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Titulo:

Eficacia y seguridad de la budesonida por inhalación en el tratamiento del asma pediátrica en el servicio de urgencias: revisión sistemática y metanálisis

Tipo de estudio: revisión sistemática y metanálisis
Año: 2020
Resultados:
Se incluyeron 21 ECA con 12.787 sujetos. El metanálisis reveló que la BUD ha reducido la tasa de hospitalización y empeoramiento del asma ; mejoró significativamente las funciones pulmonares como FEV1 (Varianza inversa (IV): 1.05, p <0.0001, I ² = 94%), PEFR (IV: 1.40, p <0.0001, I ² = 87%), PEF matutino (IV: 1.04, p <0.0001, I ² = 91%) y PEF vespertino (IV: 1.29, p <0,0001, I ² = 92%) en comparación con el control. Además, las incidencias de eventos adversos como Faringitis (M – H, RE-OR 0.88, en 95% CI, p = 0.69, I ² = 0%), Sinusitis (M – H, RE-OR 0.78, p = 0.79, I ² = 0%), Infecciones respiratorias (M – H, RE-OR 0.96, p = 0.46, I ² = 0%), Otitis media (M – H, RE-OR 0.82, p = 0.32, I ² = 12 %) y Fiebre (M – H, RE-OR 0,78, p = 0,64, I ² = 0%) fueron casi iguales entre BUD y control.
Conclusión: La inhalación de BUD en dosis altas puede beneficiar a los pacientes pediátricos al minimizar el empeoramiento del asma y la tasa de hospitalización, junto con la mejora de las funciones pulmonares, con reacciones adversas insignificantes a los medicamentos.
https://link.springer.com/article/10.1007/s43440-020-00098-y

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Background

This study was aimed to evaluate the beneficial role of inhalation budesonide(BUD) in improving the pulmonary functions, and reducing the hospital admission rate, worsening of asthma and commonly encountered adverse events in pediatric asthma.

Methods

The electronic search was performed using PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials) and Google scholar databases to identify the randomized control trials(RCTs).

Results

21 RCTs involving 12,787 subjects were included. The meta-analysis revealed that the BUD has reduced the hospitalization rate (Mantel-Haenszel (M-H), random effects odd ratio (RE-OR) of 0.34, p = 0.003, I ² = 75%), and worsening of asthma (M-H, RE-OR 0.38, p = 0.001, I ² = 73%); significantly improved the pulmonary functions such as FEV1 (Inverse variance (IV): 1.05, p < 0.0001, I ² = 94%), PEFR (IV: 1.40, p < 0.0001, I ² = 87%), morning PEF (IV: 1.04, p < 0.0001, I ² = 91%), and evening PEF (IV: 1.29, p < 0.0001, I ² = 92%) compared to control. Further, the incidences of adverse events like Pharyngitis (M-H, RE-OR 0.88, at 95% CI, p = 0.69, I ² = 0%), Sinusitis (M-H, RE-OR 0.78, p = 0.79, I ² = 0%), Respiratory infections (M-H, RE-OR 0.96, p = 0.46, I ² = 0%), Otitis media (M-H, RE-OR 0.82, p = 0.32, I ² = 12%) and Fever (M-H, RE-OR 0.78, p = 0.64, I ²  = 0%) were almost same between BUD and control.

Conclusion

The outcomes of the meta-analysis suggest that high-dose inhalation BUD could benefit the pediatric patients in minimizing the worsening of asthma and hospitalization rate, along with improving the pulmonary functions, with negligible adverse drug reactions.

Graphic abstract

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Efficacy and safety of inhalation budesonide in the treatment of pediatric asthma in the emergency department: a systematic review and meta-analysis - Pharmacological Reports

# data[].attributes.attachment_link.description
Background This study was aimed to evaluate the beneficial role of inhalation budesonide(BUD) in improving the pulmonary functions, and reducing the hospital admission rate, worsening of asthma and commonly encountered adverse events in pediatric asthma. Methods The electronic search was performed using PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials) and Google scholar databases to identify the randomized control trials(RCTs).

