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).

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.

Analysis of Fenoterol and Ipratropium Transfer from Human Lung Tissue into Human Plasma Using a Dynamic Dialysis Model.

Aims: The aim of the current study was to establish a simple and yet as much as possible physiologic approach for a simulation of the pulmonary absorption process to compare different inhaled drugs or drug formulations. Methodology: We designed a dialysis setting that allowed monitoring the drug release from human lung tissue into a continuous-flow plasma compartment. For proof-of-concept experiments we chose the glucocorticoid fluticasone propionate (FP) as model compound. For subsequent experiments we selected a commercially available metered dose inhaler delivering a fixed combination of the short-acting ß2-agonist fenoterol and the muscarinic antagonist ipratropium bromide. Results: With the novel dynamic dialysis model we observed high drug transport rates from the lung tissue into plasma including an elimination phase. The concentration profile in the plasma compartment of our model system was similar to the plasma concentration courses after inhalation of FP. Compared to FP significantly higher drug fractions of fenoterol and ipratropium bromide were released into plasma and the transfer of ipratropium was more pronounced compared to fenoterol. Again, concentration profiles in plasma were alike to those described in clinical studies. Conclusion: We suggest that this model is appropriate for rapid assessment of comparative diffusion behaviour of drugs or drug formulations from lung tissue into plasma.

Inhibition of LPS-induced expression of myeloid differentiation factor 88 by fenoterol is associated with its anti-inflammatory effect / 实用医学杂志

Objective To explore the molecular mechanism of inhibition of LPS-induced inflammation by fenoterol, a β2 adrenoceptor agonist in monocyte. Methods Concentrations of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and MCP-1 from cell supernatants from THP-1 cells and wild type or MyD88- / - mice peritoneal macrophages stimulated by LPS in the presence or absence of fenoterol were determined by use of an ELISA system. Expression of MyD88 (myeloid differentiation factor 88) stimulated by LPS in the presence or absence of fenoterol were determined by Western blot. Results Fenoterol inhibited LPS-induced activation of MyD88 and secretion of inflammatory cytokines (TNF-α, MCP-1, and IL-1β). The reaction of MyD88- / - mice peritoneal macrophages to LPS was much lower than that of the wild type mice peritoneal macrophages. Conclusions MyD88 plays an important role in inflammation induced by LPS. The inhibition of LPS-induced expression of MyD88 by fenoterol is associated with its anti-inflammatory effect.

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.

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.

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.

The Efficacy of Nebulized 3 Percent Hypertonic Saline Solution and Fenoterol in Infants with Bronchiolitis / 소아과

PURPOSE: To evaluate the effect of inhaled hypertonic saline solution in hospitalized infants with bronchiolitis. METHODS: A randomized double blind trial was performed from October 2003 to May 2004. A total of eighty patients <1 year of age with a clinical diagnosis of acute viral bronchiolitis were enrolled and assigned to receive either of the following:inhalation of 2 mL(0.5 mg) fenoterol added to 2 mL of 0.9 percent saline solution(group 1; n=40) or 2 mL(0.5 mg) fenoterol added to 2 mL of 3 percent saline solution(group 2; n=40). This therapy was repeated at six hours interval after admission. They were evaluated daily just before and 20 minutes after nebulization. The outcome measures included changes in clinical severity score(based on respiratory rate, presence of wheezing, retraction, and general condition) after nebulization and duration of hospitalization. RESULTS: In the clinical severity score, a significant improvement was observed during the 72 hours of hospitalization in both groups(P<0.05). The basic clinical severity scores before inhalation were decreased significantly faster in group 2 as compared to group 1 on each day of treatment(P<0.05). The mean duration of hospital stay was significantly reduced in group 2 than group 1(5.9+/-1.9 days versus 7.4+/-2.0 days, P<0.05). No adverse effects were associated with inhaled therapy. CONCLUSION: These results suggest that a nebulized 3 percent saline solution plus 0.5 mg fenoterol may be more effective than a 0.9 percent saline solution plus 0.5 mg fenoterol in accelerating the clinical recovery of infants with viral bronchiolitis.

The Efficacy of Nebulized Epinephrine Versus Fenoterol in Hospitalized Infants with Acute Bronchiolitis / 소아과

PURPOSE: Acute bronchiolitis is a lower respiratory tract disease, resulting from inflammatory obstruction of the small airway. The main treatment of acute bronchiolitis is supportive but, numerous investigators have examined the efficacy of beta agonist as bronchodilators. In acute bronchiolitis, mucosal edema in the bronchioles may be an important cause of airway obstruction therefore, an alpha and beta agonist might be useful in the treatment of this disease. So we examined the efficacy and safety of repeated nebulized epinephrine compared to fenoterol. METHODS: This randomized double blind study involved 106 hospitalized infants with wheezing, under one year age and acute onset of respiratory distress. They were randomly separated into two groups, and treated with either nebulized 0.1% epinephrine 0.5 mg in 3.5 mL of 0.9% saline solution (group 1; n=50) or nebulized fenoterol 0.5 mg in 2 mL of 0.9% saline solution(group 2; n=50). This therapy was repeated at six hour intervals after hospital admission. Observations were made at admission and just before, 30 minutes after nebulization. The primary outcome measures used were the degree of change in clinical scores. The secondary outcome measures used were the length of the hospital stay. RESULTS: A significant improvement in the clinical score was noted during 72 hours of hospitalization in both groups(P<0.001). But, there were no significant differences between the groups in clinical score improvement. There were no significant differences between the groups in the length of the hospital stay(P=0.055). No adverse effects were associated with nebulized therapy. CONCLUSION: There were no group differences in the effectiveness of therapy for infants hospitalized with acute bronchiolitis.

Comparison of fenoterol, ipratropium bromide and their combination in asthma.

The present study was designed to determine the extent of additivity of response to combination therapy of ipratropium bromide (I) (40 meg; 2 puffs) and fenoterol hydrochloride (F) (100 ug; 2 puffs) in 16 adults asthmatic patients who are responsive to I. The study design was a randomized, double-blind cross-over trial. The trial was a double blind cross over deign employing placebo, I, F and combination. All test medications significantly improved both FEV1 and FVC than placebo. Analysis of improvements in pulmonary function tests using area under the curve estimations suggested that the order of the test medications by the patients and the physicians showed the significantly better ratings of the combination than all other test medications (p < 0.05). No significant changes in pulse rate, blood pressure and electrocardiogram were observer in all treatment groups. No side effects were reported by all patients during the whole trial period.