137-143
• 20 Molina V, Carbajal D, Arruzazabala L, Mas R. Effect of D-003 on intravascular platelet aggregation induced with collagen in rats. J Med Food. 2005; 8: 232-236
• 21 Molina V, Arruzazabala ML, Carbajal D, Mas R. D-003, a new compound with effects on arachidonic acid metabolites. Prostagl Leuktr Ess Fatty Acids. 2002; 67: 19-24
• 22 Molina V, Arruzazabala ML, Carbajal D, Mas R. Synergistic effect of D-003 and aspirin on experimental thrombosis model. Prostagl Leukotr Ess Fatty Acids. 2003; 68: 305-310
• 23 Castaño G, Mas R, Fernández L, Illnait J, Gámez R, Lόpez E et al. Assessment of the effects of D-003, a new antiplatelet and lipid-lowering compound, in healthy volunteers. Drugs R &D. 2002; 3: 337-348
• 24 Arruzazabala ML, Carbajal D, Mas R, Molina V, Castaño G. Effects of D-003 a new compound purified from sugar cane wax on platelet aggregation in healthy volunteers: A randomized double-blinded clinical study. Clin Drug Invest. 2003; 23: 107-118
• 25 Arruzazabala ML, Mas R, Molina V, Carbajal D, Fernández L, Illnait J et al. Effects of D-003, a new substance purified from sugar cane wax, on platelet aggregation and plasma levels of arachidonic acid metabolites in healthy volunteers. Int J Pharmacol Clin Res. 2004; XXIV: 5-64
• 26 Arruzazabala ML, Molina V, Carbajal D, Fernández L, Mas R, Castaño G et al. Effects of D-003, a mixture of very long chain fatty acids purified from sugar cane wax, at 5 and 10 mg/d on platelet aggregation in healthy volunteers. Int J Phamacol Clin Res. 2005; XXV: 29-39
• 27 Gámez R, Mendoza S, Más R, Noa M, Arruzazabala ML, Carbajal D et al. Dose-dependent cholesterol-lowering effects of D-003 on normocholesterolemic rabbits. Curr Ther Res. 2000; 61: 460-468
• 28 Castaño G, Menéndez R, Mas R, Ledon N, Fernández JC, Pérez JL et al. Effects of D-003 on lipid profile and lipid peroxidation in healthy volunteers. Clin Drug Invest. 2003; 23: 193-203
• 29 Castaño G, Mas R, Fernández L, Illnait J, Lόpez E, Gámez R et al. Effects of D-003 on lipid profile of patients with Type II hypercholesterolemia: a Phase II clinical study. Clin Drug Invest. 2003; 23: 789-802
• 30 Méndez E, Marrero D, Laguna A. González V GC determination of long chain fatty acids that compose D-003 in 5-mg film-coated tablets. J Pharm Biomed Anal. 2003; 31: 613-620
• 31 Born G. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature (London). 1962; 194: 927-930
• 32 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18: 499-502
• 33 Menéndez R, Mas R, Pérez Y, Gonzalez RM, Jimenez S. Ci-nética de la radiactividad total (RT) tras la administraciόn oral y endovenosa de dosis únicas de Acido 3H-octaco-sanoico a ratas. Acta Farm Bonaerense. 2005; 24: 48-60
• 34 Grodzinska L, Starzyk D, Bieron K, Goszcz A, Korbut R. Simvastatin effects in normo- and hypercholesterolaemic patients with peripheral arterial occlusive disease: a pilot study. Basic Clin Pharmacol Toxicol. 2005; 96: 413-419
• 35 Leone A. Biochemical markers of cardiovascular damage from tobacco smoke. Curr Pharm Des. 2005; 11: 2199-2208
• 36 Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ et al. Reduction of LDL-cholesterol by 25 to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol. 1995; 15: 678-682
• 37 Castaño G, Más R, Arruzazabala ML, Noa M, Illnait J, Fernández JC et al. Effects of policosanol, pravastatin on lipid profile, platelet aggregation, endothelemia in older hypercholesterolemic patients. Int J. Clin Pharm Res. 1999; XIX: 105-116
• 38 Tekten T, Ceyhan C, Ercan E, Onbasili AO, Turkoglu C. The effect of atorvastatin on platelet function in patients with coronary artery disease. Acta Cardiol. 2004; 59: 311-315
• 39 Puccetti L, Pasqui AL, Pastorelli M, Bova G, Di Renzo M, Leo A et al. Platelet hyperactivity after statin treatment discontinuation. Thromb Haemost. 2003; 90: 476-82