Clinical Comparison Of Different Treatment Regimens And Experimental Study Of Mechanism Of Of Oral Propranolol In Infantile Hemangiomas

Chapter1 Clinical comparison of different treatment regimens of oral propranolol in infantile hemangiomasPart I Comparison of different doses of oral propranolol in infantile hemangiomasBackground:Infantile hemangioma(IH)is one of the the commonest tumors in children,and the incidence of the tumor is generally between 5%and 10%.The incidence of hemangioma in very low birth weight and premature infants can be as high as 20%-30%.There are many treatments and drugs,but there is no ideal treatment.Since 2008,propranolol was incidentally found to have good curative effect in infantile hemangioma.Due to its impressive efficacy and safety profile,propranolol has become the first-line therapy for IH worldwide and in a remarkably short time.The dosage of children was 0.5-1.0 mg/kg/d recommended by propranolol instructions.European experts consensus reported:The standard dose in the majority of studies reported to date is 2 mg/kg/day with a range of dosing between 0.5 and 3.0 mg/kg.Studies comparing 2 and 3 mg/kg/day have not been reported yet.Since both regimes,2 and 3 mg/kg/day have documented efficacy and safety,the recommended dose of propranolol is 2-3 mg/kg/day.Considering Chinese are more sensitive to propranolol,Chinese experts recommend dosage:1?1.5 mg/kg/day,the maximum is not more than 2 mg/kg/day.Although propranolol has been a first-line drug in infantile hemangiomas,it still belongs to the off-label drug use.However,there is no consensus about the therapeutic dose.But the following problems:first,propranolol can penetrate the blood-brain barrier and influence on the development of nervous system and is lack of long-term follow-up study,so the potential adverse effects are not clear;some studies show that the incidence of adverse reactions increased following the dose increased.Second,propranolol treatment in infantile hemangioma belongs to the ultra manual medication,more researches are needed to provide theory evidence.Third,the commonly used doses are higher than propranolol prescribed for children.Objectives:To study the efficacy of different doses of propranolol in the treatment of infantile hemangiomas,so as to provide an ideal dosage for clinical treatment.Methods:From September 2015 to October 2016,Follow the diagnosis of infantile hemangioma in children,and in accordance with the inclusion criterias of hemangioma infants.According to randomized and controlled principle,and different doses of oral propranolol,the patients were assigned to receive two propranolol regimens,Treatment group A(N=45):propranolol at a dose of 1 mg/kg/d;Treatment group B(N=44):propranolol at a dose of 2 mg/kg/d.(1 or 2mg of propranolol base per kilogram per day.divided into two doses).The effective rate,cure rate and adverse effects rate were compared at the six months after treatment.The duration of the treatment was compared after 12 months' treatment,and the recurrence rate was compared at the three months after being cured.Results:Treatment group A:the average age of initiation of propranolol treatment was 3.7 months(1-9 months),and the average duration of propranolol treatment was 11.1 months(3-18 months).Treatment for 6 months,45 children were evaluated as follows:grade ?(bad)1 case,grade ?(middle)3 cases,grade ?(good)14 cases,grade ?(excellent)27 cases,the effective rate was 91.1%,the cure rate was 60%.The incidence of adverse reactions was 13.3%.The duration of treatment was 7.6±2.7 months.The cure rate of group A at 12 months was 86.7%.The recurrence rate was 9.5%.Treatment group B:the average age of initiation of propranolol treatment was 3.8 months(1-9 months),and the average age of discontinution of propranolol treatment was 10.3 months(3-18 months).Treatment for 6 months,44 children were evaluated as follows:grade I(bad)2 cases,grade II(middle)2 cases,grade III(good)8 cases,grade IV(excellent)32 cases,the effective rate was 90.9%,the cure rate was 72.7%.The incidence of adverse reactions was 15.9%The duration of treatment was 6.2±1.9 months.The cure rate of group B at 12 months was 88.6%.The recurrence rate was 11.9%.The effective rate of the two groups was not statistically significant(P>0.05).The effective rate of the two groups reached the mass level.The cure rate of the two groups at 6 months was statistically