Volume 4, Issue 3 (9-2019)
J Res Dent Maxillofac Sci 2019, 4(3): 5-14 |
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MalekiGorji M, Golestaneh A. Histological Evaluation of the Effect of Sildenafil and Pentoxifylline on Mandibular Fracture Healing in Rats. J Res Dent Maxillofac Sci 2019; 4 (3) :5-14
URL: http://jrdms.dentaliau.ac.ir/article-1-259-en.html
URL: http://jrdms.dentaliau.ac.ir/article-1-259-en.html
1- Postgraduate student, department of oral and maxillofacial surgery
2- Assistant professor, department of oral and maxillofacial surgery, Islamic Azad University, Isfahan (Khorasgan) branch, Isfahan, Iran ,drgolestaneh@gmail.com
2- Assistant professor, department of oral and maxillofacial surgery, Islamic Azad University, Isfahan (Khorasgan) branch, Isfahan, Iran ,
Abstract: (3142 Views)
Background and Aim: Despite the advances in maxillofacial surgery, impaired bone healing remains a concern for surgical teams. Effects of sildenafil and pentoxifylline on healing of bone fractures have not been well investigated. This study aimed to assess the effects of sildenafil and pentoxifylline phosphodiesterase inhibitors on healing of mandibular fractures in rats.
Materials and Methods: In this animal study, 48 Wistar rats were randomly divided into six groups (n=8). Mandibular fracture was induced in all rats. After the surgical procedure, C2 group (control, 2 weeks) received saline, S2 group (sildenafil, 2 weeks) received 10 mg/kg sildenafil, and P2 group (pentoxifylline, 2 weeks) received 50 mg/kg pentoxifylline. The rats were sacrificed after 2 weeks. C6 (control, 6 weeks), S6 (sildenafil, 6 weeks), and P6 (pentoxifylline, 6 weeks) groups received pharmaceutical therapy as in C2, S2, and P2 but were sacrificed after 6 weeks. The samples then underwent histological analysis. Data were analyzed using SPSS 22 via one-way analysis of variance (ANOVA) and Tukey’s post-hoc test.
Results: The mean rate of healing of mandibular fractures in S2 and P2 was significantly higher than that in C2 after 2 weeks (P<0.001). The mean rate of healing of fractures in P2 was higher than that in S2 after 2 weeks (P=0.04). The mean rate of healing of fractures in S6 (P=0.001) and P6 (P=0.004) was significantly higher than that in C6 after 6 weeks but no significant difference was noted between P6 and S6 in this respect (P=0.53).
Conclusion: Sildenafil and pentoxifylline can be used as adjuncts to enhance bone healing.
Materials and Methods: In this animal study, 48 Wistar rats were randomly divided into six groups (n=8). Mandibular fracture was induced in all rats. After the surgical procedure, C2 group (control, 2 weeks) received saline, S2 group (sildenafil, 2 weeks) received 10 mg/kg sildenafil, and P2 group (pentoxifylline, 2 weeks) received 50 mg/kg pentoxifylline. The rats were sacrificed after 2 weeks. C6 (control, 6 weeks), S6 (sildenafil, 6 weeks), and P6 (pentoxifylline, 6 weeks) groups received pharmaceutical therapy as in C2, S2, and P2 but were sacrificed after 6 weeks. The samples then underwent histological analysis. Data were analyzed using SPSS 22 via one-way analysis of variance (ANOVA) and Tukey’s post-hoc test.
Results: The mean rate of healing of mandibular fractures in S2 and P2 was significantly higher than that in C2 after 2 weeks (P<0.001). The mean rate of healing of fractures in P2 was higher than that in S2 after 2 weeks (P=0.04). The mean rate of healing of fractures in S6 (P=0.001) and P6 (P=0.004) was significantly higher than that in C6 after 6 weeks but no significant difference was noted between P6 and S6 in this respect (P=0.53).
Conclusion: Sildenafil and pentoxifylline can be used as adjuncts to enhance bone healing.
