New possibilities in the treatment of infantile hemangiomas with propranolol

Infantile hemangioma (IH) is a common benign vascular tumor that occurs mainly in premature and female infants, localizing predominantly on the head and neck. The incidence among full-term newborns, according to various authors, ranges from 1.1-2.6% to 10-12%. Infantile hemangioma is diagnosed at birth or shortly thereafter. A feature of infantile hemangioma is the possibility of rapid growth during the first weeks and months of life, with the formation of a gross cosmetic defect and disruption of vital functions.

Hemangiomas are part of a large group of vascular anomalies. During the study of this pathology, many different classifications have been developed. This work is based on the classification accepted in world practice, proposed by the International Society for the Study of Vascular Anomalies (ISSVA), according to which all vascular anomalies should be divided into vascular tumors and vascular malformations (developmental defects).

Infantile hemangioma is the most common vascular tumor. Congenital hemangiomas (CH) are similar to infantile hemangioma. Their peculiarity is maximum intrauterine tumor growth, which often reaches large sizes at birth and may have foci of necrosis as a manifestation of spontaneous regression that has already begun.

Rare vascular tumors include tufted angiomas and Kaposiform hemangioendotheliomas; they can be combined with consumption thrombocytopenia (Kazakh-Merritt syndrome).

Vascular malformations are usually either not visible at birth or are disguised as hemangiomas. They are not characterized by either spontaneous regression or rapid growth. An increase in the volume of the lesion is possible during periods of physiological stretching.

Infantile hemangioma goes through four phases in its development. The first phase (rapid proliferation) is characterized by rapid growth, then tumor growth slows down and a slow proliferation phase occurs. In the stabilization phase, the tumor does not grow, and in the involution phase, it undergoes reverse development.

In most patients, the rapid proliferation phase lasts from 1 to 4 months, the slow proliferation phase lasts up to 6 months, the stabilization phase lasts up to a year, and after a year, the involution phase.

Pathological growth of endothelial cells plays a key role in the pathogenesis of infantile hemangioma. During embryogenesis, blood vessels and blood cells are formed from the mesoderm. Under the influence of specific angiogenesis activators, the mesoderm differentiates into hemangioblasts and, unevenly compacting, forms angiogenic groups: endothelial cells are formed from the external cells of the angiogenic group, and blood cells are formed from the internal ones.

Infantile hemangioma originates from hemangioblasts. Hemangioma cells express markers from hematopoietic and endothelial cells. Subsequently, the differentiated angiogenic group turns into a primary vascular tube (vasculogenesis), and then the growth of already formed vascular tubes occurs, their unification into a closed vascular network (angiogenesis). Normal angiogenesis completely ends by birth and is resumed only during periods of rapid growth, in some diseases and conditions (ischemia, trauma) as a compensatory reaction, as well as in various pathological conditions (for example, tumors).

Regulation of angiogenesis is a complex multifactorial process, but two factors can be identified as the main regulators: VEGF - vascular endothelial growth factor, dependent on the phase, and FRF - fibroblast growth factor, which increases in the phase of rapid proliferation and decreases, and then completely disappears in the phases of stabilization and involution.

In 85-90% of cases, infantile hemangiomas undergo spontaneous regression before school age, and in the involution phase, apoptosis markers are determined in tumor cells. The mechanism of the onset of infantile hemangioma reduction is unclear. It is known that their reduction is associated with an increase in the number of mast cells and a fivefold increase in the number of apoptotic cells, a third of which are endothelial.

In 10-15% of cases, infantile hemangiomas require intervention in the proliferative phase due to life-threatening localization (respiratory tract), local complications (ulceration and bleeding), gross cosmetic defect and psychological trauma.

Until now, therapy for infantile hemangioma has been fairly standardized - glucocorticoids (prednisolone or methylprednisolone) have been used for a fairly long time and in high doses. If hormonal therapy is ineffective, a second-line drug, interferon, is prescribed, and if it is ineffective, vincristine.

