Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors.

The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (q2LOO = 0.60, r2 = 0.80 and r2pred = 0.91), partial-least-square (PLS) regression (q2LOO = 0.83, r2 = 0.62 and r2pred = 0.70) and sequential minimal optimization (SMO) regression (q2LOO = 0.70, r2 = 0.80 and r2pred = 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CLpro by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CLpro inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CLpro. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.Communicated by Ramaswamy H. Sarma.

Atosiban efficacy and safety in pregnant women with threatened preterm delivery: systematic review of the literature with network meta-analysis / Eficacia y seguridad de atosiban en mujeres gestantes con diagnóstico de amenaza de parto pretérmino: revisión sistemática de la literatura con metaanálisis en red

ABSTRACT Objective: To assess the efficacy and safety of atosiban in pregnant women with risk of preterm delivery as compared to nifedipine, indomethacin, terbutaline, fenoterol and placebo. Materials and methods: A systematic literature review was carried out in eight electronic databases, including Medline, Central, and Embase, using free and standardized search terms. Outcomes assessment included time delay until delivery, neonatal mortality, ratio of adverse maternal events, and ratio of neonatal complications. The quality of the evidence was evaluated per study and for the body of evidence and, whenever feasible, the information was synthesized into a meta-analysis. Alternatively, a narrative summary was presented. Results: Eleven studies were included. Atosiban did not show any statistically significant differences in terms of delaying delivery versus other uterine contraction inhibitors. The neonatal mortality was lower compared to indomethacin (RR = 0.21; 95% CI: 0.05 to 0.92), and the percentage of total maternal adverse events was lower compared to fenoterol (RR = 0.16; 95% CI: 0.08 to 0.31), nifedipine (RR = 0.48; 95% CI: 0.3 to 0.78), and terbutaline (RR = 0.44; 95% CI: 0.28 to 0.71). Conclusions: Atosiban has similar efficacy for delivery delay in patients with risk of preterm delivery as compared to other agents (moderate certainty), showing some advantages regarding neonatal mortality (low certainty) versus indomethacin, and compared to fenoterol, nifedipine and terbutaline in terms of maternal adverse events (moderate certainty).

RESUMEN Objetivo: evaluar la eficacia y seguridad de atosiban en gestantes con amenaza de parto pretérmino comparado con nifedipino, indometacina, terbutalina, fenoterol y placebo. Materiales y métodos: se realizó una revisión sistemática de la literatura en ocho bases de datos electrónicas (Medline, Central, Embase, entre otras), mediante términos de búsqueda libres y estandarizados. Los desenlaces evaluados incluyeron tiempo de retardo del parto, mortalidad neonatal, proporción de eventos adversos maternos y proporción de complicaciones neonatales. Se evaluó la calidad de la evidencia por estudio y para el cuerpo de evidencia, y se sintetizó la información mediante metaanálisis, cuando fue posible; de lo contrario, se resumió de forma narrativa. Resultados: se incluyeron once estudios. Atosiban no mostró diferencias estadísticamente significativas en retardo del parto contra otros uteroinhibidores. Mostró menor mortalidad neonatal que la indometacina (RR = 0,21; IC 95 %: 0,05 a 0,92), y menor proporción de eventos adversos maternos totales que el fenoterol (RR = 0,16; IC 95 %: 0,08 a 0,31), el nifedipino (RR = 0,48; IC 95 %: 0,3 a 0,78) y la terbutalina (RR = 0,44; IC 95 %: 0,28 a 0,71). Conclusiones: atosiban tiene una eficacia similar para retardar el parto ante la amenaza de un parto pretérmino con otros comparadores (certeza moderada), con ventajas frente a indometacina en mortalidad neonatal (certeza baja) y frente a fenoterol, nifedipino y terbutalina en eventos adversos maternos (certeza moderada).

Myoclonus induced by salbutamol: A case report

Salbutamol is a ß2 adrenergic agonist widely prescribed in patients with obstructive and restrictive lung diseases. The main side effects associated with its use are tachycardia and tremor. Myoclonus is an involuntary, irregular, abrupt, brief and sudden muscular contraction, which can be generalized, focal or multifocal. We report the case of a 61-year-old patient presenting with myoclonus difficult to treat who showed improvement only after the definitive discontinuation of the ß2 adrenergic agonist. We describe the clinical findings, the interventions, and the outcomes related to the onset of myoclonus secondary to the use of salbutamol, as well as the possible genesis and importance of this adverse effect. We used the CARE guidelines to delineate the clinical case. Although myoclonus secondary to the use of different drugs has been described in the literature, as far as we know this is the fourth report of salbutamol-induced myoclonus to date.

