The effects of suppressing the biological stress systems on social threat-assessment following acute stress.

RATIONALE: Stress is associated with increased sensitivity to threat. Previous investigations examining how stress affects threat processing have largely focused on biomarker responses associated with either the sympathetic-nervous-system (SNS) or the hypothalamus-pituitary-adrenal (HPA) axis. OBJECTIVES: We pharmacologically suppressed activations of SNS, HPA, or both, prior to stress and investigated how each stress system modulates social threat assessment. METHODS: One hundred sixty-one healthy men and women were randomized in a between-subject design, to one of four pharmacological or placebo conditions: dexamethasone-placebo, placebo-propranolol, dexamethasone-propranolol, or placebo-placebo. Participants provided threat assessments for angry and neutral human faces on a baseline day, and immediately after stress induction on a testing day. RESULTS: With both systems responding normally to stress (placebo-placebo), threat assessment was higher for neutral faces compared with angry. Compared with placebo, SNS suppression resulted in increased threat assessment for angry faces. HPA suppression resulted in decreased threat assessment for neutral and angry faces. When both systems were suppressed, there was an increase in threat assessment for angry faces, and no difference from placebo for neutral. CONCLUSION: Our findings demonstrated that when intact, the biological stress systems adaptively support organisms during stress by focusing attention towards specific stimuli that are relevant to the threat. Dysregulations of the stress systems result in important system specific consequences on threat evaluation, such that suppression of either stress system alone resulted in reduced threat assessment for contextually relevant threatening stimuli, whereas when both systems were suppressed, individuals appear indiscriminately attentive to all potential threats in the environment, resulting in increased threat processing of both contextually relevant and irrelevant stimuli. Given that stress-related psychopathologies have been associated with dysregulations of the stress systems and biased responses to social threat, a systematic understanding of the mechanisms that underlie how stress systems modulate social threat assessment is needed, and can provide important insights into the cognitive processes that are involved in the development and maintenance of stress-related psychopathologies.

Association of Weight-Adjusted Caffeine and ß-Blocker Use With Ophthalmology Fellow Performance During Simulated Vitreoretinal Microsurgery.

Importance: Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance. Objectives: To establish weight-adjusted cutoffs for caffeine and ß-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons. Design, Settings, and Participants: This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg). Interventions: Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days. Main Outcomes and Measures: An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons. Results: Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, -53.0; 95% CI, -99.3 to -6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, -12.0; 95% CI, -21.2 to -2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, -51.0; 95% CI, -77.6 to -24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, -16.0; 95% CI, -31.8 to -0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03). Conclusions and Relevance: The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.

Assessment of Oral Propranolol Administration for Infantile Hemangioma in Oral and Maxillofacial Region Aided by Ultrasonography.

BACKGROUND: Propranolol has become the first-line therapy for the treatment of complicated infantile hemangioma. However, there are still many queries regarding the hemangioma volume in relation to drug's dose and duration. OBJECTIVE: The aim of this study was to evaluate the therapeutic effect of oral propranolol for treating infantile hemangiomas in the oral and maxillofacial region aided by gray scale ultrasonography (GSU). MATERIALS AND METHODS: Twelve patients with infantile hemangioma, age ranged between 2 and 11 months, have been treated with oral propranolol for 6 months' period. They received a dose of 1 mg/kg per body weight per day, increased after 1 week to 2 mg/ kg per body weight per day maintenance for 24 weeks. The changes in tumor sizes were evaluated by ultrasonography (GSU) using 4-points scale system: excellent, good, fair, poor) RESULTS:: All infants less than 6 months of age showed more hemangiomas regression in size in comparison with of those aged >6 months (P value 0.042) as a rapid response. After the 24 week; 5 patients had excellent results, 4 patients had good results, 2 patients had fair results, and only 1 patient had poor results. None of the treated infants showed rebound phenomena after cessation of treatment. CONCLUSION: Oral propranolol at dose of 2 mg/kg/day in 2 divided doses for 24 weeks aided by GSU is shown to be a safe and effective treatment of infantile hemangioma during the proliferative phase.

Safety assessment during initiation and maintenance of propranolol therapy for infantile hemangiomas.