Glucocorticoids are especially effective in the early proliferation phase with high levels of VEGF, which is the main target for steroids. They inhibit tumor growth and reduce its size. The frequency of stabilization and incomplete remission reaches 30-60% with the first signs of improvement only in the 2nd-3rd week. Prednisolone per os is usually prescribed at a dose of 5 mg / kg for 6-9 weeks, then at a dose of 2-3 mg / kg for another 4 weeks, alternating intake - the next 6 weeks. Steroids with this dosing regimen should be discontinued gradually to avoid adrenal crisis and resumption of hemangioma growth.

Interferon alpha-2a or 2b (1x10 ⁶ - 3x10 ⁶ U/m2) induces early involution of large hemangiomas by blocking the migration of endothelial and smooth muscle cells, as well as fibroblasts by reducing the production of collagen and basic fibroblast growth factor with the first signs of regression after 2-12 weeks of treatment.

The efficacy of vincristine is close to 100% at a dosage regimen of 0.05-1 mg/m2 ^by infusion once a week with initial signs of involution after 3 weeks of treatment.

However, when using standard drugs, serious side effects often occur. When treating with prednisolone - cataract, obstructive hypertrophic cardiomyopathy, diabetes, liver steatosis; with interferon - fever, myalgia, leukopenia, hemolytic anemia, pulmonitis, interstitial nephritis; with vincristine - constipation, pain in the lower jaw, peripheral neuropathy, myelotoxicity.

Alternative methods of treating infantile hemangiomas include laser surgery, sclerosants and embolic agents, cryodestruction, surgery, or various combinations thereof. However, even in these cases it is not always possible to achieve the desired result.

Therefore, great interest was aroused by new information about a promising drug for the pharmacotherapy of vascular hyperplasia - propranolol, which has long been known as an antihypertensive drug.

Propranolol is a non-selective beta-blocker with antianginal, hypotensive and antiarrhythmic effects. Non-selectively blocking beta-adrenergic receptors, it has a negative chrono-, dromo-, bathmo- and inotropic effect (slows down the heart rate, inhibits conduction and excitability, reduces myocardial contractility).

For many years, propranolol has been used not only in adults to treat hypertension, but also in children with cardiac pathology to correct congenital heart defects and arrhythmias. In the process of treating cardiac pathology in children, employees of the Bordeaux hospital (France), headed by Dr. S. Leaute-Labreze, discovered that propranolol can inhibit growth and cause regression of hemangiomas. In a child with a combined pathology - obstructive hypertrophic cardiomyopathy and persistent nasal hemangioma, the next day after the start of treatment with propanol, it was noted that the tumor became softer and darker.

The dose of corticosteroids, which had been used to treat the hemangioma with little success, was reduced, but the tumor continued to shrink. After stopping corticosteroid treatment, the hemangioma did not grow again, and its surface became completely flat by the 14th month of the child's life.

The second observation at the same hospital was made in a child with a superficial infantile capillary hemangioma localized on the right side of the head, which prevented opening of the right eye. Despite treatment with corticosteroids, the tumor continued to grow. In addition, MRI revealed the presence of intracervical lesions causing compression of the trachea and esophagus. Ultrasound performed on the patient showed an increase in cardiac output, in connection with which treatment with propranolol was started at a dose of 2 mg/kg/day. Seven days later, the child was able to open the right eye, and the mass near the parotid gland had significantly decreased in size. Treatment with prednisolone was discontinued by the child's 4th month of life, and there was no relapse of growth. By the 9th month, the right eye opened satisfactorily and no serious visual impairment was noted.

After written informed consent was obtained from the parents, propranolol was started in nine additional children with severe or disfiguring infantile capillary hemangiomas. All patients experienced a change in color of the hemangiomas from intense red to purple and a noticeable softening of the lesion within 24 hours of starting treatment. The hemangiomas then continued to regress until they were nearly flat, with residual telangiectasia of the skin. No systemic adverse effects were reported.

