Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Free Access

Topical Timolol Maleate 0.5% for Infantile Hemangioma: Its Effectiveness Compared to Ultrapotent Topical Corticosteroids - A Single-Center Experience of 278 Cases

Danarti R. · Ariwibowo L. · Radiono S. · Budiyanto A.

Author affiliations

Department of Dermatology and Venereology, Faculty of Medicine, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia

Corresponding Author

Dr. Retno Danarti, MD

Department of Dermatology and Venereology, Faculty of Medicine

Universitas Gadjah Mada, Gedung Radiopoetro Lantai 3, Jalan Farmako Sekip Utara

Yogyakarta 55281 (Indonesia)

E-Mail danarti@ugm.ac.id

Related Articles for ""

Dermatology 2016;232:566-571

Abstract

Background: Infantile hemangioma (IH) may have implications on parental distress and cosmetic disfigurement. To date, ultrapotent corticosteroids are used as a treatment of choice for superficial IH. However, due to their side effects and sometimes lack of IH regression, it is necessary to find alternative topical therapies. Timolol maleate 0.5% solution and gel are nonselective β-blockers that could inhibit proliferation and trigger regression of IH. Objective: To evaluate the efficacy of topical ultrapotent corticosteroids and timolol maleate 0.5% solution and gel for superficial IH. Patients and Methods: The study design was prospective. Two hundred and seventy-eight patients diagnosed as having superficial IH were enrolled from the outpatient clinic of the Department of Dermatology and Venereology, Dr. Sardjito Hospital, Yogyakarta, Indonesia, from January 2009 to December 2014. Patients were divided into three groups: A = treated with topical ultrapotent corticosteroid, B = timolol maleate 0.5% solution and C = timolol maleate 0.5% gel. Patients were followed for 6 months to evaluate the lesion. Lesion size was measured from scaled photodocumentation with the software program ImageJ®. Results: There were significant differences in IH size after treatment with timolol maleate 0.5% solution compared with ultrapotent corticosteroids (p < 0.001) and timolol maleate 0.5% gel compared with ultrapotent corticosteroids (p < 0.001). There was no significant difference in IH lesions after treatment with timolol maleate 0.5% solution versus gel (p = 0.744). Conclusion: Timolol maleate 0.5% solution and gel were significantly superior to topical ultrapotent corticosteroids in size reduction of superficial IH.

© 2016 S. Karger AG, Basel


Introduction

Infantile hemangioma (IH) is the most prevalent benign vascular tumor in children [1,2]. It is estimated to occur in about 4-10% of infants in the first year of life [2]. The disease is often present at birth, although it may not be noticed until a few weeks later when the lesion begins its proliferative phase. During the first 9 months of age, the lesion grows rapidly, then stabilizing. Involution is complete in most children by 4 years of age [3]. The majority of lesions are benign, regress spontaneously, and do not require treatment, but no reliable indicators predict the degree and rate of involution. As the lesions may be a significant source of parental distress, cosmetic disfigurement, and morbidity, appropriate management and optimizing patient outcomes are needed [4,5].

Previous topical treatment for hemangiomas has included ultrapotent topical corticosteroids, which are most effective for superficial, small, and uncomplicated hemangiomas [6]. However, it has at least a 27% nonresponse rate and is associated with skin hypopigmentation and atrophy [6,7,8]. Another topical treatment was imiquimod 5% cream, which is effective and safe in the treatment of superficial and mixed hemangiomas [9,10,11]. However, it has crusting and scars as potential side effects [11,12].

Topical β-blockers are a promising alternative in the treatment of IHs since they can improve the therapeutic efficacy and reduce systemic adverse effects of IH [13]. Likewise, systemic propranolol with a starting dose of 2 mg/kg/day has also been reported as safe and effective in the treatment of IH [14,15].

