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1.  Propranolol intervention therapy for infants with facial hemangioma 
Contemporary Oncology  2012;16(5):432-434.
Aim of the study
The current study aimed to evaluate the clinical efficacy and adverse effects of small doses of propranolol intervention therapy for infants with infantile facial hemangioma in the proliferation stage.
Material and methods
A total of 22 patients including 9 males and 13 females with an average age of 5.5 months were enrolled. These patients were diagnosed with facial hemangioma. During the first week of hospitalization, the patients were requested to take propranolol according to their weight (1.0 mg/kg to 1.5 mg/kg once daily). After hospital discharge, the patients were requested to take propranolol consistently and were reassessed every two weeks. We closely observed the process, recorded information about the size, color, and texture of the hemangioma, coped with the adverse effect during the treatment, and evaluated the clinical efficacy of propranolol.
Results
The color of the hemangioma faded 24 h after taking propranolol. After 3 months to 9 months of observation, we obtained the following clinical efficacies: level I, 0; level II, 2; level III, 13; and level IV, 7. The effective rate was 100%. The heart rate of 22 patients became slower than before treatment, 2 patients had slight diarrhea that disappeared after treatment, and there was no serious adverse effect during the entire process.
Conclusions
With the advantages of minor side effects, convenience, safety, and evident efficacy, the administration of small doses of propranolol is a good method for treating hemangioma in infants.
doi:10.5114/wo.2012.31774
PMCID: PMC3687440  PMID: 23788923
infants; propranolol; hemangioma
2.  Propranolol in Treatment of Huge and Complicated Infantile Hemangiomas in Egyptian Children 
Background. Infantile hemangiomas (IHs) are the most common benign tumours of infancy. Propranolol has recently been reported to be a highly effective treatment for IHs. This study aimed to evaluate the efficacy and side effects of propranolol for treatment of complicated cases of IHs. Patients and Methods. This prospective clinical study included 30 children with huge or complicated IHs; their ages ranged from 2 months to 1 year. They were treated by oral propranolol. Treatment outcomes were clinically evaluated. Results. Superficial cutaneous hemangiomas began to respond to propranolol therapy within one to two weeks after the onset of treatment. The mean treatment period that was needed for the occurrence of complete resolution was 9.4 months. Treatment with propranolol was well tolerated and had few side effects. No rebound growth of the tumors was noted when propranolol dosing stopped except in one case. Conclusion. Propranolol is a promising treatment for IHs without obvious side effects. However, further studies with longer follow-up periods are needed.
doi:10.1155/2014/541810
PMCID: PMC4034713  PMID: 24899888
3.  Beta-blockers for the treatment of problematic hemangiomas 
OBJECTIVE:
To examine treatment indications, efficacy and side effects of oral beta-blockers for the treatment of problematic hemangiomas.
METHODS:
A retrospective review of patients with hemangiomas presenting to the Alberta Children’s Hospital Vascular Birthmark Clinic (Calgary, Alberta) between 2009 and 2011 was conducted. The subset of patients treated with oral beta-blockers was further characterized, investigating indication for treatment, response to treatment, time to resolution of indication, duration of treatment, occurrence of rebound growth and side effects of therapy.
RESULTS:
Between 2009 and 2011, 311 new patients with hemangiomas were seen, of whom 105 were treated with oral beta-blockers. Forty-five patients completed beta-blocker treatment while the remainder continue to receive therapy. Indications for treatment were either functional concerns (68.6%) or disfigurement (31.4%). Functional concerns included ulceration (29.5%), periocular location with potential for visual interference (28.6%), airway interference (4.8%), PHACES syndrome (3.8%), auditory interference (0.95%) and visceral location with congestive heart failure (0.95%). The median age at beta-blocker initiation was 3.3 months; median duration of therapy was 10.6 months; and median maximal treatment dose was 1.5 mg/kg/day for propranolol and 1.6 mg/kg/day for atenolol. Ninety-nine patients (94.3%) responded to therapy with size reduction, colour changes, softened texture and/or healing of ulceration. Rebound growth requiring an additional course of therapy was observed in 23 patients. Side effects from beta-blockers included cool extremities (26.7%), irritability (17.1%), lower gastrointestinal upset (14.3%), emesis (11.4%), hypotension (10.5%), poor feeding (7.6%), lethargy (4.8%), bronchospasm (0.95%) and rash (0.95%). Side effects did not result in complete discontinuation of beta-blocker treatment in any case; however, they prompted a switch to a different beta-blocker preparation in some cases. Resolution of the primary indication, requiring a median time of three months, occurred in 87 individuals (82.9%).
CONCLUSIONS:
Treatment of infantile hemangiomas with oral beta-blocker therapy is highly effective and well tolerated, with more than 94% of patients demonstrating a response to treatment and 90% showing resolution of the primary functional indication for treatment.