The staff of the Children's Clinical Hospital of Zurich (Switzerland) conducted a retrospective analysis of data from December 2008 to December 2009 on the efficacy of propranolol as a first-line drug for the treatment of vascular hyperplasia, as well as its effect on hemodynamics. The evaluation was carried out in a homogeneous group of children with proliferating problem hemangiomas treated with propranolol (2 mg/kg/day). Problem hemangiomas were defined as hemangiomas that inevitably lead to functional or cosmetic defects in the absence of treatment. The study included patients aged 9 months or younger, who had undergone a complete 2-day in-hospital examination, and who had not received previous corticosteroid therapy. Parents of the patients had to give consent for the use of the drug for an off-label purpose. Apart from propranolol treatment, no alternative or adjuvant therapy was given (two infants had previously been treated with laser therapy without success - their tumors continued to increase in size).

The outcome was assessed by photographs using a visual analogue scale (VAS), ultrasound data and, when necessary, ophthalmologic examination. Response to therapy and hemodynamic parameters were recorded from the start of therapy over a long period at fixed time points. Twenty-five children (mean age 3.6 (1.5-9.1) months) were included in the study. The mean follow-up time was 14 (9-20) months and 14 patients completed the treatment course at a mean age of 14.3 (11.4-22.1) months with a mean treatment duration of 10.5 (7.5-16) months. All patients after 7 months showed a significant decrease in the intensity of hemangioma staining (to - 9 according to VAS) and a significant decrease in the size of hyperplasia (to - 10 according to VAS). The mean lesion thickness detected by ultrasound at the beginning of treatment and after 1 month was 14 (7-28) mm and 10 (5-23) mm, respectively. In children with lesions of the periocular areas, astigmatism and amblyopia resolved within 8 weeks. The overall tolerability of the drug was good, no hemodynamic changes were noted. In general, adverse events during treatment with propranolol are very minor compared with the serious side effects of corticosteroids and interferon-a (development of spastic diplegia with a probability of up to 25%). No significant differences in susceptibility were found between deep and superficial hemangiomas, but there was some impression that superficial hemangiomas leave behind telangiectatic changes in the skin, while deep hemangiomas are more likely to disappear completely.

In two of the 14 patients who completed the course of treatment, slight regrowth and darkening of the hyperplasia were observed 8 weeks after stopping therapy. These patients were re-treated with propranolol for 11 and 8.5 months, respectively, with successful results. Recurrences apparently occurred in about 20-40% of cases. It is noteworthy that regrowth of hemangiomas after stopping therapy was also observed in children older than 12-14 months, i.e., at the time when the proliferative phase of hyperplasia is believed to be already completed. This unexpected phenomenon may indicate that propranolol retards the natural growth of hemangiomas. Signs indicating the possibility of regrowth after stopping treatment are not yet known. However, recurrences of hemangiomas are usually mild, and patients respond well to retreatment.

The studies by Swiss doctors were distinguished by strict selection criteria, describing groups of patients of different ages, with different stages and courses of hemangiomas and receiving alternative therapy along with propranolol. The excellent effect and good tolerability of propranolol were confirmed and it was proposed to use it as a first-line drug for the treatment of childhood hemangiomas.

J. Goswamy et al. reported the use of propranolol (2 mg/kg/day, divided into 3 doses) in 12 children (9 girls) with a mean age of 4.5 months for 1-9 weeks (mean 4 weeks) who were previously treated with corticosteroids as first-line therapy. There were no side effects with propranolol treatment, except for transient bradycardia in one patient, which resolved spontaneously. The authors suggest that propranolol may be a preferred option for the treatment of infantile hemangioma as a first-line drug.

Similar results were obtained by YBJin et al. in a prospective study of propranolol as a first-line drug for the treatment of infantile hemangioma in 78 children with an average age of 3.7 months (1.1-9.2 months). Therapy lasted an average of 7.6 months (2.1-18.3 months). After a week of treatment, hemangioma regression was observed in 88.5% of cases, and after 1 month - in 98.7%. Before treatment, ulceration of hemangiomas occurred in 14 patients, it resolved after 2 months of treatment with propranolol. Mild side effects of propranolol were observed in 15.4% of cases, and recurrent hemangioma growth after stopping treatment - in 35.9%.