Mioclonías inducidas por salbutamol / Myoclonus induced by salbutamol: A case report

Resumen El salbutamol es un agonista adrenérgico β2 ampliamente empleado en pacientes con enfermedades pulmonares obstructivas y restrictivas. Sus principales efectos secundarios son la taquicardia y el temblor. Las mioclonías son contracciones musculares involuntarias, irregulares, bruscas, breves y repentinas, y pueden ser generalizadas, focales o multifocales. Se presenta el caso de un paciente de 61 años con mioclonías de difícil manejo que solo presentó mejoría tras la suspensión definitiva del agonista adrenérgico β2. Se describen los hallazgos clínicos, las intervenciones y el resultado en las mioclonías asociadas con el uso de salbutamol y se discuten la posible génesis y la importancia de este efecto adverso. Para documentar el caso, se siguieron las recomendaciones de las guías para el reporte de casos (CAse REport, CARE). Aunque en diversos estudios se han descrito mioclonías secundarias al uso de diferentes fármacos, hasta donde se sabe, este sería el cuarto reporte de un caso asociado específicamente con el uso del salbutamol.

Abstract Salbutamol is a β2 adrenergic agonist widely prescribed in patients with obstructive and restrictive lung diseases. The main side effects associated with its use are tachycardia and tremor. Myoclonus is an involuntary, irregular, abrupt, brief and sudden muscular contraction, which can be generalized, focal or multifocal. We report the case of a 61-year-old patient presenting with myoclonus difficult to treat who showed improvement only after the definitive discontinuation of the β2 adrenergic agonist. We describe the clinical findings, the interventions, and the outcomes related to the onset of myoclonus secondary to the use of salbutamol, as well as the possible genesis and importance of this adverse effect. We used the CARE guidelines to delineate the clinical case. Although myoclonus secondary to the use of different drugs has been described in the literature, as far as we know this is the fourth report of salbutamol-induced myoclonus to date.

Evaluación clínico-flujométrica en exacerbaciones agudas de asma bronquial, tratados con fenoterol, en un Servicio de Emergencia, en adultos / Clinical-flowmetry evaluation in the acute exacerbations of bronchial asthma, treated with fenoterol, Emergency Service, in adults

Problema: "¿Cuáles son los cambios clínico-flujométricos observados en pacientes con exacerbaciones agudas de asma bronquial leve, moderado y severo, con nebulización convencional en el servicio de emergencia del Hospital Nacional Arzobispo Loayza?". Objetivo: determinar los cambios en la función pulmonar medida con PEF y cambios clínicos en exacerbaciones agudas leves, moderadas o severas del asma bronquial en adultos sometidos a nebulización convencional. Metodología: Es un estudio descriptivo, observacional, prospectivo, realizado en emergencia del Hospital Nacional Arzobispo Loayza; se evaluó 136 pacientes mayores de 18 años con exacerbación aguda leve, moderada y severa de asma bronquial, nebulizados con fenoterol, con un IC de 95 por ciento, z de 1.96, potencia de 80 por ciento (para una muestra de131 pacientes); se excluyeron enfermedades respiratorias y cardiacas crónicas y asma casi fatal, etc. Se midió la variación del PEF, la mejoría clínica, estancia en la sala de emergencia, requerimiento de hospitalización y recaídas. Se estimó las frecuencias absolutas y relativas de cada variable y en algunos casos se sometió a pruebas de significación estadística para determinar las diferencias. La información se presenta en cuadros y gráficos. Resultados: Se reclutó 136 pacientes asmáticos, 108 mujeres, y 28 varones, 56 casos leves (41.2 por ciento), 60 casos moderados (44.1 por ciento) y 20 severos (14.7 por ciento); la edad promedio de los casos fue de 36.3 años, siendo de 50.6 años en el grupo de mayor severidad. Todos usaban beta agonistas como broncodilatador, y más de la mitad (55.9 por ciento) usaba corticoides en cualquiera de sus formas, el 35 por ciento usaba corticoides vía oral en sus crisis. La mayoría (64.7 por ciento) esperaba más de 1 día de inicio de la crisis para atenderse, todos los grupos tuvieron variación de la frecuencia cardiaca tras la nebulización siendo el de mayor taquicardia en el grupo de severo. No se registraron casos de...

