Gutiérrez MA, Gámez MR, Mas FR, Noa PM, Valle CM, Nodal FC

Language: Spanish
References: 46
Page: 275-288
PDF size: 176.59 Kb.

ABSTRACT

Introduction: D-004, a lipid extract from royal palm (Roystonea regia) fruit constituted by a reproducible mixture of fatty acids, mainly oleic, palmitic, lauric and myristic, has shown to be effective in experimental models of prostate hyperplasia.
Objective: summarize the partial results (18 months) of the study on carcinogenicity by repeated and long-term exposure of Sprague Dawley rats to D-004, to be completed in the planned period of 24 months.
Methods: sprague Dawley rats of both sexes were randomly distributed into four groups (50 rats/sex/group): one group was the vehicle control and three were treated with D-004 (500, 1000 and 1500 mg/kg, respectively). Treatments were administered orally by gastric intubation. This report includes the results obtained so far (18 months) concerning body weight, clinical observations, mortality and frequency of appearance of tumors.
Results: mortality is low: 8.3% in treatment groups and 9% in controls. A reduction in survival time was not observed, and daily observations did not reveal any signs of toxicity attributable to the treatment. The time of appearance and the frequency of tumors in treated animals and controls were statistically similar in both sexes.
Conclusions: oral administration of D-004 (500–1500 mg/kg) to rats during the first 18 months of the study did not show any evidence of early carcinogenicity or toxicity associated with the treatment.

REFERENCES

1. Abdollah F, Briganti A, Suardi N, Castiglione F, Gallina A, Capitanio U, et al. Metabolic syndrome and Benign Prostatic Hyperplasia: Evidence of a potential relationship, hypothesized etiology, and prevention. Korean J Urol. 2011;52:507-16.

2. Schwinn DA, Roehrborn CG. Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193-9.

3. Schmidt LJ, Tindall DJ. Steroid 5α-reductase inhibitors targeting BPH and prostate cancer. J Steroid Biochem Mol Biol. 2011;125:32-8.

4. Azimi H, Khakshur AA, Aghdasi I, Fallah-Tafti M, Abdollahi M. A review of animal and human studies for management of benign prostatic hyperplasia with natural products; perspective of new pharmacological agents. Inflammation & Allergy - Drug Targets. 2012;11:207-21.

5. Abe M, Ito Y, Oyunzul L, Oki- Fujino T, Yamada S. Pharmacologicall Relevant receptor Binding Characteristcs and 5a- reductasa inhibitory activity of free fatty acids contained in Saw Palmetto Extract. Biol Pharm Bull. 2009,32(4):646-50.

6. Raman P, David L, DeWitt G, Muraleedharan G. Lipid peroxidation and cyclooxygenase enzyme inhibitory activities of acidic aqueous extracts of some dietary supplements. Phytotherapy Res. 2007;22(2):204-12.

7. Baron A, Mancini M, Caldwell E, Cabrelle A, Bernardi P, Pagano F. Serenoa repens extract targets mitochondria and activates the intrinsic apoptotic pathway in human prostate cancer cells. BJU Int. 2009;103(9):1275-83.

8. Arruzazabala ML, Molina V, Carbajal D. Composition changes of lipid extract of Roystonea regia fruits of different ripening stages influence their effects on testosterone-induced prostate enlargement in rats. Lat Am J Pharm. 2008;27(1): 41-5.

9. Arruzazabala ML, Carbajal D, Mas R. Preventive effects of D-004, a lipid extract from Cuban royal palm (Roystonea regia) fruits, on prostate hyperplasia induced with testosterone on intact and castrated rodents. Drugs Exptl Clin Res. 2004;30:227-34.

10. Carbajal D, Arruzazabala ML, Mas R. Effect of D-004, a lipid extract from Cuban royal palm fruit, on inhibiting prostate hyperplasia induced with testosterone and dihydrotestosterone in rats. Curr Ther Res Clin & Exptl. 2004;65: 505-14.

11. Noa M. Arruzazabala ML, Carbajal D. Effect of D-004, a lipid extract from Cuban royal palm fruit, on histological changes of prostate hyperplasia induced with testosterone in rats. Int J Tiss React. 2005;27:203-12.

12. Arruzazabala ML, Mas R, Carbajal D, Molina V. Effect of D-004, a lipid extract from Cuban royal palm fruit, on in vitro and in vivo effects mediated by α adrenoceptors in rat. Drugs R & D. 2005;6:281-289.