A. Zvulunov et al. reported on the results of treatment with propranolol (2.1 mg/kg/day, range from 1.5 to 3 mg/kg/day, for 1-8 months, average 3.6 months) in 42 pediatric patients (age from 7 to 12 months) with hemangiomas in the postproliferative phase. The visual hemangioma scale index decreased from 6.8 to 2.6 as a result of treatment (p < 0.001). Before treatment, the value of this index decreased by 0.4% per month, and during treatment with propranolol - by 0.9% (p < 0.001). Side effects were minor and were observed in 4 patients: 2 had transient sleep disorders, 1 had transient dyspnea, and 1 had drowsiness. In no case was it necessary to interrupt treatment with propranolol. Based on these results, the authors make a reasonable conclusion that propranolol has unique efficacy in the treatment of hemangiomas and can be recommended as a first-line drug for the treatment of infantile hemangioma not only in the proliferative but also in the postproliferative phase.

Thus, according to the literature, the results of using propranolol in infantile hemangioma for 3 years indicate obvious advantages of this drug over previously used prednisolone, interferon, and vincristine:

• stopping not only growth, but also reducing the size of the tumor with a 100% result;
• the first signs of improvement (change in color and density of the tumor) already on the first day of treatment;
• significant reduction in the natural course of infantile hemangioma;
• possibility of discontinuing glucocorticoids;
• shorter duration of treatment;
• rare and treatable relapses;
• fewer and milder side effects;
• cheapness of the drug;
• multidirectional mechanism of action.

Let us consider the mechanism of action of propranolol in more detail. Propranolol causes vasoconstriction of the hemangioma. As is known, it is regulated by various endogenous factors, among which the key role is played by the mediator of the autonomic nervous system, adrenaline, which is capable of causing vasoconstriction by activating beta1-adrenoreceptors, or vasodilation by activating beta2-adrenoreceptors. Depending on the partial pressure of oxygen and carbon dioxide, the vascular tone increases or decreases accordingly. In addition, this tone is regulated by other mediators that either constrict the vessels (endothelin-1, angiotensin II, vasopressin) or dilate them (prostacyclin, nitric oxide, dopamine).

The vasodilatory effect of adrenaline, caused by activation of beta2-adrenoreceptors, is mediated by a cascade of biochemical signal transmission. Beta2-receptors activated by adrenaline interact with the Gs-protein in endothelial cells. This trimeric GTP-binding protein, upon interaction with the receptor, disintegrates into the α-subunit, which is activated upon exchange of GDP for GTP, and the β-γ-subunit (it may have its own activity), the α-subunit interacts with the membrane enzyme adenylate cyclase. Adenylate cyclase catalyzes the conversion of ATP to cyclic adenosine monophosphate (cAMP), which acts as a second messenger and activates protein kinase A (cAMP-dependent A-kinase). Then, the activated catalytic subunits of A-kinase phosphorylate various proteins that are its substrates. In this case, the phosphate group is transferred from ATP to a specific amino acid residue (seri or threonine). In endothelial cells, activated A-kinase stimulates NO synthase, which leads to an increase in the formation and release of NO. In turn, NO diffuses into smooth muscle cells, where it activates soluble guanylate cyclase, which catalyzes the formation of cyclic guanosine monophosphate (cGMP). The latter activates protein kinase G, which induces vascular relaxation by phosphorylating myosin.

Propranolol inhibits the vasodilatory effect of adrenaline by blocking beta2-adrenoreceptors. As a result of vasoconstriction, blood flow to the tumor decreases, the color of the tumor and its tension changes (becomes softer) 1-3 days after the start of treatment.

