Skip to main content
SpringerLink
Log in

Assessment of the Effects of D-003, a New Antiplatelet and Lipid-Lowering Compound, in Healthy Volunteers

A Phase I Clinical Study

  • Original Research Article
  • Published:
Drugs in R & D Aims and scope Submit manuscript

Abstract

Objective: To investigate the effects of D-003 on the bleeding time (BT) and lipid profile of healthy human volunteers.

Methods: This single-blind, randomised, placebo-controlled, parallel-group study was conducted in healthy volunteers. Step 1 investigated the effects of single doses of D-003 5, 25 or 50mg on BT in comparison with placebo. Step 2 investigated the effects of 30 days of D-003 5, 25 or 50 mg/day compared with placebo on lipid profile with an interim assessment at 14 days. BT, lipid profile, physical and haematological safety indicators were measured and adverse events (AEs) recorded.

Both steps were followed by a 14- or 30-day washout period

Results: Step 1: D-003 25 and 50mg significantly increased mean BT 2 hours after administration compared with baseline, but a significant difference versus placebo occurred only with the 50mg dose. Individual values from participants taking this dose, however, remained within normal limits. This effect was reversible. BT values obtained 2 hours after drug administration showed a moderate dose-dependent relationship. No drug-related changes in safety indicators were found with D-003.

Step 2: After 7 days on D-003 50 mg/day, BT was significantly increased compared with baseline and placebo up to the end of the active treatment period. However, all individual values for participants taking this dosage remainedwithin the normal range. This effect was reversible by the end of the washout period. After 30 days, D-003 (5, 25 and 50 mg/day) significantly reduced serum TC (by 13.3 to 17.4%) and LDL-C (by 11.6 to 22.6%) levels, and raised HDL-C levels (by 14.6 to 29.7%), but did not affect triglyceride levels. The significant increase in HDL-Cwas observed after 14 days on treatment. The effects on the lipid profile were reversible by the end of the 30-day washout period, although after 14 days of washout the effects on HDL-C and LDL-C still remained significant, revealing a certain persistence of effect. Eight participants (four receiving placebo and four receiving D-003 5, 25 or 50 mg/day) reported a total of nine AEs, none of which were drug-related. Of these patients, only two treated with D-003 25 and 50 mg/day discontinued treatment.

Conclusions: D-003 in single or repeated doses (50mg) induced significant and reversible increases in BT. In addition, repeated doses (5, 25 and 50 mg/day) significantly and reversibly lowered serum LDL-C and TC levels and significantly raised serum HDL-C levels. These effects were reversible by 30 days after the end of treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. Murray CJL, López AD. Alternate projections of mortality and disability by cause 1990–2020. Global Burden disease Study. Lancet 1997; 349: 1498–504

    Article  PubMed  CAS  Google Scholar 

  2. Brown MS, Goldstein JL. Heart Attacks: Gone with the Century. Science 1996; 272: 629–30

    Article  PubMed  CAS  Google Scholar 

  3. Falk E, Fernández-Ortiz A. Role of thrombosis in atherosclerosis and its complications. Am J Cardiol 1995; 75: B1–7

    Article  Google Scholar 

  4. Euroaspire Study group: European Society of Cardiology survey of secondary prevention of coronary heart disease: Principal results. Eur Heart J 1997; 18: 1569–1582

    Article  Google Scholar 

  5. Wood D. European and American recommendations for coronary heart disease prevention. Eur Heart J 1998; 19 Suppl A: A12–9

    PubMed  Google Scholar 

  6. Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497

    Article  Google Scholar 

  7. Pyorala K, De Backer G, Graham I, et al. Prevention of coronary heart disease in clinical practice: Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J 1994; 15: 1300–31

    PubMed  CAS  Google Scholar 

  8. 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. BMJ 1994; 308: 81–106

    Article  Google Scholar 

  9. Wilson JM, Ferguson JJ. Platelet-endothelial interactions in atherothrombotic disease: therapeutic implications. Clin Cardiol 1999; 22: 687–98

    Article  PubMed  CAS  Google Scholar 

  10. Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–1389

    Google Scholar 

  11. Sacks FM, Pfeffer MA, Moyé LA, et al. for the Cholesterol and Recurrent Events Trial Investigators: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 35: 1001–9

    Article  Google Scholar 

  12. Tonkin A, Aylward P, Colqhoun D, et al. Prevention of cardiovascular events and deaths with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57

    Article  Google Scholar 

  13. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–7

    Article  PubMed  CAS  Google Scholar 

  14. Weis S, Clearfield M, Downs JR, et al. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): Primary prevention of acute major coronary events in women and men with average cholesterol. In: Grundy S. Cholesterollowering therapy: Evaluation of clinical trial evidence. New York, Basel: Marcel Dekker Inc, 2000: 151–172

    Google Scholar 

  15. The Lipid Research Clinics Coronary Primary Prevention Trial results. I: Reduction in the incidence of coronary heart disease. JAMA 1984; 251: 351–64

    Article  Google Scholar 

  16. The Lipid Research Clinics Coronary Primary Prevention Trial results. II: The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 365–74

    Article  Google Scholar 

  17. Frick MH, Elo O, Happa K, et al. Helsinki Heart Study: Primary- prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237–45

    Article  PubMed  CAS  Google Scholar 

  18. Troche CJ, Tacke J, Hinzpeter B, et al. Cost-effectiveness of primary and secondary prevention in cardiovascular diseases. Eur Heart J 1998; 19 Suppl C: C59–65