Problem: "What are the clinical-flowmetry changes observed in patients with acute exacerbations of mild, moderate and severe bronchial asthma, with conventional nebulization in the emergency service of the National Hospital Arzobispo Loayza?” Objective: To determine changes in pulmonary function measured by PEF and clinical changes in mild, moderate or severe acute exacerbations of asthma in adults undergoing conventional nebulization. Methodology: A descriptive, observational, prospective study, conducted in emergency at National Hospital Arzobispo Loayza; 136 patients over 18 with mild, moderate and severe acute exacerbation of bronchial asthma, nebulized with fenoterol, with 95 per cent Cl, z 1.96, power of 80 per cent (for a sample of 131 patients) was evaluated; chronic respiratory and heart diseases and near-fatal asthma were excluded, etc. PEF variation, clinical improvement, stay in the emergency room, hospitalization requirement and relapse was measured. Absolute and relative to each variable and in some cases subjected to tests to determine statistical significance of differences was estimated frequencies. The information is presented in tables and graphs. Results: 136 asthmatic patients, 108 women and 28 men, 56 mild cases (41.2 per cent), moderate 60 cases (44.1 per cent) and 20 severe (14.7 per cent) were enrolled; the average age of the cases was 36.3 years, with 50.6 years in the group of greater severity. All beta agonists used as a bronchodilator, and more than half (55.9 per cent) used steroids in any form, 35 per cent used oral corticosteroids in their crisis. Most (64.7 per cent) waited more than 1 day of onset of the crisis to be addressed, all groups had variation in heart rate after nebulization tachycardia being the most severe in the group. No cases of fatal or near-fatal asthma were recorded. The stand by time and stay for treatment was variable, being the most severe cases prolonged length of stay, and the members of the SIS. A...

Efectividad del tratamiento de la amenaza de parto pretérmimo con progesterona natural micronizada / Effectiveness of treatment of threatened labor preterm micronized natural progesterone

Objetivo: Evaluar la efectividad de la progesterona natural micronizada administrada vía oral y del fenoterol administrado vía endovenosa, en el tratamiento de las pacientes con diagnóstico de amenaza de parto pretérmino. Métodos: Estudio experimental tipo ensayo terapéutico en pacientes que acudieron al Hospital Universitario de Caracas. Resultados: 15 pacientes del grupo estudio con progesterona presentaron resultados satisfactorios (X² = 155,837, df = 18); del grupo control, 13 pacientes con resultados satisfactorios (X² = 133,093, df = 18). La efectividad absoluta en el grupo de estudio fue de 0,68 contra 0,59 del grupo control (X² = 0,393; df = 1; P < 0,531). Conclusiones: Los tratamientos con progesterona natural micronizada y fenoterol demostraron ser inhibitorios de la dinámica uterina, a partir de la segunda hora de iniciado el tratamiento, evitando su progreso hacia trabajo de parto en un 90 %. La progesterona natural micronizada es efectiva en el tratamiento de la amenaza de parto pretérmino y se debe considerar su uso como alternativa terapéutica.

Objective: To evaluate the effectiveness of micronized natural progesterone administered orally and intravenously administered fenoterol in the treatment of patients with a diagnosis of preterm labor. Method: The type of therapeutic trial in patients attended at the Hospital Universitario de Caracas. Results: 15 patients in the progesterone study showed satisfactory results (X² = 155.837 df = 18); the control group, 13 patients with satisfactory results (X² = 133.093 df = 18). The absolute effectiveness in the study group was 0.68 against 0.59 in the control group (X² = 0.393 df = 1, P < 0.531). Conclusions: Treatment with micronized natural progesterone and fenoterol proved inhibitory uterine dynamics from the second hour of starting treatment preventing its progress toward labor by 90 %. The micronized natural progesterone is effective in the treatment of preterm labor and should be considered as an alternative therapeutic use.

Further evidence of the importance of RIT1 in Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder consisting of short stature, short and/or webbed neck, distinctive facial features, cardiac abnormalities, cryptorchidism, and coagulation defects. NS exhibits genetic heterogeneity, associated with mutated genes that participate in RAS-mitogen-activated protein kinase signal transduction. Recently, a new gene (RIT1) was discovered as the causative gene in 17 of 180 Japanese individuals who were negative for the previously known genes for NS and were studied using exome sequencing (four patients), followed by Sanger sequencing (13 patients). The present study used the same technique in 70 Brazilian patients with NS and identified six with RIT1 missense mutations. Thus, we confirm that RIT1 is responsible for approximately 10% of the patients negative for mutations in the previously known genes. The phenotype includes a high frequency of high birth weight, relative macrocephaly, left ventricular hypertrophy, and ectodermal findings, such as curly hair, hyperpigmentation, and wrinkled palms and soles. Short stature and pectus deformity were less frequent. The majority of patients with a RIT1 mutation did not show apparent intellectual disability. Because of the relatively high frequency of mutations in RIT1 among patients with NS and its occurrence in different populations, we suggest that it should be added to the list of genes included in panels for the molecular diagnosis of NS through targeted next-generation sequencing.

Nifedipine versus fenoterol in the management of preterm labor: a randomized, multicenter clinical study.

