New possibilities in the treatment of infantile hemangiomas with propranolol

Infantile hemangioma (IG) is a common benign vascular tumor that occurs mainly in preterm and female infants, with localization mainly on the head and neck. The incidence among term infants is, according to different authors, from 1.1-2.6% to 10-12%. Infantile hemangioma is determined at birth or soon after it. 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 a violation 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 international classification accepted 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 (malformations).

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

Rarely encountered vascular tumors include "tufted" angiomas and kaposiiform hemangiendotheliomas, they can be combined with thrombocytopenia of consumption (the Caza-bach-Merritt syndrome).

Vascular malformations are usually not seen at birth or masked for hemangiomas. For them, neither spontaneous regress nor rapid growth is characteristic. Increased lesion is possible during periods of physiological stretching.

In its development, infantile hemangioma undergoes four phases. The first phase (rapid proliferation) is characterized by rapid growth, then the growth of the tumor slows down and a slow proliferation phase begins. During the stabilization phase, the tumor does not grow, but during the involution phase it undergoes reverse development.

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

The pathological growth of endothelial cells plays a key role in the pathogenesis of infantile hemangioma. In the process of embryogenesis, blood vessels and blood cells are formed from the mesoderm. Under the influence of specific activators of angiogenesis, the mesoderm is differentiated into hemangioblasts and, unevenly compacted, forms angiogenic groups: endothelium cells are formed from external cells of the angiogenic group, and blood cells from internal cells.

Infantile hemangioma is derived from hemangioblasts. Cells of hemangiomas express markers from hemopoietic, and endothelial cells. In the future, the differentiated angiogenic group is transformed into a primary vascular tube (vasculogenesis), and then the already formed vascular tubes grow, and they merge into a closed vascular network (angiogenesis). Normal angiogenesis completely ends at birth and resumes only during periods of rapid growth, with certain diseases and conditions (ischemia, trauma) as a compensatory reaction, as well as in various pathological conditions (eg, tumors).

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

In 85-90% of cases, infantile hemangiomas undergo spontaneous regression before the onset of school age, while in the phase of involution tumor markers are determined by apoptosis markers. The mechanism of the onset of the reduction of infantile hemangioma is not clear. 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 cells.

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

Until now, the therapy of infantile hemangioma has been sufficiently standardized - quite long and in high doses glucocorticoids (prednisolone or methylprednisolone) were used. With the ineffectiveness of hormone therapy, a second-line drug, interferon, was prescribed, and with its ineffectiveness, vincristine.

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

Interferon alfa-2a or 2b (1x10 ⁶ - Zh10 ⁶ units / m2) induces early involution of hemangiomas large, blocking the migration of endothelial and smooth muscle cells, and fibroblasts by reducing collagen production and basic fibroblast growth factor with the first signs of regression after 2-12 ned. Treatment.

The effectiveness of vincristine is close to 100% with a dosage regimen of 0.05-1 mg / m ² infusion once a week with initial signs of involution after 3 weeks of treatment.

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

Alternative methods of treatment of children's hemangiomas are laser surgery, sclerosants and embolizing substances, cryodestruction, surgery or their various combinations. However, in these cases it is not always possible to achieve the desired result.

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

Propranolol is a non-selective beta-blocker with antianginal, hypotensive and antiarrhythmic effect. Unselectively blocking beta-adrenoreceptors, it has a negative chrono-, dromo-, batmo- and inotropic effect (it cuts the heart rate, inhibits conduction and excitability, reduces myocardial contractility).

For many years, propranolol has been used not only in adults for the treatment of hypertension, but also in children with cardiac pathology for the correction of congenital heart diseases and arrhythmias. During the treatment of cardiac pathology in children, the staff of the hospital in Bordeaux (France), led by Dr. S. Leaute-Labreze, found that propranolol can inhibit growth and cause regression with hemangiomas. In a child with a combined pathology - obstructive hypertrophic myocardiopathy and persistent nasal hemangioma, the next day after the initiation of treatment with propanol, it was noted that the tumor became softer and darker.

The dose of corticosteroids, which were used to treat hemangioma with little success, was reduced, but the tumor continued to decrease. After cessation of treatment with corticosteroids, the growth of the hemangioma did not resume, and its surface became absolutely flat by the 14th month. Life of the child.

The second observation in this same hospital was made in a child with superficial pediatric capillary hemangioma located on the right side of the head, which did not allow to open the right eye. Despite treatment with corticosteroids, the tumor continued to increase. In addition, MRI revealed the presence of intra-articular structures that cause compression of the trachea and esophagus. The ultrasound made to 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 his right eye, and the formation near the parotid gland significantly diminished in size. Treatment with prednisolone was discontinued by the 4th month. Child's life, recurrence of growth did not arise. By the 9th month. Satisfactorily opened the right eye and there was no serious visual impairment.