Topical timolol has been reported to inhibit the growth and promote regression of superficial IHs [10,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. However, concerns have been raised regarding systemic absorption because it is 4-10 times as potent as propranolol [34], and there are reports of sleep disturbances [17]. This study is aimed to evaluate the effectiveness of ultrapotent topical corticosteroids, 0.5% timolol maleate solution and gel for superficial IH.

Patients and Methods

For further details, see the supplementary materials (for all online suppl. material, see www.karger.com/doi/10.1159/000448396) [6,7] (fig. 1).

Fig. 1

Flowchart of the Research Methods.

http://www.karger.com/WebMaterial/ShowPic/519017

Results

The study included 278 children (203 female and 75 male infants, ratio 2.7:1) with superficial IH who had adequate follow-up. Characteristics of the sample of this study are shown in table 1. There were no significant differences in sex, age of patients, age of IH lesions' appearance, birth weight, gestational age, maternal age, and location of the lesion between the groups.

Table 1

Clinical characteristics and treatment

http://www.karger.com/WebMaterial/ShowPic/519019

Within 6 months following the initiation of treatment with ultrapotent topical corticosteroids, timolol 0.5% solution and gel, diminution of color of the hemangiomas were noted in all children (fig. 2, 3, 4). A significant decrease in size area (mm2) of the lesions after 6 months of treatment between the three groups had a significant statistical difference (table 2). Analyses with the Kruskal-Wallis test and post hoc test with the Mann-Whitney test showed that timolol maleate 0.5% solution was better in size reduction of IH lesions compared with ultrapotent corticosteroid (p < 0.001); timolol maleate 0.5% gel was better than ultrapotent corticosteroid (p < 0.001), and no significant differences were seen between timolol maleate 0.5% solution and timolol maleate 0.5% gel (p = 0.744). No children were excluded from our study, and no adverse effects were recorded during the treatment period. Until 6 months of topical treatment with ultrapotent topical steroids or timolol maleate 0.5% solution and gel, no patients were changed to systemic treatment.

Table 2

Comparison of the IH area (mm2) after treatment for 6 months

http://www.karger.com/WebMaterial/ShowPic/519018

Fig. 2

Patient with superficial IH before (a) and after treatment (b) with 0.05% clobetasol propionate for 6 months.

http://www.karger.com/WebMaterial/ShowPic/519016

Fig. 3

Patient with superficial IH before (a) and after treatment (b) with 0.5% timolol maleate solution for 6 months.

http://www.karger.com/WebMaterial/ShowPic/519015

Fig. 4

Patient with superficial IH before (a) and after treatment (b) with 0.5% timolol maleate gel for 6 months.

http://www.karger.com/WebMaterial/ShowPic/519014

Discussion

IHs typically grow in early infancy followed by spontaneous involution. The initial proliferative phase begins in the first 2 weeks of life, then followed by a plateau phase. The involution phase starts at after the first year and is continued until 4-6 years [35,36]. In our study, the initial age for the first appearance of IHs was 4 weeks, compatible with previous studies [17,36]. There were no significant statistical differences in birth weight between the three groups, and the subjects had no history of low birth weight, incompatible with the study of Ho et al. [37]. The ages of initial treatment in our study were between 5.5 and 6 months, i.e. in the proliferative phase. Treatment in the proliferative phase would give the most satisfactory results, while the lesion is growing, hence there is potential to halt development, reduce the size of the lesion, reduce its effect on surrounding structures, and finally improve the cosmesis of patients [5]. Xu et al. [38] found that the therapeutic response of children who started treatment with propranolol ointment between the ages of 0-3 versus 3-6 or 6-10 months had a statistically significant difference. Yu et al. [32] noted that patients treated with timolol before the age of 6 months had higher lesion regression rates than those treated between 6 and 12 months. Topical timolol 0.1% gel was more effective in the proliferation than the involution phase [26]. In all of our subjects, topical ultrapotent corticosteroids and topical timolol 0.5% were associated with growth arrest and a reduction in redness and thickness within the first 4 weeks of treatment. The limitation of our study was that we did not measure IHs without treatment (or placebo), hence we could not assess spontaneous regression.