1. Vasodilation. Control of vascular tone, beta-adrenergic agonist causes vasodilation via NO release. In contrast, beta-adrenergic antagonists such as propranolol cause vasoconstriction (via inhibition of NO synthesis and release).
2. Angiogenesis. Beta-adrenergic agonists stimulate the synthesis of proangiogenic factors (growth factors (VEGF and bFGF) and matrix metalloproteinases (MMP-2 and MMP-9)) and activate proangiogenic cascades (ERK/MAPK), which is accompanied by increased angiogenesis. Propranolol reduces the level of proangiogenic proteins and inhibits the ERK/MAPK cascade, which is accompanied by a decrease in angiogenesis.
3. Apoptosis. Beta-adrenergic agonists inhibit apoptosis via src. In contrast, beta-blockers induce apoptosis.

Propranolol also reduces VEGF expression. In the proliferative phase of hemangioma, the formation of collagenase IV, proangiogenic factors increases: vascular endothelial growth factor (VEGF) and, to a lesser extent, fibroblast growth factor. During hemangioma involution, their formation decreases. Tissue inhibitor of metalloproteinase (TIMP) is expressed only in the involution phase of hemangioma. Under hypoxia, VEGF expression increases due to increased transcription of the hypoxia-inducible factor HIF-la: oxygen deficiency leads to an increase in the intracellular concentration of HIF-la in its active form. HIF-la induces transcription of the VEGF gene, resulting in increased proliferation of nearby endothelial cells and secretion of proteases (metalloproteinases), which are necessary for the reorganization of the extracellular matrix, coordination of vascular cell differentiation (endothelial cells, smooth muscle cells, pericytes) and angiogenesis. Newly formed vessels increase oxygen delivery, which leads to a decrease in the level of the active form of HIF-la and subsequent expression of VEGF. Therefore, there are physiological mechanisms regulating angiogenesis with changes in partial pressure of oxygen.

Importantly, VEGF expression is controlled not only by oxygen partial pressure (via HIF-la) but also by adrenergic stimulation. It has been shown that epinephrine and norepinephrine can induce VEGF expression. Src is a mediator of protein kinase A, which belongs to the family of cytoplasmic tyrosine kinases involved in the extracellular signal-dependent kinase (ERK)/mitogen-stimulated protein kinase (MAPK) signal transduction cascade. ERK and MAPK are serine/threonine kinases that phosphorylate nuclear transcription factors that regulate the expression of many genes involved in the control of proliferation. VEGF itself has proangiogenic effects, at least in part due to activation of the ERK/MAPK cascade. Thus, stimulation of beta2-adrenergic receptors can activate endothelial cell proliferation via two different mechanisms: upregulation of the ERK/MAPK signaling pathway (probably via src, which is not associated with a cell receptor) and induction of VEGF release, which itself can activate the ERK/MAPK cascade. Therefore, beta-blockers such as propranolol, by reducing VEGF expression, inhibit angiogenesis. Considering that impaired endothelial cell proliferation is of key importance in the pathogenesis of hemangioma, the ability of beta-blockers to suppress VEGF activity may explain their pronounced effect on hemangioma proliferation. Interestingly, a similar effect has been found for corticosteroids, which are still used to treat hemangiomas.

Another feature of beta-blockers is their effect on the activity of matrix metalloproteinases (MMPs), which are soluble and membrane-bound proteinases that catalyze the degradation and transformation of extracellular matrix proteins. They play a key role in physiological and pathophysiological processes such as cell proliferation, migration and adhesion, embryogenesis, wound healing, and angiogenesis processes involved in tumor growth and metastasis. Under physiological conditions, MMP activity is regulated at various levels: transcription, activation of inactive precursors (cymogens), interaction with extracellular matrix components, and inhibition by endogenous inhibitors such as TIMP.

Children with hemangiomas in the proliferative phase have elevated levels of MMP-2 and MMP-9 isoenzymes in the blood and tissue samples. MMP-9 is involved in endothelial cell migration and tubulogenesis (the initial stage of angiogenesis). Inhibition of MMP-9 has been shown to slow angiogenesis in human microvascular endothelial cells.

There is evidence that the expression of MMP-9 and MMP-2 is regulated by beta-adrenergic receptors. The increase in MMP-2 and MMP-9 expression caused by agonists (epinephrine and norepinephrine) is inhibited by propranolol. The decrease in MMP-9 expression by propranolol leads to inhibition of endothelial cell tubulogenesis, which is the mechanism of the antiangiogenic effect of propranolol.

