Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile Hemangioma: A Randomized Clinical Trial.

Importance: Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic ß-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events. Objective: To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH. Design, Setting, and Participants: 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. Interventions: Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d. Main Outcomes and Measure: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02505971.

Application of a colorimetric technique in quality control for printed pediatric orodispersible drug delivery systems containing propranolol hydrochloride.

The feasibility of a colorimetric technique was investigated in CIELAB color space as an analytical quality control method for content uniformity of printed orodispersible pediatric delivery systems. Inkjet printing was utilized to fabricate orodispersibe film formulations containing propranolol hydrochloride in a colored ink base using three different edible substrates. A thin sweetener coating layer of saccharin was successfully included in the final dosage forms for palatability purposes using a casting knife. Optical microscopy, scanning electron microscopy and scanning white light interferometry analyses were conducted to study the effect of printing on the surface morphology and topography of the substrates. Differential scanning calorimetry and attenuated total reflectance infrared spectroscopy were used to study the solid state properties and possible interactions between the drug and the excipients. The inkjet printing technique deposited precise and uniform escalating doses (0.08-3.16mg) of the active pharmaceutical ingredient onto the substrates (R(2)≥0.9934). A disintegration test with clear end-point detection confirmed that all the substrates meet the requirements of the Ph. Eur. to disintegrate within 180s. The colorimetric technique proved to be a reliable method to distinguish the small color differences between formulations containing an escalating dose of propranolol hydrochloride.

Dispersive liquid-liquid microextraction of propranolol enantiomers from human plasma based on the solidification of a floating organic droplet.

BACKGROUND: A dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet was developed and validated for the extraction of propranolol enantiomers from human plasma. The studied enantiomers were extracted from diluted and alkalized plasma samples using 1-undecanol as the extracting solvent. HPLC-fluorescence detection analyses were carried out on a chiral column, using n-hexane-ethanol (80:20, v/v) plus 0.2% triethylamine as the mobile phase, at a flow rate of 0.8 ml/min. The significant factors in the microextraction procedure, including extracting and disperser solvents volume, solution pH and salt contents were optimized by using a central composite design and the response surface methodology. RESULTS: Under optimized conditions, the mean recoveries were approximately 14% with linear responses over the 0.5-100 ng/ml concentration range for both enantiomers. The LOQ was 0.5 ng/ml (S/N = 10). Intra-day (n = 5) and inter-day (n = 3) assay precision (1 and 50 ng/ml) showed RSD lower than 8 and 9.5% for studied enantiomers, respectively. Finally, the method was successfully used for the determination of propranolol enantiomers in plasma samples obtained after single drug administration of racemic propranolol tablet to three healthy volunteers. The plasmatic concentrations of (-)-(S)-PROP were higher than those of (+)-(R)-PROP in all times after oral administration of the racemic drug. CONCLUSION: The obtained results proved that the proposed method is a powerful technique for sample preparation, providing suitable recoveries, efficient cleanup, high selectivity and sensitivity and low consumption of organic solvent for determination of the studied enantiomers in plasma samples after oral administration of the racemic drug to volunteers.

Avaliação da qualidade de comprimidos de propranolol e enalapril distribuídos no sistema público de saúde em uma cidade do sul do Brasil / Evaluation of the quality of propranolol and enalapril tablets supplied in the public health system in a southern Brazilian city

A aquisição de medicamentos no serviço público de saúde brasileiro através de licitação com critério de menor preço gera preocupação com a qualidade dos produtos distribuídos à população. O objetivo deste trabalho foi avaliar a qualidade dos comprimidos de Enalapril 10 mg e Propranolol 40 mg adquiridos através de processo licitatório e distribuídos na rede pública de saúde de um município catarinense durante o período de um ano. Foram analisados: o aspecto visual, o peso médio, a friabilidade, o teor de fármaco e o tempo de dissolução. De um total de sete lotes, cinco apresentaram desvio da qualidade. Encontraram-se irregularidades no aspecto visual, peso médio, friabilidade e teor de princípio ativo. A avaliação dos medicamentos além de assegurar que os medicamentos dispensados na rede pública possuem qualidade e que podem ser utilizados com segurança pelos pacientes é também uma ferramenta para a qualificação de fornecedores e um subsídio para o aprimoramento do processo licitatório. Sugere-se a implantação de um sistema de gestão da qualidade que inclua a qualificação de fornecedores, o aperfeiçoamento do processo de licitação, incluindo especificações claras sobre a qualidade dos medicamentos adquiridos, bem como o monitoramento da qualidade integrado a ações de farmacovigilância.

The acquisition of medication by the Brazilian public health service through bidding processes based on the lowest price criterion is a source of concern with respect to the quality of the products offered to the population. The scope of this work was to evaluate the quality of Enalapril 10 mg and Propranolol 40 mg tablets bought via the bidding process and supplied by the public health system in a city in the state of Santa Catarina, Brasil, over the course of a year. The visual aspect, weight variation, friability, drug content and dissolving time were analyzed. Out of seven lots, five presented quality deviation. Irregularities were found in the visual aspect, weight variation, friability and active ingredient. The evaluation of the quality of medication, besides ensuring the quality of the products supplied by the health system and safe usage by patients, is also a tool to evaluate medical supply companies and ensure the enhancement of the bidding process. The implementation of a management system that includes the evaluation of medical supply companies, improvement of the bidding process with clear specifications about the quality of the medicines bought are all recommended to ensure product safety.

[Evaluation of the quality of propranolol and enalapril tablets supplied in the public health system in a southern Brazilian city]. / Avaliação da qualidade de comprimidos de propranolol e enalapril distribuídos no sistema público de saúde em uma cidade do sul do Brasil.

