Hemangiomas Infantis e Bloqueadores-Beta: 10 Anos Depois da Revolução Terapêutica

Katarína Kieselová, Felicidade Santiago

Resumo


O hemangioma infantil é o tumor vascular mais frequente da infância, que se caracteriza por um rápido crescimento nos primeiros meses de vida, seguido de uma involução espontânea e progressiva nos primeiros anos. Apesar da sua benignidade e regressão espontânea, em cerca de 10% dos casos, os hemangiomas infantis acarretam um impacto funcional ou estético negativo, exigindo, portanto, um tratamento eficaz. Em 2008, a descoberta acidental do efeito benéfico do propranolol no hemangioma infantil, revolucionou a abordagem terapêutica deste tumor vascular, sendo atualmente considerado o tratamento de primeira linha. Neste artigo, pretende-se rever sucintamente os avanços da última década no tratamento do hemangioma infantil e analisar os dados publicados relativamente à utilização clínica de propranolol. Adicionalmente, serão abordados outros tratamentos emergentes que poderão, no futuro, alargar o arsenal terapêutico do hemangioma infantil.


Palavras-chave


Antagonistas Adrenérgicos beta/uso terapêutico; Hemangioma/tratamento; Lactente; Neoplasias da Pele/ tratamento; Propranolol; Timolol

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Referências


Kilcline C, Frieden IJ. Infantile hemangiomas: how common are they? A systematic review of the medical

literature. Pediatr Dermatol. 2008; 25:168–73. doi: 10.1111/j.1525-1470.2008.00626.x.

Léauté-Labrèze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet. 2017;390:85-94. doi: 10.1016/

S0140-6736(16)00645-0.

Carvalho R, IFreitas I, Henrique M, Cardoso J. Propranolol e hemangioma infantil. Rev Soc Port Dermatol Venereol.

;69: 495-9.

Léaute-Labrèze C, Dumas de la RE, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas

of infancy. N Engl J Med. 2008;358: 2649–51. doi: 10.1056/NEJMc0708819.

European Medicines Agency. Hemangiol EPAR. 2014. [accessed 2018 Oct 1]. Available at: https://www.ema.

europa.eu/documents/assessment-report/hemangiol--epar-public-assessment-report_en.pdf

Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, et al. Initiation and use of propranolol

for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131:128–40. doi: 10.1542/peds.2012-1691.

Borgstrom L, Johansson C, Larsson H, Lenander R. Pharmacokinetics of propranolol. J Pharmacokinet Biopharm.

;9:419-29.

Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action.

Br J Dermatol. 2010;163:269–74. doi: 10.1111/j.1365--2133.2010.09848.x.

Rotter A, de Oliveira ZNP. Infantile hemangioma: pathogenesis and mechanisms of action of propranolol. J

Dtsch Dermatol Ges. 2017; 15:1185–90. doi: 10.1111/ddg.13365.

Munabi NC, England RW, Edwards AK, Kitajewski AA, Tan QK, Weinstein A, et al. Propranolol targets hemangioma

stem cells via camp and mitogen-activated protein kinase regulation. Stem Cells Transl Med. 2016; 5:45-55. doi:

5966/sctm.2015-0076.

Kum JJ, Khan ZA. Mechanisms of propranolol action in infantile hemangioma. Dermatoendocrinol. 2015;6:e979699.

doi: 10.4161/19381980.2014.979699.

Ozeki M, Nozawa A, Hori T, Kanda K, Kimura T, Kawamoto N, et al. Propranolol for infantile hemangioma:

Effect on plasma vascular endothelial growth factor. Pediatr Int. 2016;58:1130-5. doi: 10.1111/ped.12981.

Dornhoffer JR, Wei T, Zhang H, Miller E, A Cleves M, Richter GT. The expression of renin-angiotensin-aldosterone

axis components in infantile hemangioma tissue and the impact of propranolol treatment. Pediatr Res. 2017;82:155-63. doi: 10.1038/pr.2017.93.

Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile haemangiomas: an update

on potential mechanisms of action. Br J Dermatol. 2015; 172:24–32.doi: 10.1111/bjd.13388.

Sun B, Dong C, Lei H, Gong Y, Li M, Zhang Y, et al. Propranolol inhibits proliferation and invasion of hemangioma-

derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway. Chem Biol Interact. 2018;294:28-33. doi: 10.1016/j.cbi.2018.08.018.

Yao TH, Pataer P, Regmi KP, Gu XW, Li QY, Du JT, et al. Propranolol induces hemangioma endothelial cell apoptosis

via a p53 BAX mediated pathway. Mol Med Rep. 2018;18:684-94. doi: 10.3892/mmr.2018.9013.

