Propranolol repurposing for Infantile hemangioma (IH) is the most common vascular tumor of infancy, They are the most common soft-tissue tumors of childhood.

1. Drug information center ( DIC )
Propranolol repurposing for infantile
hemangiomas
Presented by Mesfin Mamuye

2. Presentation outline ;.
• Introduction to infantile hemangiomas
• Introduction to propranolol
• New mechanism of action
• Result of clinical study
• Recommendation
• References

3. Infantile hemangioma (IH)
• Infantile hemangioma (IH) is the most common
vascular tumor of infancy, They are the most
common soft-tissue tumors of childhood.
• The lesions are usually not detectable at birth
but appear during the first 4 to 6 weeks of life.
• For reasons unknown, IH affects more females
than males, and is also more prevalent in
premature and Caucasian babies.
[Chiller, K.G., D. Passaro, and I.J. Frieden 2014].

4. Continue…
• Frequency of infantile hemangiomas
at particular sites is as follows: around
Head and neck - 60% , Trunk - 25% ,
Extremities - 15%.
• The area involving such as: face or site at
high risk for ulceration causing airway
obstraction, dysfunction, hemorrhage or
disfigurement and infection.
[ Xiao Q, Zhang B, Yu W 2015]

7. There are three general types of infantile
hemangiomas:
• Superficial hemangiomas, which occur on the
outer layers of the skin, are typically bright red to
purple in color.
• Deep hemangiomas, which grow under the skin
in the fat, may be blue, purple or even skin color
(if they are deep enough under the skin surface).
• Mixed hemangiomas are the most common
type of hemangioma. These hemangiomas have
both superficial and deep components.
[ Stark E et al ; 2016]

8. PATHOPHYSIOLOGY
• IHs are vascular tumors that involve the
proliferation of benign endothelial like cells
that possess histochemical markers. these
markers are also present on placental blood
vessels.
• The immunohistochemical profile
differentiates IH from other vascular
birthmarks or tumors.
[Waner M,et.al,2010]

9. Continue…
• The pathophysiology associated with the
unique natural history of these lesions, with
initial rapid proliferation followed by gradual
involution and regression, has not been
completely elucidated.
• Recent data suggest an endothelial progenitor
cell as the source of origin of the tumors.
[Kleinman ME, et al,2013]

10. Diagnosis
• Hemangioma tumors are generally diagnosed visually.
Additional tests may be performed to assess size and
morphology.
• Ultrasound. This test uses sound waves to construct an
image of the tumor, allowing clinicians to inspect the
degree of vascularization.
• Imaging tests. Magnetic resonance imaging (MRI)
and computed tomography (CT) are used to determine
tumor size and proximity to other tissues.
• Biopsy. A tissue biopsy is performed if cancer or a
legion other than a hemangioma is suspected.
[Price et al.2011 ]

11. Management of IH
Medical care of clinically significant hemangiomas
has been limited to a few medications:
corticosteroids, interferon alfa, vincristine, &
imiquimod. surgery, and radiotherapy. pulsed dye
laser
- Beta-blockers, most specifically Propranolol,
have recently been serendipitously been shown to
induce involution of infantile hemangiomas.
[Frieden IJ, et al 2014]

12. propranolol
Introduction
• It is non selective beta blocker , the action of
epinephrine and norepinephrine on beta -1 and
beta -2 adrenergic receptors blocker.
• Propranolol is being used for cardiovascular
indication such as : hypertension, angina
pectoris , tachyarrhythmia , myocardial
infraction, and other non- cardiogenic
indications including essential tremor ,
migraine, cluster headaches and
thyrotoxicosis.
[Stroch CH, Hoeger PH 2016]

13. Pharmacokinetics
• Propranolol is a highly lipophilic drug achieving
high concentrations in the brain.
• Propranolol is rapidly and completely absorbed, with
peak plasma levels achieved about 1–3 hours after
ingestion. Approximately 90% of circulating propranolol
is bound to plasma proteins (albumin and alpha1 acid
glycoprotein).
• Co administration with food appears to
enhance bioavailability.
• The main metabolite 4-hydroxypropranolol, with a
longer half life from 3 to 6 hours. excreted in the
urine. [Stapleton MP ,2010 ]

14. New Mechanisms of Action
β2-adrenergic receptors are present on
endothelial cells of infantile hemangiomas.
The proposed mechanism of action of
propranolol in hemangiomas included
vasoconstriction, apoptosis of capillary
endothelial cells, and decreased the
production of vascular endothelial growth
factor and fibroblastic growth factor.
[Kum JJ, Khan ZA. 2015]

15. Result of clinical study
• performed a randomized controlled trial of
oral propranolol in 460 infants aged 1 to 5
months with infantile hemangiomas (IH).
Patients administered a dose of 3.4 mg/kg
per day exhibited a 60% rate of successful
treatment (complete or nearly complete
resolution of the target hemangioma),
compared with a 4% rate among those
treated with placebo.
[ Léauté-Labrèze et al. 2015 ]

16. Continue…
• conducted a randomized controlled trial in 40 children
between the ages of 9 weeks and 5 years with facial IHs.
Children younger than 6 months were admitted to the
hospital for monitoring after their first dose at weeks 1
and 2. No significant hypoglycemia, hypotension, or
bradycardia occurred. Significant decrease in IH redness
and elevation occurred in the propranolol group at weeks
12 and 24 .The authors concluded that propranolol
hydrochloride administered orally at 2 mg/kg per day
reduced the volume, color, and elevation of focal and
segmental IH in infants younger than 6 months and
children up to 5 years of age.
• [ Hogeling et al. (2011) ]

17. Adverse effects
• Most frequent adverse effects after taken
propranolol for IH reported were sleep
disturbances (3.7%) and asymptomatic or
unspecified hypotension (2.8% ), followed by
somnolence (2.2%), cool or mottled extremities
(1.7%), pulmonary symptoms including
wheezing (1.4%), asymptomatic or unspecified
bradycardia (0.9%), hypoglycemia (0.9%),
gastroesophageal reflux or GI upset (0.7%),
symptomatic hypotension (0.3%), and
symptomatic bradycardia (0.1%).
[ Drolet BA, Frommelt PC, et al 2013 ]

18. Figure 1: Infantile hemangioma- red-purplish lobulated like macules at the lateral
postural aspect of back at first contact with patient (Picture courtesy of Wu Jianbo,
Department of Dermatology and Venereology at Zhongnan Hospital of Wuhan
University).

