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  • Original Article
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Oral sildenafil citrate lacks genotoxicity and cytotoxicity in a primate model: Callithrix jacchus

Journal of Perinatology volume 26, pages 423–427 (2006)Cite this article

Abstract

Objective:

To determine sildenafil citrate (SC) genotoxicity and cytotoxicity in the Callithrix jacchus.

Study design:

Fifteen organisms were assigned to one of three groups as follows: experimental (25 mg/kg of SC); negative control (glucose solution 5%); and positive control (3 mg/kg of cytocine arabinoside). Systemic hemodynamic changes were monitored in each animal before and after each treatment. A drop of blood was obtained before and after the treatment at 24–120 h. Smears were made and the frequency of micronucleated erythrocytes (MNE), micronucleated polychromatic erythrocytes (MNPCE) and polychromatic erythrocytes (PCE) was counted.

Results:

No significant differences in MNE, MNPCE and PCE were found in the group that received sildenafil and negative control. A significant increase in genotoxicity and cytotoxicity was observed in the positive control group. No changes were observed in systemic hemodynamic changes.

Conclusion:

The macro-dose of SC lacks genotoxic, cytotoxic or systemic hemodynamic changes effects in this species.

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References

  1. Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB . Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000; 105: 14–20.

    Article  CAS  Google Scholar 

  2. Finer NN, Barrington KJ . Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 4; 2001: CD000399.

    Google Scholar 

  3. Cooke JP . A novel mechanism for pulmonary arterial hypertension? Circulation 2003; 108: 1420–1421.

    Article  Google Scholar 

  4. Travadi JM, Patote SK . Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review. Pediatr Pulmonol 2003; 36: 529–535.

    Article  CAS  Google Scholar 

  5. Baquero H, Soliz A, Neira F, Venegas ME, Sola A . Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006 (in press).

  6. Haworth SG . Pulmonary hypertension in the young. Heart 2002; 88: 658–664.

    Article  Google Scholar 

  7. Sergei D, Rybalkin ChY, Karin E, Bornfeldt JA . Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003; 93: 280–291.

    Article  Google Scholar 

  8. Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC . Medical therapy for pulmonary arterial hypertension. Chest 2004; 126: 35S–62S.

    Article  Google Scholar 

  9. Moreno L, Losada B, Cogollado AL, Lodi F, Lugnier C . Postnatal maturation of phosphodiesterase 5 (PDE5) in piglet pulmonary arteries: activity, expression, effects of PDE 5 inhibitors, and role of the nitric oxide/cyclic GMP pathway. Pediatr Res 2004; 56: 563–570.

    Article  CAS  Google Scholar 

  10. Buck ML . Sildenafil for the treatment of pulmonary hypertension in children. Pediatr Pharm 2004; 10: 5–8.

    Google Scholar 

  11. Ichinose F, Erana-Garcia J, Hromi J, Yehuda R, Jones R, Krim L . Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001; 29: 1000–1005.

    Article  CAS  Google Scholar 

  12. Shekerdemian LS, Ravn HB, Penny DJ . Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Respir Crit Care Med 2002; 165: 1098–1102.

    Article  Google Scholar 

  13. Abrams D, Schulze-Neick I, Magee AG . Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000; 84: E4.

    Article  CAS  Google Scholar 

  14. Prasad S, Wilkinson J, Gatzoulis MA . Sildenafil in primary pulmonary hypertension. N Engl J Med 2000; 343: 1342–1343.

    Article  CAS  Google Scholar 

  15. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A . Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104: 424–428.

    Article  CAS  Google Scholar 

  16. Ortiz-Quezada F . Sildenafil en el tratamiento de la hipertensión pulmonar. Curr Sex Health Rep 2004; 2: 2–10.

    Google Scholar 

  17. Atz AM, Wessel DL . Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999; 91: 307–310.

    Article  CAS  Google Scholar 

  18. Schmid W . The micronucleus test. Mutat Res 1975; 31: 9–15.

    Article  CAS  Google Scholar 

  19. Heddle JA, Cimino MC, Hayashi M, Romagna F, Shelby M, Tucker J et al. Micronuclei as an index of cytogenetic damage: past, present and future. Environ Mol Mutagen 1991; 18: 277–291.

    Article  CAS  Google Scholar 

  20. Schmezer P, Pool BL, Lefevre PA, Callander RD, Ratpan F, Tinwell H et al. Assay-specific genotoxicity of n-nitrosodibenzylamine to the rat liver in vivo. Environ Mol Mutagen 1990; 15: 190–197.

    Article  CAS  Google Scholar 

  21. Zúñiga G, Torres-Bugarín O, Ramírez-Muñoz MP, Delgado-Lamas JL, De Loza-Saldaña R, Cantú JM . Micronucleated erythrocytes in splenectomized patients with and without chemotherapy. Mutat Res 1996; 361: 107–112.

    Article  Google Scholar 

  22. Torres-Bugarín O, De Anda-Casillas A, Ramírez-Muñoz MP, Sánchez-Corona J, Cantú JM, Zúñiga G . Determination of diesel genotoxicity in firebreathers by micronuclei and nuclear abnormalities in buccal mucosa. Mutat Res 1998; 413: 277–281.

    Article  Google Scholar 

  23. Torres-Bugarín O, Zamora Perez AL, Esparza-Flores A, López-Guido B, Feria-Velasco A, Cantú JM et al. Eritrocitos micronucleados en niños esplenectomizados con y sin quimioterapia. Bol Med Hosp Infant Mex 1999; 56: 212–217.