PMCID: PMC3891114  PMID: 24431932
Beta-blocker; Hemangioma; Indications; Propranolol; Side effects; Treatment efficacy
4.  Nonselective β-blocker propranolol for orbital and periorbital hemangiomas in infants: a new first-line of treatment? 
Purpose
To determine the effectiveness and possible side effects of using propranolol for the treatment of orbital and periorbital infantile hemangiomas.
Methods
Infants with periorbital or orbital hemangiomas who had not received either local or systemic corticosteroids were recruited. The changes in tumor size, color, and texture, and any side effects of the drug were recorded.
Results
Fifteen infants with a mean age of 8.13 ± 4.7 months were treated according to the set protocol. A change in the color and texture of the hemangioma occurred in the first week following treatment. Mean duration of treatment was 7.67 ± 3.96 months. The size of hemangiomas decreased from a mean of 2.4 ± 0.9 cm to a mean of 1.6 ± 1.0 cm 3 months after treatment (P = 0.001). One patient had to stop the drug because of peripheral vascular ischemia. Another case had the dose reduced to control a mild hyperglycemia. Serious side effects were not observed. A single case of tumor regrowth (8.3%) was recorded.
Conclusion
Treatment of 1–2 mg/kg/day propranolol proved to be effective and associated with minimal side effects. It is likely to replace steroids as the first-line of treatment of hemangiomas in infants.
doi:10.2147/OPTH.S24141
PMCID: PMC3225462  PMID: 22140311
orbital and periorbital hemangioma; β-blockers; propranolol; corticosteroids; adrenal suppression
5.  Oral Propranolol for Treatment of Pediatric Capillary Hemangiomas 
Purpose
To report the long-term results of treatment of pediatric capillary hemangiomas with oral propranolol.
Methods
Three infants, 3 to 4 months of age, with periocular capillary hemangiomas were treated with oral propranolol solution (Inderal, 20mg/5ml) 2-3 mg/kg per day divided in 2 doses. Propranolol was continued up to the end of the first year of life and tapered over 2-3 weeks. All infants were followed for 20 months. Lesion size and evolution were assessed during the follow-up period.
Results
Significant improvement was noted in all patients in the first 2 months of therapy with slow and continuous effect throughout the follow-up period. No serious complications were observed.
Conclusion
Oral propranolol can be used as a first line agent in children with capillary hemangiomas.
PMCID: PMC3520472  PMID: 23275821
Oral Propranolol; Capillary Hemangioma
6.  Management of periorbital hemangioma by intralesional glucocorticoids and systemic propranolol: a single-center retrospective study 
Periorbital hemangioma may lead to the vision impairment so effective treatment should be adopted in time. In this study, we made a retrospective analysis of intralesional glucocorticoids and systemic propranolol in the management of periorbital hemangioma. From Jan. 2006 to Dec. 2013, twenty-five children with periorbital hemangioma were enrolled into this study. Among them, sixteen children accepted intralesional injection of compound betamethasone preparation. Eight children accepted systemic propranolol. One child accepted both of the two treatments. The follow-up period ranged from 6 months to 60 months. The results showed that in the patients with intralesional compound betamethasone preparation, 13/16 patients’ tumors involuted completely. 3/16 patients’ tumors didn’t involute completely at the end of follow-up. In the patients with systemic propranolol, 8/8 patients’ tumors involuted almost completely. One patient didn’t respond to intralesional glucocorticoids, and so switched to systemic propranolol, which lead to the involution of tumor finally. The adverse effects in the patients with intralesional glucocorticoids included local soft tissue atrophy, local ulcer, and Cushing-like manifestations, which occurred in three patients respectively. In the patients with systemic propranolol, mild diarrhoea occurred in one child. According to our observation, both of intralesional glucocorticoids and systemic propranolol achieved good results in the management of periorbital hemangioma. Systemic propranolol showed superiority in efficacy and safety. We recommend systemic propranolol as the first-line therapy. However, for the children who can’t tolerate systemic propranolol, intralesional glucocorticoids still is a feasible choice.
PMCID: PMC4057847  PMID: 24955168
Periorbital hemangioma; intralesional glucocorticoids; systemic propranolol
7.  Propranolol for Infantile Haemangiomas: Experience from a Tertiary Center 
Aim:
Infantile haemangiomas are the most common tumor of infancy. We report the use of propranolol for treatment of problematic and complicated haemangiomas.
Patients and Methods:
Propranolol was given to 52 children with mean age of 18.2 months at onset of treatment. After clinical and electrocardiographic evaluations, propranolol was administered with a starting dose of 2 mg/kg per day, given in 3 divided doses. Monthly follow up was done, response to oral propranolol therapy and any complications of therapy were recorded. Response to propranolol was classified as Complete Response, Excellent Response, Partial Response and Non Responder.