    PubMed  Google Scholar 

  19. González L, Marrero D, Laguna A, et al. Mixture of primary fatty acids of high molecular weight obtained from sugar cane wax and its pharmaceutical uses. Republic of South Africa: Laboratorios Dalmer SA, 1998 Dec 30: patent 98–2744

    Google Scholar 

  20. Molina V, Arruzazabala ML, Carbajal D, et al. Antithrombotic effects of D003. Pharmacol Res 2000; 42: 137–43

    Article  PubMed  CAS  Google Scholar 

  21. Molina V, Arruzazabala ML, Carbajal D, et al. Effects of D-003 on serum and plasma thromboxane B2 and prostaciclin levels in experimental models. Prostaglandins Leukot Essent Fatty Acids. In press

  22. Gámez R, Mendoza S, Mas R, et al. Dose-dependent cholesterol- lowering effects of D-003 on normocholesterolemic rabbits. Curr Ther Res Clin Exp 2000; 61: 8–16

    Article  Google Scholar 

  23. Menéndez R, Mas R, Amor AM et al: Inhibition of cholesterol biosynthesis in cultured fibroblasts by D-003, a mixture of very long chain saturated fatty acids. Pharmacol Res 2001, 44: 299–304

    Article  PubMed  Google Scholar 

  24. Mas R. Policosanol. Drugs Future 2000; 25: 569–86

    Article  CAS  Google Scholar 

  25. Gámez RA, Mas R, Noa M, et al. Six-month study of the oral toxicity of D-003 in Sprague Dawley rats. Drugs R&D. In press 2002

    Google Scholar 

  26. Mendoza S, Gámez R, Noa M, et al. The effects of D-003 and policosanol on the lipid profile and endothelemia cells in normocholesterolemic rabbits: a head to head comparison. Curr Ther Res Clin Exp 2001; 62: 209–20

    Article  CAS  Google Scholar 

  27. Gámez R, Más R, Noa M, et al. Acute and subchronic oral toxicity of D-003 in rats. Toxicol Lett 2000; 118: 31–41

    Article  PubMed  Google Scholar 

  28. Gámez R, González JE, Rodeiro I, et al. In vivo genotoxic evaluation of D-003, a mixture of very long-chain aliphatic acids. J Med Food 2001; 4: 85–92

    Article  PubMed  Google Scholar 

  29. Gámez R., Rodeiro I, Fernández I, et al. A preliminary evaluation of the cytotoxic and genotoxic potential of D-003: a mixture of very long chain fatty acids. Teratog Carcinog Mutagen 2001. In press

    Google Scholar 

  30. Arruzazabala ML, Carbajal D, Más R, et al. Cholesterol-lowering effects of policosanol in rabbits. Biol Res 1994; 27: 205–8

    PubMed  CAS  Google Scholar 

  31. Seigler L, Wu WT. Separation of serum high-density lipoprotein for cholesterol determination: Ultracentrifugation vs precipitation with sodium phosphotungstate and magnesium chloride. Clin Chem 1981; 27: 838–41

    PubMed  CAS  Google Scholar 

  32. Friedewald WT, Levy IR, 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

    PubMed  CAS  Google Scholar 

  33. O’Brien PC, Shampo MA. Statistical considerations for performing multiple tests in a single experiment. Comparing two therapies with respect to several endpoints. Mayo Clin Proc 1988; 63: 1140–3

    Article  PubMed  Google Scholar 

  34. Schafer AI. Antiplatelet therapy. Am J Med 1996; 101: 199–209

    Article  PubMed  CAS  Google Scholar 

  35. McTavish D, Faulds D, Goa KL. Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 1990; 40: 238–59

    Article  PubMed  CAS  Google Scholar 

  36. Coukell AJ, Marham A. Clopidogrel. Drugs 1997; 54: 745–50

    Article  PubMed  CAS  Google Scholar 

  37. Menéndez R, Mas R, Pérez Y, et al. Inhibition of rat lipoprotein lipid peroxidation by the oral administration of D-003. Can J Physiol Pharmacol. In press

  38. Aviram M. Macrophages, LDL oxidation and atherosclerosis. In: Jacotot B, Mathé D, fruchart JC, editors. Atherosclerosis XI International Congress. Series 1155. Singapore: Excerpta Medica Elsevier Science, 1998: 483–492

    Google Scholar 

Download references

Acknowledgements

This study was sponsored through a research grant approved by the Scientific Technical Council of the Havana City West Scientific Organization.

Author information

Authors and Affiliations

  1. Medical Surgical Research Center, Havana City, Cuba

    Gladys Castaño, Ernesto López & Juan A. Gutiérrez

  2. Center of Natural Products, National Center for Scientific Research, PO Box 6880 or 6990, Cubanacán Havana City, Cuba

    Rosa Más, Lilia Fernández, José Illnait, Julio C. Fernández, Rafael Gámez & Estrella Alvarez

Authors
  1. Gladys Castaño
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosa Más
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lilia Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ernesto López
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan A. Gutiérrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José Illnait
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julio C. Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rafael Gámez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Estrella Alvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosa Más.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castaño, G., Más, R., Fernández, L. et al. Assessment of the Effects of D-003, a New Antiplatelet and Lipid-Lowering Compound, in Healthy Volunteers. Drugs R&D 3, 337–348 (2002). https://doi.org/10.2165/00126839-200203050-00008

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00126839-200203050-00008

Keywords

Search

Navigation