SA08290744B1 - Use of a Beta Blocker for the Manufacture of a Medicament for the Treatment of Hemangiomas - Google Patents

Abstract

Abstract The present invention relates to the use of a beta blocker for the manufacture of a drug for treatment of hemangiomas, for example treatment of hemangiomas. A beta blocker may be a non-selective beta-blocker, eg propranolol. The present invention provides an alternative to known compounds, eg corticosteroids, interferon or vincristine, generally used for the treatment of hemangiomas.

Description

Use of a beta blocker for the manufacture of ‎a medicament for the treatment of hemangiomasFull description BACKGROUND OF THE INVENTIONThe present invention relates to the use of a beta blocker for the manufacture of ‎a medicament for the treatment of hemangiomas hemangiomas les eg infantile hemangiomas ° also discovered a method for treatment of hemangiomas Ales using the present invention. | b in the following text; Illustrated References References related to documents and publication cited are also included in the list of references after the “JU” part of the specification. General description of the invention Yee Infantile capillary hemangiomas Hemangiomas in children Generally very characteristic of the skin and liver The TH infantile pilonidal hemangiomas (IH) infantile hemangiomas are the most common soft tissue tumors of infancy, occurring in 701 children under one year of age as revealed in Frieden Uet al “‘Children’ hemangiomas: current knowledge; future directions; laboratory procedures.

The 111 is made from a complex mixture of cell types, including the majority of LA blanket cell types; Associated with endothelial cells dendritic cells mast cells endothelial cells cell types derived from proliferating leg tumor hemangiomas originally as declared in the document [1] and from By Bielenberg D.R. et al « “Progressive growth of infantile cutaneous hemangiomas directly correlates with quantitative hyperplasia and adjacent epidermal angiogenesis and inversely correlates with expression of endogenous angiogenesis inhibitor ¢INF-beta.

Int.

J. Boye E, et al. [01] Oncol.; 14:401-408 Leakage susceptibility and behavior of WA endothelial cell types modified from hemangioma Clin Invest 2001;107:745-52 hemangioma 417] It is suggested that lay hemangioma results from clonal expansion of an endothelial prodromal cell; which may be derived from a haematopoietic cell 0, a lineage cell as reported in [1]. Molecular IH endothelial cells display a distinct phenotype characterized by positive immunohistochemical positivity in the document:] 1[indoleamine 7,7-dioxygenase, indoleamine Y = LYVE (IDO) 2,3-dioxygenase are both positive in TH phase I and missing during maturation to the hematopoietic phenotype; Jil glucose Lewis Y Ag (Le Y), )1- Glut) 1 FcRyll, merosin, CCRS, Yo 15 . Twist-and-growth regulators (TH) are still a bad concept; But he showed that during their growth stage; Two major pro-angiogenic factors are involved: the primary fibroblast growth rate (BFGF) and the vascular endothelial growth rate (VEGF) present in situ. But also in blood and urine as declared in the document [1] and in Mancini AJ. et al “Propagation and apoptosis within infantile capillary hemangiomas 0 Viper” 1996-A.m.; 18:505-514.

J.

Dermatopathol

¢ in addition; Hybridization in situ of the VEGF receptor (VEGF-R) in proliferating IH showed that VEGF Rs spread regularly throughout the hemangioma and not after collecting into blood vessels. during the TH growth phase; Histological studies showed that both CWA endothelial and interstitial cell types in the proliferating state (MIB 1 stain is strongly positive) as an indicator in Mancini etal of proliferation and apoptosis of infantile capillary hemangiomas. is enjoying. Dermatopathol 1996;18:505-14 On the other hand, during the convolution phase markers of apoptotic cells are shown as reported in Razon 1.1. et alg [01] ¢ "Increased apoptosis coinciding with the onset of bypass in infantile hemangiomas D 1998; 5:189-195 [11] Microcirculation 0 One hypothesis to explain endothelial cell apoptosis in infantile capillary hemangioma hemangiomas express Y= ICAM on the cell surface; but an alternative possibility may be the loss of catalytic factors [VEGF Jie JV] The adrenergic system is the main regulator of cardiovascular function. Capillary cell types endothelial cells express beta receptors. -beta 2-adrenergic verb as accusative in D'Angelo Ve ma.6; cAMP dependent protein kinase inhibits mitogenic action of vascular endothelial growth rate and fibroblast growth rate in capillary cell types by inhibiting the activation of J.