After the written informed consent was received from the parents, propranolol was given to nine more children with severe or disfiguring children's capillary hemangiomas. In all patients, 24 hours after the start of treatment, a color change was observed with hemangiomas from intensely red to violet and a noticeable softening of the lesion. After that, the hemangiomas continued to regress until they became almost flat, with residual telangiectasia of the skin. No systemic side effects were reported.

Employees of the Children's Clinical Hospital in Zurich (Switzerland) conducted a retrospective analysis of the data from December 2008 to December 2009 on the effectiveness 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 proliferative problem hemangiomas against treatment with propranolol (2 mg / kg / day). Problem hemangiomas were defined as hemangiomas, which inevitably entail functional or cosmetic defects in the absence of treatment. Patients no older than 9 months old who underwent a full 2-day nosocomial examination were included in the study, provided there was no previous corticosteroid therapy. Parents of patients had to consent to the use of the drug for indirect purposes. In addition to treatment with propranolol, no alternative or adjuvant therapy has been performed (two infants were previously unsuccessfully given laser therapy - their tumors continued to increase in size).

The result was estimated from photographs using a visual analog scale (VAS), according to ultrasound and, if necessary, an ophthalmologic examination. Susceptibility to therapy and hemodynamic parameters were recorded from the beginning of therapy for a long period at fixed times. Twenty-five children were included in the study (mean age 3.6 (1.5-9.1) months). The mean follow-up time was 14 (9-20) months. And 14 patients completed treatment at an average age of 14.3 (11.4-22.1) months. With an average duration of treatment of 10.5 (7.5-16) months. In all patients after 7 months. A significant decrease in the intensity of hemangioma staining (up to -9 in VAS) and a significant decrease in hyperplasia (up to -10 VAS) were observed. The thickness of lesions detected by ultrasound, at the beginning of treatment and after 1 month, averaged 14 (7-28) mm and 10 (5-23) mm, respectively. In children with lesions of the periocular sites, astigmatism and amblyopia were eliminated 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 small compared with serious side effects of corticosteroids and interferon-a (the development of spastic diplegia with a probability of up to 25%). There were no significant differences in susceptibility between deep and superficial hemangiomas, but there was some impression that superficial hemangiomas leave after themselves telangiectasis skin changes, while deep hemangiomas are more likely to disappear completely.

In two of the 14 patients who underwent treatment, a slight re-growth and darkening of the hyperplasia were observed 8 weeks after the cessation of therapy. These patients were re-assigned treatment with propranolol 11 and 8.5 months. Respectively with a successful outcome. Relapses, apparently, occurred in about 20-40% of cases. It is noteworthy that the repeated growth of hemangiomas after stopping therapy was also observed in children older than 12-14 months, i.e., at a time when the proliferation of hyperplasia is believed to have been completed. This unexpected phenomenon may indicate that propranolol inhibits natural growth of hemangiomas. Signs indicating the possibility of resumption of growth after discontinuation of treatment are not yet known. However, recurrences of hemangiomas usually occur easily, and patients respond well to repeat therapy.

Strict criteria for the selection differed the research of Swiss doctors, which described groups of patients of different ages who had different stages and currents of hemangiomas and received alternative therapy along with propranolol. The excellent effect and good tolerability of propranolol was confirmed and it was suggested to use it as a first-line drug for the treatment of children's hemangiomas.

J. Goswamy et al. Reported the use of propranolol (2 mg / kg / day, divided into 3 doses) in 12 children (9 girls) with an average age of 4.5 months for 1-9 weeks. (on average - 4 weeks), who were previously treated with corticosteroids as first-line therapy. There were no side effects in the treatment of propranolol, with the exception of transient bradycardia in one patient, which disappeared on its own. The authors believe that propranolol may be the 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 the use of propranolol as the 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 months). After a week of treatment, regression of the hemangioma was observed in 88.5% of cases, and after 1 month. - in 98.7%. Before treatment, ulceration of hemangiomas occurred in 14 patients, it took place after 2 months. Treatment with propranolol. Weak side effects of propranol were in 15.4% of cases, repeated growth of hemangiomas after discontinuation of treatment - in 35.9%.