BACKGROUND: Propranolol is an effective method of treatment for infantile hemangiomas (IH). A recent concern is a shift of the therapy into outpatient settings. OBJECTIVES: The aim of the study was to evaluate the safety of initiating and maintaining propranolol therapy for IH. MATERIAL AND METHODS: The study involved 55 consecutive children with IH being treated with propranolol. The patients were assessed in the hospital at the initiation of the therapy and later in outpatient settings during and after the therapy. Each time, the following monitoring methods were used: physical examination, cardiac ultrasound (ECHO), electrocardiography (ECG), blood pressure (BP), heart rate (HR), and biochemical parameters: blood count, blood glucose, aspartate transaminase (AST), alanine transaminase (ALT), and ionogram. The therapeutic dose of propranolol was 2.0 mg/kg/day divided into 2 doses. RESULTS: Four children were excluded during the qualification or the initiation of propranolol; a total of 51 patients were subject to the final analysis. All the children presented clinical improvement. There was a significant reduction in the mean HR values only at the initiation of propranolol. There were no changes in HR during the course of the therapy. Blood pressure values were within normal limits. Both systolic and diastolic values decreased in the first 3 months. Bradycardia and hypotension were observed sporadically, and they were asymptomatic. Electrocardiography did not show significant deviations. The pathological findings of the ECHO scans were not a contraindication to continuing the therapy. There were no changes in biochemical parameters. Apart from 1 symptomatic case of hypoglycemia, other low glucose episodes were asymptomatic and sporadic. The observed adverse effects were mild and the propranolol dose had to be adjusted in only 6 cases. CONCLUSIONS: Propranolol is effective, safe and well-tolerated by children with IH. The positive results of the safety assessment support the strategy of initiating propranolol in outpatient settings. Future studies are needed to assess the benefits of the therapy in ambulatory conditions.

Cloridrato de propranolol (solução oral 3, 75 mg/mL) para pacientes com hemangioma infantil / Propranolol hydrochloride (oral solution 3. 75 mg/mL) for patients with childhood hemangioma