13. Arruzazabala ML, Mas R, Molina V, Noa M, Carbajal D, Mendoza N. Effects of D-004, a lipid extract from the Cuban royal palm fruit on atypical prostate hyperplasia induced by phenylephrine in rats. Drugs R &D. 2006;7:233-241.

14. Ravelo Y, Molina V, Jiménez S, Oyarzábal A, Pérez Y, Mas R. Effect of oral administration of D-004, a lipid extract from Roystonea regia fruits, on xyleneinduced ear oedema in mice. Lat Am J Pharm. 2011;30(9):1744-8.

15. Pérez Y, Molina V, Mas R, Menéndez R, González RM, Oyarzábal A, y colaboradores. Ex vivo antioxidant effects of D-004, a lipid extract from Roystonea regia fruits, on rat prostate tissue. Asian J Androl. 2008;10:659-66.

16. Lopez E, Molina V, Illnait J, Oyarzábal A, Fernández L, Mas R, y colaboradores. Antioxidant effects of D-004, a lipid extract from the Roystonea regia fruits, on the plasma of healthy men. Asian J Androl. 2007;11:385-92.

17. Gutiérrez A, Gámez R, Más R, Noa M, Pardo B, Goicochea E, et al. Toxicología aguda del D-004 en conejos. Rev. CENIC Cien. Biol. 2007;38 (2): 99-102.

18. Gámez R, Mas R, Noa M, Menéndez R, García H, Rodríguez Y, et al. Oral acute and subchronic toxicity of D-004, a lipid extract from Roystonea regia fruits, in rats. Drugs Exp Clin Res. 2005;31(3):101-8.

19. Gutiérrez A, Gámez R, Mas R, Noa M, Pardo B, Marrero G, et al. Oral subchronic toxicity of a lipid extract from Roystonea regia fruits, in mice. Drug Chem Toxicol. 2008; 31: 217-228.

20. Pardo B, Gutiérrez A, Gámez R, Noa M, Marrero G. Six-Month oral Toxicity of D-004, a lipid extract from Roystonea regia fruits, in Sprague Dawley rats: a preliminary study. Rev CNIC Cien. Biol. 2009;40(3): 161-165.

21. Gutiérrez A, Gámez R, Noa M, Mas R, Arencibia D, Pardo B, et al. One year oral Toxicity of D-004, a lipid extract from Roystonea regia fruits, in Sprague Dawley rats. Food Chem Tox. 2011;49: 2855-2861.

22. Gutiérrez A, Marrero G, Gámez R, Fernández I, Curveco D, García H. Evaluación del D-004 en el Ensayo de Ames por incorporación directa a placa. Revista CENIC Ciencias Biológicas. 2005; 36 (Especial):15-21.

23. Marrero G, Gutiérrez A, Pardo B, Gámez R, Curveco D. Evaluación del efecto genotóxico del D-004 en ratones NMRI empleando la electroforesis alcalina de células individuales en gel (Ensayo cometa). Rev. CNIC Cien. Biol. 2007;38 (3):200-3.

24. Fernández I, Gámez R, Gutiérrez A, García H. Evaluación Genotóxica in vivo del D-004 en el Ensayo de Micronúcleos en Médula Ósea en Ratones. Revista CENIC Ciencias Biológicas. 2005;36 (Especial): 11-14.

25. Gutiérrez A, Gámez R, Arencibia D, Pardo B, García H. Evaluación del potencial genotóxico del D-004, para inducir aberraciones cromosómicas en médula ósea de ratones. Revista CENIC Ciencias Biológicas. 2010;41(Especial): 30-34.

26. Arencibia DF, Gámez R, Gutiérrez A, Pardo B, Curveco D, García H y Goicochea E. Evaluación Genotóxica del D-004 en el ensayo de la morfología de la cabeza del espermatozoide en ratas Sprague Dawley. Rev. Toxicol. 2009;26:127-130.

27. Arencibia D, Gámez R, Gutiérrez A, Pardo B, Noa M, Mas R, et al. Evaluación Genotóxica del D-004 en el Ensayo de la Morfología de la Cabeza del Espermatozoide en Ratones OF-1. Rev. CNIC Cien. Biol. 2009;40 (1): 29-32.

28. Pardo B, Gutiérrez A, Gámez R, Mendoza S, Noa M, Mas R, et al. Estudio de los posibles efectos estrogénicos del D-004. Rev. CENIC Cien. Biol. 2007;38 (2) 103-106.