Results:
Total 49 patients showed significant improvement after propranolol therapy out of which 4 patients were complete responder, 30 patients (56.7%) were excellent responders; 15 patients (28.8%) were partial responders. 3 patients (5.7%) had growth of haemangiomas despite propranolol therapy and were classified as non-responder. Side effect like hypotension, rashes, gastroesophageal reflux was reported by 3 patients. In our study mean duration of treatment was 6.5 months. At the end of treatment propranolol was stopped by with gradual tapering of dose over a period of 2 weeks.
Conclusion:
Propranolol administered orally at 2 mg/kg per day has rapid effective therapeutic effect in treatment of ulcerated haemangiomas and it appears to be a valuable and effective treatment option for infantile haemangiomas beyond the proliferative phase, and esthetically disfiguring haemangiomas.
doi:10.4103/0974-2077.129975
PMCID: PMC3996789  PMID: 24761098
Adverse effects; infantile haemangiomas; propranolol; ulcerated haemangiomas
8.  Evaluation of intralesional propranolol for periocular capillary hemangioma 
Background:
The purpose of this study was to evaluate the use of intralesional propranolol injection in the management of periocular capillary hemangioma.
Methods:
A prospective study was performed in 22 consecutive patients with periocular hemangioma. Twelve patients underwent intralesional propranolol injection and ten patients underwent intralesional triamcinolone injection. The size of the lesion was measured serially every week during the first month, every 2 weeks for the second month, and then monthly for another 2 months. The refractive error and degree of ptosis if present were measured before injection and at the end of the study.
Results:
There was reduction in the size of hemangioma, astigmatic error, and degree of ptosis in both groups. The difference in outcome between both groups was not statistically significant. Rebound growth occurred in 25% of the propranolol group and 30% of the steroid group but responded to reinjection. No adverse effects were reported during or after intralesional propranolol injection.
Conclusion:
Intralesional propranolol injection is an alternative and effective method for treatment of infantile periocular hemangioma.
doi:10.2147/OPTH.S22909
PMCID: PMC3162293  PMID: 21887095
propranolol; intralesional; periocular capillary hemangioma
9.  Propranolol therapy of infantile hemangiomas: efficacy, adverse effects, and recurrence 
Pediatric Surgery International  2013;29(6):575-581.
Objective
To evaluate the efficacy, adverse effects, and recurrence of oral propranolol for treatment of infantile hemangioma.
Methods
Participants were treated with oral propranolol three times daily, with inpatient monitoring of adverse effects. The starting dosage was 2 mg/kg per day, which had been for the remaining duration of treatment. Therapy duration was planned for 4–6 months; if there was significant relapse, the period of treatment was extended. A photograph based severity scoring assessment was performed by three observers to evaluate efficacy by visual analog scale (VAS).
Results
Sixty-one infants [median age 3.3 (1.2–8.1) months] were included in the study. The median follow-up-time was 15 (6–20) months and 53 patients completed treatment at a median age of 10.3 (8.4–18.1) months, after a duration of 8.5 (4.5–14) months. In all patients, there was significant fading of color [with a VAS of −9 (−6 to −9) after 6 months] and significant decrease in size of the infantile hemangiomas [with a VAS of −8 (−3 to −10) after 6 months]. We did not observe any life-threatening adverse effects. The therapy was interrupted due to temporary aggravation of pre-existing bronchial asthma in one child. Four cases presented partial recurrences.
Conclusions
Oral propranolol 2 mg/kg per day was a well-tolerated and effective treatment, mild adverse effects, and low recurrence for infantile hemangiomas. Propranolol should now be used as a first-line treatment in hemangiomas when intervention is required. Also, prospective studies should be needed in determining the most effective treatment dosage, optimum treatment duration, and exact mechanism of action of propranolol in future.
doi:10.1007/s00383-013-3283-y
PMCID: PMC3657346  PMID: 23519547
Propranolol; Infantile hemangiomas; Efficacy; Adverse effects; Recurrence
10.  Oral Propranolol for the Treatment of Periorbital Infantile Hemangioma: A Preliminary Report from Oman 
Purpose:
To investigate the efficacy and safety of oral propranolol in the management of periorbital infantile hemangioma in four subjects.
Materials and Methods:
Consecutive patients who presented with periorbital capillary hemangioma with vision-threatening lesions were prospectively enrolled in this study between January 2009 and October 2010. All subjects underwent treatment with 2 mg/kg/day oral propranolol. All subjects underwent ocular, systemic, and radiologic evaluations before treatment and at periodic intervals after starting therapy. Side effects from therapy were also evaluated.
Results:
Four subjects, between 3 months and 19 months of age, with periorbital hemangioma were enrolled in this study. Two subjects had been previously treated with oral corticosteroids with unsatisfactory response. All subjects had severe ptosis, with the potential for deprivation amblyopia. Three subjects had orbital involvement. After hospital admission, oral propranolol was initiated in all subjects under monitoring by a pediatric cardiologist. Subsequent therapy was performed with periodic out-patient monitoring. All subjects had excellent response to treatment, with regression of periorbital and orbital hemangioma. There were no side effects from therapy.