A. Zvulunov et al. Reported the results of treatment with propranolol (2.1 mg / kg / day, range 1.5 to 3 mg / kg / day, for 1-8 months, an average of 3.6 months.) 42 sick children (age from 7 to 12 months) with hemangiomas in the post-proliferative phase. The index of the visual scale of hemangiomas as a result of treatment decreased from 6.8 to 2.6 (p <0.001). Before treatment, the value of this indicator decreased for the month by 0.4%, and in the 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 valid conclusion that propranolol has a 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 post-proliferative phase.

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

• suspension of not only growth, but also a reduction in the size of the tumor with a 100% result;
• the first signs of improvement (changes in color and density of the tumor) as early as the first day of treatment;
• a significant reduction in the time course of the natural course of infantile hemangioma;
• the possibility of cancellation of glucocorticoids;
• less duration of treatment;
• rare and recurrent relapse;
• less number and ease of side effects;
• cheapness of the drug;
• multidirectional mechanism of action.

Let us consider in more detail the mechanism of action of propranolol. Propranolol causes a narrowing of the vessels of the hemangioma. It is known that it is regulated by various endogenous factors, among which the mediator of the autonomic nervous system adrenaline plays a key role, which can cause vasoconstriction, activating beta1-adrenoreceptors, or vasodilation, activating beta2-adrenoreceptors. Depending on the partial pressure of oxygen and carbon dioxide, the tone of the vessels is increased or decreased accordingly. In addition, this tone is regulated by other mediators, which either narrow the vessels (endothelin-1, angiotensin II, vasopressin), or expand them (prostacyclin, nitric oxide, dopamine).

The vasodilating effect of epinephrine, caused by the activation of beta2-adrenoreceptors, is mediated by a cascade of biochemical signal transmission. Adrenaline-activated beta2 receptors interact with Gs-protein in endothelial cells. This trimeric GTP-binding protein, when interacting with the receptor, breaks down into an α-subunit which, upon the exchange of GDF with GTP, is activated, and the beta-y subunit (it may have intrinsic 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 secondary mediator and activates protein kinase A (cAMP-dependent A-kinase). The activated catalytic subunits of A-kinase then phosphorylate various proteins, which are its substrates. This transfers the phosphate group from ATP to a specific amino acid residue (series 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 the smooth muscle cells, where it activates the soluble guanylate cyclase that catalyzes the formation of cyclic guanosine monophosphate (cGMP). The latter activates protein kinase G, which induces vascular relaxation by phosphorylation of myosin.

Propranolol inhibits the vasodilator action of adrenaline by blocking beta2-adrenoreceptors. As a result of the narrowing of the blood vessels, the blood flow in the tumor decreases, the color of the tumor changes and its intensity becomes (milder) 1-3 days after the start of treatment.

1. Vasodilation. Vascular tone control, beta-adrenergic agonist causes vasodilation through the release of NO. In contrast, beta-adrenergic antagonists, such as propranolol, cause vasoconstriction (by inhibiting synthesis and releasing NO).
2. Angiogenesis. Beta-adrenergic agonists stimulate the synthesis of pro-angiogenic 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 pro-angiogenic proteins and inhibits the ERK / MAPK cascade, which is accompanied by a decrease in angiogenesis.
3. Apoptosis. Beta-adrenergic agonists inhibit apoptosis with src. In contrast, beta-blockers indicate apoptosis.

Propranolol also reduces the expression of VEGF. In the proliferative phase of hemangioma, the formation of collagenase IV, pro-angiogenic factors: endothelial growth factor (VEGF) and, to a lesser extent, fibroblast growth factor, increases. With involution of hemangioma, their formation decreases. The tissue inhibitor of metalloproteinase (TIMP) is expressed only in the phase of involution of the hemangioma. When hypoxia increases, VEGF expression increases due to increased transcription of the factor induced by HIF-la hypoxia: oxygen deficiency leads to an increase in the intracellular concentration of HIF-la in the active form. HIF-la induces transcription of the VEGF gene, resulting in increased proliferation of nearby endothelial cells and secrete proteases (metalloproteinases), which are necessary for the reorganization of the extracellular matrix, coordination of differentiation of vascular cells (endothelial cells, smooth muscle cells, pericytes) and angiogenesis. The newly formed vessels increase the oxygen delivery, which leads to a decrease in the level of the active form of HIF-la and the subsequent expression of VEGF. Consequently, there are physiological mechanisms for regulating angiogenesis when the partial pressure of oxygen changes.