19. • Figure 2: Infantile hemangioma-after one month of treatment on topical propranolol.
(Picture courtesy of Wu Jianbo, Department of Dermatology and Venereology at
Zhongnan Hospital of Wuhan University).

20. Figure 3: Infantile hemangioma-after three months of treatment on topical propranolol.
(Picture courtesy of Wu Jianbo, Department of Dermatology and Venereology at
Zhongnan Hospital of Wuhan University).

21. Dose
• Oral propranolol in infant is started with an
initial dose of 0.5 mg/kg/day, and gradually
is increased up to 2-3 mg/kg/day divided
into 2-3 daily dose after clearance of
cardiopulmonary contraindications. The
treatment is usually stopped at 12-24
months of age, but occasionally longer
treatment may be required because of
recurrences .
[ McGee P, Miller S, et al.2013]

22. Clinical trial
• Breast cancer patients who received
propranolol for hypertension displayed
reduced metastasis and cancer
recurrence.
• Propranolol Hydrochloride in Treating
Patients with Prostate Cancer Undergoing
Surgery

23. • Other beta- blockers such as atenolol and
nadolol may provide similar efficacy to
propranolol in IH treatment, have cohort-
blinded study comparing atenolol to
propranolol for treatment of IH. Among all
23 pt thirteen was with atenolol and ten
with propranolol. The results showed that
atenolol had 53.8% of complete response
and propranolol had 60% .
[ abarzua –araya et al.2014 ]

24. Recommendation
• examined if propranolol therapy is safe
and effective and superior to oral
corticosteroids for treating infantile
hemangiomas (IHs). [Price et al (2011) ]
• Propranolol has been approved by the Food
and Drug Administration (FDA), specifically
for the treatment of hemangiomas.
[Society for Pediatric Dermatol,2013].

25. Reference
• Chiller, K.G., D. Passaro, and I.J. Frieden, Hemangiomas of infancy: clinical
characteristics, morphologic subtypes, and their relationship to race,
ethnicity, and sex. Arch Dermatology, 2002. 138(12): p. 1567-76.
• Xiao Q, Zhang B, Yu W 2015. propranolol therapy of infantile
hemangiomas , pediatric surg. Int 29(6) : 575-581.
• Stark E et al : types of infantile hemangiomas: a review. Archives of
Disease in Childhood 2016 ; 96: 890-893.
• Waner M,et.al(2010). GLUT1: a newly discovered immune histochemical marker
for juvenile hemangiomas. Hum Pathol. ;31(1):11–22
• Kleinman ME, et al(2013). Hypoxia-induced mediators of stem/progenitor cell
trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc
Biol.;27(12):2664–2670
• Price, C.J., et al., laboratory diagnosis for Infantile Hemangiomas A
Multicenter Retrospective Analysis. Archives of Dermatology, 2011. 147(12):
p. 1371-1376.

26. .
• Frieden IJ, Eichenfield LF, Esterly NB, Geronemus R, Mallory SB
Guidelines of care for hemangiomas of infancy. American Academy of
Dermatology Guidelines/Outcomes Committee. J Am Acad Dermatol
1997;37:631-7
• Stroch CH, Hoeger PH (2016) propranololfor infantile hemangiomas : insights into the
molecular mechanism of action. Br J Dermatol 163(2) : 269- 274 .
• Stapleton MP (2010). "Sir James Black and propranolol. The role of the
basic sciences in the history of cardiovascular pharmacology" Texas Heart
Institute Journal. 24 (4): 336–42. PMC 325477 . PMID 9456487.
• Kum JJ, Khan ZA. Mechanisms of propranolol action in infantile
hemangioma. Dermatoendocrinol 2015;6:e979699.
• Leaute-Labreze, C., et al., Propranolol for severe hemangiomas of
infancy. N Engl J Med, 2015. 358(24): p. 2649-51.
• Lawley, L, et al. Propranolol Treatment for Hemangioma of Infancy: Risks
and Recommendations. Pediatric Dermatology 2009, Vol.26 No.5 610-614.

27. • Hogeling M, Adams S, Wargon O. A randomized controlled trial of
propranolol for infantile hemangiomas. Pediatrics. 2011;128(2):e259-e266.
• McGee P, Miller S, Black C, Hoey S. propranolol for infantile hemangioma: A
review of current dosing regime in a regional pediatric hospital, Ulster Med
J. 2013; 82: 16-20.
• Abarzua-Araya A, et al, atenolol vs propranolol for the infantile
hemangiomas; A treatment randomized controlled study. J am Acad.
Dermatol. 2014; 168:222-224 .
• Drolet BA, Frommelt PC, chamlin SL, Haggstrom A, Bauman NM, Chiu YE,
et al. Infantile and use of propranolol for infantile hemangioma; report of a
consensus conference. Pediatrics. 2013; 131: 128- 140.
• Society for Pediatr Dermatol(2013). Propranolol treatment of infantile
hemangiomas: anticipatory guidance for parents and caretakers;30(1):155-
159.