Cell Biochem. ¢" Raf [V7] 1997; 67:353-366 which modulates NO release causing endothelium-dependent vasodilation. In addition, beta-adrenergic receptors are subject to Alle G receptors. Protein coupling and when activated by catecholamine adrenergic action they can promote AL cellular signaling 0 transduction pathways as advertised in G, et al 00 L:126. Ischemic neovascularization enhanced by beta 2-adrenergic receptors. Verb overexpression: an innovative role for the endothelial-adrenergic system Cire [VY] Res 2005;97:1182-1189 Beta receptor stimulation can coax salient pathway modifications

Transfusion from vasculature (Laid) VEGF degradation Jie or BFGF As reported in [DIY] it is shown that increased cAMP levels inhibit VEGF and endothelial cell proliferation driven by bFGF pharmacological elevations or beta-adrenergic receptors beta-adrenergic action intermediates in a mitotic cAMP block induce activation of a MAPK signaling pathway leading to blockade of Y=Raf activity by increased PKA activity [JY]0 In addition; It is shown that beta blocker blockade can induce apoptosis in capillary transplanted endothelial cell types as reported in Sommers Smith SK. et al ¢ "Beta blockade induces apoptosis in capillary cultured endothelial cell types"; A cell outside the body Dev.

Biol. 2002; Ve 38:298-304 In spite of their benign self-limited separation; TH is rarely responsible during their recurrent phase for local complications Jie ulceration or bleeding. The so-called disturbing HI is revealed for example in Enjolras 0. et al. 'Care of serious childhood hemangioma: a review from Als Yo+ Pediatrics £91618:8-88[;] It can impair vital or sensory functions especially when it is found respectively on the superior airways and tropics.Yo In addition; 111 causes at least a transient morphological distortion that causes psychiatric illness first in the parents and later in the affected children as revealed in the document [1]. And in Tanner 1.1.etal; “Growing Up with Facial Hemangioma: -101:446 1998 Parent and Child Coping and Adaptation, Pediatrics”, [Y] 452 Systemic or intralesional corticosteroids used as treatment The first, 0, is for difficult wounds during the proliferative stage as reported in Bennett ML et al; Effective corticosteroid use for cutaneous hemangiomas sala Evidence-based evaluation [1]. Arch.

Dermatol. 2001; 137:1208-13 Yvaq

> z on any CLA even at higher doses (7 to © mg/kg bw/day); Estimated response to processing range from 0? to 77680 as declared in the documents [1][©] and [4]. Adverse effects are transient and limited Jie sale Cushingoid facies Huge It suppresses growth but may cause more concern Concern -hypertrophic myocardiopathy © Other treatment options include interferon alfa-2a and 20 (£4) To 7560 from full response with 1-healing? mP/mU/day) (millions of units per (m?) but the risk of neurotoxicity has been reported in children under one year of age; as revealed in the documents [1] 5 ] 110 Vincristine is also used for its antagonistic properties. Twisting as stated in the document [1] but its negative aspects are 0 well-known extrinsic neuropathy; constipation; and blood toxicity. (Lia) New anti-vascular agents avastatin Je is contraindicated in young children due to their side effects. Moreover Because more patients are treated with infants or young children, patient tolerance of known compounds gets the most basic importance. Vo thus needs to find more efficient alternative and less toxic compounds for the treatment of oH in particular infantile capillary hemangiomas the present invention fulfills These and other needs: Propranolol is a well-tolerated, non-selective beta-blocker that has been used generally in young children for cardiac references as reported by Villain E et al in the reduced yo-incident of cardiac events with beta-blocking therapy. beta-blocking in children with prolonged Eur syndrome.