The pathogenesis of IH is not completely understood and is likely multifactorial [39,40,41,42,43]. Increased risk factors for IH include Caucasian race, female gender, prematurity, low birth weight, and being the product of multiple gestations [44,45,46]. In our study, the female:male subject ratio was about 2.7:1, in accordance with previous studies [37,47]. Two hundred and seventy-eight subjects only had a solitary lesion, similar to the study of Boye et al. [36]. IH lesions in our patients were predominantly located on the head and neck, similar to some studies [17,48,49].

From the literature search, no published report can be found, comparing treatment of IH with ultrapotent topical corticosteroids, timolol maleate 0.5% solution, and timolol maleate 0.5% gel. Chakkittakandiyil et al. [17] conducted a retrospective cohort study to compare 0.1 and 0.5% timolol maleate gel using a visual analog scale, based on photographic documentation of each patient's lesion. A study from Ariwibowo and Danarti found that timolol maleate 0.5% solution was better than corticosteroids (mometasone furoate and triamcinolone cream) in reducing the size of superficial IH [50].

Ultrapotent topical corticosteroids have antiproliferative and vasoconstrictive effects which may play a role in treating superficial IH [51,52]. The 2005 series of 35 patients of Garzon et al. [6] showed that 35% had a good response to clobetasol propionate 0.05% or betamethasone dipropionate 0.05%, but another 38% had only a partial response.

Regression of IHs treated using 0.5% timolol solution and gel in our studies occurred earlier than spontaneous regression which is generally not observed before the age of 9-12 months. However, this promising result needs to be confirmed in prospective randomized control trials on topical β-blocker administration for IHs which should address dose, duration, and mode of application. There was no adverse effect reported from our study. Adverse reactions due to topical corticosteroids for IH have been reported by Pandey et al. [8]. The topical use of β-blockers for IH was mostly safe; however, there were reports of sleep disturbance [17] and mild pruritus [20]. Our 6-year study of IH treatment in a tertiary referral hospital supports the safety and effectiveness of 0.5% timolol maleate solution and gel compared with topical ultrapotent corticosteroids.

Conclusions

The surface area reduction of superficial IHs treated with timolol maleate 0.5% solution and gel was greater than in those treated with topical ultrapotent corticosteroids. Neither group experienced any adverse effect.

Acknowledgments

We thank Cendo Pharmaceutical Industries for providing timolol gel 0.5%. This study has been supported in part by a grant from the Ministry of Research, Technology, and Higher Education of the Republic of Indonesia and the Board of Research and Community Service, Universitas Gadjah Mada, under contract No. 33/LPPM/2015.

Statement of Ethics

The study had been approved by the Medical and Health Research Ethics Committee of the Medical Faculty, Universitas Gadjah Mada.

Disclosure Statement

The authors have no conflicts of interest to disclose.