PURPOSE: To compare the efficacy of nifedipine and fenoterol in the management of threatened preterm labor (TPL). METHODS: A randomized and multicenter study assessing the tocolytic effect of nifedipine versus fenoterol in patients admitted to the participating maternity units with a diagnosis of TPL and a cost-savings study for economic assessment. For a power of 80% and an α error equal to 0.05, 132 consecutive patients were recruited during the study period; 66 patients were assigned to each group. A χ(2) analysis and a mean differences test were performed according to variable types and survival curves per intention-to-treat. RESULTS: Demographics were similar in both groups. The latency period was similar in both groups (26.7 vs. 25.6; p = 0.3). There were no differences in the results obtained. Nifedipine failed more frequently to obtain tocolysis when used as a first-line agent (80 vs. 90%, p = 0.0001). The group treated with fenoterol showed more drug adverse events (57.8 vs. 19.0%, p = 0.0001). The economic assessment did not evidence a significant difference in terms of cost savings between groups treated with either drug. CONCLUSION: The present study failed to demonstrate either clinical or economic superiority of any of the two drugs used in TPL management. The highest failure percentage of nifedipine when used as a first-line agent should encourage further research.

Validation of new analytical methodology for determining fenoterolhydrobromide by HPLC: application in pharmaceutical products

Fenoterol hydrobromide is a B2-adrenergic agonist agent used for asthma and chronic obstructive pulmonary disease treatment. HPLC methodology was developed and validated for quantitative determination of fenoterol hydrobromide. The methodology was achieved by using a reversed-phase C18column, (150 mm ¡Á 3.9 mm i.d., 5 ¦Ìm) Thermo. The mobile phase was consisted of acetonitrile: water(30:70, v/v) with 0,1% triethylamine, pH adjusted to 5.0 with formic acid and flow rate of 1.0 mL.min-1with UV detection at 276 nm. The concentration range was from 0.025 to 0.15 mg.mL-1, and the correlation coefficient of analytical curve was >0.999. The detection limit and the quantifying limit (QL) were 0.003mg.mL-1 and 0.012 mg.mL-1, respectively. Intra- and interday relative standard deviations were ¡Ü2.0%. Themetho dology accuracy showed the percentage mean of 99.53%. The described technique was found to be simple, rapid, precise, accurate and sensitive; the advantages over the others current methodologies arethe low-cost and low-polluting conditions. Owing to its simplicity and reliable results, this methodology is suitable to be used in quality control of pharmaceutical drugs containing fenoterol hydrobromide as active componente. (AU)

Validation of new analytical methodology for determining fenoterolhydrobromide by HPLC: application in pharmaceutical products

Fenoterol hydrobromide is a B2-adrenergic agonist agent used for asthma and chronic obstructive pulmonary disease treatment. HPLC methodology was developed and validated for quantitative determination of fenoterol hydrobromide. The methodology was achieved by using a reversed-phase C18column, (150 mm ¡Á 3.9 mm i.d., 5 ¦Ìm) Thermo. The mobile phase was consisted of acetonitrile: water(30:70, v/v) with 0,1% triethylamine, pH adjusted to 5.0 with formic acid and flow rate of 1.0 mL.min-1with UV detection at 276 nm. The concentration range was from 0.025 to 0.15 mg.mL-1, and the correlation coefficient of analytical curve was >0.999. The detection limit and the quantifying limit (QL) were 0.003mg.mL-1 and 0.012 mg.mL-1, respectively. Intra- and interday relative standard deviations were ¡Ü2.0%. Themetho dology accuracy showed the percentage mean of 99.53%. The described technique was found to be simple, rapid, precise, accurate and sensitive; the advantages over the others current methodologies arethe low-cost and low-polluting conditions. Owing to its simplicity and reliable results, this methodology is suitable to be used in quality control of pharmaceutical drugs containing fenoterol hydrobromide as active componente.

Fenoterol e salbutamol via inalatória em cães: aspectos clínico, hemogasométrico e eletrocardiográfico / Fenoterol and salbutamol inhalation in dogs: clinical, haemogasometric and electrocardiographic aspects

Avaliaram-se, por meio de exame clínico, hemogasométrico e eletrocardiográfico, os efeitos do salbutamol e do fenoterol, administrados por via inalatória em cães. Doze cães foram distribuídos em dois grupos: os do grupo FE receberam fenoterol na dose de 2 gotas/5kg de peso vivo, diluídas em solução de cloreto de sódio 0,9 por cento por aparelho de inalação, e os do grupo SA receberam salbutamol pelo dosador de aerossol, na dose de 100mg. Foram avaliados: frequência cardíaca (FC), frequência respiratória (FR), temperatura retal (TR), pressão arterial sistólica (PAS), hemogasometria e eletrocardiograma antes e após 30min, duas horas e seis horas do uso dos fármacos. Discreta estimulação cardíaca ocorreu nos animais do grupo SA duas horas após sua administração em relação ao momento-controle, e tremores foram predominantes nestes animais. Diminuição da PAS e aumento da FR foram observados nos dois grupos, e não houve alteração significativa da onda T, da hemogasometria e do eletrocardiograma em ambos os grupos. O fenoterol provocou menor estimulação cardíaca e menos tremores comparado ao salbutamol, foi mais seguro e houve maior facilidade, menor custo e menor gasto de tempo na administração do salbutamol por inalador dosimetrado em relação ao fenoterol por nebulização.(AU)