It is important to note that the expression of VEGF is controlled not only by the partial pressure of oxygen (with the participation of HIF-la), but also as a result of adrenergic stimulation. It has been shown that epinephrine and norepinephrine can induce VEGF expression. Src is a protein kinase A mediator that belongs to the family of cytoplasmic tyrosine kinases involved in the cascade of signaling of extracellular signal-dependent kinases (ERK) / mitogen-stimulating protein kinases (MAPK). ERK and MAPK are serine / threonine kinases that phosphorylate nuclear transcription factors that regulate the expression of many genes involved in controlling proliferation. VEGF itself has pro-angiogenic effects, at least in part, due to the activation of the ERK / MAPK cascade. Thus, with the stimulation of beta2-adrenergic receptors, the proliferation of endothelial cells can be activated by two different mechanisms: increasing the activity of the ERK / MAPK signaling pathway (probably through src not bound to the cell receptor) and induction of VEGF release, which itself can activate the ERK / MAPC cascade . Therefore, beta-blockers, such as propranolol, lowering the expression of VEGF, inhibit angiogenesis. Taking into account that the violation of proliferation of endothelial cells is of key importance in the pathogenesis of hemangioma, the ability of beta-blockers to suppress VEGF activity can explain their pronounced effect on the proliferation of hemangiomas. It is interesting to note that a similar effect has been identified for corticosteroids which are still used to treat hemangiomas.

Another feature of beta-blockers is their effect on the activity of matrix metalloproteinases (MMP) related to 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.

In children with hemangiomas in the proliferative phase, increased levels of isoenzymes MMP-2 and MMP-9 in blood and tissue samples were revealed. MMP-9 is involved in the migration of endothelial cells and tubulogenesis (the initial stage of angiogenesis). It has been shown that inhibition of MMP-9 slows the angiogenesis of endothelial cells of human microvessels.

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

The processes of apoptosis are regulated by a number of capsas, procapsase and proteins of the B-cell family of lymphoma 2 (bcl-2). A low level of apoptosis is observed in the proliferative phase in hemangiomas. However, in the involution phase, the frequency of apoptosis is increased 5-fold, and the expression of the bcl-2 protein inhibiting apoptosis is reduced in parallel. Blockade of beta-adrenergic receptors with propranolol can induce apoptosis in various cells: in endothelial cells or in pancreatic cancer cells. Interestingly, beta1-selective blocker metoprolol has a much less pronounced apoptotic effect, and beta2-selective blocker butoxamine strongly induces apoptosis as compared to propranolol. Consequently, the induction of apoptosis may be another possible mechanism for the therapeutic action of propranolol against children's hemangiomas.

With all the advantages of propranolol, it, like any remedy, is not devoid of shortcomings - side effects. This is a well-known bradycardia, hypotension, AV-blockade, bronchospasm (usually in atopic children), Raynaud's syndrome, rarely - skin-allergic reactions.

If such violations are present initially, this is a contraindication to the appointment of propranolol. Hence 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 reach the optimum level of milk intake and the chances of developing spontaneous hypoglycemia are high. Most infants with hemangiomas receiving treatment are older and have sufficient nutritional status.

Propranolol is used in young children for various indications (hypertension, congenital heart disease, supraventricular tachycardia, prolonged QT syndrome, thyrotoxicosis) at a dose of up to 8 mg / kg / day. In the treatment with propranolol hemangiomas, complications such as hypotension, sinus bradycardia, and hypoglycemia were observed, which were not of serious clinical significance, but indicated the need for careful monitoring and monitoring of all infants with hemangiomas in the treatment with propranolol. The possible side effects of propranolol are much less clinically important than the serious side effect (spastic diplegia) of previously used anti-angiogenic drugs, such as interferon-a. The undesirable effects of corticosteroid therapy are also well known.

The proposed dosage regimen of propranolol - 2-3 mg / kg in 2-3 doses - does not take into account the individual characteristics of patients. The degree of biotransformation of propranolol differs significantly in different patients, and in connection with this, when the same dose of the drug is administered, concentrations that differ from each other by a factor of 10-20 can be obtained. This is due to the fact that propranolol is metabolized with the participation of the cytochrome B-450 isoenzyme CYP2D6, which has genetic polymorphism. The entire population is divided into slow, fast and normal metabolizers. The result of the mutation of the CYP2D6 gene may be the lack of synthesis of this enzyme, the synthesis of a defective protein lacking activity or with reduced activity. The prevalence of slow metabolizers among various ethnic groups varies greatly. It is known that in the European population, including among the Russians, there are 5-10% of them.

The clinical significance of slow metabolism is the increased effect of propranolol administered at usual therapeutic doses and the much more frequent and early (due to lower clearance) side effects such as hypotension, bradycardia, AV blockade and bronchospasm.

Rapid metabolizers for CYP2D6 are carriers of a mutant allele, which is a doubling (duplication) of the CYP2D6 gene.