References

  1. Frieden IJ: Infantile hemangioma research: looking backward and forward. J Invest Dermatol 2011;131:2345-2348.
  2. Kanada KN, Merin MR, Munden A, Friedlander SF: A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr 2012;161:240-245.
  3. Couto RA, Maclellan RA, Zurakowski D, Greene AK: Infantile hemangioma: clinical assessment of the involuting phase and implications for management. Plast Reconstr Surg 2012;130:619-624.
  4. Leaute-Labreze C, Prey S, Ezzedine K: Infantile haemangioma. II. Risks, complications and treatment. J Eur Acad Dermatol Venereol 2011;25:1254-1260.
  5. Painter SL, Hildebrand GD: Review of topical beta blockers as treatment for infantile hemangiomas. Surv Ophthalmol 2016;61:51-58.
  6. Garzon MC, Lucky AW, Hawrot A, Frieden IJ: Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol 2005;52:281-286.
  7. Pope E, Krafchik BR, Macarthur C, Stempak D, Stephens D, Weinstein M, Ho N, Baruchel S: Oral versus high-dose pulse corticosteroids for problematic infantile hemangiomas: a randomized, controlled trial. Pediatrics 2007;119:e1239-e1247.
  8. Pandey A, Gangopadhyay AN, Sharma SP, Kumar V, Gupta DK, Gopal SC: Evaluation of topical steroids in the treatment of superficial hemangioma. Skinmed 2010;8:9-11.
  9. Barry RB, Hughes BR, Cook LJ: Involution of infantile haemangiomas after imiquimod 5% cream. Clin Exp Dermatol 2008;33:446-449.
  10. Hu L, Huang HZ, Li X, Lin XX, Li W: Open-label nonrandomized left-right comparison of imiquimod 5% ointment and timolol maleate 0.5% eye drops in the treatment of proliferating superficial infantile hemangioma. Dermatology 2015;230:150-155.
  11. Qiu Y, Ma G, Yang J, Hu X, Chen H, Jin Y, Lin X: Imiquimod 5% cream versus timolol 0.5% ophthalmic solution for treating superficial proliferating infantile haemangiomas: a retrospective study. Clin Exp Dermatol 2013;38:845-850.
  12. Qiu Y, Ma G, Lin X, Jin Y, Chen H, Hu X: Treating protruding infantile hemangiomas with topical imiquimod 5% cream caused severe local reactions and disfiguring scars. Pediatr Dermatol 2013;30:342-347.
  13. Kunzi-Rapp K: Topical propranolol therapy for infantile hemangiomas. Pediatr Dermatol 2012;29:154-159.
  14. 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;228:136-144.
  15. Ben-Amitai D, Halachmi S, Zvulunov A, Raveh E, Kalish E, Lapidoth M: Hemangiomas of the nasal tip treated with propranolol. Dermatology 2012;225:371-375.
  16. Calvo M, Garcia-Millan C, Villegas C, Fueyo-Casado A, Buron I: Topical timolol for infantile hemangioma of the eyelid. Int J Dermatol 2013;52:603-604.
  17. Chakkittakandiyil A, Phillips R, Frieden IJ, Siegfried E, Lara-Corrales I, Lam J, Bergmann J, Bekhor P, Poorsattar S, Pope E: Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study. Pediatr Dermatol 2012;29:28-31.
  18. Chambers CB, Katowitz WR, Katowitz JA, Binenbaum G: A controlled study of topical 0.25% timolol maleate gel for the treatment of cutaneous infantile capillary hemangiomas. Ophthal Plast Reconstr Surg 2012;28:103-106.
  19. Chan H, McKay C, Adams S, Wargon O: RCT of timolol maleate gel for superficial infantile hemangiomas in 5- to 24-week-olds. Pediatrics 2013;131:e1739-e1747.
  20. Khunger N, Pahwa M: Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol 2011;164:886-888.
  21. Moehrle M, Leaute-Labreze C, Schmidt V, Rocken M, Poets CF, Goelz R: Topical timolol for small hemangiomas of infancy. Pediatr Dermatol 2013;30:245-249.
  22. Ni N, Langer P, Wagner R, Guo S: Topical timolol for periocular hemangioma: report of further study. Arch Ophthalmol 2011;129:377-379.
  23. Ohnishi K, Tagami M, Morii E, Azumi A: Topical treatment for orbital capillary hemangioma in an adult using a beta-blocker solution. Case Rep Ophthalmol 2014;5:60-65.
  24. Pope E, Chakkittakandiyil A: Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol 2010;146:564-565.
  25. Rizvi SA, Yusuf F, Sharma R, Rizvi SW: Management of superficial infantile capillary hemangiomas with topical timolol maleate solution. Semin Ophthalmol 2015;30:62-64.
  26. Semkova K, Kazandjieva J: Topical timolol maleate for treatment of infantile haemangiomas: preliminary results of a prospective study. Clin Exp Dermatol 2013;38:143-146.