Through physical examination, blood gas and the electrocardiographic effects of salbutamol and fenoterol, administered by inhalation in dogs was assessed. Twelve dogs were distributed into two groups: EF group animals received a fenoterol dose of 2 drops/5kg bodyweight, diluted in sodium chloride 0.9 percent inhalation device and animals in the SA group received salbutamol through aerosol feeder at a dose of 100µg. Rectal temperature (RT), heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), blood gas and electrocardiogram before and after 30min., 2h and 6 h after drug were evaluated. Mild cardiac stimulation occurred in SA group animals 2 hours after its administration compared to the control group, and tremors were predominant in these animals. A decrease in SBP and an increase in RR were observed in both animal groups and no significant alteration of the T wave in the electrocardiogram and blood gas analysis in both groups were observed. The fenoterol caused less cardiac pacing and shivering compared to salbutamol, which was more secure. However, there was more ease, lower cost and less time spent in the administration of salbutamol administered through metered-dose inhaler compared to fenoterol nebulization.(AU)

Budesonida, Beclometasona, Fenoterol, Salbutamol, Formoterol e Salmeterol para o tratamento da Doença Pulmonar Obstrutiva Crônica (DPOC) / Budesonide, Beclomethasone, Fenoterol, Salbutamol, Formoterol and Salmeterol for the treatment of Chronic Obstructive Pulmonary Disease

A doença pulmonar obstrutiva crônica (DPOC) caracteriza-se por sinais e sintomas respiratórios associados à limitação da capacidade ventilatória, sendo geralmente causada por exposição inalatória crônica a material particulado, principalmente decorrente de tabagismo. Broncodilatadores inalatórios constituem a base do tratamento sintomático da DPOC, promovendo alívio da dispneia e melhorando a capacidade para o exercício. São os medicamentos de escolha para o manejo sintomático de portadores da doença em todos os estádios. Quando administrados por aerossol, os broncodilatadores ß2-adrenérgicos de ação curta levam à broncodilatação de início rápido, em 1-5 min, e o efeito terapêutico entre 2-4 horas. São usados sob demanda nos casos de DPOC leve com sintomas intermitentes, e em esquema fixo em pacientes com sintomas freqüentes, diários ou contínuos. Podem ser usados em esquema "se necessário" em associação com broncodilatadores de longa ação. A falta de resposta espirométrica aguda ao broncodilatador não exclui um possível benefício em longo prazo. Portadores de DPOC em estádio avançado (III e IV) frequentemente persistem sintomáticos e com limitação funcional significativa, apesar do uso de broncodilatadoresde curta ação em esquema fixo. Salmeterol e formoterol são administrados por via inalatória e levam à broncodilatação através dos mesmos mecanismos dos agonistas adrenérgicos de curta ação, com a diferença de que a broncodilatação dura por até 12 horas. O salmeterol é o mais seletivo de todos os agonistas ß2, tendo menor atividade sobre os receptores ß1 cardíacos em relação ao formoterol. Tratamento com corticoide inalatório em portadores de DPOC moderada e grave levou à pequena redução nas exacerbações em estudos clínicos em comparação a placebo. O benefício é de baixa magnitude e possivelmente transitório, sendo que portadores de DPOC com VEF1 (volume expiratório forçado) inferior a 50% do previsto e com mais de duas exacerbações ao ano apresentaram os maiores benefícios. O benefício dos corticóides inalatórios é considerado um efeito de classe, não havendo diferenças de eficácia entre os representantes. As diferenças são basicamente farmacocinéticas, e maior potência não se traduz em maior eficácia clínica. Os membros da CONITEC presentes na 1ª reunião extraordinária do plenário do dia 04/07/2012 recomendaram a incorporação dos medicamentos budesonida, beclometasona, fenoterol, salbutamol, formoterol e salmeterol para o tratamento da DPOC, conforme PCDT a ser elaborado pelo Ministério da Saúde, com ampliação para os seguintes CIDs: J44.0 Doença pulmonar Obstrutiva Crônica com infecção respiratória aguda do trato respiratório inferior; J44.1 Doença pulmonar obstrutiva crônica com exacerbação aguda não especificada e J44.8 Outras formas especificadas de Doença Pulmonar Obstrutiva Crônica.

Heliox and forward-leaning posture improve the efficacy of nebulized bronchodilator in acute asthma: a randomized trial.

