ZusammenfassungHintergrund und ZieleInfantile Hämangiome können sowohl durch systemische Propranolol‐ als auch durch Neodym:YAG‐Farbstofflaser‐Kombinationstherapie erfolgreich behandelt werden. In ...dieser retrospektiven Studie wurden Wirksamkeit und Sicherheit der sequenziellen und parallelen Therapie komplizierter Hämangiome, die mit beiden Verfahren behandelt wurden, evaluiert.Patienten und Methoden30 Kinder mit 48 komplizierten Hämangiomen wurden mit Propranolol‐ und Neodym: YAG‐Farbstofflaser‐Kombinationstherapie behandelt. Im Fotovergleich wurde die prozentuale Remissionsrate durch drei Untersucher anhand einer vierstufigen Skala bewertet (I: 0–25 %, II: 26–50 %, III: 51–75 % und IV: 76–100 %).ErgebnisseElf Kinder erhielten parallel Propranolol‐ und Lasertherapie (A), zwölf Kinder wurden nach Propranolol lasertherapiert (B) und sieben Kinder erhielten nach Lasertherapie Propranolol (C). Ein Kind konnte aufgrund einer Auswanderung ins Ausland nicht abschließend ausgewertet werden. Eine starke Verbesserung (IV) wurde bei 23/29 (79,3 %) aller behandelten Kinder festgestellt (A: 90,9 %, B 75 %, C 66,7 %). Die mittlere Dauer der Propranolol‐Therapie bei allen Kindern betrug 8,6 Monate (A: 8,9 Monate, B: 8,2 Monate, C: 8,9 Monate). Im Mittel erfolgten 2,33 Laserbehandlungen pro Hämangiom (A: 1,95, B: 3,2, C: 1,91). Schwerwiegende Nebenwirkungen durch die Propranolol‐ und Lasertherapie wurden nicht beobachtet.SchlussfolgerungenPropranolol‐ und Neodym: YAG‐Farbstofflaser‐Kombinationstherapie können sequenziell oder parallel sicher und effektiv eingesetzt werden und sich sinnvoll ergänzen.
Propranolol hydrochloride is a safe and effective medication for treating infantile hemangiomas (IHs), with decreases in IH volume, color, and elevation.
Forty children between the ages of 9 weeks ...and 5 years with facial IHs or IHs in sites with the potential for disfigurement were randomly assigned to receive propranolol or placebo oral solution 2 mg/kg per day divided 3 times daily for 6 months. Baseline electrocardiogram, echocardiogram, and laboratory evaluations were performed. Monitoring of heart rate, blood pressure, and blood glucose was performed at each visit. Children younger than 6 months were admitted to the hospital for monitoring after their first dose at weeks 1 and 2. Efficacy was assessed by performing blinded volume measurements at weeks 0, 4, 8, 12, 16, 20, and 24 and blinded investigator scoring of photographs at weeks 0, 12, and 24.
IH growth stopped by week 4 in the propranolol group. Significant differences in the percent change in volume were seen between groups, with the largest difference at week 12. Significant decrease in IH redness and elevation occurred in the propranolol group at weeks 12 and 24 (P = .01 and .001, respectively). No significant hypoglycemia, hypotension, or bradycardia occurred. One child discontinued the study because of an upper respiratory tract infection. Other adverse events included bronchiolitis, gastroenteritis, streptococcal infection, cool extremities, dental caries, and sleep disturbance.
Propranolol hydrochloride administered orally at 2 mg/kg per day reduced the volume, color, and elevation of focal and segmental IH in infants younger than 6 months and children up to 5 years of age.
Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited.
We performed a multicenter, randomized, ...double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs.
Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol.
This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).
Given the widespread use of propranolol in infantile hemangioma (IH) it was considered essential to perform a systematic review of its safety. The objectives of this review were to evaluate the ...safety profile of oral propranolol in the treatment of IH.
We searched Embase and Medline databases (2007-July 2014) and unpublished data from the manufacturer of Hemangiol/Hemangeol (marketed pediatric formulation of oral propranolol; Pierre Fabre Dermatologie, Lavaur, France). Selected studies included ≥10 patients treated with oral propranolol for IH and that either reported ≥1 adverse event or effect (AE) or planned to capture AEs. Data capture was standardized and extracted study design, demographic characteristics, IH characteristics, intervention, and safety outcomes. AEs were assigned a system organ class and preferred term.