  27. Sorrell J, Chamlin SL: Topical timolol 0.5% gel-forming solution for small deep facial infantile hemangiomas. Pediatr Dermatol 2013;30:592-594.
  28. Thomas J, Kumar P, Kumar DD: Ulcerated infantile haemangioma of buttock successfully treated with topical timolol. J Cutan Aesthet Surg 2013;6:168-169.
  29. Weissenstein A, Straeter A, Villalon G, Bittmann S: Topical timolol for small infantile hemangioma: a new therapy option. Turk J Pediatr 2012;54:156-158.
  30. Xue K, Hildebrand GD: Topical timolol maleate 0.5% for infantile capillary haemangioma of the eyelid. Br J Ophthalmol 2012;96:1536-1537.
  31. Xue K, Hildebrand GD: Deep periocular infantile capillary hemangiomas responding to topical application of timolol maleate, 0.5%, drops. JAMA Ophthalmol 2013;131:1246-1248.
  32. Yu L, Li S, Su B, Liu Z, Fang J, Zhu L, Huang M, Shan W, Song D, Ye B, Luo C: Treatment of superficial infantile hemangiomas with timolol: evaluation of short-term efficacy and safety in infants. Exp Ther Med 2013;6:388-390.
  33. Oranje AP, Janmohamed SR, Madern GC, de Laat PC: Treatment of small superficial haemangioma with timolol 0.5% ophthalmic solution: a series of 20 cases. Dermatology 2011;223:330-334.
  34. McMahon P, Oza V, Frieden IJ: Topical timolol for infantile hemangiomas: putting a note of caution in ‘cautiously optimistic'. Pediatr Dermatol 2012;29:127-130.
  35. Boscolo E, Bischoff J: Vasculogenesis in infantile hemangioma. Angiogenesis 2009;12:197-207.
  36. Boye E, Jinnin M, Olsen BR: Infantile hemangioma: challenges, new insights, and therapeutic promise. J Craniofac Surg 2009;20 (suppl 1):678-684.
  37. Ho NT, Lansang P, Pope E: Topical imiquimod in the treatment of infantile hemangiomas: a retrospective study. J Am Acad Dermatol 2007;56:63-68.
  38. Xu G, Lv R, Zhao Z, Huo R: Topical propranolol for treatment of superficial infantile hemangiomas. J Am Acad Dermatol 2012;67:1210-1213.
  39. Greenberger S, Bischoff J: Pathogenesis of infantile haemangioma. Br J Dermatol 2013;169:12-19.
  40. Chen TS, Eichenfield LF, Friedlander SF: Infantile hemangiomas: an update on pathogenesis and therapy. Pediatrics 2013;131:99-108.
  41. Janmohamed SR, Madern GC, de Laat PC, Oranje AP: Educational paper: pathogenesis of infantile haemangioma, an update 2014. Part I. Eur J Pediatr 2015;174:97-103.
  42. Barnes CM, Christison-Lagay EA, Folkman J: The placenta theory and the origin of infantile hemangioma. Lymphat Res Biol 2007;5:245-255.
  43. Bischoff J. Progenitor cells in infantile hemangioma. J Craniofac Surg 2009;20(suppl 1):695-697.
  44. Li J, Chen X, Zhao S, Hu X, Chen C, Ouyang F, Liu Q, Ding R, Shi Q, Su J, Kuang Y, Chang J, Li F, Xie H: Demographic and clinical characteristics and risk factors for infantile hemangioma: a Chinese case-control study. Arch Dermatol 2011;147:1049-1056.
  45. Drolet BA, Swanson EA, Frieden IJ: Infantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants. J Pediatr 2008;153:712-715.
  46. Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ: Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr 2007;150:291-294.
  47. Bree AF, Siegfried E, Sotelo-Avila C, Nahass G: Infantile hemangiomas: speculation on placental trophoblastic origin. Arch Dermatol 2001;137:573-577.
  48. Bonifazi E, Milano A, Colonna V: Evaluation of safety and efficacy of a galenic preparation of 1% propranolol in 89 cases of cutaneous infantile hemangioma. Eur J Pediatr Dermatol 2013;23:93-104.
  49. Abarzua-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;70:1045-1049.
  50. Ariwibowo L, Danarti R: Comparison of efficacy between topical corticosteroid, timolol maleat 0.5% eye drop, and education observation in managing infantile hemangioma. Regional Conference of Dermatology (Asian-Australasian) and 6th Annual Meeting of the Asian Academy of Dermatology and Venereology (abstract). Danang, 2014.
  51. Theletsane T, Redfern A, Raynham O, Harris T, Prose NS, Khumalo NP: Life-threatening infantile haemangioma: a dramatic response to propranolol. J Eur Acad Dermatol Venereol 2009;23:1465-1466.
  52. Peridis S, Pilgrim G, Athanasopoulos I, Parpounas K: A meta-analysis on the effectiveness of propranolol for the treatment of infantile airway haemangiomas. Int J Pediatr Otorhinolaryngol 2011;75:455-460.