Heart J. 2004; 25:1405-11 « QT [1]; By Fritz KUL et al, the effect of beta blockade on symptomatic hypertrophic cardiomyopathy with dexamethasone.

dexamethasone in premature children: three studies and a review. -1998:18:38 J Perinatol <[V] 44 and by Kilian 16. In hypertension in the causes and treatment of two boys; J.

Perinat.[A] Neonatal Nurs. 2003: 4 However, this beta blocker and beta blockers in general have not been previously tried or detected for use in the treatment of hemangiomas. The present inventors are the first one to have tried and observed that beta blockers may be efficient for Tas to control the growth of TH and even to treat JH. Experimental observations and results are provided in the present application. cella] Las in Jol feature; The present invention provides the use of a beta blocker de lial as a drug for treatment of hemangiomas Ve 'beta blocker' also refers here to an agent that blocks the beta receptor; an agent that beta-adrenergic receptor blocking action; beta-blocking agent or agent or blocking agent or beta or agent blocking the beta-adrenergic receptor; action or any other class denoting a chemical ale wherein it inhibits Binding of agonists, natural or synthetic, to beta adrenergic receptors Action of any kind (beta = beta2; beta ti ¢ beta2 Y—0 -? beta3 or others). beta blocker Lind) may be a non-selective beta-blocker ¢ beta Y = selective beta blocker; alpha mixture/1-beta adrenergic agonists beta Y = jill Selective beta blocker A beta blocker may also be a mixture of two or more beta blockers .beta blocker tid Y. The beta blocker that may be used in the present invention is disclosed in Goodman and ( Gilman's The Pharmacological Principle of Therapeutics, Eleventh Edition; Chapter 01 pages 1 Don't Got You [Ya] 0011

A non- when non-selective beta-blocker “all” is preferred; According to the invention is used; He may choose, for example, from a group that includes selective beta-blocker medroxalol levobunolol labetalol carvedilol carteolol bucindolol alprenolol propafenone pindolol penbutolol oxprenolol nadolol metipranolol mepindolol beta a sodium channel blocking drug that also a beta-adrenergic receptor antagonist (propafenone) or salts accepted in the form of timolol (sotalol propranolol verb) ¢ pharmaceutical adrenergic propranolol from that source; Any mixture thereof may be used. Of the present invention; He may opt for a lida selective beta-blocker using Y= when beta “6110101016 bisoprolol” betaxolol “of the group includes 1 m1 of 21600101:2 vaccine JE tract. 1601701016 metoprololiesmolol 0 Essential sympathomimetic May have sympathomimetic activity beta blocker Lindl blocker oxprenolol™ labetalol™ carvedilol™ wrist betaxololcacebutolol (Jie also propranolol propranolol ¢ pindolol ¢ <penbutolol or an acceptable salt propranolol beta blocker Preferably » propranolol beta blocker or a mixture of propranolol or propranolol L in a pharmaceutical form thereof; eg 1

Vie to 1:1; With the amount of that propranolol and propranolol L that. The mixture may be a mixture, may be propranolol, an acceptable salt in pharmaceutical form propranolol 1:1, for example, or any other preparation of propranolol chlorohydrates propranolol chlorohydrates Whether or not the preparation alters or modifies the kinetic properties Pharmacokinetics or Metabolism » propranolol -propranolol from propranolol 0 according to the present invention; The drug may be a drug for the treatment of infantile capillary hemangiomas

According to the present invention; The medicine may also be a medicine to treat other hemangiomas; For example JU those selected from the group include hemangioma (eg hemangioma epithelioid; frontal hemangioma; spindle cell hemangioma); grouped into a tuft of chemangioma vascular endothelial tumors (eg kaposiform; hemangioma in von Hippel-Lindau syndrome; angiofibroma and angiolipidoma in Bourneville disease; pyogenic granulomatosis; eg Adley's sarcoma; Kaposi's alleviation of enlarged arteriovenous malformations; widespread hemangioma. Reference {Colls M.