INTRODUÇÃO: Os hemangiomas infantis (HI) são os tumores vasculares benignos mais comuns na infância, presentes em cerca de 4%-5% da população. A grande maioria dos HI não apresenta complicações nem necessita de intervenção terapêutica, mas alguns deles podem estar associados a alterações estéticas relevantes e morbidade manifesta. São caracterizados por uma fase de rápida proliferação de vasos sanguíneos no primeiro ano de vida, seguida por uma fase de involução, na qual ocorre uma regressão gradual do tecido vascular, que é substituído por tecido fibroso, e uma fase na qual não há mais modificação na lesão, chamada involuída. Para pacientes com HI complicados, que necessitam tratamento, a conduta medicamentosa é a escolha para a maioria dos pacientes. As principais opções terapêuticas são o propranolol, os glicocorticoides e a alfainterferona. Contudo, antes da escolha terapêutica, é fundamental a avaliação do risco/benefício de cada uma das opções. TECNOLOGIA: Cloridrato de Propranolol (Promangiol®). PERGUNTA: O uso do Cloridrato de Propranolol (Promangiol®) 3,75 mg/mL de solução oral é mais eficaz, seguro ou custo-efetivo em pacientes com hemangioma infantil proliferativo quando comparado as alternativas já disponíveis atualmente no SUS? EVIDÊNCIAS CIENTÍFICAS: Os estudos demostram eficácia e segurança do Cloridrato de Propranolol em comparação ao placebo, mas nenhum estudo que avaliasse comparativamente as duas formas farmacêuticas de Cloridrato de Propranolol (comprimido e solução oral), ou outros comparadores foi encontrado. Portanto não podemos inferir sobre a superioridade, inferioridade ou igualdade entre Promangiol® e as alternativas já disponíveis no SUS. Também não encontramos nenhum estudo que avaliou adesão ao tratamento ou qualidade de vida entre os comparadores. AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-utilidade, os dados de eficácia e efetividade resultaram em um total de anos de vida ajustados à qualidade de 15,45 anos para o Cloridrato de Propranolol (Promangiol®) e de 10,80 para o placebo (resultado considerando desconto). O resultado incremental foi de 4,65 anos de vida ganhos ajustados à qualidade para o Promangiol® (propranolol) quando comparado com a opção de tratamento placebo. A relação entre esses dois resultados é a taxa de custo-utilidade incremental. Esse foi de R$ 776,34/QALY ganho para o Promangiol® (propranolol) comparado com placebo. O modelo possui grandes limitações nos dados de utilidades e no levantamento dos custos, limitando a interpretação dos resultados. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário estimado da incorporação do Cloridrato de Propranolol (Promangiol®) solução oral 3,75 mg/ml no SUS, dados os parâmetros considerados, é de R$166.086.958,58 em cinco anos. O valor anual do impacto variou entre R$ 12.987.986,92 (2019) e R$50.674.403,28 (2023). O modelo possui grandes limitações na análise, o que inviabiliza a interpretação dos resultados. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foi encontrada uma tecnologia nova no horizonte para tratamento do hemangioma infantil: o nadolol suspensão oral. O estudo clínico NCT02505971, de fase 3, que está em andamento, compara nadalol com propranolol suspensão oral. A previsão de término do estudo é dezembro de 2018. CONSIDERAÇÕES: Embora o Cloridrato de Propranolol tem sido usado off-label durante vários anos para o tratamento de hemangioma infantil, ainda devemos ser cautelosos quanto à sua segurança. O perfil de segurança do tratamento em longo prazo em pacientes pediátricos ainda não foi estabelecido. Além disso, apesar das evidências clínicas demonstradas nos estudos apresentados, uma redução de preço seria necessária para justificar o financiamento da tecnologia. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros presentes em sua 71º reunião ordinária, no dia 04 de outubro de 2018, deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar desfavorável à incorporação do Cloridrato de Propranolol (Promangiol®) 3,75 mg/mL de solução oral para tratamento de pacientes com hemangioma infantil proliferativo. CONSULTA PÚBLICA: Foram recebidas 5 contribuições técnico-científicas e 35 contribuições de experiência e opinião durante o período de consulta pública, entre 16 de outubro a 05 de novembro de 2018. Dentre as contribuições, a maioria foram contrárias à recomendação da CONITEC. Nenhuma evidência científica adicional foi encontrada nas contribuições. Os principais argumentos abordados foram a segurança de dosagem, formulação especifica para pacientes pediátricos e eficácia comprovada da tecnologia. O plenário da CONITEC entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da CONITEC presentes na 73ª reunião ordinária, nos dias 05 e 06 de dezembro de 2018, deliberaram, por unanimidade, a não recomendação de incorporação ao SUS do medicamento Cloridrato de Propranolol (Promangiol®) solução oral. Foi assinado em 06 de dezembro o registro de deliberação nº 412/2018 pela não incorporação do Cloridrato de Propranolol (Promangiol®) solução oral ao SUS. DECISÃO: Não incorporar o cloridrato de propranolol (solução oral 3,75 mg/ml) para pacientes com hemangioma infantil, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 89, publicada no Diário Oficial da União (DOU) nº 249, seção 1, página 434, em 28 de dezembro de 2018.

Safety of Oral Propranolol for Infantile Hemangioma.

OBJECTIVES: The safety of oral propranolol for infantile hemangioma has not yet been studied at population level since the pediatric use marketing authorization was obtained in Europe. METHODS: A survey of a nationwide, claim-based observational cohort of children <3 years old, with at least 1 delivery of oral propranolol between July 2014 and June 2016, was performed by using the database of the French National Health Insurance system. Standardized morbidity ratios (SMRs) were calculated by using, from the same database, a representative random sample of nonexposed subjects. The main outcomes were hospitalizations for cardiovascular (conduction disorders, bradycardia, and hypotension), respiratory (bronchial hyperactivity and bronchospasm), or metabolic events (hypoglycemia and hyperkalaemia), identified through the hospitalization diagnostic codes of the International Classification of Diseases, 10th Revision. The main analysis was conducted separately on "healthy" children (N = 1484), that is, free from of any prespecified underlying disease and on children with 1 of these underlying diseases (N = 269). RESULTS: In all, 1753 patients <3 years of age had at least 2 deliveries of oral propranolol. In the healthy population, we observed 2 cardiovascular events (SMR = 2.8 [0-6.7]), 51 respiratory events (SMR = 1.7 [1.2-2.1]), and 3 metabolic events (SMR = 5.1 [0-10.9]). In the population with an underlying disease (mainly congenital heart disease), we observed 11 cardiovascular events leading to an SMR of 6.0 (2.5-9.6). SMRs were not significantly raised for respiratory or metabolic events in this "nonhealthy" population. CONCLUSIONS: In this study on a large continuous nationwide claims database, we confirm the safety profile of oral propranolol in healthy children to be good.