Author Contacts

Dr. Retno Danarti, MD

Department of Dermatology and Venereology, Faculty of Medicine

Universitas Gadjah Mada, Gedung Radiopoetro Lantai 3, Jalan Farmako Sekip Utara

Yogyakarta 55281 (Indonesia)

E-Mail danarti@ugm.ac.id


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: December 21, 2015
Accepted: July 13, 2016
Published online: September 03, 2016
Issue release date: January 2017

Number of Print Pages: 6
Number of Figures: 4
Number of Tables: 2

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Frieden IJ: Infantile hemangioma research: looking backward and forward. J Invest Dermatol 2011;131:2345-2348.
  2. Kanada KN, Merin MR, Munden A, Friedlander SF: A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr 2012;161:240-245.
  3. Couto RA, Maclellan RA, Zurakowski D, Greene AK: Infantile hemangioma: clinical assessment of the involuting phase and implications for management. Plast Reconstr Surg 2012;130:619-624.
  4. Leaute-Labreze C, Prey S, Ezzedine K: Infantile haemangioma. II. Risks, complications and treatment. J Eur Acad Dermatol Venereol 2011;25:1254-1260.
  5. Painter SL, Hildebrand GD: Review of topical beta blockers as treatment for infantile hemangiomas. Surv Ophthalmol 2016;61:51-58.
  6. Garzon MC, Lucky AW, Hawrot A, Frieden IJ: Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol 2005;52:281-286.
  7. Pope E, Krafchik BR, Macarthur C, Stempak D, Stephens D, Weinstein M, Ho N, Baruchel S: Oral versus high-dose pulse corticosteroids for problematic infantile hemangiomas: a randomized, controlled trial. Pediatrics 2007;119:e1239-e1247.
  8. Pandey A, Gangopadhyay AN, Sharma SP, Kumar V, Gupta DK, Gopal SC: Evaluation of topical steroids in the treatment of superficial hemangioma. Skinmed 2010;8:9-11.
  9. Barry RB, Hughes BR, Cook LJ: Involution of infantile haemangiomas after imiquimod 5% cream. Clin Exp Dermatol 2008;33:446-449.
  10. Hu L, Huang HZ, Li X, Lin XX, Li W: Open-label nonrandomized left-right comparison of imiquimod 5% ointment and timolol maleate 0.5% eye drops in the treatment of proliferating superficial infantile hemangioma. Dermatology 2015;230:150-155.
  11. Qiu Y, Ma G, Yang J, Hu X, Chen H, Jin Y, Lin X: Imiquimod 5% cream versus timolol 0.5% ophthalmic solution for treating superficial proliferating infantile haemangiomas: a retrospective study. Clin Exp Dermatol 2013;38:845-850.
  12. Qiu Y, Ma G, Lin X, Jin Y, Chen H, Hu X: Treating protruding infantile hemangiomas with topical imiquimod 5% cream caused severe local reactions and disfiguring scars. Pediatr Dermatol 2013;30:342-347.
  13. Kunzi-Rapp K: Topical propranolol therapy for infantile hemangiomas. Pediatr Dermatol 2012;29:154-159.
  14. 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;228:136-144.
  15. Ben-Amitai D, Halachmi S, Zvulunov A, Raveh E, Kalish E, Lapidoth M: Hemangiomas of the nasal tip treated with propranolol. Dermatology 2012;225:371-375.
  16. Calvo M, Garcia-Millan C, Villegas C, Fueyo-Casado A, Buron I: Topical timolol for infantile hemangioma of the eyelid. Int J Dermatol 2013;52:603-604.
