Oral propranolol combined with topical timolol for compound infantile hemangiomas: a retrospective study.
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ABSTRACT:
SUBMITTER: Ge J
PROVIDER: S-EPMC4730155 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
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Project description:BackgroundEpidemiological studies evaluating treatments for infantile hemangiomas have produced inconsistent results. A meta-analysis of published data was conducted to investigate the effectiveness and safety of oral propranolol versus other treatments for infantile hemangiomas.MethodsA meta-analysis was conducted based on literature (published from 1960 to December 1, 2014) found on the PubMed, EMBASE, and OVID search engines. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the outcome measures. Heterogeneity, publication bias and subgroup analysis were performed.ResultsA total of 61 studies involving 5,130 participants met the inclusion criteria. Propranolol was found to be a more effective modality in treating IHs (ORs = 0.92; 95%CI, 0.89-0.95) and had fewer complications compared to the other treatments including systemic steroids (ORs = 0.68; 95% CI, 0.59-0.76); laser ablation (ORs = 0.55; 95% CI, 0.43-0.67); other beta-adrenergic blockers (ORs = 0.56; 95% CI, 0.50-0.61) and surgery (ORs = 0.55; 95% CI, 0.28-0.81). A subgroup analysis of propranolol showed that a dose of 2 mg/kg/day or more yielded better outcomes (ORs = 0.92; 95% CI, 0.88-0.95; ORs = 0.95; 95% CI, 0.89-1.00), and IHs that had not been previously treated had better responses to propranolol treatment (ORs = 0.95; 95% CI, 0.91-0.98).ConclusionsThe meta-analysis demonstrated that propranolol was more effective and safer than other therapies in treating IHs. It provides strong evidence for supporting the use of propranolol as a first-line therapy for IHs.
| S-EPMC4573957 | biostudies-literature
Project description:Although the efficacy of propranolol for the treatment of infantile hemangiomas (IHs) has been well documented, there is a paucity of clinical data regarding the safety and tolerance of propranolol in neonates. A prospective study of 51 patients less than 30 days of age with severe IH was conducted. All patients were admitted to the hospital for monitoring during initial propranolol treatment at day 0 with dose adjustments at days 7 and 28. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), blood glucose (BG) levels and potential side effects were evaluated during treatment. There were significant decreases in mean heart rate and SBP after the initiation of propranolol therapy (P < 0.05). In contrast, no significant differences in mean DBP and BG levels were observed after each dose during hospitalization (P > 0.05). Bradycardia and hypotension were noted in at least 1 recorded instance in 11.8% and 5.9% of patients, respectively. These hemodynamic changes were not persistent and were asymptomatic. Two patients who had a history of neonatal pneumonia reported severe bronchial hyperreactivity during treatment. This study demonstrated that propranolol administered to properly selected young infants was safe and well tolerated. However, close monitoring should be considered in high-risk young patients.
| S-EPMC5431448 | biostudies-literature
Project description:Infantile hemangiomas (IHs) are the most common benign tumors in early childhood. They show a distinctive mechanism of tumor growth in which a rapid proliferative phase is followed by a regression phase (involution). Propranolol is an approved treatment for IHs, but its mechanism of action remains unclear. We integrated and harmonized microRNA and mRNA transcriptome data from newly generated microarray data on IHs with publicly available data on toxicological transcriptomics from propranolol exposure, and with microRNA data from IHs and propranolol exposure. We identified subsets of putative biomarkers for proliferation and involution as well as a small set of putative biomarkers for propranolol's mechanism of action for IHs, namely EPAS1, LASP1, SLC25A23, MYO1B, and ALDH1A1. Based on our integrative data approach and confirmatory experiments, we concluded that hypoxia in IHs is regulated by EPAS1 (HIF-2α) instead of HIF-1α, and also that propranolol-induced apoptosis in endothelial cells may occur via mitochondrial stress.