Wassef Tumors and Vascular Anomalies, Classification, Pathology, and Imaging [Y +] Ann Chir Plast Esth 2006; 51:263-281 0 anatomic pathological classification 0 reveals these active metastasis tumors. A drug may be in any form that can be administered to a human or an animal. abuse may be carried out directly; for example net or substantially net; or after mixing a beta blocker with a pharmaceutically acceptable carrier and/or medium. Tas of the present invention; The medicine may be a syrup or an injectable solution. vo according to the present invention; The drug may be an oral drug selected from a group that includes a liquid formulation. oral excitable dosage form; oral powder; multimolecular system; Spreadable dosage form. For example; when a drug is a drug to be taken orally; It may be in the form of a liquid formulation selected from the range including lotion; syrup; hanging; Oral lozenges and drops. when 0 the drug is in the form of an oral effervescent dose; He may choose from the group include discs; grains; powders. when the drug is in the form of an oral powder or a multimolecular system; He may choose from the group ‎Jody cereal; grains; Small tablets and fine granules. When the drug is in the form of Z form Yva4 y. dispersible dose; He may choose from the range including dispersible tablets; medical. ale; lyophilized wafers; thin layers; chewable tablet; opportunities and capsule; according to the present invention; The medicine may be a medicine for the buccal and sublingual routes; Selected from the group include buccal or sublingual tablets; preparation of adhesive mucus; JE Lozenges; Oral mucus drops and sprays.‎ 0 According to the present invention; The drug may be a drug for topical intradermal administration; For example selected from the group includes ointment, cream, gel, lotion, patch and foam. According to the present invention; The medication may be a nasal medication; Examples selected from the collection include nasal drops; nasal spray; nasal powder. According to the present invention; The medicine may be a rectal medicine; eg 5.hard gelatin eg. 2 capsules or capsules according to the present invention. The drug may be a drug for parenteral administration; For example, under the skin. Intramuscularly into a vein. The expert in the art clearly understands that the expression 'form' as used herein refers to the drug may be in the form of JU (the pharmaceutical formulation of the drug for its practical use. For example, 0 mg/mL); © Avlocardyl® eg Je) to choose from the group including an injectable form

Efferalgan® eg (Jo 77); Oral suspension Efferalgan® Syrup (eg

Doliprane® gram); Powder (eg 1 Dafalgan® pill (eg AF) 1 mg); spray; transdermal patch (eg 10 Zoltum® mg); granules (eg 0 hr) or topical form (Cream; Lotion; Yi ana © Cordipatch® JU Sabeel ©

Chibroxine and Betneval® as Dermoval creme® (eg (collyrium® respectively). collyre®

11 | In these examples; blocker beta For example on the beta blocker Lill cited above; for example propranolol; The active ingredient may add to or may replace the medicines listed. A pharmaceutically acceptable vector may be known pharmaceutically as a vector used for restricted administration of a beta blocker to a human or to an animal; Depending on the topic. For example; This carrier may choose from the group include for example monomethoxy polyethyleneglycol (eg as in Viraferonpeg®) or liposome (eg as in Ambizome®-) medium may be defined as a medium used for beta-blocker administration beta blocker to a human or an animal. (eg JUS this media may choose from the set include for example cremophor 0 (eg as in (Sandimmun® or Ae) cellulosis for example as In Avlocardyl® LP 001 mg). According to the present invention, the drug may include any acceptable and pharmacologically efficient dose of a beta blocker for the treatment of hemangiomas, for example. body cally for example from ?to mg/kg of body weight/day In a second feature, the present invention provides a treatment method for suffering from hemangioma 0 also disclosed. This method includes the step of taking the aforementioned beta blocker Lidl.