significant(P<0.05).The incidence of adverse effects was not statistically significant(P>0.05).Treatment with group A required longer treatment time.The recurrence rate of the two groups after 3 months withdrawal was no statistical difference(P>0.05).Concluctions:1.The propranolol doses at 1mg/kg/d and 2mg/kg/d in the treatment of infantile hemangiomas are safe and effective.With the dose increase,the effective rate and adverse effect rate have no significant difference at 6 months.The cure rate of high dose is superior to the low dose at 6 months.2.The cure rates between the two groups have no difference at 12 months,but low dose treatment need longer treatment time.Low dose propranolol dose not increase the recurrence rate in infantile hemangiomas.3.The dosage of propranolol recommended by propranolol indication is 0.5-1.0 mg/kg/d.Considering the long-term adverse effects and off-label drug use and over dosage,1 mg/kg/d treatment doses is administered to children who have significant therapeutic effects.Low dose at 1mg/kg/d can be used as a common dose of propranolol in infantile hemangiomas.4.To further study the effects of different doses of adverse reactions about height and weight,nervous system and other forward,a multicenter and prospective study with large sample should be made for dose selection,and even propranolol will be approved in infantile hemangiomas by the China Food and Drug Administration(CFDA).Part ? Comparison of different administration frequency of oral propranolol in infantile hemangiomasBackgrounds:Infantile hemangioma(IH)is one of the commonest tumors in infancy,the incidence of neonatal 2-3%,the incidence of less than one year old infants is between 4-10%.Most hemangiomas have only minor clinical signs.However,about 10%of the patients' lesions cause appearance disorders,disrupt normal tissue,and even endanger life,so the infantile hemangiomas requires active treatments.There are many treatment methods,including surgery and nonoperative treatment,among which drug therapy is widely used.However,higher rates of relapse and adverse events have made medical personnels seek better therapies.Propranolol has been used in the treatment of infantile hemangiomas since 2008.Because of its good curative effect and high safety and low recurrence rate,Propranolol is widely used in infantile hemangiomas,quickly become the first-line drug.But it still belongs to the off-label drug use,and no consensus formed in the daily administration times.The result of a questionnaire in America experts consensus:Dosing was twice daily for 38%and 3 times daily for 47%,with the remaining 15%dosing 3 times daily initially with a change to twice daily when the child was older.No reasons were mentioned for the change of administration frequency.Currently,propranolol is not targeted at infants and young children and is difficult to take medicine.Objectives:To compare the effects of different administration frequency of oral propranolol in infantile hemangiomas,and provide a safe,convenient and effective administration frequency for clinical treatment of infantile hemangiomas.Methods:From October 2016 and February 2017,children with infantile hemangiomas were diagnosed and met the inclusion criterias.There were 37 cases of children who were enrolled into this study.Following the randomized and control principle,according to the oral propranolol administration times,the patients were divided into two groups,treatment group 1(N= 19):the dose of propranolol was 2mg/kg/d,the frequency was 2 times per day;treatment group 2(N=18):the dose of propranolol was 2 mg/kg/d,the frequency was 3 times per day.The effective rate,cure rate and adverse effects rate were compared between the two groups after six months'treatment.Results:37 cases of infantile hemangiomas were treated.After oral administration of propranolol,the tumor tension decreased,the color changed from bright red to purplish red.As the tension decreased,the size of the tumors was smaller.The curative effect was evaluated at 6 months after treatment.The results of treatment were categorized into four grades.The treatment group 1(19 cases):grade ?(bad)1 case,grade ?(middle)0 case,grade III(good)4 cases,grade IV(excellent)14 cases,the effective rate was 94.7%.the cure rate was 73.7%;There were one case of asymptomatic bradycardia,1 cases of diarrhea,no hypotension,hypoglycemia,vomiting,cold limbs and sleeping disorders.The incidence of adverse reactions was 10.5%.The treatment group 2(18 cases):grade ?