| S-EPMC7039967 | biostudies-literature
Project description:Propranolol has become the first choice therapy for complicated Infantile Hemangiomas (IH). The pharmacokinetics of propranolol were evaluated after repeated oral administration of a new pediatric solution of propranolol at 3 mg kg-1 day-1 given twice daily (BID) in infants (77-243 days) with IH. A population model was built to describe the pharmacokinetics of propranolol in infants and to simulate different dosing regimens. One hundred and sixty-seven plasma concentrations from 22 infants were used in the population analysis. Weight effect was tested on apparent clearance and volume of distribution. Monte-Carlo simulations were performed for 4 dosing regimens: BID dosing with irregular or strict 12-hour intervals and 2 different 3 time daily dosing (TID) regimens. The best model was a one-compartment model with first-order absorption and elimination rates. The weight affected the clearance but not the volume. Typical oral clearance was estimated at 3.06 L hour-1 kg-1 (95% CI: 1.14-8.61 L hour-1 kg-1), close to adult clearance data. When regular BID dosing was compared to TID or irregular BID regimens, simulated median Cmin and Cmax were <20% different. To conclude, a model using a weight allometric function on clearance was established and confirmed that the dose in mg/kg should be used without adaptation by range of age in treatment of complicated IH. The simulations support the use of a BID dosing preferably to a TID dosing thanks to close Cmin and Cmax at steady state between both regimen and showed the possibility of irregular BID dosing, allowing early administration in the evening when needed.
| S-EPMC5925426 | biostudies-literature
Project description:ObjectiveThis study aimed to make use of real-world medical records to explore the clinical characteristics, treatments, and outcomes of infantile hemangiomas in southeastern China.MethodsThis study applied a retrospective observational method using real-world data derived from the electronic medical records of the Foshan Women and Children Hospital, southeastern China dated between June 2014 and June 2019.ResultsA total of 2427 patients with infantile hemangiomas were recruited in this study, including 942 (38.8%) males and 1485 (61.2%) females. Among the participants, 620 (25.5%) were high-risk infantile hemangioma, 449 (18.5%) were medium risk, and 1358 (56.0%) were low risk. A total of 14 treatment patterns in clinical practice were identified. The top 3 treatment patterns in each group of risk levels were the same: laser therapy, a combination of laser therapy and topical timolol maleate, and topical timolol maleate. The outcomes of the top 3 treatment patterns were significantly (P < 0.05) different in each risk group.ConclusionAmong the top 3 treatment patterns, laser therapy or a combination of laser therapy and topical timolol maleate were more likely to have an "Excellent" outcome.
| S-EPMC8685728 | biostudies-literature
Project description:Infantile hemangiomas (IH) are common vascular tumours. IH have a characteristic natural course. They proliferate rapidly during the early infantile period followed by a period of gradual regression over several years. Most of the uncomplicated IH undergo spontaneous involution, with a small proportion of cases requiring intervention. These are children with IH in life-threatening locations, local complications like haemorrhage, ulceration and necrosis and functional or cosmetic disfigurements. Systemic corticosteroids have been the first line of treatment for many years. Recently, non-selective beta-blockers, such as oral propranalol and topical timolol, have emerged as promising and safer therapies. Other treatment options include interferon ? and vincristine which are reserved for life-threatening haemangiomas that are unresponsive to conventional therapy. This review mainly focuses on the current trends and evidence-based approach in the management of IH.
| S-EPMC4134656 | biostudies-literature
Project description:Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. This has led to the widespread use of propranolol for the treatment of large and life-threatening hemangiomas of infancy. Infants receiving propranolol require monitoring to ensure that they do not suffer from side effects related to beta blockade. The exact mechanism of activity of propranolol in hemangioma of infancy is unknown. In this study, we treated hemangioma stem cells with both beta blockade active S- and inactive R-propranolol and looked for genes that were coordinately regulated by this treatment. Among the genes commonly downregulated, Angiopoietin-like 4 (ANGPTL4) was among the most regulated. We confirmed that propranolol isomers downregulated ANGPTL4 in endothelial cells, with greater downregulation of ANGPTL4 using the beta blockade inactive R-propranolol. ANGPTL4 is present in human hemangiomas of infancy. Finally, R-propranolol inhibited the growth of bEnd.3 hemangioma cells in vivo. The implication of this is that hemangioma growth can be blocked without the side effects of beta blockade. Given that humans have been exposed to racemic propranolol for decades and thus to R-propranolol, clinical development of R-propranolol for hemangiomas of infancy and other angiogenic diseases is warranted.