YY

; In addition to the formulations beta blocker Gn and hemangioma blockers usable as defined above. Z beta blocker Lin and useful for blocker administration This beta blocker can be taken with direct injections of a beta blocker (JE) as a way of taking »in addition to a drink; Of course, it is preferred for infants. The administration may be defined to allow the delivery of a pharmaceutically acceptable and efficient dose for the treatment of a tumor ©* to 1 eg; Treatment of vascular hemangiomas may include doses of mg/kg body weight per day, eg from to; mg / kg of body weight / day. Administration may be carried out in a single dose or with multiple doses per day. 0 Experimentally demonstrated anti-angiogenic effect. blocker beta Related to Turem Gallery Lad Other searches have been carried out by the current creators

WA is present at the beta-adrenergic surface of the beta-adrenergic receptor in vascular hemangioma 0 (see examples below). This confirms findings of hemangioma of beta endothelial cell types acquired with the present invention, providing physiological explanations and confirming the mechanism of action of the beta-blockers propranolol within the framework of the present invention. This also confirms the link between the efficacy of propranolol blocker .beta blocker lin and its activity as a blocker of fluids for use of avastatin Jie since the new anti-angiogenic agents of previous art Y. According to the invention propranolol the use of propranolol “riba” in young children because of their impact

The current drug constitutes a safe alternative to JAL corticosteroids and even to interferon or vincristine. Propranolol is a non-selective beta-blocker with intrinsically weak sympathomimetic activity; Its dramatic therapeutic effect on 111© can be explained by three mechanisms: .1 an exogenous vasoconstrictor effect that induces cell hypoxia; Propranolol is responsible for a vasoconstrictor accessory unit; This effect is immediately visible on the 111 processor. Decreased expression of VEGF and bFGF genes via down-regulation of the Raf/MAPK HIF pathway (Giatromanoloki A, Arvanitidou V, Hatzimichael A, 0 087 HIF-2alpha). [VV] Simopoulos C, Sivridis # 0/ Activation of the VEGF pathway in cutaneous capillary angiomas (Shyu KG, Liou JY, Wang BW, Fang WJ, Chang H). Cardiovedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha. and the rate of vascular endothelial growth in the heart of a mouse for further pressure loading.409-420:12;2005 (I YA] J Biomed Sci. LY Apoptosis causes an effect on WA endothelial capillary cell types.'oe In experimental results revealed the following; changes in color from intense red to purple; were associated with a marked reduction of edema observed in infants presented with LTH This effect could induce chronic hypoxia of a hemangioma responsible for arresting the spread of endothelial chelation .cell types | However; in the experiment of the inventor; the progressive improvement of TH under the treatment of propranolol | 0 It is suggested to make a force bearing on the growth rates BASE is not clear either in this field targets of treatment endothelial cells cell types: themselves » or other cells such as interstitial cells or mast cells. The third mechanism included

Ve first apoptosis induced by blockade of beta types cell endothelial cell TH likely to explain involution .beta blocker in two of the presented cases; hemangioma however regrowth of hemangioma do not support this hypothesis. in addition; In the case of JH when treatment was stopped during the second proliferative phase; The inventors did not find signs of a cell despondent with bodies using histochemistry

Ag adhesion? Anti-caspases to the immuno-histochemical immunoassay Widespread now in neonates or children Beta blocker Use of beta-blockers «Lad

Villain as presented in the document QT Patients with Good Tolerance in Cardiac Disease as Prolonged Syndrome Low Cardiac Events with Beta-Blocker Therapy in Children with Long-Term Bala"; E. et al. Hypertrophic Cardiomyopathy" [1 ] Eur. Heart J. 2004; 25:1405-1411 “QT syndrome 0 on beta blocker myopathy” effect of beta blockade (Fritz 16.1. et al, as presented in the document) in children Before maturity: dexamethasone hypertrophic heart obstructed symptomatic impulse dexamethasone as shown in pall or hypertension [V] J Perinatol 1998;18:38-44 Three studies and review.