In such patients, one should expect a decrease in the therapeutic effect due to accelerated biotransformation and elimination of the drug, so propranolol should be given at an elevated dose of 3 mg / kg or more often 4 times a day.

However, even with the normal level of metabolism of propranolol, 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 semi-elimination. Accordingly, the frequency of administration of the drug should be reduced or the dose reduced to 1 / 4-1 / 2 of the initial dose. Therefore, it would be advisable in patients with infantile hemangioma, before prescribing propranolol, to determine the initial activity of CYP2D6, which will allow the identification of groups of individuals with slow, rapid and normal metabolism of propranolol to select the appropriate dosage regimen for this patient in order to optimize the dose of propranolol and its therapeutic effect. At the same time, if it is impossible to determine the isoenzymes of cytochrome P450, propranolol can be started with a starting dose of 1 mg / kg with a frequency of 2 times a day, and in the absence of a marked change in the frequency of cardiac contractions, arterial pressure or any other side effects, the recommended level of 2 mg / kg 3 times a day.

Given the above, the authors suggest the following tactics of monitoring patients who are prescribed propranolol.

In the first 6 hours after prescribing propranolol, the blood pressure and pulse are monitored every hour. In the absence of side effects, the child is released for home treatment and then inspected 10 days later, then once a month - to assess the tolerability of the drug. In this case, blood pressure and pulse, weight (for dose adjustment) are measured. If possible, an ultrasound measurement of the tumor is performed on the 60th day of treatment. In each visit, the tumor is photographed. A regular centimeter tape can also be used to measure the tumor.

Clinical studies of the use of propranolol for the treatment of infantile hemangioma were conducted in the RCCH (Moscow).

The aim of the study was to determine the indications, to work out the treatment regimens, to monitor the drug therapy and the effectiveness criteria for the treatment of angiogenesis blockers by infantile hemangioma.

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

All patients included in the study were prescribed propranolol for a period of 6 months. The starting dose is 1 mg / kg / day. With an undetectable tumor regression, the dose was increased to 3 mg / kg / day or prednisolone was prescribed additionally, and in patients older than 1 year, endovascular occlusion was performed.

Before the treatment began, a detailed description of the local status and photographing was carried out. After the appointment of therapy for 7 days, the local status was assessed daily, then - once a month.

To determine the safety of therapy in patients before the appointment of treatment, electrocardiography with an assessment of heart rate and atrioventricular conduction was performed. During the first 7 days. Heart rate was measured daily, and on the seventh day electrocardiography (hereinafter - monthly) was performed. Patients over 10 years of age were also monitored for arterial blood pressure and external respiration function.

With the development of bradycardia, atrioventricular blockades of II-III degrees, arterial hypotension and bronchial obstruction, therapy was discontinued.

The results were evaluated by stopping growth and reducing the size of the hemangioma, reducing its density and brightness, as well as healing of trophic disorders at the surface of the tumor and the absence of negative clinical dynamics.

The six-month treatment was completed in 10 patients, in 6 patients the treatment was discontinued due to side effects, in 29 - the treatment was continuing. All patients who completed treatment had complete regression of the hemangioma, but three patients required an increase in the dose of propranolol, and one had endovascular occlusion. In continuing treatment, hemangiomas are at different stages of regression, but the rate of regression varies. In 11 patients, it was inadequate, which required correction of treatment: increasing the dose of propranolol (10 patients), adding other treatments, including corticosteroids (3 patients) and endovascular occlusion (5 patients).

As a result of our studies, we can conclude that propranolol is effective and sufficiently safe in the treatment of infantile hemangioma and can be used as a first-line preparation. The pronounced therapeutic effect of propranolol against growth of hemangiomas can be due to three molecular mechanisms: vasoconstriction, inhibition of angiogenesis, and induction of apoptosis. All of them can be involved in all stages of treatment: early (change in color of the surface by hemangiomas), intermediate (stopping the growth of hemangioma) and late (regression of the tumor). Apoptosis does not always lead to a complete regression of the hemangioma and after the cessation of treatment with propranolol, its growth can resume. Treatment should last until the completion of the proliferative phase of hemangioma. To develop a protocol for the optimal dosing of each patient, further research is needed.

Prof. Yu. A. Polyaev, prof. S. S. Postnikov, Cand. Honey. Sciences AA Mylnikov, Cand. Honey. RV Garbuzov, A. G. Narbutov. New possibilities in the treatment of infantile hemangiomas with the help of propranolol // Practical medicine. 8 (64) December 2012 / volume 1

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