Conclusions:
Oral propranolol for periorbital hemangioma was effective in all the four subjects. Oral propranolol may be appropriate for patients who are nonresponsive to intralesional or systemic steroids. In patients with significant orbital involvement and lesions causing vision-threatening complications, oral propranolol can be the primary therapy.
doi:10.4103/0974-9233.90131
PMCID: PMC3249815  PMID: 22224018
Amblyopia; Infants; Orbital Hemangioma; Propranolol
11.  Rapamycin Suppresses Self-Renewal and Vasculogenic Potential of Stem Cells Isolated from Infantile Hemangioma 
Infantile hemangioma (IH) is a common childhood vascular tumor. Although benign, some hemangiomas cause deformation and destruction of features or endanger life. The current treatments, corticosteroid or propranolol, are administered for several months and can have adverse effects for the infant. We designed a high-throughput screen to identify FDA-approved drugs that could be used to treat this tumor. Rapamycin, an mTOR inhibitor, was identified based on its ability to inhibit proliferation of a hemangioma-derived stem cell population, human vasculogenic cells we had previously discovered. In vitro and in vivo studies show that Rapamycin reduces the self-renewal capacity of the hemangioma stem cells, diminishes differentiation potential, and inhibits the vasculogenic activity of these cells in vivo. Longitudinal in vivo imaging of blood flow through vessels formed with hemangioma stem cells shows that Rapamycin also leads to regression of hemangioma blood vessels, consistent with its known anti-angiogenic activity. Finally, we demonstrate that Rapamycin-induced loss of stemness can work in concert with corticosteroid, the current standard therapy for problematic hemangioma, to block hemangioma formation in vivo. Our studies reveal that Rapamycin targets the self-renewal and vascular differentiation potential in patient-derived hemangioma stem cells and suggests a novel therapeutic strategy to prevent formation of this disfiguring and endangering childhood tumor.
doi:10.1038/jid.2011.300
PMCID: PMC3213330  PMID: 21938011
12.  Treatment of alarming head and neck infantile hemangiomas with interferon-α2a: a clinical study in eleven consecutive patients 
Objective
To evaluate the efficacy and adverse effects of interferon-α2a in the treatment of alarming infantile hemangiomas in the head and neck region.
Patients and methods
From January 2009–December 2010, a subcutaneous injection of interferon-α2a was applied to eleven infants with giant multifocal or segmental hemangiomas at a dose of 3 million units/m2 per day. All patients did not respond to propranolol or corticosteroids. The age at initiation of interferon-α2a therapy ranged from 3 days to 8 months (median: 4 months). The duration of therapy ranged from 2–4.5 months (median: 3 months). Eight patients received medication for 3 months, one patient for 4.5 months, and two patients for 2 months.
Results
Nine patients had a reduction in tumor mass of 95%; two patients’ tumors decreased in size by 75%. The overall response rate was 100%. The main adverse effects included fever, diarrhea, and anorexia, which resolved after stopping the medication. No serious adverse effect was observed.
Conclusion
Short-term treatment with interferon-α2a can be used as a safe and effective treatment for alarming infantile hemangiomas that are resistant to propranolol or corticosteroids, and that endanger the proper functioning of the affected organ or the patient’s life.
doi:10.2147/DDDT.S67682
PMCID: PMC4324326
hemangioma; interferon-α; head and neck; adverse effect
13.  Treatment process for capillary hemangioma 
Background
Hemangiomas, usually, present at the first few months of life and are the most common benign tumor in children. There are various therapeutic methods for hemangioma. Capillary hemangioma is a type of hemangiomas.
The steps of treatment of a child with capillary hemangioma in Taleghani Hospital of Gorgan, Iran, are reported.
Case report
In this report, it is described an 18-month-old child with capillary hemangioma on the right side of face. She was presented to the hematologic clinic of Taleghani Hospital of Gorgan. Three drugs, including prednisolon, propranolol and interferon alpha-2b (IFN-α-2b), were used for treating this patient. At the end of treatment, good results were obtained. After that, laser therapy was performed for fading the lesions.
Conclusion
Prescription of drug was our first choice for treating capillary hemangioma and it had a positive result without any complications. We used propranolol and IFN-α-2b for treating capillary hemangioma because of their better effect on this patient.
PMCID: PMC4173033  PMID: 25254092
hemangioma; propranolol; interferon alpha
14.  Propranolol Inhibition of β-Adrenergic Receptor Does Not Suppress Pathologic Neovascularization in Oxygen-Induced Retinopathy 
Purpose.
Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects.
Methods.
Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups.
Results.
None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor.
Conclusions.
Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
doi:10.1167/iovs.12-9691
PMCID: PMC3376075  PMID: 22491401
15.  Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma 
Oncotarget  2013;5(1):161-172.
Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective β-adrenergic receptor antagonist propranolol hydrochloride.
Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, and not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express β2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.
PMCID: PMC3960198  PMID: 24389287
Neuroblastoma; propranolol; beta-adrenergic receptor; p53; p73
16.  Distribution of Propranolol in Periocular Tissues: A Comparison of Topical and Systemic Administration 
Abstract
Purpose
Oral propranolol has become a promising treatment of capillary hemangiomas (CHs) despite concerns of side effects associated with systemic beta-blockers. The objective of this study was to investigate the distribution of propranolol in periocular tissues and in plasma after topical application of propranolol as compared with intravenous and oral administration of propranolol.
Methods
Each rabbit received propranolol as ophthalmic solution (1%) in one eye (1.5 mg dose), intravenous injection (1.5 mg dose), or commercially available propranolol oral solution (5 mg dose). The periocular tissues (e.g., eyelids and extraocular muscles) and blood were collected and assayed for propranolol.
Results
After topical instillation of 1.5 mg propranolol, high amounts of propranolol were rapidly delivered to the eyelids and extraocular muscles (4−32 μg/g at 1 h after dosing). The drug in these tissues was slowly cleared, and significant amounts of the drug (>0.4 μg/g) were still present at 24 h after the topical application. After oral administration of a clinically relevant dose of 5 mg propranolol, the drug concentrations in the periocular tissues were relatively low (<0.4 μg/g) at 1 h after dosing and generally undetectable at 8 h after dosing. After an intravenous injection of 1.5 mg propranolol, the drug concentrations in the eyelids and extraocular muscles were in the range of 0.2−1 μg/g at 1 h after dosing. The plasma concentration of the drug after the intravenous injection was significantly higher than that after topical application of the same dose. The higher drug concentrations in the periocular tissues of the treated eyes as compared with untreated eyes suggest direct penetration of the drug into the periocular tissues from the administration site after topical application.
Conclusions
Topical administration can provide increased concentrations of propranolol in the periocular tissues and, thus, is superior to systemic administration for the treatment of periocular CH.
doi:10.1089/jop.2011.0055
PMCID: PMC3197082  PMID: 21810027
17.  Propranolol Accelerates Adipogenesis in Hemangioma Stem Cells and Causes Apoptosis of Hemangioma Endothelial Cells 
Plastic and reconstructive surgery  2012;130(5):1012-1021.
Background
Infantile hemangiomas (IHs) can cause significant morbidity during proliferation, yet there is no FDA-approved treatment. IHs are believed to form from stem cells (HemSCs), which differentiate towards an endothelial cell (HemECs) phenotype. Recently, propranolol has demonstrated effectiveness in the treatment of complicated IHs. We hypothesize that propranolol facilitates IH involution by altering cellular behavior in both HemECs and HemSCs.
Methods
HemECs and HemSCs were isolated from resected IH specimens. Cells were treated with 100μM propranolol for 48 hours, and apoptosis determined by presence of Annexin V antibody. Proliferation of HemSCs and HemECs were assessed after treatment with 50μM or 100μM propranolol, or vehicle for 72 and 96 hours respectively. Adipogenesis was induced in HemSCs with and without propranolol. Pro-adipogenic genes PPARδ, PPARγ, C/EBPα, C/EBPβ, C/EBPδ, RXRα and RXRγ were analyzed by quantitative PCR (qPCR).
Results
Annexin V levels were increased in propranolol-treated HemECs, but not in HemSCs. Proliferation of HemSCs and HemECs was inhibited by propranolol in a dose-dependent manner. Propranolol-treated HemSCs demonstrated accelerated adipogenesis when compared to untreated controls. Transcript levels of adipogenesis-associated genes C/EBPβ (p<0.05), RXRγ (p<0.05), and PPARγ (p<0.02) were significantly increased when treated with 50μM or 100μM propranolol, and C/EBPδ (p<0.05), RXRα (p<0.05), PPARδ (p<0.01) transcripts were increased when treated with 100μM propranolol. C/EBPα transcript levels remained unchanged at either dose.