Type of Study: Original article |
Subject:
Oral & maxillofacial surgery
References
1. 1. Glória JCR, Fernandes IA, da Silveira EM, de Souza GM, Rocha RL, Galvao EL et al. Comparison of Bite Force with Locking Plates versus Non-Locking Plates in the Treatment of Mandibular Fractures: A Meta-Analysis. Int Arch Otorhinolaryngol. 2018 Apr;22(2):181-9. [DOI:10.1055/s-0037-1604056] [PMID] [PMCID]
2. Uçan MC, Koparal M, Ağaçayak S, Gunay A, Ozgoz M, Atilgan S, et al. Influence of caffeic acid phenethyl ester on bone healing in a rat model. J Int Med Res. 2013 Oct;41(5):1648-54. [DOI:10.1177/0300060513490613] [PMID]
3. Fernández JR, Gallas M, Burguera M, Viaño JM. A three-dimensional numerical simulation of mandible fracture reduction with screwed miniplates. J Biomech. 2003 Mar;36(3):329-37. [DOI:10.1016/S0021-9290(02)00416-5]
4. Durmuş K, Turgut NH, Doğan M, Tuncer E, Özer H, Altuntaş EE, et al. Histopathological evaluation of the effect of locally administered strontium on healing time in mandibular fractures: An experimental study. Adv Clin Exp Med. 2017 Oct;26(7):1063-7. [DOI:10.17219/acem/65477] [PMID]
5. Hausman MR, Schaffler MB, Majeska RJ. Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone. 2001 Dec;29(6):560-4. [DOI:10.1016/S8756-3282(01)00608-1]
6. Dincel YM, Alagoz E, Arikan Y, Caglar AK, Dogru SC, Ortes F, et al. Biomechanical, histological, and radiological effects of different phosphodiesterase inhibitors on femoral fracture healing in rats. J Orthop Surg (Hong Kong). 2018 May-Aug;26(2):2309499018777885. [DOI:10.1177/2309499018777885] [PMID]
7. Hankenson KD, Zimmerman G, Marcucio R. Biological perspectives of delayed fracture healing. Injury. 2014 Jun;45 Suppl 2:S8-S15. [DOI:10.1016/j.injury.2014.04.003] [PMID] [PMCID]
8. Cook JJ, Summers NJ, Cook EA. Healing in the new millennium: bone stimulators: an overview of where we've been and where we may be heading. Clin Podiatr Med Surg. 2015 Jan;32(1):45-59. [DOI:10.1016/j.cpm.2014.09.003] [PMID]
9. Chao EY, Inoue N. Biophysical stimulation of bone fracture repair, regeneration and remodelling. Eur Cell Mater. 2003 Dec;6:72-84. [DOI:10.22203/eCM.v006a07] [PMID]
10. Massari L, Caruso G, Sollazzo V, Setti S. Pulsed electromagnetic fields and low intensity pulsed ultrasound in bone tissue. Clin Cases Miner Bone Metab. 2009 May;6(2):149-54.