    Google Scholar 

  24. Zúñiga-González G, Torres-Bugarín O, Zamora-Perez A, Gómez-Meda BC, Ramos-Ibarra ML, Martínez-González S et al. Differences in the number of micronucleated erythrocytes among young and adult animals. Spontaneous micronuclei in 43 species. Mutat Res 2001; 494: 161–167.

    Article  Google Scholar 

  25. Zúñiga-González G, Gómez-Meda BC, Zamora-Perez A, Ramos-Ibarra ML, Batista-González CM, Espinoza-Jiménez S et al. Induction of micronuclei in proestrus vaginal cells from colchicine- and cyclophosphamide-treated rats. Environ Mol Mutagen 2003; 42: 306–310.

    Article  Google Scholar 

  26. Gómez-Meda BC, Zúñiga-González GM, Zamora-Perez A, Ramos-Ibarra ML, Batista-González CM, Torres-Mendoza BM . Folate supplementation of cyclophosphamide-treated mothers diminishes micronucleated erythrocytes in peripheral blood of newborn rats. Environ Mol Mutagen 2004; 44: 174–178.

    Article  Google Scholar 

  27. Zamora-Perez A, Zúñiga-González GM, Gómez-Meda BC, Ramos-Ibarra ML, Batista-González CM, Torres-Bugarín O . Induction of micronucleated cells in the shed skin of salamanders (Ambystoma sp.) treated with colchicine or cyclophosphamide. Environ Mol Mutagen 2004; 44: 436–440.

    Article  CAS  Google Scholar 

  28. Zúñiga-González GM, Gómez-Meda BC, Zamora-Perez AL, Ramos-Ibarra ML, Batista-González CM, Lemus-Varela ML et al. Micronucleated erythrocyte frequencies in old and new world primates: measurement of micronucleated erythrocyte frequencies in peripheral blood of Callithrix jacchus as a model for evaluating genotoxicity in primates. Environ Mol Mutagen 2005; 46: 253–259.

    Article  Google Scholar 

  29. Poole T . The UFAW Handbook on the Care & Management of Laboratory Animals, 6th edn. Longman Scientific & Technical: Essex, England, 1994, pp 546–581.

    Google Scholar 

  30. Diario Oficial. Secretaría de Agricultura, Ganadería y Desarrollo Rural 2001 Norma Oficial Mexicana NOM-062-ZOO-2001. Especificaciones técnicas para la producción, cuidado y uso de los animales de laboratorio.

  31. Hayashi M, MacGregor JT, Gatehouse DG, Adler ID, Blakey DH, Dertinger SD et al. In vivo rodent erythrocyte micronucleus assay. II. Some aspects of protocol design including repeated treatments, integration with toxicity testing, and automated scoring. Environ Mol Mutagen 2000; 35: 234–252.

    Article  CAS  Google Scholar 

  32. Klaassen CD . Casarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill: New York, 2001, pp 26–27, 83–104.

    Google Scholar 

  33. Carroll WD, Dhillon R . Sildenafil as a treatment for pulmonary hypertension. Arch Dis Child 2003; 88: 827–828.

    Article  CAS  Google Scholar 

  34. Cunha KS, Reguly ML, Graf O, de Andrade HH . Somatic recombination: a major genotoxic effect of two pyrimidine antimetabolic chemotherapeutic drugs in Drosophila melanogaster. Mutat Res 2002; 514: 95–103.

    Article  CAS  Google Scholar 

  35. Severin I, Padieu M, Lhuguenot JC, Chagnon MC . Toxic interaction between hidroxyurea and 1-beta-D-arabino-furanosylcytosine on the DNA of a human hepatoma cell line (HEPG2). Toxicol Lett 2003; 145: 303–311.

    Article  CAS  Google Scholar 

  36. Zúñiga-González G, Torres-Bugarín O, Zamora-Perez A, Gómez-Meda BC, Ramos-Ibarra ML, Gallegos-Arreola MP et al. Induction of micronucleated erythrocytes in mouse peripheral blood after cutaneous application of 5-fluorouracil. Arch Med Res 2003; 34: 141–144.

    Article  Google Scholar 

  37. Hayashi M, Morita T, Ishidate M . An application of acridine orange fluorescent staining to the micronucleus test. Mutat Res 1983; 120: 241–247.

    Article  CAS  Google Scholar 

  38. Hayashi M, Morita T, Kodama Y, Sofuni T, Ishidate M . The micronuclei assay with mouse peripheral blood reticulocytes using acridine orange-coated slides. Mutat Res 1990; 245: 245–249.

    Article  CAS  Google Scholar 

  39. Shekerdemian LS, Ravn HB, Penny DJ . Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatr Res 2004; 55: 413–418.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Goddard Scholarship and Children's Research Center Fund (AS), Emory University, Atlanta, GA, USA.

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Authors and Affiliations

  1. Departamento de Neonatología, Hospital de Pediatría, Unidad Médica de Alta Especialidad, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México

    M L Lemus-Varela

  2. Neonatal–Perinatal Fellowship Program, Emory University School of Medicine, Atlanta, GA, USA

    A Sola

  3. Laboratorio de Mutagénesis, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México

    B C Gómez-Meda, A L Zamora-Perez, M L Ramos-Ibarra, C M Batista-González & G M Zúñiga-González

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  1. M L Lemus-Varela
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  6. C M Batista-González
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Correspondence to M L Lemus-Varela.

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Lemus-Varela, M., Sola, A., Gómez-Meda, B. et al. Oral sildenafil citrate lacks genotoxicity and cytotoxicity in a primate model: Callithrix jacchus. J Perinatol 26, 423–427 (2006). https://doi.org/10.1038/sj.jp.7211518

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  • DOI: https://doi.org/10.1038/sj.jp.7211518

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