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TITULO:
Seguridad de los corticosteroides inhalados en el tratamiento del asma persistente

TIPO SE ESTUDIO:
Revisión sistemática

AÑO:
2006

AUTOR:
Stephen P. Peters

RESULTADOS:
Los efectos oculares de los corticosteroides inhalados y los efectos de los corticosteroides inhalados sobre la densidad mineral ósea y la función suprarrenal son mínimos en los pacientes que reciben las dosis recomendadas de corticosteroides inhalados. Además, una gran cantidad de datos del Registro Médico de Nacimientos de Suecia no muestra un mayor riesgo de resultados perinatales adversos cuando se administra budesonida inhalada a mujeres embarazadas con asma.

CONCLUSIONES:
Los corticosteroides inhalados tienen efectos sistémicos mínimos en la mayoría de los pacientes cuando se toman en las dosis recomendadas. Los beneficios de la terapia con CSI superan claramente los riesgos del asma no controlada, y los CSI deben prescribirse de forma rutinaria como terapia de primera línea para niños y adultos con enfermedad persistente.

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Abstract

Objective: Inhaled corticosteroids (ICSs) are the most effective medications available for patients with persistent asthma of all severities and currently are recommended as the preferred asthma controller therapy by the National Heart, Lung and Blood Institute. Nevertheless, lingering concerns about potential adverse systemic effects of ICSs contribute to their underuse. This review discusses the safety of ICSs with respect to potential systemic effects of most concern to physicians and patients.

Methods: Articles reporting on the safety of ICSs in children and adults with persistent asthma were identified from the Medline database from January 1966 through December 2003, reference lists of review articles and international respiratory meetings.

Results: Ocular effects of ICSs and ICS effects on bone mineral density and adrenal function are minimal in patients maintained on recommended ICS doses. One-year growth studies in children have shown decreased growth velocity with ICSs, but long-term studies with inhaled budesonide and beclomethasone show no effect on final adult height, suggesting that these effects are transient. In addition, extensive data from the Swedish Medical Birth Registry show no increased risk of adverse perinatal outcomes when inhaled budesonide is administered to pregnant women with asthma.

Conclusions: ICSs have minimal systemic effects in most patients when taken at recommended doses. The benefits of ICS therapy clearly outweigh the risks of uncontrolled asthma, and ICSs should be prescribed routinely as first-line therapy for children and adults with persistent disease.

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A Glance at the Use of Glucocorticoids in Rare Inflammatory and Autoimmune Diseases: Still an Indispensable Pharmacological Tool?

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# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / administration & dosage

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / adverse effects*

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / therapeutic use

# data[].attributes.attachment_link.keywords[]
hypothalamo-hypophyseal system / drug effects

# data[].attributes.attachment_link.keywords[]
ocular hypertension / chemically induced

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Safety of inhaled corticosteroids in the treatment of persistent asthma - PubMed

# data[].attributes.attachment_link.description
ICSs have minimal systemic effects in most patients when taken at recommended doses. The benefits of ICS therapy clearly outweigh the risks of uncontrolled asthma, and ICSs should be prescribed routinely as first-line therapy for children and adults with persistent disease.