Propranolol pharmacokinetics in infants treated for Infantile Hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.

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.

Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal.

Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following ß-adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic ß-adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and ß-blockade (AUCPropranolol-AUCSaline, ß-REE) and as a percent (%) of control (AUCPropranolol÷AUCSaline × 100). ß-REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: ß-REE R = -0.58, P = 0.03; %REE R = -0.56, P = 0.04; NE: ß-REE R = -0.55, P = 0.0535; %REE R = -0.54, P = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity.

Assessment of Haemodynamic Response to Nonselective Beta-Blockers in Portal Hypertension by Phase-Contrast Magnetic Resonance Angiography.

A significant unmet need exists for accurate, reproducible, noninvasive diagnostic tools to assess and monitor portal hypertension (PHT). We report the first use of quantitative MRI markers for the haemodynamic assessment of nonselective beta-blockers (NSBB) in PHT. In a randomized parallel feasibility study in 22 adult patients with PHT and a clinical indication for NSBB, we acquired haemodynamic data at baseline and after 4 weeks of NSBB (propranolol or carvedilol) using phase-contrast MR angiography (PC-MRA) in selected intra-abdominal vessels. T1 mapping of liver and spleen was undertaken to assess changes in tissue composition. Target NSBB dose was achieved in 82%. There was a substantial reduction from baseline in mean average flow in the superior abdominal aorta after 4 weeks of NSBB therapy (4.49 ± 0.98 versus 3.82 ± 0.86 L/min, P = 0.03) but there were no statistically significant differences in flow in any other vessels, even in patients with >25% decrease in heart rate (47% of patients). Mean percentage change in liver and spleen T1 following NSBB was small and highly variable. In conclusion, PC-MRA was able to detect reduction in cardiac output by NSBB but did not detect significant changes in visceral blood flow or T1. This trial was registered with the ISRCTN registry (ISRCTN98001632).

A new analysis of heart rate variability in the assessment of fetal parasympathetic activity: An experimental study in a fetal sheep model.

Analysis of heart rate variability (HRV) is a recognized tool in the assessment of autonomic nervous system (ANS) activity. Indeed, both time and spectral analysis techniques enable us to obtain indexes that are related to the way the ANS regulates the heart rate. However, these techniques are limited in terms of the lack of thresholds of the numerical indexes, which is primarily due to high inter-subject variability. We proposed a new fetal HRV analysis method related to the parasympathetic activity of the ANS. The aim of this study was to evaluate the performance of our method compared to commonly used HRV analysis, with regard to i) the ability to detect changes in ANS activity and ii) inter-subject variability. This study was performed in seven sheep fetuses. In order to evaluate the sensitivity and specificity of our index in evaluating parasympathetic activity, we directly administered 2.5 mg intravenous atropine, to inhibit parasympathetic tone, and 5 mg propranolol to block sympathetic activity. Our index, as well as time analysis (root mean square of the successive differences; RMSSD) and spectral analysis (high frequency (HF) and low frequency (LF) spectral components obtained via fast Fourier transform), were measured before and after injection. Inter-subject variability was estimated by the coefficient of variance (%CV). In order to evaluate the ability of HRV parameters to detect fetal parasympathetic decrease, we also estimated the effect size for each HRV parameter before and after injections. As expected, our index, the HF spectral component, and the RMSSD were reduced after the atropine injection. Moreover, our index presented a higher effect size. The %CV was far lower for our index than for RMSSD, HF, and LF. Although LF decreased after propranolol administration, fetal stress index, RMSSD, and HF were not significantly different, confirming the fact that those indexes are specific to the parasympathetic nervous system. In conclusion, our method appeared to be effective in detecting parasympathetic inhibition. Moreover, inter-subject variability was much lower, and effect size higher, with our method compared to other HRV analysis methods.

