Topical Isoxsuprine in experimentally induced hypertrophic scar in rabbits

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Mohammed j Manna Manna
Muhannad Sami Jalil Jalil
Murtadha S Jabu Jabu



Hypertrophic scars are pathological scars which result from exaggerated skin proliferation following a wound and injury. Although many theories have been implicated for keloidogenesis, the precise pathophysiological cause is still masked. Different treatment strategies have been tried in their management,but there is no satisfactory option for treating hypertrophic scar currently; moreover the standard steroid therapy is associated with numerous local side effects, and there is a need for researches in new treatment
options. The aim of this study is to evaluate the role of topical isoxsuprine in experimentally induced hypertrophic scar in rabbits. In the current experimental study, 40 healthy male albino rabbits between 12 and 14 months of age were studied. These rabbits were categorized into five groups: healthy animal group (n = 8), hypertrophic scar without treatment (n = 8), hypertrophic scar treated with triamcinolone acetonide gel (n = 8), and hypertrophic scar treated with isoxsuprine gel (n = 8). Histological assessment of skin biopsy, including the conventional hematoxylin and eosin stain, and immunohistochemistry for
transforming the growth factor beta 1 level (TGF-?1) and collagen 3 alpha1 (COLIII?I) in skin tissue was done. The immunohistochemical score of TGF-? and collagen III was highest in group 2 (hypertrophic scar without treatment), followed by group 3 (hypertrophic scar treated with triamcinolone acetonide gel) and group 4 (hypertrophic scar treated with isoxsuprine gel) – no significant difference between them since p >
0.05, and then by group 1 (healthy control group). Regarding histopathological scores of inflammation, the scar height, and scar index, the scores were highest in was highest in group 2 (hypertrophic scar without treatment), followed by group 3 (hypertrophic scar treated with triamcinolone acetonide gel) and group 4 (hypertrophic scar treated with isoxsuprine gel) – no significant difference between them since p > 0.05,with the exception of index of scar, and then by group 1 (healthy control group). It was concluded that isouxoprine in a topical formulation greatly reduced inflammation and scar formation in deep wounds in a manner comparable to that seen with triamcinolone. 