Wnek A, Andrzejewska E, Kobos J, Taran K, Przewratil P. Molecular and immunohistochemical expression of apoptotic

proteins Bax, Bcl-2 and Caspase 3 in infantile hemangioma tissues as an effect of propranolol treatment. Immunol Lett. 2017; 185:27–31.

Luo Y, Zeng Y, Zhou B, Tang J. A retrospective study of propranolol therapy in 635 infants with infantile hemangioma.

Pediatric Dermatol. 2015;32:151–2. doi: 10.1111/pde.12308.

Sagi L, Zvulunov A, Lapidoth M, Ben Amitai D. Efficacy and safety of propranolol for the treatment of infantile hemangioma: a presentation of ninety-nine cases. Dermatology. 2014;228:136–44. doi: 10.1159/000351557.

Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA, Duarte AM, et al. Propranolol vs corticosteroids for infantile

hemangiomas: a multicenter retrospective analysis. Arch Dermatol. 2011;147:1371-6. doi: 10.1001/archdermatol.

203.

Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, Guibaud L, Baselga E, Posiunas G, et al. A randomized, controlled

trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015; 372:735-46. doi: 10.1056/NEJMoa1404710.

Caussé S, Aubert H, Saint-Jean M, Puzenat E, Bursztejn AC, Eschard C, et al. Propranolol-resistant infantile

haemangiomas. Br J Dermatol. 2013; 169:125-9. doi: 10.1111/bjd.12417.

Novoa M, Baselga E, Beltran S, Giraldo L, Shahbaz A, Pardo-Hernandez H, et al. Interventions for infantile

haemangiomas of the skin. Cochrane Database Syst Rev. 2018; 4:CD006545. doi: 10.1002/14651858.CD006545.pub3.

Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C, Mazereeuw-Hautier J, Prey S, Lebbé G, et al. Safety of

oral propranolol for the treatment of infantile hemangioma: a systematic review. Pediatrics. 2016; 138: pii:

e20160353.

Droitcourt C, Kerbrat S, Rault C, Botrel MA, Happe A, Garlantezec R, et al. Safety of oral propranolol for infantile

hemangioma. Pediatrics. 2018; 141: pii: e20173783. doi: 10.1542/peds.2017-3783. .

Wang C, Wang Q, Xiang B, Chen S, Xiong F, Ji Y. Effects of propranolol on neurodevelopmental outcomes

in patients with infantile hemangioma: a case-control study. Biomed Res Int. 2018; 2018:5821369. doi:

1155/2018/5821369.

Moyakine AV, Spillekom-van Koulil S, van der Vleuten CJM. Propranolol treatment of infantile hemangioma is

not associated with psychological problems at 7 years of age. J Am Acad Dermatol. 2017; 77:105–8. doi:

1016/j.jaad.2017.01.025.

Moyakine AV, Herwegen B, van der Vleuten CJM. Use of the Hemangioma Severity Scale to facilitate treatment decisions for infantile hemangiomas. J Am Acad Dermatol. 2017; 77:868-73. doi: 10.1016/j.jaad.2017.06.003.

Lund EB, Chamlin SL, Mancini AJ. Utility of routine electrocardiographic screening before initiation of propranolol for infantile hemangiomas. Pediatr Dermatol. 2018 ;35:e233-4. doi: 10.1111/pde.13508.

Tang LY, Hing JW, Tang JY, Nishikawa H, Shahidullah H, Browne F, et al. Predicting complications with pretreatment

testing in infantile haemangioma treated with oral propranolol. Br J Ophthalmol. 2016; 100:902–6. doi: 10.1136/bjophthalmol-2015-307284.

Hoeger PH, Harper JI, Baselga E, Bonnet D, Boon LM, Ciofi Degli Atti M, et al. Treatment of infantile haemangiomas:

recommendations of a European expert group. Eur J Pediatr. 2015;174:855-65. doi: 10.1007/s00431-015-

-0.

Fogel I, Ollech A, Zvulunov A, Valdman-Greenshpon Y, Atar Snir V, Friedland R, et al. Safety profile during initiation

of propranolol for treatment of infantile haemangiomas in an ambulatory day-care hospitalization setting.

J Eur Acad Dermatol Venereol. 2018; 32:2004-9. doi: 10.1111/jdv.14955.

Hagen R, Ghareeb E, Jalali O, Zinn Z. Infantile hemangiomas: what have we learned from propranolol?

Curr Opin Pediatr. 2018; 30:499-504. doi: 10.1097/MOP.0000000000000650.

Del Frari L, Léauté-Labrèze C, Guibaud L, Barbarot S, Lacour JP, Chaumont C, et al. Propranolol pharmacokinetics

in infants treated for infantile hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.