A total of 83 of 398 identified literature records met the inclusion criteria, covering 3766 propranolol-treated patients. The manufacturer's data for 3 pooled clinical trials (435 propranolol-treated patients) and 1 Compassionate Use Program (1661 patients) were included. AE data were reported for 1945 of 5862 propranolol-treated patients. The most frequently reported AEs included a range of sleep disturbances, peripheral coldness, and agitation. The most serious AEs (atrioventricular block, bradycardia, hypotension, bronchospasm/bronchial hyperreactivity, and hypoglycemia-related seizures) were managed by decreasing doses or temporary/permanent discontinuation of propranolol. Limitations included the variety of included study designs; monitoring, collection, and reporting of AE data; small sample sizes for some articles; and the wide scope of review.
Oral propranolol is well tolerated if appropriate pretreatment assessments and within-treatment monitoring are performed to exclude patients with contraindications and to minimize serious side effects during treatment.
Propranolol, a chiral drug with two configurations, i.e., (R)-propranolol hydrochloride (RPH) and (S)-propranolol hydrochloride (SPH), has racemes that can be used in clinical diagnosis due to their ...synergistic effects. SPH has a β-receptor blocking effect, and RPH has an antiarrhythmic effect. In pH 4.6 Britton-Robinson (BR) buffer solution, both RPH and SPH can react with erythrosine B to form 1:1 ion-association complexes. In the SPH-Ery B reaction system, a remarkable enhancement of the resonance Rayleigh scattering (RRS) signal located at 338nm was observed. However, a similar phenomenon was not obvious and was unstable in the RPH-Ery B reaction system. Based on this result, a simple, novel and sensitive method for the determination of SPH was proposed based on the RRS technique. The linear range and limit of detection were 0.0680~4.0µgmL−1 and 20.6ngmL−1, respectively. Additionally, the spectroscopic approaches of frequency doubling scattering (FDS) and second-order scattering (SOS) were also proposed for SPH detection in this article. The interaction information regarding the mechanism of the reaction, suitable reaction conditions, influencing factors and the effects of mixed solutions were our investigation aims. The method had been applied to the determination of SPH in fresh serum and urine samples of healthy human subjects with satisfactory results.
The figure is RRS spectra of SPH and RPH react with Ery B. From Fig a, it can be seen that RRS intensities of single SPH, RPH and Ery B is very weak under optimum conditions. When SPH and RPH react with Ery B to form two binary complexes, the new spectra of RRS appeared with their intensities enhanced remarkably. While the intensity of RRS of SPH-Ery B is higher than that of RPH-Ery B, and the latter is very instable. Fig b shows that the enhancement of RRS intensities is directly proportional to the concentration of SPH at 338nm. So RRS method can be applied to the quantitative determination of trace SPH. Display omitted
•(S)- and (R)-propranolol HCl can react with erythrosine B to form complex systems.•The effects of two systems on resonance Rayleigh scattering spectra are different.•The differences could be the basis of simultaneous determination of RPH and SPH.•We propose a simply, rapid and sensitive RRS method for determining SPH.•The possible mechanism for RRS enhancement of SPH- Ery B system was discussed.
Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic β-blockers, such as nadolol, may be preferable in individuals who ...experience propranolol unresponsiveness or adverse events.
To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH.
This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement.
Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d.
Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale.
The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions.
Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required.
ClinicalTrials.gov Identifier: NCT02505971.
A GO-FAM labeled aptamer (Hydroxyfluorescein labeled aptamer)-propranolol fluorescent light switch was constructed for chiral propranolol recognition. In the absence of S-propranolol, the FAM-labeled ...aptamers were adsorbed by GO and the fluorescence quenching of the system was carried out. In the presence of S-propranolol, the FAM-labeled aptamers were closely bound to S-propranolol to restore the fluorescence of the system. The method is simple, sensitive and highly specific for the recognition of S-propranolol. It can be used for the recognition of chiral propranolol.
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•High selectivity due to the introduction of specific aptamers.•GO as a quenching agent with strong adsorption and the phenomenon is obvious.•The identification of S-propranolol in racemic propranolol and its quantitative detection without separation were realized.