J. Perinat. “Hypertension in Causes and Treatment in Newborns” Kilian K. et al Document. [A] Neonatal Nurs 2003; 17: 65-740 This invention is also illustrated by the following examples in connection with the accompanying drawings which are not to be construed as limitation. Fig. - .propranolol A former block stimulant; Before starting propranolol treatment 0

z Vo - Figure ¥ an image illustrating the characteristic of a hemangioma just seven days after initiation of propranolol treatment according to the present invention. - Figure © An image showing experimental results at 7 months of age where the child is still continuing to be treated according to the present invention and previous systemic steroid treatment stopped © 2 months ago. Figure 4 is a photograph illustrating experimental results in 4 months of propranolol treatment according to the present invention. Figure © Image obtained with immuno-histochemistry showing that the beta? Yu shown on endothelial cells IH cell types 1 - Figure 7 obtained a picture with the method of immunohistochemistry display that 11171 alpha (red dye) showed on endothelial cells JH cell types we : 1 Jiao the first experiments according to the present invention ie Jibs male infant presented with TH including the nasal pyramid. at two months of age; Systemic steroids presented because of dyspnea associated with nasal septum and adenoid necrosis. After one month's treatment in ? mg / kg body weight / day (mg / kg / day] eprednisolone Hemangioma established; but nasal necrosis progressed 0 Since the infant refused progressively to take 0 tablets “prednisolone” we provided a dose Equivalent to betamethasone in drops (+0.0 mg/

kg/day). in ; months of age; The hemangioma stopped growing and the ulcer inside my nose healed. The nasal ulcerations had healed, however; Jal returned on a control visit with tachycardia at 0880 to Yoo bpm; It has been associated with a systolic heart murmur. Cardiac sonogram showing hypertrophic cardiomyopathy © concern hypertrophic myocardiopathy obstructed; Justification for the decrease in betamethasone dosage betamethasone dosage? to ? mg/kg body weight/day (mg/kg/day). Laie thus began treatment with the beta blocker Vin - propranolol (IUPAC chemical name: (2RS)-1-[1-methylethyl)amino]-3(naphtalen-1yloxy)propan-2-ol ) in ¥ 0 mg/kg/day. Propranolol has been administered as a capsule containing commercial propranolol powder. after the day on which the propranolol dallas started where the ey hemangioma changed color from intense red to purple; And soft. Betamethasone was replaced by prednisolone which tapered down and stopped 1 weeks after propranolol inoculation. Propranolol Vo despite a decrease in systemic steroids; 111 still continues to improve. in life © V5 months when the steroids stopped; No return to normal in size or coloration of TH can be observed. at 4 months of age; the child is still on propranolol; Hypertrophic cardiomyopathy is caused by recurrent corticosteroids. The TH level of daa was persistently single skin dilated capillaries on an orange-yellow dyscolored skin background; And complements 0 inside the nose and dean necrosis -intranasal and columella necrosis

'Vv

Example 9: The second experiment according to the present invention

the second infant; the male is a triplet Born at “0 weeks”; presented since birth 111 sub-flat, which includes the entire right upper limb and the right fronto- parietal and superior eyelid areas.

° at 1 month of age a subcutaneous component developed in ¥ areas including the superior eyelid;

Paraauricular area and axillary fold. Because of the risk of visual deprivation prednisolone started in? mg/kg/day.

anyway; After two weeks of treatment where the condition is not under control, we decide to increase prednisolone in mg/kg/day for two weeks.

01 In spite of this feeding system; 111 Continue to enlarge and in two months to open the eyelid of the age were impossible; The right side of the face is disfigured by a massive tumor as shown in Gale Fig. 1. In addition the axillary fold is occupied by a TH component and a tumor measuring lab © cm in diameter.

Magnetic resonance imaging (MRI) did not show any intracerebral anomalies, but revealed that 111 included the extra orbital and intraconal regions and was responsible for the exophthalmos.

0 in addition; MRI showed that parodital 111 was in continuity with a Jal compressive component of the neck leading to tracheoesophageal deviation; The axillary mass measured 1 mm X £0 mm 7 500 mm and extended to the right pulmonary Aad.

My cardiac sonography showed an increased cardiac output. Prednisolone dose converted to? mg/kg/day and treatment with propranolol 1 » propranolol 00 mg/kg/day; According to the present invention; seem.