Conclusions
These results show that propranolol increased apoptosis of HemECs but not HemSCs, and accelerated adipogenesis of HemSC. Thus, propranolol likely accelerates involution to fibrofatty residuum.
doi:10.1097/PRS.0b013e318267d3db
PMCID: PMC3668332  PMID: 23096601
18.  Induction of apoptosis in infantile hemangioma endothelial cells by propranolol 
Propranolol, a non-selective β-blocker, is emerging as an effective treatment for complicated hemangiomas. The aim of this study was to investigate the molecular mechanism(s) underlying the therapeutic effects of propranolol against hemangiomas, using primary infantile hemangioma endothelial cells (IHECs). IHECs were treated with various concentrations of propranolol and morphological changes and apoptosis were assessed. Changes in the expression levels of apoptosis-related genes were examined. Annexin-V staining revealed that propranolol at 40, 50 and 60 μg/ml caused a concentration-dependent increase in the apoptosis of IHECs. Morphological analyses revealed that exposure to 50 μg/ml propranolol resulted in typical apoptotic changes, including shrinkage, the formation of apoptotic bodies and retention of plasma membrane integrity. Gene expression analyses revealed that propranolol treatment led to a marked increase in the expression of caspase-8, cytochrome c, apoptosis-inducing factor, caspase-3 and poly (ADP-ribose) polymerase 1, as well as a concomitant reduction in lamin B1 expression. Our data collectively demonstrate that propranolol induces apoptosis of IHECs through activation of the intrinsic and extrinsic apoptotic pathways, which represents an important mechanism for its therapeutic effects against infantile hemangiomas.
doi:10.3892/etm.2013.1159
PMCID: PMC3786814  PMID: 24137229
hemangioma; apoptosis; mitochondria; mechanism; propranolol
19.  Successful Treatment of Mild Pediatric Kasabach-Merritt Phenomenon with Propranolol Monotherapy 
Case Reports in Hematology  2014;2014:364693.
Kasabach-Merritt phenomenon (KMP) is relatively rare in childhood and adolescents with high mortality rate because of its hemorrhagic complications and unresponsiveness to treatments such as corticosteroids, vincristine, intravascular embolization, and/or surgery. Propranolol, a β-adrenergic receptor blocker, has a promising efficacy against vascular tumors such as infantile hemangiomas. But limited and variable data has been reported regarding the role of propranolol in treatment of KMP. We herein reported the successful treatment of mild pediatric KMP with propranolol monotherapy in a case of a five-week-old child with kaposiform hemangioendothelioma with successful treatment of both clinical and hematologic responses. After eight months of follow-up, patient still had stable cutaneous lesion while receiving propranolol monotherapy. Regular hematologic monitoring was done in order to detect any late relapse of the disease. Six months after discontinuation of propranolol, patient has still remained free of hematologic relapse, and primary cutaneous lesion has become a pale pink, 1 cm sized skin lesion.
doi:10.1155/2014/364693
PMCID: PMC4054805  PMID: 24963423
20.  The effect of propranolol versus placebo on resident surgical performance. 
PURPOSE: To determine whether propranolol can decrease surgical tremor and anxiety in residents performing ocular microsurgery without impairing patient or physician safety. METHODS: In this randomized, double-masked, crossover study, 5 third-year ophthalmology residents ingested a capsule containing either propranolol, 40 mg, or placebo 1 hour prior to performing ophthalmic microsurgery. All residents were healthy men under age 30 years. Prior to commencement of the study, all participants had successfully been administered a test dose of propranolol without side effects. The study took place over a 10-week period. At the conclusion of each case, both the resident and attending surgeon observer independently completed a form grading, on a sliding scale: (1) amount of overall tremor; (2) amount of tremor during placement of the first 3 sutures after lens or nucleus extraction; (3) anticipated difficulty of the case; (4) actual difficulty with the case; and (5) anxiety (surgeon only). In addition, the type of procedure performed, complications encountered, and surgeon side effects were recorded. The data were analyzed with a 2-way analysis of variance for unbalanced data. RESULTS: A total of 73 surgical cases were performed; the surgeons were administered propranolol for 40 cases and placebo for 33. As judged by the resident surgeon, there was a highly significant effect of propranolol in decreasing anxiety (P = .0058), reducing surgical tremor overall (P < .0001), and reducing tremor while placing the first 3 sutures following lens extraction (P < .0001). There was no treatment-by-surgeon interaction for any of the measures. Complications and difficulty of the case, as judged by both the resident and attending surgeons, were not significantly different in the propranolol versus placebo groups (P > .05). There were no side effects reported or observed in any of the surgeons. CONCLUSIONS: Propranolol, 40 mg, administered 1 hour prior to surgery, significantly decreases tremor and anxiety in the surgeon without untoward effects to the surgeon and the patient. However, it is unknown whether decreased tremor and anxiety improved surgical outcome.
PMCID: PMC1298399  PMID: 10360293
21.  Trauma Reactivation Plus Propranolol Is Associated With Durably Low Physiological Responding During Subsequent Script-Driven Traumatic Imagery 
Objective:
In a previous, double-blind, placebo-controlled study, patients with posttraumatic stress disorder (PTSD) showed lower physiological response during script-driven traumatic imagery 1 week after receiving a single dose of propranolol given after the retrieval of a traumatic memory. We hypothesized that this effect would extend beyond 1 week using a modified treatment approach.