In this work, specific aptamers with affinity for S-propranolol were screened by SELEX technology based on the graphene oxide (GO) adsorption platform, and a GO-FAM labeled aptamer-propranolol fluorescent optical switch system was constructed for the recognition of chiral propranolol. It was found that the fluorescence quenching of FAM labeled aptamer could be caused by the adsorption of GO. However, when S-propranolol was introduced, S-propranolol could pull out the aptamer adsorbed by GO, and the fluorescence of the system could be restored. But, R-propranolol could not be realized. Therefore, a simple and sensitive fluorescent optical switch system was established to identify chiral propranolol and perform highly sensitive detection of S-propranolol.
Infantile hemangiomas (IHs) are common neoplasms composed of proliferating endothelial-like cells. Despite the relative frequency of IH and the potential severity of complications, there are ...currently no uniform guidelines for treatment. Although propranolol has rapidly been adopted, there is significant uncertainty and divergence of opinion regarding safety monitoring, dose escalation, and its use in PHACE syndrome (PHACE = posterior fossa, hemangioma, arterial lesions, cardiac abnormalities, eye abnormalities; a cutaneous neurovascular syndrome characterized by large, segmental hemangiomas of the head and neck along with congenital anomalies of the brain, heart, eyes and/or chest wall). A consensus conference was held on December 9, 2011. The multidisciplinary team reviewed existing data on the pharmacologic properties of propranolol and all published reports pertaining to the use of propranolol in pediatric patients. Workgroups were assigned specific topics to propose protocols on the following subjects: contraindications, special populations, pretreatment evaluation, dose escalation, and monitoring. Consensus protocols were recorded during the meeting and refined after the meeting. When appropriate, protocol clarifications and revision were made and agreed upon by the group via teleconference. Because of the absence of high-quality clinical research data, evidence-based recommendations are not possible at present. However, the team agreed on a number of recommendations that arose from a review of existing evidence, including when to treat complicated IH; contraindications and pretreatment evaluation protocols; propranolol use in PHACE syndrome; formulation, target dose, and frequency of propranolol; initiation of propranolol in infants; cardiovascular monitoring; ongoing monitoring; and prevention of hypoglycemia. Where there was considerable controversy, the more conservative approach was selected. We acknowledge that the recommendations are conservative in nature and anticipate that they will be revised as more data are made available.
Hemangiomas are the most common benign vascular tumors of infancy. Although most infantile hemangiomas (IHs) have the ability to involute spontaneously after initial proliferation and resolve without ...consequence, intervention is required in a subset of IHs, which develop complications resulting in ulceration, bleeding, or aesthetic deformity. The primary treatment for this subset of IHs is pharmacological intervention, and propranolol has become the new first-line treatment for complicated hemangiomas. Here, we evaluated the efficacy of propranolol on proliferation IH in a clinical cohort including 578 patients.
We retrospectively reviewed a total of 578 IH patients who were treated with oral propranolol from January 2010 to December 2012. Responses to the propranolol treatment were graded as: excellent, good, poor, or no response. Based on the response to propranolol treatment (once daily at a dose of 1.0 mg/kg for patients younger than 2 months; twice daily at daily total dose of 2 mg/kg for patients older than 2 months), additional pharmacotherapies or surgery were used for IH patients for satisfactory clinical outcome.
Five hundred and sixty (96.9%) of 578 IH patients in our study responded to oral propranolol treatment, and the response rate was significantly different for different ages of patients (
<0.05), with the youngest patients having the highest response rate. The mean time of treatment was 6 months (range, 3-12 months). For example, response rate to propranolol was 98.1% in patients younger than 2 months, compared with 93.3% in patients older than 2 months and younger than 8 months, and 73.7% in patients older than 8 months. One hundred and thirty one patients who exhibited incompletely involuted hemangiomas were further treated with timolol maleate (n=89) or pulsed dye laser (n=42). One hundred and seventeen (89.3%) of 131 patients showed a positive response. There were no instances of life-threatening complications after propranolol. However, minor side effects were observed including 10 (1.73%) cases of sleep disturbance, 7 (1.21%) cases of diarrhea, and 5 (0.86%) cases of bronchospasm.
IH requires early intervention. During the involution phase, tapering propranolol dosage can be done to minimize side effects before discontinuing treatment. For patients exhibiting telangiectasia and chromatosis after propranolol treatment, administration of a 0.5% solution of timolol maleate or pulse dye laser is an effective therapeutic approach for complete involution.
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