BACKGROUND: Heliox and forward-leaning posture (torso inclined forward at 50-60° with the elbows resting on the thighs) are adjuncts in the administration of nebulized bronchodilator to patients with acute asthma. METHODS: We randomized 59 patients who presented to the emergency department in severe asthma crisis, into 4 treatment groups: nebulized bronchodilator + oxygen; nebulized bronchodilator + oxygen + forward-leaning posture; nebulized bronchodilator + heliox; and nebulized bronchodilator + heliox + forward-leaning posture. Before and after the bronchodilator treatments the subjects were seated with torso erect, breathing room air. Each subject received 2 doses, 20 min apart, of nebulized fenoterol (2.5 mg) plus ipratropium bromide (0.25 mg) in 3 mL of 0.9% saline, delivered with a semi-closed valved aerosol reservoir. The nebulizer was run with oxygen or 80:20 heliox. The post-treatment pulmonary function tests were performed 15 min after the second nebulization. The group's mean age was 35.1 ± 13.6 y, and there were 20 men and 39 women. RESULTS: The oxygen + forward-leaning-posture group had a greater FEV(1) improvement than the oxygen group (59% vs 38%, P = .02). The heliox + forward-leaning-posture group had a greater FEV(1) improvement than the oxygen group (103% vs 38%, P = .001) and the heliox group (103% vs 42%, P = .03). The heliox group had greater reduction in respiratory rate than the oxygen group (P = .03). The heliox + forward-leaning-posture group had significantly greater peak expiratory flow improvement than any of the other groups. CONCLUSIONS: Heliox plus forward-leaning posture during bronchodilator nebulization improves bronchodilator efficacy in patients with severe acute asthma. (ClinicalTrials.gov registration NCT00922350).

The economic impact of severe asthma to low-income families.

BACKGROUND: To estimate the direct and indirect costs of severe asthma and the economic impact of its management to low-income families in Salvador, Brazil. METHODS: One hundred and ninety-seven patients with severe asthma and referred to a state-funded asthma center providing free treatment were evaluated. At registration, they were asked about family cost-events in the previous year and had a baseline assessment of lung function, symptoms and quality of life. During the subsequent year, they were reassessed prospectively. RESULTS: One hundred-eighty patients concluded a 12-month follow-up. Eighty-four percent were female patients, and the median family income was US$ 2955/year. Forty-seven percent of family members had lost their jobs because of asthma. Total cost of asthma management took 29% of family income. After proper treatment, asthma control scores improved by 50% and quality of life by 74%. The income of the families increased by US$ 711/year, as their members went back to work. The total cost of asthma to the families was reduced by a median US$ 789/family/year. Consequently, an annual surplus of US$ 1500/family became available. CONCLUSIONS: Family costs of severe asthma consumed over one-fourth of the family income of the underprivileged population in a middle-income country. Adequate management brings major economic benefit to individuals and families.

1,8-Cineole induces relaxation in rat and guinea-pig airway smooth muscle.

OBJECTIVES: 1,8-Cineole is a monoterpene with anti-inflammatory, vascular and intestinal smooth muscle relaxant activity. We have evaluated the potential bronchodilatatory activity of this compound. METHODS: 1,8-Cineole was tested against carbachol, histamine, K+ 80 mM and ovalbumin-induced bronchial contractions in Wistar rat or guinea-pig tissues. Some of the guinea-pigs had been previously sensitized with an intramuscular injection of 5% (w/v) ovalbumin/saline solution. Control animals received 0.3 ml saline. In separate experimental groups the response to 1,8-cineole (1-30 mg/kg), phenoterol (0.05-5 mg/kg) or vehicle (0.3% Tween in saline) was studied. KEY FINDINGS: 1,8-Cineole decreased, in vivo, rat bronchial resistance with similar efficacy as phenoterol (66.7 +/- 3.2% vs 72.1 +/- 5.3%). On the other hand, the maximal relaxant response to 1,8-cineole in carbachol-precontracted rat tracheas was 85.5 +/- 5.7% (IC50 = 408.9 (328-5196) microg/ml) compared with 80.2 +/- 4.8% (IC50 = 5.1 (4.3-6.1) microg/ml) with phenoterol. The addition of 1,8-cineole to guinea-pig tracheal rings tonically contracted with K+ 80 mM induced a concentration-related relaxation. The maximal relaxation elicited by 1,8-cineole was 113.6 +/- 11.7% (IC50 127.0 (115.9-139.2) microg/ml) compared with 129.7 +/- 14.6% (IC50 0.13 (0.12-0.14) microg/ml) achieved after phenoterol administration. In addition, the incubation of tracheal rings with 1,8-cineole (100, 300 or 1000 microg/ml), 15 min before inducing phasic contractions with K+ 80 mM, decreased the maximal amplitude of the contraction by 31.6 +/- 4.6, 75.7 +/- 2.7 and 92.2 +/- 1.5%, respectively. In another set of experiments, neither the maximal response nor the IC50 for the 1,8-cineole-induced relaxation were different between normal and ovalbumin-sensitized tissues. Moreover, the relaxation of bronchial rings contracted after exposure to 1 microg/ml ovalbumin occurred at a faster rate in rings pre-incubated with 1,8-cineole when compared with rings pre-incubated with vehicle only (Tween 0.3%). Therefore, in the first minute after the antigen challenge, the tracheal tissue relaxed after the peak contraction by 6.5, 21.4 (P < 0.05 vs control) and 66.9% (P < 0.05 vs control) in the presence of 100, 300 or 1000 microg/ml 1,8-cineole, respectively. CONCLUSIONS: 1,8-Cineole relaxed rat and guinea-pig (nonsensitized and ovalbumin-sensitized) airway smooth muscle by a nonspecific mechanism.