(bad)0 case,grade ?(middle)0 case,grade ?(good)4 cases,grade IV(excellent)13 cases,the effective rate was 94.4%,the cure rate was 72.2%.There were one case of pale lips and vomiting,1 case of diarrhea,no other adverse reactions,and the incidence of adverse reactions was 11.1%.There was no significant difference in the effective rate of treatment and the cure rate(P>0.05).The incidence of adverse reactions between the two groups was low,the difference was not statistically significant(P>0.05).Conclusions:1.The administration frequencies of oral propranolol by 2mg/kg/d in infantile hemangiomas both 3 times per day and 2 times per day are safe and effective.The effective rate,cure rate and the incidence of adverse effects are not diffrent.2.In consideration of the age of children,they are so yong that suffering from medication.In order to alleviate the pain of children suffering from medication and lighten the burden of parents or guardian,the administration frequency of 2 times per day is recommended.3.A multicenter,large sample prospective study should be made,including the pharmacokinetic and pharmacodynamic indicators.The further theoretical basis for the selection of the frequency of medication should be provided.Chapter 2 Experimental study of mechanism of oral propranolol in infantile hemangiomasBackgrounds:Infants hemangiomas(IHs)are the most common congenital benign tumor of infants,accounting for 60%located on head and neck.Most of them are located on the superficial places,seriously affecting the beauty.According to the biological classification method made by Mullliken,the disease was grouped into hemangiomas and vascular malformations.The proliferation and fading process of IHs are closely associated with the abnormal cell proliferation,differentiation and maturation of vascular endothelial cells,so the researches of the pathogenesis and treatment in IHs are focused on the angiogenesis and angiogenic factors.Hypoxia inducible factor-la(HIF-la)is one of the most important cytokine factors secreted at the condition of cell hypoxia.HIF-1? could promote angiogenesis in the process of tumor growth.High expression of HIF-1? could regulate a variety of downstream target genes including vascular endothelial growth factor(VEGF)signal,which promote new angiogenesis,relieve insufficient blood supply of tumors cells,make tumors rapid growth.Objectives:To examine the expression level of HIF-1? in IHs tissues and cells using western blot and RT-qPCR assays.It was to explore the biological cell functions of hemangiomas edothelial cells after HIF-la over-expression or knock-down.To explain mechanism of propranolol in the treatment of infantile hemangioma,and provide a theoretical basis for propranolol treatment of infantile hemangioma.Methods:A total of 10 cases of IHs were enrolled.Fresh tissues were collected after the radical resecsion.The expression of HIF-la was detected in normal vascular tissues,IH tissues,or the IH tissues with propranolol treatment.The hemangioma endothelial cells(HemECs)were cultured in vitro.The cell proliferation,apoptosis,migration and tube capacity were determined after HIF-la over-expression or knock-down using the determined by CCK-8 method,flow cytometry instrument,scratch test and pipe capacity.The expression levels of HIF-1? were measured via RT-qPCR and western blot methods.Results:Compared with the normal vascular tissue,HIF-1? expression levels were significantly up-regulated in IH tissues.The expression level of HIF-1? was decreased in IH tissues after the treatment with propranolol.HIF-la expression level was in the manners of concentration and time dependent when HemECs treated with propranolol.Moreover,HIF-1? knockdown in hemangiomas cells and propranolol treatment could remarkably decrease the cells proliferation,migration,tube formation and promote cell apoptosis,on the contrary in HIF-la overexpression hemangiomas cells.Conclusions:1.It was indicated that propranolol inhibited the proliferation of IHs by the regulation of HIF-1?.2.Propranolol and HIF-1? affect the biological function of HemECs,and they interact with each other and have opposite effects on hemangioma endothelial cells.3.A randomized and controlled study with large sample is needed to further clarify the mechanism of propranolol in infantile hemangiomas.