| S-EPMC6825155 | biostudies-literature
Project description:BackgroundInfantile Hemangiomas (IHs) are common benign vascular tumors of infancy that may have serious consequences. The research on diagnostic markers for IHs is scarce.MethodsThe "limma" R package was applied to identify differentially expressed genes (DEGs) in developing IHs. Plugin ClueGO in Cytoscape software performed functional enrichment of DEGs. The Search Tool for Retrieving Interacting Genes (STRING) database was utilized to construct the PPI network. The least absolute shrinkage and selection operator (LASSO) regression model and support vector machine recursive feature elimination (SVM-RFE) analysis were used to identify diagnostic genes for IHs. The receiver operating characteristic (ROC) curve evaluated diagnostic genes' discriminatory ability. Single-gene based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was conducted by Gene Set Enrichment Analysis (GSEA). The chemicals related to the diagnostic genes were excavated by the Comparative Toxicogenomics Database (CTD). Finally, the online website Network Analyst was used to predict the transcription factors targeting the diagnostic genes.ResultsA total of 205 DEGs were singled out from IHs samples of 6-, 12-, and 24-month-old infants. These genes principally participated in vasculogenesis and development-related, endothelial cell-related biological processes. Then we mined 127 interacting proteins and created a network with 127 nodes and 251 edges. Furthermore, LASSO and SVM-RRF algorithms identified five diagnostic genes, namely, TMEM2, GUCY1A2, ISL1, WARS, and STEAP4. ROC curve analysis results indicated that the diagnostic genes had a powerful ability to distinguish IHs samples from normal samples. Next, the results of GSEA for a single gene illustrated that all five diagnostic genes inhibited the "valine, leucine, and isoleucine degradation" pathway in the development of IHs. WARS, TMEM2, and STEAP4 activated the "blood vessel development" and "vasculature development" in IHs. Subsequently, inhibitors targeting TMEM2, GUCY1A2, ISL1, and STEAP4 were mined. Finally, 14 transcription factors regulating GUCY1A2, 14 transcription factors regulating STEAP4, and 26 transcription factors regulating ISL1 were predicted.ConclusionThis study identified five diagnostic markers for IHs and further explored the mechanisms and targeting drugs, providing a basis for diagnosing and treating IHs.
| S-EPMC9731762 | biostudies-literature
Project description:Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. order to gain further insights in the mechanisms of action of R-propranolol in vivo, we subjected vehicle- and R-propranolol-treated tumors to RNAseq analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that choline metabolism was the pathway most affected by R-propranolol treatment. Consistent with this, the most highly regulated gene by R-propranolol treatment was Betaine-Homocysteine Methyl Transferase (Bhmt). Other genes that are involved in tumor suppressive activities such as Early Growth Response 1 (Egr1) and AP-1 subunit, which are both transcription factors implicated in tumor suppression. Egr1 regulates important tumor suppressors such as PTEN and p53, and upregulates tumor necrosis factor α (TNF-α). Fos, which has been known to be rearranged and expressed frequently in epithelioid hemangioma, was also upregulated in R-propranolol-treated samples. The genes identified in the RNAseq analysis pose as interesting targets for further investigations.
2019-10-04 | GSE138403 | GEO
Project description:This study aimed to characterize the population pharmacokinetics and exposure-response relationship of propranolol (Hemangiol® Syrup for Pediatric) in infants with infantile hemangioma. Using nonlinear mixed-effects modeling with 63 pooled sets of plasma concentration-time data from 32 Japanese patients aged 35-150 days, we described the disposition of propranolol adequately by a 1-compartment model with first-order absorption. The estimated population mean apparent clearance and apparent central volume of distribution were 9.34 L/h and 146 L, respectively. Body weight and postnatal age influenced the population pharmacokinetic model. The clinical end points-success (complete or nearly complete resolution of the target hemangioma) and failure-at weeks 12 and 24 were characterized by logistic regression using the area under the concentration-time curve (AUC), estimated from the final population pharmacokinetic model, as an exposure predictor. The logistic regression showed that a higher AUC was associated with a higher probability of successful treatment. At each exposure level, probability of successful treatment was correlated with gestational age and treatment duration. Model-predicted probabilities of successful treatment were consistent with actual results in the clinical trial. Simulations using several dosing regimens indicated that oral propranolol at 3 mg/kg per day was effective and would be appropriate for treating Japanese infants. These simulation results can support optimization of dosing regimens, such as selecting amounts, treatment durations, and dosing intervals, for clinical use.
| S-EPMC6175224 | biostudies-literature