Determinação espectrofotométrica do bromidrato de fenoterol em preparações farmacêuticas / Spectrophotometric determination of fenoterol hydrobromide in pharmaceutical preparations

Um método espectrofotométrico simples foi desenvolvido para a determinação do bromidrato de fenoterol (BF) em comprimidos, gotas e xarope, como princípio ativo único e associado aoibuprofeno. O método se baseia na reação de acoplamento oxidativo do BF com o 3-metil-2-benzotiazolinona hidrazona (MBTH), na presença de sulfato cérico, como agente oxidante. Amistura de BF, MBTH e sulfato cérico, em meio ácido, produz um composto colorido (vermelho castanho) com máximo de absorção a 475 nm. A curva de calibração foi linear num intervalo deconcentração de 3,0 a 12,0 μg/mL, com coeficiente de correlação linear de 0,9998. Os parâmetros experimentais que afetam o desenvolvimento e a estabilidade do produto colorido foramcuidadosamente estudados e otimizados. O método foi aplicado em amostras comerciais e simuladas, obtendo-se coeficientes de variação entre 0,25 % a 0,82 % e médias de recuperação do padrão que variaram de 98 % a 102 %. O método proposto mostrou-se exato, preciso, linear e não é passível de interferência de excipientes, para as formas farmacêuticas comprimidos e gotas. Não houve interferência do ibuprofeno que consta de uma dasformulações analisadas, associado ao BF. Quanto ao xarope, houve interferência do veículo sugerindo reações de seus componentes com o MBTH.

A simple spectrophotometric method has been developed for the determination of fenoterol hydrobromide (FH) in TABELA IV - Valores obtidos em termos de fatores de resposta (FR), considerando a concentração de BF e respectivas absorvâncias determinadas em 475 nm, a partir do placebo da amostra B. Os valores expressam a média de três determinações Concentração Concentração Absorvância Fator deteórica encontrada Resposta (μg/mL) (μg/mL) (FR) 6,0 5,93 0,4895 0,082557,0 6,89 0,5633 0,08176 8,0 8,12 0,6571 0,08092 9,0 9,09 0,7471 0,08219 10,0 10,04 0,8144 0,08112FR médio = 0,08171; DP = 0,0006912; CV = 0,85%. tablets, drops and syrup, as the only active principle andassociated with ibuprofen. The method is based on the oxidative coupling reaction of the FH with 3-methyl-2-benzothiazolinone hydrazone (MBTH) and ceric sulphate as oxidant reagent. The mixture of the drug, MBTH andceric sulfate, in acid medium, produces a red brown color compound, with absorption maximum at 475 nm. Thecalibration curve was linear over a concentration range from 3.0 to 12.0 μg/mL, with correlation coefficient of0.9998. The different experimental parameters affecting the development and stability of the color compound werecarefully studied and optimized. The method was applied successfully to assay FH in dosage forms and simulatedsamples. The coefficient of variation was from 0.25 % to 0.82 % and average recoveries of the standard from 98 % to 102 %. The excipients (tablets and drops) did not interfere in the analysis and the results showed that method can be used for determination of the FH isolated or associated with ibuprofen with precision, accuracy and specificity. In case of syrup, the interference in the analysis suggests apossible reaction between vehicle components with MBTH.

[Effect of hypocapnia/alkalosis on the fluid filtration rate in isolated and perfused rabbit lungs]. / Efecto de la hipocapnia/alcalosis sobre la tasa de filtración de liquidos en pulmones aislados y perfundidos de conejos.

Hypocapnia/alkalosis is a consequence of several lung and metabolic pathologies. The aim of this study was to determine whether the increase of fluid filtration rate (FFR) that occurs during Hypocapnia/alkalosis circumstances is determined by hypocapnia, alkalosis or both. 7 groups were formed (N=36) using isolated rabbit lungs. Group 1: Control (PCO2 6%, pH: 7.35-7.45); Group 2 (n=6): Hypocapnia/Alkalosis (CO2 1%, pH: 7.9); Group 3 (n=6): Hypocapnia/Normo-pH (CO2 1% pH 7.35-7.45), Group 4 (n=6) Normocapnia/Alcalosis (CO2 6%, pH: 7.9). Fenoterol, papaverine and hydrocortisone were added to Groups 5, 6 and 7 (n=4) respectively, all under Normocapnia/Alkalosis. FFR and Pulmonary Arterial Pressure (Pap) were considerably higher in group 2 than in control (FFR: 1.92g/min +/- 0.6 vs 0.0 g/min +/- 0.006). A strong influence exerted by pH was observed when Group 3 and group 4 were compared (FFR: 0.02 g/min +/- 0.009 vs 2.3 g/min +/- 0.9) and (Pap: 13.5 cmH2O +/- 1.4 vs 90 cmH2O +/- 15). A reduced effect was observed in groups 5 and 6 (papaverine and hydrocorisone) and a totally abolished effect was observed in group 7 (fenoterol) (FFR: 0.001 +/- 0.0003 mL/min and Pap: 14 +/- 0.8 cmH2O). Pulmonary edema induced by Hypocapnia/alkalosis is a consequence of alkalosis and not of hypocapnia. This effect could be due to inflammatory damage in the lung parenchyma and alkalosis-mediated vasoconstriction.