11. Perry AC, Prpa B, Rouse MS, Piper KE, Hanssen AD, Steckelberg JM, et al. Levofloxacin and trovafloxacin inhibition of experimental fracture-healing. Clin Orthop Relat Res. 2003 Sep;(414):95-100. [DOI:10.1097/01.blo.0000087322.60612.14] [PMID]
12. Zandi M, Dehghan A, Amini P, Rezaeian L, Doulati S. Evaluation of mandibular fracture healing in rats under zoledronate therapy: A histologic study. Injury. 2017 Dec;48(12):2683-2687. [DOI:10.1016/j.injury.2017.10.026] [PMID]
13. Colnot C, Lu C, Hu D, Helms JA. Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development. Dev Biol. 2004 May 1;269(1):55-69. [DOI:10.1016/j.ydbio.2004.01.011] [PMID]
14. Lienau J, Schell H, Epari DR, Schütze N, Jakob F, Duda GN, et al. CYR61 (CCN1) protein expression during fracture healing in an ovine tibial model and its relation to the mechanical fixation stability. J Orthop Res. 2006 Feb;24(2):254-62. [DOI:10.1002/jor.20035] [PMID]
15. Keramaris NC, Calori GM, Nikolaou VS, Schemitsch EH, Giannoudis PV. Fracture vascularity and bone healing: a systematic review of the role of VEGF. Injury. 2008 Sep;39 Suppl 2:S45-57. [DOI:10.1016/S0020-1383(08)70015-9]
16. Diwan AD, Wang MX, Jang D, Zhu W, Murrell GA. Nitric oxide modulates fracture healing. J Bone Miner Res. 2000 Feb;15(2):342-51. [DOI:10.1359/jbmr.2000.15.2.342] [PMID]
17. Baldik Y, Talu U, Altinel L, Bilge H, Demiryont M, Aykac-Toker G. Bone healing regulated by nitricoxide: an experimental study in rats. Clin Orthop Relat Res. 2002 Nov;(404):343-52. [DOI:10.1097/00003086-200211000-00051] [PMID]
18. Derici H, Kamer E, Unalp HR, Diniz G, Bozdag AD, Tansug T, et al. Effect of sildenafil on wound healing: an experimental study. Langenbecks Arch Surg. 2010 Aug;395(6):713-8. [DOI:10.1007/s00423-009-0471-2] [PMID]
19. Histing T, Marciniak K, Scheuer C, Garcia P, Holstein JH, Klein M, et al. Sildenafil accelerates fracture healing in mice. J Orthop Res. 2011 Jun;29(6):867-73. [DOI:10.1002/jor.21324] [PMID]
20. Vidavalur R, Penumathsa SV, Zhan L, Thirunavukkarasu M, Maulik N. Sildenafil induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin, hemeoxygenase and vascular endothelial growth factor. Vascul Pharmacol. 2006 Aug;45(2):91-5. [DOI:10.1016/j.vph.2006.03.010] [PMID]
21. Hart K, Baur D, Hodam J, Lesoon-Wood L, Parham M, Keith K, et al. Short- and long-term effects of sildenafil on skin flap survival in rats. Laryngoscope. 2006 Apr;116(4):522-8. [DOI:10.1097/01.mlg.0000200792.67802.3b] [PMID]
22. Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem. 2005 Apr 1;280(13):12944-55. [DOI:10.1074/jbc.M404706200] [PMID]
23. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol. 2001;108:671-680. [DOI:10.1067/mai.2001.119555] [PMID]
24. Delanian S, Porcher R, Rudant J, Lefaix JL. Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J Clin Oncol. 2005 Dec 1;23(34):8570-9 [DOI:10.1200/JCO.2005.02.4729] [PMID]
25. Ward A, Clissold SP. Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987 Jul;34(1):50-97. [DOI:10.2165/00003495-198734010-00003] [PMID]
26. Bayat M, Amini A, Rezaie F, Bayat S. Patents of Pentoxifylline Administration on Some Diseases and Chronic Wounds. Recent Pat Regen Med. 2014;4(2):137-43. [DOI:10.2174/2210296504666140813194744]
27. Vashghani Farahani MM, Masteri Farahani R, Mostafavinia A, Abbasian MR, Pouriran R, Noruzian M, et al. Effect of Pentoxifylline Administration on an Experimental Rat Model of Femur Fracture Healing With Intramedullary Fixation. Iran Red Crescent Med J. 2015 Dec 28;17(12):e29513. [DOI:10.5812/ircmj.29513] [PMID] [PMCID]
28. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil. from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 2006 Aug;5(8):689-702. [DOI:10.1038/nrd2030] [PMID]
29. Koneru S, Varma Penumathsa S, Thirunavukkarasu M, Vidavalur R, Zhan L, Singal PK, et al. Sildenafil mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1. J Cell Mol Med. 2008 Dec;12(6B):2651-64. [DOI:10.1111/j.1582-4934.2008.00319.x] [PMID] [PMCID]
30. Kinoshita T, Kobayashi S, Ebara S, Yoshimura Y, Horiuchi H, Tsutsumimoto T, et al. Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice. Bone. 2000 Dec;27(6):811-7. [DOI:10.1016/S8756-3282(00)00395-1]
31. Labib GS, Farid RM. Osteogenic effect of locally applied Pentoxyfilline gel: in vitro and in vivo evaluations. Drug Deliv. 2015 Dec;22(8):1094-1102. [DOI:10.3109/10717544.2014.884193] [PMID]
32. Kahenasa N, Sung EC, Nabili V, Kelly J, Garrett N, Nishimura I. Resolution of pain and complete healing of mandibular osteoradionecrosis using pentoxifylline and tocopherol: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Apr;113(4):e18-23. [DOI:10.1016/j.oooo.2011.10.014] [PMID]
33. Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck. 2005 Feb;27(2):114-23. [DOI:10.1002/hed.20121] [PMID]
34. Aydin K, Sahin V, Gürsu S, Mercan AS, Demir B, Yildirim T. Effect of pentoxifylline on fracture healing: an experimental study. Eklem Hastalik Cerrahisi. 2011 Dec;22(3):160-5.