  17. Chakkittakandiyil A, Phillips R, Frieden IJ, Siegfried E, Lara-Corrales I, Lam J, Bergmann J, Bekhor P, Poorsattar S, Pope E: Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study. Pediatr Dermatol 2012;29:28-31.
  18. Chambers CB, Katowitz WR, Katowitz JA, Binenbaum G: A controlled study of topical 0.25% timolol maleate gel for the treatment of cutaneous infantile capillary hemangiomas. Ophthal Plast Reconstr Surg 2012;28:103-106.
  19. Chan H, McKay C, Adams S, Wargon O: RCT of timolol maleate gel for superficial infantile hemangiomas in 5- to 24-week-olds. Pediatrics 2013;131:e1739-e1747.
  20. Khunger N, Pahwa M: Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol 2011;164:886-888.
  21. Moehrle M, Leaute-Labreze C, Schmidt V, Rocken M, Poets CF, Goelz R: Topical timolol for small hemangiomas of infancy. Pediatr Dermatol 2013;30:245-249.
  22. Ni N, Langer P, Wagner R, Guo S: Topical timolol for periocular hemangioma: report of further study. Arch Ophthalmol 2011;129:377-379.
  23. Ohnishi K, Tagami M, Morii E, Azumi A: Topical treatment for orbital capillary hemangioma in an adult using a beta-blocker solution. Case Rep Ophthalmol 2014;5:60-65.
  24. Pope E, Chakkittakandiyil A: Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol 2010;146:564-565.
  25. Rizvi SA, Yusuf F, Sharma R, Rizvi SW: Management of superficial infantile capillary hemangiomas with topical timolol maleate solution. Semin Ophthalmol 2015;30:62-64.
  26. Semkova K, Kazandjieva J: Topical timolol maleate for treatment of infantile haemangiomas: preliminary results of a prospective study. Clin Exp Dermatol 2013;38:143-146.
  27. Sorrell J, Chamlin SL: Topical timolol 0.5% gel-forming solution for small deep facial infantile hemangiomas. Pediatr Dermatol 2013;30:592-594.
  28. Thomas J, Kumar P, Kumar DD: Ulcerated infantile haemangioma of buttock successfully treated with topical timolol. J Cutan Aesthet Surg 2013;6:168-169.
  29. Weissenstein A, Straeter A, Villalon G, Bittmann S: Topical timolol for small infantile hemangioma: a new therapy option. Turk J Pediatr 2012;54:156-158.
  30. Xue K, Hildebrand GD: Topical timolol maleate 0.5% for infantile capillary haemangioma of the eyelid. Br J Ophthalmol 2012;96:1536-1537.
  31. Xue K, Hildebrand GD: Deep periocular infantile capillary hemangiomas responding to topical application of timolol maleate, 0.5%, drops. JAMA Ophthalmol 2013;131:1246-1248.
  32. Yu L, Li S, Su B, Liu Z, Fang J, Zhu L, Huang M, Shan W, Song D, Ye B, Luo C: Treatment of superficial infantile hemangiomas with timolol: evaluation of short-term efficacy and safety in infants. Exp Ther Med 2013;6:388-390.
  33. Oranje AP, Janmohamed SR, Madern GC, de Laat PC: Treatment of small superficial haemangioma with timolol 0.5% ophthalmic solution: a series of 20 cases. Dermatology 2011;223:330-334.
  34. McMahon P, Oza V, Frieden IJ: Topical timolol for infantile hemangiomas: putting a note of caution in ‘cautiously optimistic'. Pediatr Dermatol 2012;29:127-130.