Assessment of the effectiveness of topical propranolol 4% gel for infantile hemangiomas.

BACKGROUND: Infantile hemangiomas (IHs) are the most common vascular tumors in children. Because of their benign character and natural involution, the vast majority of IHs do not require any treatment. In the past few years, topical beta blockers have been reported to be an effective treatment of superficial IHs. OBJECTIVE: We sought to evaluate the clinical effectiveness and safety profile of topical propranolol 4% gel for the treatment of IHs. METHODS: A retrospective study of all cases of IHs treated with topical propranolol 4% gel between 2013 and 2015 was performed. All patients were evaluated in a pediatric dermatology unit of a tertiary medical center. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. RESULTS: The study included 63 patients with a total of 75 IHs. Of the total number of IHs, 43 (57.3%) showed a good response to treatment, 19 (25.3%) a partial response, and 13 (17.33%) poor or no response, thus 62 (82.6%) had good or partial response to treatment. Age at treatment initiation, treatment time, thickness of the superficial component, and size of the lesions were shown to predict response to therapy. Out of the entire examined group, only two patients reported minor local side effects manifested by irritation, redness, and scaling of the treated area. No systemic adverse effects were reported. LIMITATIONS: This is an uncontrolled retrospective study. CONCLUSION: Propranolol 4% gel is a safe and efficient topical therapy for IH.

An in-vitro-in-vivo taste assessment of bitter drug: comparative electronic tongues study.

OBJECTIVES: The efficiency of the Astree e-tongue and Taste Sensing system TS5000Z for the evaluation of the taste masking effect of hot melt extruded formulations was investigated in this study. METHODS: Hot melt extrusion (HME) processing was optimized using Randcastle single screw extruder (USA) to manufacture extrudates with desirable characteristics. Cationic model drug propranolol HCl (PRP) was processed with the anionic polymers - Eudragit L100 (L100) and Eudragit L100-55 (Acryl-EZE). Solid state of the drug in polymer matrices was evaluated by scanning electron microscopy (SEM), differential scanning calorimetry, particle size analysis, Fourier transform infrared (FTIR) and Nuclear magnetic resonance (NMR) analysis. In-vitro taste masking efficiency of the two polymers was performed by using two different e-tongues (Astree e-tongue and TS5000Z). The results obtained from both e-tongues were further compared and contrast to find out the sensor outputs in all formulations. KEY FINDINGS: Solid state analysis of the extruded formulations revealed the presence of amorphous PRP. Both e-tongues were able to detect the taste masking variations of the extrudates and were in good agreement with the in-vivo results obtained from a panel of six healthy human volunteers (R(2) > 0.84). However, each e-tongue sensor demonstrated different sensitivity, suggesting a careful consideration of the experimental findings during melt extrusion, is necessary for the development of taste-masked formulations. Furthermore, FTIR spectroscopy and NMR studies revealed possible drug polymer intermolecular interactions as the mechanism of successful taste masking. CONCLUSIONS: HME can effectively be used to manufacture taste-masked extruded formulations, while both e-tongues demonstrated satisfactory taste analysis for the development of taste-masked formulations.

Propranolol and periocular capillary hemangiomas: assessment of refractive effect.

PURPOSE: To assess the effects of systemic propranolol on refractive error in infants with periocular capillary hemangiomas. METHODS: A single-center study of consecutive patients with capillary hemangiomas treated with systemic propranolol. Refractive data were analyzed using Long's matrix formalism and the methods of Harris and Kaye. RESULTS: Seventeen patients were included. At 6 months postoperatively, hemangioma size reduced from 3,214 to 1,806 mm(3) (standard deviation: 4,122 to 2,441). Mean refractive error in the affected eye significantly reduced: -1.25/0.38 × 36 (95% confidence intervals: -5.08/1.20 × 90 to 1.64/1.43 × 180, P = .048) with a smaller change (P = .06) in the unaffected eye of -1.01/+0.31 × 3.16 (95% confidence intervals: -4.02/+1.12 × 180 to +1.49/+0.51 × 90). CONCLUSIONS: Propranolol produced a clinically significant reduction in the infants' refractive error and anisometropia. The reduction in the total refractive error and anisometropia has not been evident in previous analyses, which have concentrated on the change in the "cylinder" as the principal outcome measure.