35. National Research Council (US) Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press (US); 1996.
36. Schlundt C, El Khassawna T, Serra A, Dienelt A, Wendler S, Schell H, et al. Macrophages in bone fracture healing: Their essential role in endochondral ossification. Bone. 2018 Jan;106:78-89. [DOI:10.1016/j.bone.2015.10.019] [PMID]
37. Rotter N, Haisch A, Bücheler M. Cartilage and bone tissue engineering for reconstructive head and neck surgery. Eur Arch Otorhinolaryngol. 2005 Jul;262(7):539-45. [DOI:10.1007/s00405-004-0866-1] [PMID]
38. Vega LG. Reoperative mandibular trauma: management of posttraumatic mandibular deformities. Oral Maxillofac Surg Clin North Am. 2011 Feb;23(1):47-61, v-vi. [DOI:10.1016/j.coms.2010.12.003] [PMID]
39. Irkorucu O, Taşcilar O, Cakmak GK, Karakaya K, Emre AU, Ucan BH, et al. The effect of sildenafil on an animal model for ischemic colitis. Dig Dis Sci. 2008 Jun;53(6):1618-23. [DOI:10.1007/s10620-007-0033-9] [PMID]
40. Atalay Y, Bozkurt MF, Gonul Y, Cakmak O, Agacayak KS, Köse I, et al. The effects of amlodipine and platelet rich plasma on bone healing in rats. Drug Des Devel Ther. 2015 Apr 7;9:1973-81. [DOI:10.2147/DDDT.S80778] [PMID] [PMCID]
41. Anitua E, Sánchez M, Orive G, Andía I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials 2007 Nov;28(31):4551-60. [DOI:10.1016/j.biomaterials.2007.06.037] [PMID]
42. Yaman F, Atilgan S, Günes N, Agacayak S, Günay A, Ucan MC, et al. Phosphodiesterase-5 inhibitors may facilitate bone defect recovery. Eur Rev Med Pharmacol Sci. 2011 Nov;15(11):1301-5.