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TÍTULO:

Reacciones adversas a los medicamentos de montelukast en niños y adultos

AÑO:  2017
AUTOR: Meindina G Haarman, Florencia van Hunsel,  Tjalling W de Vries
RESULTADOS:Se estudiaron retrospectivamente todas las reacciones adversas a los medicamentos en el montelukast en niños y adultos informados a los Países Bajos Farmacovigilancia Centro Lareb y la base de datos mundial de la OMS, Vigibase ® hasta el año 2016. La depresión se informó con mayor frecuencia en la población a la base de datos global Vigibase ® (razón de posibilidades de notificación (ROR) 6,93; IC del 95%: 6,5-7,4). En VigiBase ®, la agresión se informó más en los niños (ROR, 29,77; IC del 95%: 27,5-32,2). Los dolores de cabeza se informaron con mayor frecuencia en la base de datos holandesa (ROR, 2,26; IC del 95%: 1,61-3,19). Además, las pesadillas a menudo se informan tanto para niños como para adultos en la base de datos holandesa y mundial. Ocho pacientes con Angiitis granulomatosa alérgica se reportaron a la base de datos holandesa y 563 pacientes en el Vigibase ®
CONCLUSIONES: montelukast está asociado con reacciones adversas neuropsiquiátricas como depresión y agresión. Especialmente en los niños, las pesadillas se informan con frecuencia. También se informa angitis granulomatosa alérgica, no se ha establecido una relación causal.

https://pubmed.ncbi.nlm.nih.gov/28971612/

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Adverse drug reactions of montelukast in children and adults - PubMed

# data[].attributes.attachment_link.description
Montelukast, a selective leukotriene receptor antagonist, is recommended in guidelines for the treatment of asthma in both children and adults. However, its effectiveness is debated, and recent studies have reported several adverse events such as neuropsychiatric disorders and allergic granulomatous ...

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Titulo:

Efectos cardiovasculares de los beta-agonistas en pacientes con asma y EPOC: un metaanálisis

Tipo de estudio:Metanalisis
Año:2004
Resultados:Se incluyeron en el estudio trece ensayos de dosis única y 20 ensayos de mayor duración. Una dosis única de beta (2) -agonista aumentó la frecuencia cardíaca en 9,12 latidos / min (intervalo de confianza [IC] del 95%, 5,32 a 12,92) y redujo la concentración de potasio en 0,36 mmol / L (IC del 95%, 0,18 a 0,54 ), en comparación con placebo. Para los ensayos que duraron de 3 días a 1 año, el tratamiento con agonistas beta (2) aumentó significativamente el riesgo de un evento cardiovascular (riesgo relativo [RR], 2,54; IC del 95%, 1,59 a 4,05) en comparación con placebo. El RR para la taquicardia sinusal sola fue de 3,06 (IC del 95%, 1,70 a 5,50) y para todos los demás eventos fue de 1,66 (IC del 95%, 0,76 a 3,6).
Conclusiones:
el uso de beta (2) -agonistas en pacientes con enfermedad obstructiva de las vías respiratorias aumenta el riesgo de eventos cardiovasculares adversos. El inicio del tratamiento aumenta la frecuencia cardíaca y reduce las concentraciones de potasio en comparación con el placebo. Podría ser a través de estos mecanismos, y otros efectos de la estimulación beta-adrenérgica, que los agonistas beta (2) pueden precipitar isquemia, insuficiencia cardíaca congestiva, arritmias y muerte súbita.

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Abstract

Background: beta-Adrenergic agonists exert physiologic effects that are the opposite of those of beta-blockers. beta-Blockers are known to reduce morbidity and mortality in patients with cardiac disease. beta(2)-Agonist use in patients with obstructive airway disease has been associated with an increased risk for myocardial infarction, congestive heart failure, cardiac arrest, and acute cardiac death.

Objectives: To assess the cardiovascular safety of beta(2)-agonist use in patients with obstructive airway disease, defined as asthma or COPD.

Methods: A meta-analysis of randomized placebo-controlled trials of beta(2)-agonist treatment in patients with obstructive airway disease was performed, to evaluate the short-term effect on heart rate and potassium concentrations, and the long-term effect on adverse cardiovascular events. Longer duration trials were included in the analysis if they reported at least one adverse event. Adverse events included sinus and ventricular tachycardia, syncope, atrial fibrillation, congestive heart failure, myocardial infarction, cardiac arrest, or sudden death.