Assessment of xanthan gum based sustained release matrix tablets containing highly water-soluble propranolol HCl.

The present study was carried out to develop oral sustained release tablets of propranolol HCl by different ratios of drug : matrix. Tablets were prepared by direct compression technique using xanthan gum and lactose. All the formulations (tablets) were evaluated for thickness, diameter, hardness, friability, weight variation, content of active ingredient, in vitro dissolution using USP dissolution apparatus-II and swelling index. In case of dissolution, an inverse relationship was noted between amount of xanthan gum and release rate of propranolol HCl and the drug release was gradually enhanced as the amount of the lactose increased. The direct release was observed between swelling index and xanthan gum concentration. Significant difference in different media was observed in release profile, indicating that propranolol HCI has better solubility in HCI buffer pH 1.2. Moreover, dissolution data at differing stirring speeds was also analyzed, indicating that the drug release profile was at 50 rpm comparative to 100 rpm. The kinetic treatment showed the best fitted different mathematical models (zero order, first order, Higuchi's, Hixson-Crowell and Korsmeyer Peppas model. Most of the formulations showed linearity in Higuchi's model. The drug release from these tablets was by Fickian diffusion and anomalous (non-Fickian) mechanisms.

Endocardial surface area tracking for assessment of regional LV wall deformation with 3D speckle tracking imaging.

OBJECTIVES: The aim of this experimental study was to validate area tracking by 3-dimensional (3D) speckle tracking imaging (STI) as a method to measure changes in regional left ventricular (LV) endocardial surface area with sonomicrometry and to assess the usefulness as a wall motion evaluation method compared with 1-dimensional strain parameters. BACKGROUND: A 3D-STI allows for tracking a regional endocardial surface area during a cardiac cycle. Area tracking is a new concept that regional wall motion is quantified through the magnitude of deformation in an endocardial surface area. METHODS: In each of 8 anesthetized sheep, sonomicrometry crystals were implanted on the endocardium at the LV mid and apical anterior walls. Area change ratio (ACR) that was a novel parameter obtained by area tracking was measured as percentage change in a segmental area during systole. Segmental longitudinal (LS) and circumferential strain (CS) also were measured by 3D-STI. The ACR, LS, and CS were compared with those by sonomicrometry at baseline and during pharmacological stress tests (dobutamine and propranolol infusion) and acute myocardial ischemia induced by occlusion of mid-left ascending artery. RESULTS: The strong correlation was observed between ACR measurements by 3D-STI and those by sonomicrometry (Y = -4.20 + 0.84X, r = 0.87, p < 0.001). The ACR showed significant relations with both LS and CS (LS: Y = -15.1 + 1.73X, r = 0.73, p < 0.001; CS: Y = -5.85 + 1.06X, r = 0.79, p < 0.001). ACR showed significant differences among baseline, pharmacological stress, and acute myocardial ischemia. In contrast, LS and CS were reduced significantly during acute ischemia studies compared with those during the other studies; no differences were observed among baseline, propranolol infusion, and dobutamine infusion studies. CONCLUSIONS: Area tracking by 3D-STI can estimate changes in LV regional area and might be promising for regional wall motion evaluations.

P3MC: a double blind parallel group randomised placebo controlled trial of Propranolol and Pizotifen in preventing migraine in children.

BACKGROUND: A recent Cochrane Review demonstrated the remarkable lack of reliable clinical trials of migraine treatments for children, especially for the two most prescribed preventative treatments in the UK, Propranolol and Pizotifen.Migraine trials in both children and adults have high placebo responder rates, e.g. of 23%, but for a trial's results to be generalisable "placebo responders" should not be excluded and for a drug to be worthwhile it should be clearly superior, both clinically and statistically, to placebo. METHODS/DESIGN: Two multicentre, two arm double blind parallel group randomised controlled trials, with allocation ratio of 2:1 for each comparison, Propranolol versus placebo and Pizotifen versus placebo. The trial is designed to test whether Propranolol is superior to placebo and whether Pizotifen is superior to placebo for the prevention of migraine attacks in children aged 5-16 years referred to secondary care out-patient settings with frequent migraine (2-6/4 weeks). The primary outcome measure is the number of migraine attacks during trial weeks 11 to 14. DISCUSSION: A strength of this trial is the participation of clinically well defined migraine patients who will also be approached to help with future longer-term follow-up studies. TRIAL REGISTRATION: ISRCTN97360154.