The acquisition of medication by the Brazilian public health service through bidding processes based on the lowest price criterion is a source of concern with respect to the quality of the products offered to the population. The scope of this work was to evaluate the quality of Enalapril 10 mg and Propranolol 40 mg tablets bought via the bidding process and supplied by the public health system in a city in the state of Santa Catarina, Brasil, over the course of a year. The visual aspect, weight variation, friability, drug content and dissolving time were analyzed. Out of seven lots, five presented quality deviation. Irregularities were found in the visual aspect, weight variation, friability and active ingredient. The evaluation of the quality of medication, besides ensuring the quality of the products supplied by the health system and safe usage by patients, is also a tool to evaluate medical supply companies and ensure the enhancement of the bidding process. The implementation of a management system that includes the evaluation of medical supply companies, improvement of the bidding process with clear specifications about the quality of the medicines bought are all recommended to ensure product safety.

Propranolol in the prevention of recurrent upper gastrointestinal bleeding in patients with cirrhosis undergoing endoscopic sclerotherapy. A randomized controlled trial.

The purpose of this study was to investigate the possible value of continuous administration of propranolol in the prevention of recurrent upper gastrointestinal bleeding in patients with cirrhosis undergoing chronic endoscopic sclerotherapy. Among 239 patients admitted for acute variceal bleeding, 85 with cirrhosis were randomized to receive sclerotherapy either alone (40) or in combination with propranolol (45). Sclerotherapy was carried out with an intravariceal injection of 5% ethanolamine oleate through a fiberoptic endoscope. The procedure was performed every week, until the esophageal varices at the gastroesophageal junction were too small for any further injections. Varices were reinjected if they recurred. Propranolol was given orally twice a day until heart rate was reduced by 25% in the resting position. The mean follow-up period was 23.2 and 24.2 months for sclerotherapy and the sclerotherapy plus propranolol groups, respectively. During this period a significant (P = 0.001) reduction in the recurrence of esophageal varices was observed in patients treated with the combination of sclerotherapy plus propranolol compared with those treated with sclerotherapy alone. However, the time of rebleeding from any source or from esophageal varices did not differ significantly between the two groups. In the sclerotherapy group 21 patients rebled (35 bleeding episodes) compared with 14 (22 episodes) in the combination therapy group. Patients in the sclerotherapy group were more prone to bleed from gastric varices and congestive gastropathy than patients treated with the combination of sclerotherapy plus propranolol (P = 0.012). Twenty-five patients in the endoscopic sclerotherapy group developed complications attributed to sclerotherapy compared with 23 patients in the sclerotherapy plus propranolol group. Complications directly attributable to propranolol were observed in 11 patients. Three of these patients stopped taking the drug due to heart failure (1) and flapping tremor (2). Eight patients (17.8%) died in the latter group while the corresponding figure in the sclerotherapy group was nine (22.5%). It is concluded that the continuous administration of propranolol may reduce incidences of recurrent upper gastrointestinal hemorrhage from gastric sources in patients with cirrhosis undergoing chronic sclerotherapy.

A prospective randomized study to evaluate propranolol in patients undergoing long-term endoscopic sclerotherapy.

A prospective randomized double-blind study was conducted to evaluate the efficacy of propranolol in patients with portal hypertension undergoing long-term endoscopic sclerotherapy (EST) for recurrent variceal bleeding. Consecutive patients with portal hypertension (Child's class A or B) due to cirrhosis (n = 72), non-cirrhotic portal fibrosis (n = 29) and extrahepatic portal venous obstruction (n = 13) attending the liver clinic of a tertiary care center were included in the study. All patients had had at least one documented episode of variceal bleed in the previous 4 weeks. Fifty-eight patients received propranolol and 56 received placebo in addition to weekly EST. Rebleeding occurred in 12 (21%) patients in the placebo group and 10 (17%) patients in the propranolol group during a mean follow-up period of 24.4 +/- 10.4 months in the former and 23.8 +/- 9.2 months in the latter group (P > 0.1). The number of episodes of rebleeding (14 in the placebo and 12 in the propranolol group) were also similar (P > 0.1). The median bleeding-free period was more than 40 months in both treatment groups (P > 0.1). The mean transfusion requirements and the number of hospital admissions for rebleeding were also similar in the two treatment groups (P > 0.1). Complete obliteration of varices was achieved in 44 (78.9%) patients in the placebo group and 43 (75.5%) patients in the propranolol group (P > 0.1). Recurrence of new varices was seen in two patients in the placebo and in three of those in the propranolol group. Seven patients in the placebo group and five in the propranolol group died (P > 0.1). Complications related to EST were similar in the two treatment groups but additional adverse effects were observed in the propranolol group. The cumulative incidence of rebleeding in the placebo group was 12.7 and in the propranolol group it was 11.2 per 100 patient years of follow-up. It is concluded that the addition of propranolol in patients with portal hypertension and fair hepatic function on long-term EST does not confer any additional benefit.

[Method of evaluating antiarrhythmic therapy in patients with paroxysms of supraventricular tachycardia]. / Sposob otsenki antiaritmicheskoi terapii u bol'nykh s paroksizmami nadzheludochkovoi takhikardii.

Potentialities of the non-invasive method of trans-esophagus electrostimulation of the heart were studied with regard to the selection and assessment of the effectiveness of antiarrhythmic therapy in 16 patients with paroxysms of supraventricular reciprocal tachycardia. The antiarrhythmic therapy selected by this method proved effective in 13 patients following a prolonged course of treatment. The method was highly informative in predicting the efficacy of the systemic course treatment of patients with supraventricular tachycardia paroxysms.