Results: Thirteen single-dose trials and 20 longer duration trials were included in the study. A single dose of beta(2)-agonist increased the heart rate by 9.12 beats/min (95% confidence interval [CI], 5.32 to 12.92) and reduced the potassium concentration by 0.36 mmol/L (95% CI, 0.18 to 0.54), compared to placebo. For trials lasting from 3 days to 1 year, beta(2)-agonist treatment significantly increased the risk for a cardiovascular event (relative risk [RR], 2.54; 95% CI, 1.59 to 4.05) compared to placebo. The RR for sinus tachycardia alone was 3.06 (95% CI, 1.70 to 5.50), and for all other events it was 1.66 (95% CI, 0.76 to 3.6).

Conclusion: beta(2)-Agonist use in patients with obstructive airway disease increases the risk for adverse cardiovascular events. The initiation of treatment increases heart rate and reduces potassium concentrations compared to placebo. It could be through these mechanisms, and other effects of beta-adrenergic stimulation, that beta(2)-agonists may precipitate ischemia, congestive heart failure, arrhythmias, and sudden death.

[Cardiac arrest under special circumstances].

Lott C, Truhlář A, Alfonzo A, Barelli A, González-Salvado V, Hinkelbein J, Nolan JP, Paal P, Perkins GD, Thies KC, Yeung J, Zideman DA, Soar J. Lott C, et al. Notf Rett Med. 2021 Jun 10:1-77. doi: 10.1007/s10049-021-00891-z. Online ahead of print. Notf Rett Med. 2021. PMID: 34127910 Free PMC article. Review. German.

# data[].attributes.attachment_link.keywords[]
adrenergic beta-agonists / adverse effects*

# data[].attributes.attachment_link.keywords[]
adrenergic beta-agonists / therapeutic use

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis - PubMed

# data[].attributes.attachment_link.description
beta(2)-Agonist use in patients with obstructive airway disease increases the risk for adverse cardiovascular events. The initiation of treatment increases heart rate and reduces potassium concentrations compared to placebo. It could be through these mechanisms, and other effects of beta-adrenergic ...

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TITULO:

Seguridad de agregar salmeterol al propionato de fluticasona en niños con asma

AÑO: 2016
TIPO DE ESTUDIO: Ensayo Controlado Aleatorio
RESULTADOS: Entre los 6208 pacientes, 27 pacientes del grupo de fluticasona-salmeterol y 21 del grupo de fluticasona sola tuvieron un evento grave relacionado con el asma (todos fueron hospitalizaciones); la razón de riesgo con fluticasona-salmeterol versus fluticasona sola fue de 1,28 (intervalo de confianza [IC] del 95%, 0,73 a 2,27), lo que mostró la no inferioridad de fluticasona-salmeterol (P = 0,006). Un total de 265 pacientes (8,5%) en el grupo de fluticasona-salmeterol y 309 (10,0%) en el grupo de fluticasona sola tuvieron una exacerbación grave del asma (índice de riesgo, 0,86; IC del 95%, 0,73 a 1,01).
CONCLUSION: En este ensayo que involucró a niños con asma, el salmeterol en una combinación de dosis fija con fluticasona se asoció con el riesgo de un evento grave relacionado con el asma que fue similar al riesgo con fluticasona sola.

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Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma - PubMed

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In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

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Eficacia y seguridad de los corticosteroides inhalados en relación con el propionato de fluticasona: una revisión sistemática de ensayos controlados aleatorios en asma - PubMed (nih.gov)

Titulo: Eficacia y seguridad de los corticosteroides inhalados en relación con el propionato de fluticasona: una revisión sistemática de ensayos controlados aleatorios en asma

Año y tipo de estudio : 2017, revisión sistemática de ECA
Resultados :  Ciclesonida pareció tener un impacto menor en los niveles de cortisol que Fluticasona, lo que probablemente se deba a la conversión incompleta de CIC (Ciclesonida) a metabolito activo (des-CIC) y la menor potencia de des-CIC en comparación con Fluticasona
Conclusion : Aunque no hubo diferencias significativas en los resultados evaluados después del tratamiento con diferentes Corticosteroides inhalados en la mayoría de los estudios, algunas diferencias observadas de su seguridad podrían explicarse por sus respectivas propiedades farmacodinámicas y farmacocinéticas.