Method:
Twenty-eight participants with PTSD read an account of their traumatic event once weekly for 6 consecutive weeks under the influence of open-label propranolol. One week and 4-months later, skin conductance, heart rate, and left corrugator electromyogram responses were measured while participants engaged in script-driven mental imagery of their traumatic event. Results from the 22 study participants were compared with results from treated and untreated participants in a previously published trial.
Results:
Most participants in our study were classified as non-PTSD cases at posttreatment and follow-up according to a psychophysiological discriminant function analysis. Posttreatment skin conductance and heart rate responses of the current (propranolol-treated) participants were lower than those of placebo participants from the previous study. No difference was observed between physiological responding measured posttreatment and at follow-up.
Conclusions:
Low physiological responding during script-driven traumatic imagery after treatment extends up to 4 months, demonstrating the durability of the treatment effect’s. Limitations include the absence of a placebo-controlled group and lack of physiological baseline measures. Despite these limitations, results point to the need for future trials examining the clinical efficacy of trauma reactivation plus propranolol, as it has the potential to become a novel, cost- and time-effective treatment for PTSD.
PMCID: PMC4079131  PMID: 25007116
posttraumatic stress disorder; treatment; reconsolidation; memory; propranolol; traumatic stress
22.  Role of connexins in infantile hemangiomas 
The circulatory system is one of the first systems that develops during embryogenesis. Angiogenesis describes the formation of blood vessels as a part of the circulatory system and is essential for organ growth in embryogenesis as well as repair in adulthood. A dysregulation of vessel growth contributes to the pathogenesis of many disorders. Thus, an imbalance between pro- and antiangiogenic factors could be observed in infantile hemangioma (IH). IH is the most common benign tumor during infancy, which appears during the first month of life. These vascular tumors are characterized by rapid proliferation and subsequently slower involution. Most IHs regress spontaneously, but in some cases they cause disfigurement and systemic complications, which requires immediate treatment. Recently, a therapeutic effect of propranolol on IH has been demonstrated. Hence, this non-selective β-blocker became the first-line therapy for IH. Over the last years, our understanding of the underlying mechanisms of IH has been improved and possible mechanisms of action of propranolol in IH have postulated. Previous studies revealed that gap junction proteins, the connexins (Cx), might also play a role in the pathogenesis of IH. Therefore, affecting gap junctional intercellular communication is suggested as a novel therapeutic target of propranolol in IH. In this review we summarize the current knowledge of the molecular processes, leading to IH and provide new insights of how Cxs might be involved in the development of these vascular tumors.
doi:10.3389/fphar.2013.00041
PMCID: PMC3627141  PMID: 23596415
blood vessel; angiogenesis; connexins; infantile hemangioma; β-adrenoceptor; propranolol
23.  Refractive and structural changes in infantile periocular capillary haemangioma treated with propranolol 
Eye  2011;25(12):1627-1634.
Purpose
To evaluate the optical and anatomical effects of oral propranolol treatment for infantile periocular capillary haemangioma.
Methods
All children diagnosed with infantile capillary haemangioma in 2008–2010 at a tertiary paediatric medical centre underwent comprehensive evaluation, including imaging, by a multidisciplinary team followed by oral propranolol treatment. Clinical follow-up was performed regularly until the lesions disappeared. Main outcome measures included changes in anatomical extraocular extension, refractive sphere and cylindrical power, and spherical equivalent in the involved eye before and after treatment and between the two eyes.
Results
A total of 30 patients (8 male; mean age at diagnosis, 1.6±2.8 months) participated. The lesions affected the left eye in 53.3% and were located preseptally in 83.3%. Four patients (13.3%) received steroids before propranolol. A treatment dosage of 2 mg/kg per day was started at mean age 5.0±4.5 months, 3.3±4.3 months from disease onset. Side effects occurred in 11 patients and warranted a dose reduction (to 1 mg/kg per day) in 3 and treatment termination in 1. Findings were significant for mean reduction in involved extraocular area (P<0.0001), post-treatment reduction in mean cylindrical power in involved eyes (P=0.02), pre- and post-treatment differences in mean cylindrical power between involved and uninvolved eyes (P=0.02 and P=0.01, respectively), and post-treatment change in absolute values of mean spherical power between involved and uninvolved eyes (P=0.025).
Conclusions
Early diagnosis of infantile periocular capillary haemangioma and prompt treatment with propranolol lead to a significant reduction in the involved ocular area, in astigmatism, and prevent ocular/facial disfiguration/deformation, without rebound. Propranolol is recommended as the preferred treatment compared with other accepted therapies.
doi:10.1038/eye.2011.233
PMCID: PMC3234475  PMID: 21921959
propranolol; periocular infantile capillary haemangioma; astigmatic and spherical changes
24.  Prophylactic Effects of Propranolol versus the Standard Therapy on a New Model of Disuse Osteoporosis in Rats 
Scientia Pharmaceutica  2013;82(2):357-374.