Pharmacol Res Perspect. 2018; 6:e00399. doi: 10.1002/prp2.399.

Baselga E, Dembowska-Baginska B, Przewratil P, González- Enseñat MA, Wyrzykowski D, Torrelo A, et al. Efficacy

of propranolol between 6 and 12 months of age in high-risk infantile hemangioma. Pediatrics. 2018; 142: pii:

e20173866. doi: 10.1542/peds.2017-3866.

Shah SD, Baselga E, McCuaig C, Pope E, Coulie J, Boon LM, et al. rebound growth of infantile hemangiomas

after propranolol therapy. Pediatrics. 2016; 137: pii: e20151754. doi: 10.1542/peds.2015-1754.

Admani S, Feldstein S, Gonzalez EM, Friedlander SF. Beta blockers: an innovation in the treatment of infantile hemangiomas. J Clin Aesthet Dermatol. 2014;7:37-45.

Painter SL, Hildebrand GD. Review of topical beta blockers as treatment for infantile hemangiomas. Surv Ophthalmol. 2016; 61:51-8. doi: 10.1016/j.survophthal. 2015.08.006.

Ovadia SA, Landy DC, Cohen ER, Yang EY, Thaller SR. Local administration of β-blockers for infantile hemangiomas: a systematic review and meta-analysis. Ann Plast Surg. 2015; 74:256-62. doi: 10.1097/SAP.0000000000000390.

Danarti R, Ariwibowo L, Radiono S, Budiyanto A. Topical timolol maleate 0.5% for infantile hemangioma: its effectiveness compared to ultrapotent topical corticosteroids - a single-center experience of 278 cases. Dermatology

; 232:566-71. doi: 10.1159/000448396.

Püttgen K, Lucky A, Adams D, Pope E, McCuaig C, Powell J, et alTopical timolol maleate treatment of infantile hemangiomas. Pediatrics. 2016; 138. pii: e20160355. doi: 10.1542/peds.2016-0355.

Weibel L, Barysch MJ, Scheer HS, Königs I, Neuhaus K, Schiestl C, et al. Topical timolol for infantile hemangiomas: evidence for efficacy and degree of systemic absorption. Pediatr Dermatol. 2016; 33: 184-90. doi: 10.1111/pde.12767.

Frommelt P, Juern A, Siegel D, Holland K, Seefeldt M, Yu J, et al. Adverse events in young and preterm infants receiving topical timolol for infantile hemangioma. Pediatr Dermatol. 2016; 33:405-14. doi: 10.1111/pde.12869.

Fernandes S, Amaro C, Cardoso J. Timolol no tratamento do hemangioma infantil ulcerado. Rev Soc Port Dermatol Venereol. 2013; 71:286-7.

Khan M, Boyce A, Prieto-Merino D, Svensson Å, Wedgeworth E, Flohr C. The role of topical timolol in the treatment of infantile hemangiomas: a systematic review and meta-analysis. Acta Derm Venereol. 2017; 97:1167-71. doi: 10.2340/00015555-2681.

Fernandez-Pineda I, Williams R, Ortega-Laureano L, Jones R. Cardiovascular drugs in the treatment of infantile hemangioma. World J Cardiol. 2016; 8:74-80. doi: 10.4330/wjc.v8.i1.74.

Ábarzúa-Araya A, Navarrete-Dechent CP, Heusser F, Retamal J, Zegpi-Trueba MS. Atenolol versus propranolol for the treatment of infantile hemangiomas: a randomized controlled study. J Am Acad Dermatol. 2014; 70:1045-9. doi: 10.1016/j.jaad.2014.01.905.

Tasani M, Glover M, Martinez AE, Shaw L. Atenolol treatment for infantile haemangioma. Br J Dermatol. 2017; 176:1400-2. doi: 10.1111/bjd.15317.

Pope E, Chakkittakandiyil A, Lara-Corrales I, Maki E, Weinstein M. Expanding the therapeutic repertoire of infantile haemangiomas: cohort-blinded study of oral nadolol compared with propranolol. Br J Dermatol. 2013; 168: 222–4. doi: 10.1111/j.1365-2133.2012.11131.x.

Bernabeu-Wittel J, Narváez-Moreno B, de la Torre-García JM, Fernández-Pineda I, Domínguez-Cruz JJ, Coserría-Sánchez F, et al. Oral nadolol for children with infantile hemangiomas and sleep disturbances with oral propranolol. Pediatr Dermatol. 2015; 32:853-7. doi: 10.1111/pde.12686.




DOI: http://dx.doi.org/10.29021/spdv.77.1.1008

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