43. Rajkumar DS, Faitelson AV, Gudyrev OS, Dubrovin GM, Pokrovski MV, Ivanov AV. Comparative evaluation of enalapril and losartan in pharmacological correction of experimental osteoporosis and fractures of its background. J Osteoporos. 2013;2013:325693. [DOI:10.1155/2013/325693] [PMID] [PMCID]
44. Corbett SA, Hukkanen M, Batten J, McCarthy ID, Polak JM, Hughes S. Nitric oxide in fracture repair. Differential localisation, expression and activity of nitric oxide synthases. J Bone Joint Surg Br. 1999 May;81(3):531-7. [DOI:10.1302/0301-620X.81B3.0810531]
45. Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, et al. CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol. 2006 Apr;26(8):2955-64. [DOI:10.1128/MCB.26.8.2955-2964.2006] [PMID] [PMCID]
46. Takami M, Cho ES, Lee SY, Kamijo R, Yim M. Phosphodiesterase inhibitors stimulate osteoclast formation via TRANCE/RANKL expression in osteoblasts: possible involvement of ERK and p38 MAPK pathways. FEBS Lett. 2005 Jan 31;579(3):832-8. [DOI:10.1016/j.febslet.2004.12.066] [PMID]
47. Horiuchi H, Saito N, Kinoshita T, Wakabayashi S, Tsutsumimoto T, Otsuru S, et al. Enhancement of recombinant human bone morphogenetic protein-2 (rhBMP-2)-induced new bone formation by concurrent treatment with parathyroid hormone and a phosphodiesterase inhibitor, pentoxifylline. J Bone Miner Metab. 2004;22(4):329-34. [DOI:10.1007/s00774-003-0490-y] [PMID]
48. Horiuchi H, Saito N, Kinoshita T, Wakabayashi S, Tsutsumimoto T, Takaoka K. Enhancement of bone morphogenetic protein-2-induced new bone formation in mice by the phosphodiesterase inhibitor pentoxifylline. Bone. 2001 Mar;28(3):290-4 [DOI:10.1016/S8756-3282(00)00450-6]
49. Tsutsumimoto T, Wakabayashi S, Kinoshita T, Horiuchi H, Takaoka K. A phosphodiesterase inhibitor, pentoxifylline, enhances the bone morphogenetic protein-4 (BMP-4)- dependent differentiation of osteoprogenitor cells. Bone. 2002 Sep;31(3):396-401 [DOI:10.1016/S8756-3282(02)00839-6]
50. Westerhuis RJ, van Bezooijen RL, Kloen P. Use of bone morphogenetic proteins in traumatology. Injury. Injury. 2005 Dec;36(12):1405-12 [DOI:10.1016/j.injury.2005.02.047] [PMID]
51. Einhorn TA. Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am. 2003;85 Suppl 3:82-8. [DOI:10.2106/00004623-200300003-00014] [PMID]
52. Schmidmaier G, Wildemann B, Heeger J, Gäbelein T, Flyvbjerg A, Bail HJ, et al. Improvement of fracture healing by systemic administration of growth hormone and local application of insulin-like growth factor-1 and transforming growth factor-beta1. Bone. 2002 Jul;31(1):165-72. [DOI:10.1016/S8756-3282(02)00798-6]
53. Turk C, Halici M, Guney A, Akgun H, Sahin V, Muhtaroglu S. Promotion of fracture healing by vitamin E in rats. J Int Med Res. 2004 Sep-Oct;32(5):507-12. [DOI:10.1177/147323000403200508] [PMID]
54. Rauch F, Lauzier D, Croteau S, Travers R, Glorieux FH, Hamdy R. Temporal and spatial expression of bone morphogenetic protein-2, -4, and -7 during distraction osteogenesis in rabbits. Bone. 2000 Sep;27(3):453-9. [DOI:10.1016/S8756-3282(00)00337-9]
55. Farhadieh RD, Gianoutsos MP, Yu Y, Walsh WR. The role of bone morphogenetic proteins BMP-2 and BMP-4 and their related postreceptor signaling system (Smads) in distraction osteogenesis of the mandible. J Craniofac Surg. 2004 Sep;15(5):714-8. [DOI:10.1097/00001665-200409000-00003] [PMID]
56. Emami Meibodi SH, Narimani MA, Sarkarat F, Omidsalar P. Evaluation of the Correlation between Vertical Facial Discrepancies and Cervical Vertebral Fusion. J Res Dentomaxillofac Sci. 2018;3(4):38-42. [DOI:10.29252/jrdms.3.4.38]
57. Çakir-Özkan N, Bereket C, Sener I, Alici Ö, Kabak YB, Önger ME. Therapeutic Effects of Sildenafil on Experimental Mandibular Fractures. J Craniofac Surg. 2016 May;27(3):615-20. [DOI:10.1097/SCS.0000000000002527] [PMID]
58. Gong Y, Xu CY, Wang JR, Hu XH, Hong D, Ji X, et al. Inhibition of phosphodiesterase 5 reduces bone mass by suppression of canonical Wnt signaling. Cell Death Dis. 2014 Nov 27;5:e1544. [DOI:10.1038/cddis.2014.510] [PMID] [PMCID]
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