  35. Boscolo E, Bischoff J: Vasculogenesis in infantile hemangioma. Angiogenesis 2009;12:197-207.
  36. Boye E, Jinnin M, Olsen BR: Infantile hemangioma: challenges, new insights, and therapeutic promise. J Craniofac Surg 2009;20 (suppl 1):678-684.
  37. Ho NT, Lansang P, Pope E: Topical imiquimod in the treatment of infantile hemangiomas: a retrospective study. J Am Acad Dermatol 2007;56:63-68.
  38. Xu G, Lv R, Zhao Z, Huo R: Topical propranolol for treatment of superficial infantile hemangiomas. J Am Acad Dermatol 2012;67:1210-1213.
  39. Greenberger S, Bischoff J: Pathogenesis of infantile haemangioma. Br J Dermatol 2013;169:12-19.
  40. Chen TS, Eichenfield LF, Friedlander SF: Infantile hemangiomas: an update on pathogenesis and therapy. Pediatrics 2013;131:99-108.
  41. Janmohamed SR, Madern GC, de Laat PC, Oranje AP: Educational paper: pathogenesis of infantile haemangioma, an update 2014. Part I. Eur J Pediatr 2015;174:97-103.
  42. Barnes CM, Christison-Lagay EA, Folkman J: The placenta theory and the origin of infantile hemangioma. Lymphat Res Biol 2007;5:245-255.
  43. Bischoff J. Progenitor cells in infantile hemangioma. J Craniofac Surg 2009;20(suppl 1):695-697.
  44. Li J, Chen X, Zhao S, Hu X, Chen C, Ouyang F, Liu Q, Ding R, Shi Q, Su J, Kuang Y, Chang J, Li F, Xie H: Demographic and clinical characteristics and risk factors for infantile hemangioma: a Chinese case-control study. Arch Dermatol 2011;147:1049-1056.
  45. Drolet BA, Swanson EA, Frieden IJ: Infantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants. J Pediatr 2008;153:712-715.
  46. Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ: Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr 2007;150:291-294.
  47. Bree AF, Siegfried E, Sotelo-Avila C, Nahass G: Infantile hemangiomas: speculation on placental trophoblastic origin. Arch Dermatol 2001;137:573-577.
  48. Bonifazi E, Milano A, Colonna V: Evaluation of safety and efficacy of a galenic preparation of 1% propranolol in 89 cases of cutaneous infantile hemangioma. Eur J Pediatr Dermatol 2013;23:93-104.
  49. Abarzua-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;70:1045-1049.
  50. Ariwibowo L, Danarti R: Comparison of efficacy between topical corticosteroid, timolol maleat 0.5% eye drop, and education observation in managing infantile hemangioma. Regional Conference of Dermatology (Asian-Australasian) and 6th Annual Meeting of the Asian Academy of Dermatology and Venereology (abstract). Danang, 2014.
  51. Theletsane T, Redfern A, Raynham O, Harris T, Prose NS, Khumalo NP: Life-threatening infantile haemangioma: a dramatic response to propranolol. J Eur Acad Dermatol Venereol 2009;23:1465-1466.
  52. Peridis S, Pilgrim G, Athanasopoulos I, Parpounas K: A meta-analysis on the effectiveness of propranolol for the treatment of infantile airway haemangiomas. Int J Pediatr Otorhinolaryngol 2011;75:455-460.
ppt logo Download Images (.pptx)


Figures
Thumbnail
Thumbnail
Thumbnail
Thumbnail

Tables
Thumbnail
Thumbnail