Apoptotic processes are regulated by a number of capsases, procapsases and proteins of the B-cell lymphoma 2 (bcl-2) family. In the proliferative phase, a low level of apoptosis is observed in hemangiomas. However, in the involution phase, the frequency of apoptosis increases 5-fold, and the expression of the bcl-2 protein, which inhibits apoptosis, decreases in parallel. Blockade of beta-adrenergic receptors with propranolol can induce apoptosis in various cells: in endothelial or pancreatic cancer cells. Interestingly, the beta1-selective blocker metoprolol has a significantly less pronounced apoptotic effect, and the beta2-selective blocker butoxamine induces apoptosis more strongly than propranolol. Therefore, the induction of apoptosis may be another possible mechanism of the therapeutic effect of propranolol on infantile hemangiomas.

With all the advantages of propranolol, it, like any medicine, is not without its drawbacks - side effects. These are the well-known bradycardia, hypotension, AV block, bronchospasm (usually in children with atopy), Raynaud's syndrome, and rarely - skin-allergic reactions.

If such abnormalities are present initially, this is a contraindication to the use of propranolol. Hence the careful selection of patients before starting therapy with this drug. The use of beta-blockers should be avoided during the first week of life, when newborns gradually achieve optimal milk intake and the chances of developing spontaneous hypoglycemia are high. Most infants with hemangiomas who receive treatment are older and have adequate nutrition.

Propranolol is used in young children for various indications (hypertension, congenital heart defects, supraventricular tachycardia, long QT syndrome, thyrotoxicosis) at a dose of up to 8 mg/kg/day. Complications such as hypotension, sinus bradycardia, and hypoglycemia have been observed during propranolol treatment of hemangiomas and were not of serious clinical significance, but indicated the need for careful observation and monitoring of all infants with hemangiomas treated with propranolol. Possible side effects of propranolol are of much less clinical significance compared to the serious side effect (spastic diplegia) of previously used antiangiogenic drugs such as interferon-a. The undesirable effects inherent in corticosteroid therapy are also well known.

The proposed propranolol dosing regimen - 2-3 mg/kg in 2-3 doses - does not take into account the individual characteristics of patients. The degree of propranolol biotransformation varies significantly among patients, and therefore, when prescribing the same dose of the drug, concentrations can differ from each other by 10-20 times. This is due to the fact that propranolol is metabolized with the participation of the cytochrome B-450 CYP2D6 isoenzyme, which has genetic polymorphism. The entire population is divided into slow, fast and normal metabolizers. A mutation in the CYP2D6 gene may result in the absence of synthesis of this enzyme, synthesis of a defective protein that has no activity or reduced activity. The prevalence of slow metabolizers among different ethnic groups varies greatly. It is known that in the European population, including Russians, they account for 5-10%.

The clinical significance of slow metabolism is in the enhancement of the effect of propranolol prescribed in normal therapeutic doses and the much more frequent and early (due to decreased clearance) development of side effects such as hypotension, bradycardia, atrioventricular block and bronchospasm.

CYP2D6 extensive metabolizers are carriers of a mutant allele that is a duplication of the CYP2D6 gene.

In such patients, a decrease in the therapeutic effect should be expected due to accelerated biotransformation and elimination of the drug, so propranolol should be prescribed to them in an increased dose of 3 mg/kg or more often - 4 times a day.

However, even with a normal level of propranolol metabolism, its long-term use leads to a decrease in the biotransformation of the drug, which is accompanied by an increase in the period of its half-elimination. Accordingly, the frequency of drug administration should be reduced or the dose should be reduced to 1/4-1/2 of the initial one. Therefore, it would be advisable to determine the initial activity of CYP2D6 in patients with infantile hemangioma before prescribing propranolol, which will allow identifying groups of people with slow, fast and normal metabolism of propranolol to select a dosing regimen appropriate for a given patient in order to optimize the dose of propranolol and its therapeutic effect. At the same time, if it is impossible to determine cytochrome P450 isoenzymes, propranolol treatment can be initiated with a starting dose of 1 mg / kg with a frequency of administration 2 times a day, and in the absence of a significant change in heart rate, blood pressure or any other side effects, it can be increased to the recommended level of 2 mg / kg 3 times a day.