Role of metabolites for drugs that undergo nonlinear first-pass effect: impact on bioequivalency assessment using single-dose simulations.

We investigated the effects of dose and intrasubject variability (ISV) on bioequivalence (BE) of a parent drug with a single metabolite formed by nonlinear first-pass. A BE simulation was done using a four-compartment model at doses of 17.5, 35.0, and 70.0 mg. ISV was set at either 10% or 20% for clearance and either 20% or 50% for the absorption rate constant, K(a). The ratio of Katest/Kreference was fixed at 1.00 while fraction available ratios, F(test)/F(reference), were varied from 1.00 to 1.25. Results showed the probability of passing the 90% confidence interval (CI) BE requirement for AUC(I), area-under-the-concentration curve to time infinity, and C(max), concentration maximum, were greater for the metabolite than the parent at all F(test)/F(reference) ratios. For the parent, the probability of meeting BE criteria for AUC(I) and C(max) declined from 100% to 60% at the 70 mg dose as the ISV for K(a) increased from 20% to 50% with an increased F(test)/F(reference) ratio. For the metabolite, the probability of meeting BE criteria was above 80% for all doses and ISV values and F(test)/F(reference) ratios less than 1.15. Results show that the parent, reflected absorption, is more informative for determining BE than the metabolite. Clinical data gave a similar result.

[Effect of propranolol on renal hemodynamics in patients with cirrhosis: assessment with Doppler US]. / Siroz hastalarinda propranololün renal hemodinamik etkileri: Doppler US ile degerlendirme.

PURPOSE: To determine the renal resistive index profile in cirrhotic patients before and after propranolol treatment and assess the effects of propranolol on renal hemodynamics. MATERIALS AND METHODS: Thirty-six patients with cirrhosis and ascites (decompensated group), 39 patients with cirrhosis but no ascites (compensated group) and 25 patients with normal renal and hepatic functions (control group) were studied. All had normal blood urea nitrogen and serum creatinine levels. The renal resistive index was calculated in all patients before and after oral propranolol treatment. RESULTS: Resistive index was significantly higher in the decompensated group (p<0.05) than in other groups. After propranolol treatment, resistive indices decreased in the compensated patients (p<0.05) but increased in the decompensated group (p<0.05). There was a slight but statistically insignificant increase in the control group. CONCLUSION: In patients with cirrhosis renal failure is a significant risk factor for liver transplantation. In these patients, Doppler sonography provides early detection of renal dysfunction even before renal function tests are abnormal. Doppler sonography is a useful noninvasive method to evaluate the effects of drugs on renal hemodynamics.

Comparison of closed-loop and open-loop models in the assessment of cardiopulmonary and baroreflex gains.

OBJECTIVES: Both open- and closed-loop models of beat-to-beat cardiovascular control have been suggested. We tested whether the modelling yields different results with real data while assessing cardiopulmonary and baroreflex gains. METHODS: Two autoregressive models are described to resolve causal relationships between systolic blood pressure (SBP), RR-interval (RRI) and instantaneous lung volume (ILV): a closed-loop model which takes into account both the RRI changes induced by changes in SBP and the SBP changes mediated by changes in RRI, and an open-loop model which does not have a link from RRI to SBP. The performance of the models was compared in 14 healthy men in supine and standing positions under control conditions and under conditions of beta -sympathetic and parasympathetic pharmacological blockades. Transfer function gains were computed from ILV to RRI (cardiopulmonary gain) and from SBP to RRI (baroreflex gain). The measurements were done under controlled random-interval breathing. RESULTS: The gains identified by the open-loop model tended to be higher than those from the closed-loop model, but the differences did not reach statistical significance. Importantly, the two models discriminated the changes in transfer gains between different interventions equally well. CONCLUSIONS: Because the interactions between SBP and RRI occur physiologically in a closed-loop condition, the closed-loop model provides a theoretical advantage over the open-loop model. However, in practise, it seems to be little reason to select one over the other due to methodological errors when estimating cardiopulmonary or baroreflex transfer gains.