29. Gutiérrez A, Gámez R, Noa M, Mas R , Pardo B, Valle M, et al. Evaluation of D-004 in Mature Ovariectomized Rat Uterotrophic Assays. Lat. Am. J. Pharm. 2008;27(5):710-5.

30. Fernández L, Mas R, Fernández JC, Mendoza S, Gámez R, Pardo B. Effects of D- 004, a Lipid Extract of the Fruit of the Cuban Royal Palm (Roystonea regia) or the Lipidosterolic Extract of Saw Palmetto (Serenoa repens) on the Sexual Activity in Male Rats: A controlled, experimental study. Curr Ther. 2009; 69: 65-74.

31. Carbajal D, Molina V, Mas R, Arruzazabala ML. Efecto del D-004 sobre patrones conductuales en roedores. Rev CNIC. 2007; 38: 12-17.

32. Gutiérrez A, Pardo B, Gámez R, Mas R, Noa M, Marrero G, et al. Effects of in utero exposure to D-004, a lipid extract from Roystonea regia fruits, in the male rat. Comparison with Finasteride. J Med Food. 2011;14 (12): 1663-69.

33. Gutiérrez A, Gámez R, Mas R, García H, Bucarano I, Goicochea E. Estudio teratogénico del D-004 en conejos. Rev Cubana Toxicol. 2012;1(2): 58-62.

34. Sierra R, Rodríguez E, González V, Marrero D, Vicente R. Estudios preliminares de estabilidad de un extracto lipídico de frutos de Roystonea regia (D-004) en frascos de vidrio ámbar. Rev Cubana Farm. 2010;44(3):360-6.

35. Sierra R, Rodríguez EA, Vicente R, Marrero D, González VL, Morales CL. Metodología analítica y estudio de estabilidad de las emulsiones empleadas en los estudios de toxicología preclínica del D004, sustancia de naturaleza oleosa. Rev Cubana Toxicol. 2012;1(2). (en prensa)

36. US Department of Health and Human Services, Center for Drug Evaluation and Research (CDER). Guideline for Industry: S1C(R) Addendum to Dose Selection for carcinogenicity studies of pharmaceuticals. Addition of a limit dose and related notes. ICH 1997,S1A.

37. Nakazawa M, Tawaratani T, Uchimoto H. Spontaneous neoplastic lesions in aged Sprague-Dawley rats. Exp Anim. 2001;50:99-103.

38. Giknis MLA, Clifford Ch B. Compilation of spontaneous neoplastic lesions in survival. In Crl: CD (SD) rats from control groups. Charles River Laboratories, 2004.

39. Keenan KP, Smith PF, Hertzog P. The effects of overfeeding and dietary restriction on Sprague-Dawley rat survival and early pathology biomarkers of aging. Toxicol. Pathol., 1994;22: 300-15.

40. Alemán CL, Mas RM, Rodeiro I, Noa M, Hernández C, Menéndez R, et al. Reference database of the main physiological parameters in Sprague–Dawley rats from 6 to 32 months. Lab Anim. 1998;32:457-66.

41. Alemán CL, Mas R, Noa M, Rodeiro I, Hernández C, Capote A. Carcinogenicity of policosanol in Sprague Dawley rats: A 24 months study. Teratogenesis, Carcinogenesis and Mutagenesis. 1994;14:239-49.

42. Gámez R, Noa M, Mas R, Mendoza N, Pardo B, Menéndez R, et al. Long-term carcinogenicity of D-003, a mixture of high molecular weight acids from sugarcane wax, in Sprague Dawley rats: a 24 months study. Food Chem Tox. 2007;45:2352-8.

43. Johnson MD, Gad SC. The rat. In: Gad SC, ed. Animal models in toxicology. Boca Raton, FL: CRC Press, 2007;147-275.

44. Durbin PW, Williams MH, Jeung N, Arnold JS. Development of spontaneous mammary tumors over the life-span of the female Charles River (Sprague-Dawley) rat: the influence of ovariectomy, thyroidectomy, and adrenalectomy-ovariectomy. Cancer Res. 1966;26(3):400-11.

45. Chandra M, Frith CF. Spontaneous neoplasms in aged control Fischer 344 rats. Cancer Lett. 1992;62(1):49-56.

46. Peckham JC. Animal Histopathology. In: Derelanko MJ, Hollinger MA, eds. Handbook of Toxicology. Boca Raton, Florida: CRC Press, 2002;640-732.