Taking into account the above, the authors propose the following tactics for monitoring patients prescribed propranolol.

In the first 6 hours after the administration of propranolol, blood pressure and pulse are monitored every hour. If there are no side effects, the child is released for home treatment and then examined after 10 days, then once a month - to assess the tolerability of the drug. At the same time, blood pressure and pulse are measured, weight (to adjust the dose). If possible, an ultrasound measurement of the tumor is performed on the 60th day of treatment. At each visit, the tumor is photographed. A regular measuring tape can also be used to measure the tumor.

Clinical studies of the use of propranolol for the treatment of infantile hemangioma were conducted at the Russian Children's Clinical Hospital (Moscow).

The aim of the study is to determine indications, develop treatment regimens, monitor drug therapy and criteria for effectiveness in the treatment of infantile hemangioma with angiogenesis blockers.

Patients with infantile hemangioma in the proliferative stage were selected (45 patients from 2 months to 1.5 years). The study did not include patients with contraindications to the administration of beta-blockers.

All patients included in the study were prescribed propranolol for a period of 6 months. The starting dose was 1 mg/kg/day. In case of mild tumor regression, the dose was increased to 3 mg/kg/day or prednisolone was additionally prescribed, and in patients over 1 year old, endovascular occlusion was performed.

Before the treatment, a detailed description of the local status and photography were carried out. After the therapy was prescribed, the local status was assessed daily for 7 days, then once a month.

To determine the safety of therapy, patients underwent electrocardiography with assessment of heart rate and atrioventricular conduction before treatment was prescribed. During the first 7 days, heart rate was measured daily, and on the seventh day, electrocardiography was performed (then - monthly). In patients over 10 years of age, blood pressure was also monitored and external respiratory function was assessed.

In the event of bradycardia, grade II-III atrioventricular blocks, arterial hypotension and broncho-obstruction, therapy was discontinued.

The results were assessed by the cessation of growth and reduction in the size of the hemangioma, by the reduction in its density and brightness of color, as well as by the healing of trophic disorders on the surface of the tumor and the absence of negative clinical dynamics.

Six-month treatment was completed in 10 patients, treatment was discontinued in 6 patients due to side effects, and treatment is continued in 29 patients. All those who completed treatment showed complete regression of hemangioma, but three patients required an increase in the dose of propranolol, and one patient underwent endovascular occlusion. In those continuing treatment, hemangiomas are at different stages of regression, but the rate of regression varies. In 11 patients, it is insufficient, which required treatment adjustments: an increase in the dose of propranolol (10 patients), addition of other treatment methods, including the administration of corticosteroids (3 patients) and endovascular occlusion (5 patients).

Our studies show that propranolol is effective and safe enough for treating infantile hemangioma and can be used as a first-line drug. The pronounced therapeutic effect of propranolol on hemangioma growth may be due to three molecular mechanisms: vasoconstriction, angiogenesis inhibition, and apoptosis induction. All of them may be involved in all stages of treatment: early (change in hemangioma surface color), intermediate (cessation of hemangioma growth), and late (tumor regression). Apoptosis does not always result in complete regression of hemangioma, and its growth may resume after discontinuation of propranolol treatment. Treatment should continue until the proliferative phase of hemangioma is complete. Further studies are needed to develop an optimal dosing protocol for each patient.

Prof. Yu. A. Polyaev, Prof. S. S. Postnikov, Ph.D. A. A. Mylnikov, Ph.D. R. V. Garbuzov, A. G. Narbutov. New Possibilities in the Treatment of Infantile Hemangiomas with Propranolol // Practical Medicine. 8 (64) December 2012 / Volume 1

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