VA

11 o'clock, as in the previous infant (see above for example 1); Wounds only decreased propranolol after starting propranolol seven days later; Spontaneous ophthalmic opening was likely due to a dramatic reduction in the size of the component, as shown in the image presented in the appendix of Fig. Obtained by the present invention shall be compared with that presented before the beginning of the treatment of hemangioma which illustrates the hemangioma feature 1 of Gale's figure in an image and after; Weeks of comprehensive doping treatment from prior art (2 weeks propranolol at 3 mg/kg/day and 2 weeks at © mg/kg/day). It tapered downwards while 111 continued to improve. In? Prednisolone dallas Ye months old Test sample I got on the arm» View 111 perfect. Cells exhibited suggestive of proliferating activity 1- MIB bad stain with monoclonal antibody cell types weak endothelial L111 in an infant. Chemical analysis “propranolol to evaluate a possible role of p1010m00:08 of propranolol Anti-caspase-3 single-adhesive as immuno-histochemical used 0 led but not shown » (Ozyme, Saint Quentin en Yvelines, France) and / ADL antibodies

Dre] positive immunostain stop in; months of age; Without any recurrence; Prednisolone was responsible for a moderate increase in volume of propranolol but stopped after days of propranolol treatment on the superior eyelid and paraauricular areas. Vascular hemangioma ayy 00 in ¥ mg / kg / day was successful after propranolol re-treatment propranolol 1 hour. YE only any

At 6+ months of age the opening of the call was masked and no major visual impairment was para-auricular hag and components of the axillary and subcutaneous hemangioma were not palpable 5 TH largely faded on both face and arm. the shape ? Provides an image illustrating these experimental results at 7 months of age where the child continued to take ¥ mg/kg/day propranolol (propranolol systemic steroids were discontinued 2 months ago. No component under (sala) hemangioma observed; The cutaneous component has faded to a great extent. In addition, the child does not suffer from any visual impairment. At 9 months of age, the treatment was stopped, without any re-growth of TH as shown in the appendix of Fig. 4. Example “: the third experiment according to the invention all female infant presented with correct periocular TH observed yf at ?weeks of age and localized on the inner canthus+ at 2 months of age; subcutaneous component TH extended into the orbit and defined the opening of the -superior eyelid Doppler ultrasonography showed YY TH measuring 0 millimeters in diameter and 11 millimeters in thickness.After obtaining informed consent from the parents, she was treated with propranolol (mg/kg/day).Flattening Harm observed in VY hours; followed by progressive improvement.Romy control results led days after initiation of propranolol “demonstrated a decrease in volume [1]: YY millimeter in diameter vs. YY millimeter and 1 millimeter in thickness vs. VY 00 millimeters; Without any hemodynamic-progressive improvement

Y. 111 Lass noted. Stopped after 1 month; but propranolol increases propranolol requires treatment to resume. it was unchanged and faded in color; and ultrasonography TH months of age that 1 in 0 dubcutaneous component (sala) could not discriminate any component under months without any return to normal from A stop in propranolol propranolol: tumor Vascular hemangioma as seven other children with vascular hemangioma were treated with propranolol and similar results obtained. Or interferon Tadd results what was interferon V- has an effect propranolol in the abstract; These examples clearly show that propranolol avastatin Jie since the new anti-angiogenic agents JH is strong in Lindl anti-angiogenic Propranolol may be contraindicated in young children due to their side effects ¢ Propranolol to interferon and even to interferon “Jali corticosteroids are a reasonably safe alternative to corticosteroids or vincristine p100507.” Ve Example: Comments and experimental results in a form larger tolerance ¢ propranolol Note that propranolol serendipitously their inventors used generally in young children non-selective beta-blocker non-selective beta-blocker ; Léauté-Labréze © for cardiac references; It can control the growth stage 111 as published in Propranolol Tumor and Phage Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB 0 No explanation [V1] New Engl J Med 2008, 358; 24:2650-51 From childhood. ala hemangioma