Efecto de la hipocapnia/alcalosis sobre la tasa de filtración de líquidos en pulmones aislados y perfundidos de conejos / Effect of hypocapnia/alkalosis on the fluid filtration rate in isolated and perfused rabbit lungs

La hipocapnia/alcalosis es una situación que se presenta como consecuencia de diversas patologías pulmonares o metabólicas. El objetivo de este estudio fue determinar si el aumento de la tasa de filtración de liquido (TFL) que ocurre bajo estas circunstancias, está determinado por la hipocapnia, la alcalosis o la suma de ambas. Se realizaron 7 grupos (n=36), utilizando pulmones aislados de conejos. Grupo 1: Control (PCO2 6 por ciento, pH: 7,35-7,45); Grupo 2 (n=6): Hipocapnia/Alcalosis (CO2 1 por ciento, pH: 7,9); Grupo 3 (n=6): Hipocapnia/Normo-pH (CO2 1 por ciento pH 7,35-7,45), Grupo 4 (n=6) Normocapnia/Alcalosis (CO2 6 por ciento, pH: 7,9). En los grupos 5, 6 y 7 (n=4), todos bajo condición de Normocapnia/Alcalosis se añadió fenoterol, papaverina, e hidrocortisona respectivamente. La TFL y la presión de arteria pulmonar (Pap) fueron considerablemente mayores en el grupo 2 que en el control (TFL:1,92g/min ± 0,6 vs 0,0g/min ± 0,006), observándose una marcada influencia del pH, al comparar el grupo 3 y el grupo 4 (TFL: 0,02g/min ± 0,009 vs 2,3g/min ± 0,9) y (Pap: 13,5 cmH2O ± 1,4 vs 90 cmH2O ± 15). Se observó una disminución del efecto en los grupos 5 y 6 (papaverina e hidrocortisona) y su abolición total con fenoterol (grupo 7) (TFL: 0,001 ± 0,0003 g/min y Pap: 14 ± 0,8 cmH2O). El edema pulmonar inducido por Hipocapnia/Alcalosis es consecuencia principalmente de la alcalosis y no de la hipocapnia. Dicho efecto podría ser debido a un daño inflamatorio a nivel del parénquima y a la vasoconstricción causada por la alcalosis.

Tocolysis and delayed delivery versus emergency delivery in cases of non-reassuring fetal status during labor.

AIM: To determine whether fetal intrauterine resuscitation using tocolysis and delayed delivery is better for the fetus than emergency delivery when fetal hypoxia is suspected because of a non-reassuring fetal heart-rate (FHR) pattern using conventional heart rate monitoring. METHODS: This was a prospective and randomized study, conducted between 2001 and 2004 at Pereira Rossell Hospital, Montevideo, Uruguay. The population consisted of 390 fetuses, in which intrauterine distress was diagnosed using electronic FHR monitoring. Of these, 197 were randomly assigned to the emergency delivery group and 193 to the fetal intrauterine resuscitation group. The inclusion criteria were: term singleton pregnancy, in labor, cephalic presentation, and no placental accidents. RESULTS: The time between randomization and birth was 16.9 +/- 7.6 min (mean +/- SD) for the emergency delivery group, and 34.5 +/- 11.7 min (mean +/- SD) for the resuscitation group. The relative risk (RR) of acidosis in the umbilical artery (pH < 7.1) in the emergency delivery group was 1.47 (0.95-2.27). The RR of base deficit < or =12 mEq/L in the emergency delivery group was higher than in the resuscitation group (RR = 1.48 [1.0-2.2], P = 0.04). When considering the need for admission to the neonatal care unit, the relative risk was higher in the emergency delivery group than in the resuscitation group (RR = 2.14 [1.23.3.74], P = 0.005). No maternal adverse effects were reported. CONCLUSION: Tocolysis and delayed delivery renders better immediate neonatal results than emergency delivery when fetal distress is suspected because of a non-reassuring fetal heart pattern. In addition, it may decrease the need for emergency delivery without increasing maternal and fetal adverse side-effects.