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1. Berman B, Maderal A, Raphael B. Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment. Dermatol Surg. 2017 Jan;43 Suppl 1:S3-S18. doi: 10.1097/DSS.0000000000000819. PMID: 27347634.
2. Betarbet U, Blalock TW. Keloids: A Review of Etiology, Prevention, and Treatment. J Clin Aesthet Dermatol. 2020;13(2):33-43.
3. Wolfram D, Tzankov A, Pülzl P, Piza-Katzer H. Hypertrophic scars and keloids--a review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg. 2009 Feb;35(2):171-81. doi: 10.1111/j.1524-4725.2008.34406.x. PMID: 19215252.
4. Shaheen A, Khaddam J, Kesh F. Risk factors of keloids in Syrians. BMC Dermatol. 2016;16(1):13. Published 2016 Sep 20. doi:10.1186/s12895-016-0050-5
5. Tan J. Acne and Scarring: Facing the Issue to Optimize Outcomes. J Drugs Dermatol. 2018 Dec 01;17(12):s43.
6. Boehm KS, Al-Taha M, Morzycki A, Samargandi OA, Al-Youha S, LeBlanc MR. Donor Site Morbidities of Iliac Crest Bone Graft in Craniofacial Surgery: A Systematic Review. Ann Plast Surg. 2019 Sep;83(3):352-358.
7. Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound Healing: A Cellular Perspective. Physiol Rev. 2019 Jan 01;99(1):665-706.
8. Lima RJ, Schneider TB, Francisco AMC, FrancescatoVeiga D. Absorbable suture. Best aesthetic outcome in cesarean scar1. Acta Cir Bras. 2018 Nov;33(11):1027-1036.
9. Huang C, Ogawa R. The link between hypertension and pathological scarring: does hypertension cause or promote keloid and hypertrophic scar pathogenesis? Wound Repair Regen. 2014 Jul-Aug;22(4):462-6. doi: 10.1111/wrr.12197. PMID: 24899409.
10. Farina J.A., Jr., Rosique M.J., Rosique R.G. Curbing inflammation in burn patients. Int. J. Inflam. 2013;2013:715645. doi: 10.1155/2013/715645.
11. Ogawa R. Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis. Int J Mol Sci. 2017;18(3):606. Published 2017 Mar 10. doi:10.3390/ijms18030606
12. Chiang RS, Borovikova AA, King K, et al. Current concepts related to hypertrophic scarring in burn injuries. Wound Repair Regen. 2016;24(3):466-477. doi:10.1111/wrr.12432
13. Edriss AS, Mesták J. Management of keloid and hypertrophic scars. Ann Burns Fire Disasters. 2005;18(4):202-210.
14. Ogawa R, Akita S, Akaishi S, Aramaki-Hattori N, Dohi T, Hayashi T, Kishi K, Kono T, Matsumura H, Muneuchi G, Murao N, Nagao M, Okabe K, Shimizu F, Tosa M, Tosa Y, Yamawaki S, Ansai S, Inazu N, Kamo T, Kazki R, Kuribayashi S. Diagnosis and Treatment of Keloids and Hypertrophic Scars-Japan Scar Workshop Consensus Document 2018. Burns Trauma. 2019;7:39.
15. Gao FL, Jin R, Zhang L, Zhang YG. The contribution of melanocytes to pathological scar formation during wound healing. Int J Clin Exp Med. 2013;6(7):609-613. Published 2013 Aug 1.
16. Cooke GL, Chien A, Brodsky A, Lee RC. Incidence of hypertrophic scars among African Americans linked to vitamin D-3 metabolism?. J Natl Med Assoc. 2005;97(7):1004-1009.
17. Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing - A literature review. An Bras Dermatol. 2016;91(5):614-620. doi:10.1590/abd1806-4841.20164741
18. Marzo A, Zava D, Coa K, Dal Bo L, Ismaili S, Tavazzi S, Cantoni V. Pharmacokinetics of isoxsuprine hydrochloride administered orally and intramuscularly to female healthy volunteers. Arzneimittelforschung. 2009;59(9):455-60. doi: 10.1055/s-0031-1296425. PMID: 19856793.
19. Stati T, Musumeci M, Maccari S, Massimi A, Corritore E, Strimpakos G, Pelosi E, Catalano L, Marano G. ?-Blockers promote angiogenesis in the mouse aortic ring assay. J Cardiovasc Pharmacol. 2014 Jul;64(1):21-7. doi: 10.1097/FJC.0000000000000085. PMID: 24621648.
20. Rengo G, Cannavo A, Liccardo D, et al . Vascular endothelial growth factor blockade prevents the beneficial effects of ?-blocker therapy on cardiac function, angiogenesis, and remodeling in heart failure. Circ Heart Fail. 2013 Nov;6(6):1259-67. doi: 10.1161/CIRCHEARTFAILURE.113.000329. Epub 2013 Sep 12. PMID: 24029661.
21. Caliskan, E., Gamsizkan, M., Acikgoz, G., et al. Intralesional treatments for hypertrophic scars: comparison among corticosteroid, 5-fluorouracil and botulinum toxin in rabbit ear hypertrophic scar model. Eur Rev Med Pharmacol Sci, 2016; 20(8), 1603-1608.
22. Attia M.A., El-Gibaly I., Shaltout S.E.,et al.Transbuccal permeation, anti-inflammatory activity and clinical efficacy of Piroxicam formulated in different gels. Int. J. Pharm., 2004; 276, 11–28.
23. Yagmur, C., Guneren, E., Kefeli, M., et al. The effect of surgical denervation on prevention of excessive dermal scarring: a study on rabbit ear hypertrophic scar model. Journal of Plastic, Reconstructive & Aesthetic Surgery, 2011; 64(10), 1359-1365.
24. Prignano, F., Campolmi, P., Bonan, P.,et al. Fractional CO2 laser: a novel therapeutic device upon photo-biomodulation of tissue remodeling and cytokine pathway of tissue repair. Dermatologic therapy, 2009; 22, S8-S15
25.Pullar, C. E., Le Provost, G. S., O'leary, A. P.,et al. ?2AR antagonists and ?2AR gene deletion both promote skin wound repair processes. Journal of Investigative Dermatology, 2012; 132(8), 2076-2084.?. doi:10.1038/jid.2012.108
26. Saulis, A. S., Mogford, J. H., Mustoe, T. A ,et al. Effect of Mederma on hypertrophic scarring in the rabbit ear model. Plastic and reconstructive surgery, 2002; 110(1), 177-183.
27. Longo , R E., and Sao Dimas , J. Effects of chamomilla recutita (L) on oral wound healing in rats .Cir Bucal ,2002; 16 (6), e 716-21.
28.Gál, P., Vasilenko, T., Kostelníková, M.,et al. Open wound healing in vivo: Monitoring binding and presence of adhesion/growth-regulatory galectins in rat skin during the course of complete re-epithelialization. Actahistochemica et cytochemica, 2011; 44(5), 191-199.?
29. Daniel WW . Biostatistics A foundation for analysis in the health sciences. 9th ed. Chapter seven: 7.10, determining sample size to control type II errors. 2009; P. 278.
30. Gauglitz GG. Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol. 2013;6:103-114. Published 2013 Apr 24. doi:10.2147/CCID.S35252
31.Mohammed J Manna , MohandS Jalil , Mohammed Q Y MalAllah. The Effect of Intralesional Injection of Salbutamol in Experimentally Induced Hypertrophic Scar. Annals of R.S.C.B., ISSN:1583-6258, Vol. 25, Issue 4, 2021,. 1633-1648
32. Olczyk P, Mencner ?, Komosinska-Vassev K. The role of the extracellular matrix components in cutaneous wound healing. Biomed Res Int. 2014;2014:747584. doi:10.1155/2014/747584