Disuse by bed rest, limb immobilization, or space flight causes rapid bone loss by arresting bone formation and accelerating bone resorption. Propranolol (a non-selective β-adrenergic antagonist) has been shown to improve bone properties by increasing bone formation and decreasing bone resorption in an ovariectomy-induced rat model. However, no studies have yet compared the osteoprotective properties of propranolol with well-accepted therapeutic interventions for the treatment and prevention of immobilization/disuse osteoporosis. To clarify this, we investigated the effects of propranolol compared with zoledronic acid and alfacalcidol in a new animal model of immobilization/disuse osteoporosis. Three-month-old male Wistar rats were divided into five groups with six animals in each group: (1) immobilized (IMM) control; (2) normal control; (3) IMM + zoledronic acid (50 μg/kg, intravenous single dose); (4) IMM + alfacalcidol (0.5 μg/kg, per oral daily); (5) IMM + propranolol (0.1 mg/kg, subcutaneously 5 days/week) for 10 weeks. In groups 1 and 3–5, the right hindlimb was immobilized. At the end of treatment, the femurs were removed and tested for bone porosity, bone mechanical properties, and cortical microarchitecture. Treatment with propranolol induced greater reductions in the bone porosity of the right femur and improved the mechanical properties of the femoral mid-shaft femur in comparison to the IMM control. Moreover, treatment with propranolol also improved the microarchitecture of cortical bones when compared with the IMM control, as indicated by scanning electron microscopy. The anti-osteoporotic property of propranolol was comparable with zoledronic acid and alfacalcidol. This study shows that the bone resorption induced by immobilization/disuse in rats can be suppressed by treatment with propranolol.
doi:10.3797/scipharm.1310-06
PMCID: PMC4065128  PMID: 24959400
Propranolol; Immobilization; Rat model; Osteoporosis; Bone strength
25.  Evaluation of the beta 2 adrenoceptor agonist/antagonist activity of formoterol and salmeterol. 
Thorax  1996;51(1):54-58.
BACKGROUND: Salmeterol and formoterol have a lower intrinsic activity at beta 2 receptors than isoprenaline in human bronchus in vitro. The aim of the present study was to evaluate in vivo the beta 2 agonist/antagonist activity of salmeterol and formoterol at rest with low endogenous adrenergic tone, on exercise with raised endogenous adrenergic tone, and in the presence of fenoterol, an exogenous full beta 2 receptor agonist. METHODS: Eight normal subjects were randomised to receive single doses of placebo, salmeterol 300 micrograms, formoterol 72 micrograms, or propranolol 80 mg at weekly intervals. beta 2 adrenoceptor responses were evaluated at rest, at peak exercise, and after treatment with fenoterol 2.4 mg. RESULTS: At rest salmeterol and formoterol exhibited equivalent beta 2 agonist activity with regard to decrease in serum potassium levels and increase in finger tremor, with propranolol having no effect. Salmeterol and formoterol, like propranolol, potentiated the hyperkalaemic delta response to exercise compared with placebo, consistent with beta 2 antagonism: (mean difference and 95% confidence interval (CI) compared with placebo) salmeterol 0.20 (0.02 to 0.38) mmol/l, formoterol 0.17 (0.00 to 0.34) mmol/l, propranolol 0.45 (0.08 to 0.82) mmol/l. Propranolol blunted the heart rate delta response to exercise, consistent with beta 1 blockade, whilst salmeterol and formoterol had no effect. Salmeterol and formoterol, like propranolol, attenuated the hypokalaemic, tremor, and heart rate delta responses to fenoterol compared with placebo, in keeping with beta 2 blockade: potassium, salmeterol 0.18 (0.0 to 0.36) mmol/l, formoterol 0.17 (-0.03 to 0.37) mmol/l, propranolol 0.80 (0.54 to 1.06) mmol/l; tremor, salmeterol -0.69 (-1.26 to -0.12) log units, formoterol -0.71 (-1.53 to 0.11) log units, propranolol -0.85 (-1.66 to -0.04) log units; heart rate, salmeterol -6 (-13 to 1) beats/min, formoterol -10 (-19 to -1) beats/min, propranolol -18 (-29 to -7) beats/min. CONCLUSIONS: At rest with low endogenous adrenergic tone salmeterol and formoterol showed equivalent beta 2 mediated agonist activity in terms of serum potassium and finger tremor responses. In the presence of raised endogenous adrenergic tone at peak exercise and in the presence of fenoterol (an exogenous full beta 2 receptor agonist), salmeterol and formoterol, like propranolol, exhibited beta 2 receptor antagonism as evidenced by their attenuation of beta 2 receptor mediated responses. The degree of beta 2 blockade with formoterol and salmeterol was comparable but less than with propranolol. The relevance of these findings at extrapulmonary beta 2 receptors with regard to airway beta 2 responses remains unclear and warrants further investigation.
PMCID: PMC472800  PMID: 8658370

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