Yvaq

possible from the skewed sex ratio; 5-pde activation of the HIF-7 alpha pathway and subsequent overexpression of VEGF in endothelial cells of cell types is involved in the development of cutaneous (sala Giatromanolaki et al) capillary haemangiomas in patients with cutaneous hemangiomas. Alpha Y = HIF/VEGF pathway activation in cutaneous capillary angiomas. pathology.)] [17] oY = Y eon 4d amazement; A beta-blocker study for the treatment of hyperplasia. Shyu et al «all. Cardivedilol reverses both protein 5 mRNA for alpha VEGF; 1-HIF to baseline assessed by Shyu et al; Cardiovedilol inhibits cardiac hypertrophy 5 overexpression of hypoxia factor alpha-1 and vascular endothelial growth rate in rat heart for post-pressure loading. 409-420: 12 ; 2005 (IY A] J Biomed Sci. Other searches lead to a final view of vasogenic cascade of beta-adrenergic receptors. Intracorporeal and extracorporeal action in TH and in potential genetic determinants influence

on a phenotype of HI z

Histology and immunohistochemistry. Examination of a paraffin-embedded skin sample cut into micron sections and coated with hematoxylin-eosin to assess morphology. To visualize the presence of an alpha2adrenergic receptor, verb ¥, and the expression level of “HIF1-alpha 1 WI HIF, sections hatched consecutively with a monoclonal rabbit, alpha antihuman, alpha2-adrenergic receptor, verb Y (PA1-20659, ABR). , Golden, USA) 0 or mouse monosynthetic anti-human 1 HIF - ‎(ab8366, abcam, Cambridge, UKcab 8366) 101000 Lal at night in ;*m. As a sili system, we used the (K4002, K4000 Dako, Trappes, France) Envision horseradish peroxidase Yo system, which improves sensitivity dye directed against the rabbit to the alpha-adrenergic receptor ¥ and the rat to HIF alpha-Yvaq.

A

(K3461, Dako, Trappes, France) aminoethylcarbamide sections were exposed with ba -hematoxylin counterstained.

Preliminary The results of preliminary immunohistochemistry (appendix Fig. 0) showed that the receptor immunohistochemistry as 111 cell types (appendix 1) was also shown on endothelial cells 1 alpha HIF The .111 cell types © Recently noted. Bibliography

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Tanner JL, Dechert MP, BA; Frieden LJ. Growing up with a facial hemangioma: [?] Parent and child coping and adaptation. Pediatrics. 1998; 101:446-452.

Bennett ML, Fleischer AB, Chamlin SL, Frieden 1J. Oral corticosteroid use is [v1 effective for cutaneous hemangiomas. An evidence-based evaluation. Arch 1

Dermatol 2001; 137:1208-13.

Enjolras O, Riche MC, Merland JJ, Escande JP. Management of alarming [¢] hemangiomas in infancy: a review of 25 cases. Pediatrics 1990;85:491-8.

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V, Bonnet D. Low incidence of cardiac events with beta-blocking therapy in children with long QT syndrome. European Heart J 2004; 25:1405-11.

Fritz KI, Bhat AM. Effect of beta-blockade on symptomatic dexamethasone-vl induced hypertrophic obstructive cardiomyopathy in premature infants: three case 8 reports and literature review. J Perinatol 1998:18:38-44.

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Nurs 2003; 17:65-74.

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Claims (1)

A Claims 1-1 Compound propranolol, or a pharmaceutical salt thereof, is used to manufacture a drug for the treatment of ¥ hemangiomas 1 7- A compound according to claim 0 is used in the manufacture of a drug for the treatment of capillary vascular tumors hemangiomas and/or capillary hemangiomas (sal) children capillary infantile hemangiomas eT 1 € according to protection elements 1 or oF used in the manufacture of a drug that is a fire syrup or an “injectable solution” 1 solution 4- A compound according to protection elements 1 or oF used in the manufacture of a drug that is a suspension taken through the apical suspension. 1 °- A Lad compound of 1 elements or “is used In the manufacture of a drug in a form chosen from a group consisting of pellet, powder, granule, spray ¥, cream, transdermal patch and collyirum 1 +- Compound propranolol or a pharmaceutical salt thereof used in the treatment of hemangiomas ¥ 1 - Compound propranololol or a pharmaceutical salt thereof FH of protective ingredient 1 used ¥ to treat hemangiomas Capillary hemangiomas and/or capillary hemangiomas v in children. Capillary infantile hemangiomas.