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Efficacy and safety of inhaled corticosteroids relative to fluticasone propionate: a systematic review of randomized controlled trials in asthma - PubMed

# data[].attributes.attachment_link.description
Many trials have been published comparing inhaled corticosteroid (ICS) treatments in asthma. However, mixed results necessitate the summarization of available evidence to aid in decision-making. Areas covered: This systematic review evaluated randomized controlled trials (RCTs) that compared the eff…

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Título: Reacciones adversas a los medicamentos de montelukast en niños y adultos
Año: 2017
Autor: Meindina G Haarman , Florencia van Hunsel , Tjalling W de Vries
Tipo de estudio:  ECA
Objetivo: Obtener más información sobre el perfil de seguridad de montelukast y proporcionar a los médicos prescriptores una descripción general de las reacciones adversas relevantes a los medicamentos tanto en niños como en adultos.
Resultados: La depresión se informó con mayor frecuencia en la población a la base de datos global Vigibase® (razón de posibilidades de notificación (ROR) 6,93; IC del 95%: 6,5-7,4). En VigiBase ® , la agresión se informó más en los niños (ROR, 29,77; IC del 95%: 27,5-32,2). Los dolores de cabeza se informaron con mayor frecuencia en la base de datos holandesa (ROR, 2,26; IC del 95%: 1,61-3,19). Además, las pesadillas a menudo se informan tanto para niños como para adultos en la base de datos holandesa y mundial. Ocho pacientes con Angiitis granulomatosa alérgica se reportaron a la base de datos holandesa y 563 pacientes en el Vigibase ® .
Conclusiones: Montelukast está asociado con reacciones adversas neuropsiquiátricas como depresión y agresión. Especialmente en los niños, las pesadillas se informan con frecuencia. También se informa angitis granulomatosa alérgica, aunque no se ha establecido una relación causal.
https://pubmed.ncbi.nlm.nih.gov/28971612/

# data[].attributes.attachment_link.title
Adverse drug reactions of montelukast in children and adults - PubMed

# data[].attributes.attachment_link.description
Montelukast, a selective leukotriene receptor antagonist, is recommended in guidelines for the treatment of asthma in both children and adults. However, its effectiveness is debated, and recent studies have reported several adverse events such as neuropsychiatric disorders and allergic granulomatous ...

# data[].attributes.body
https://pubmed.ncbi.nlm.nih.gov/26959519/

Título:

Seguridad de la terbutalina para el tratamiento del asma pediátrica aguda grave

Tipo de estudio: Ensayo controlado aleatorio
Año: 2018
Resultados: Hubo reducciones significativas en la presión arterial sistólica (variando entre 86% y 93% de la línea de base) y diastólica (variando entre 74% y 86% de la línea de base). Sin embargo, los valores volvieron al nivel inicial poco después de la interrupción de la perfusión. La terbutalina aumentó la frecuencia cardíaca en todos los grupos poco después del inicio (9% -13% por encima de la línea de base), que volvió a niveles por debajo de la línea de base 1 hora después de la interrupción. Los niveles séricos de potasio también se redujeron en todos los pacientes en comparación con sus valores iniciales después del inicio de la infusión de terbutalina. Sin embargo, ninguno de los sujetos requirió reemplazo de potasio.
Conclusiones: Los resultados indican que, en general, la infusión de terbutalina fue bien tolerada sin efectos adversos irreversibles del tratamiento. Aunque se produjeron alteraciones hemodinámicas y metabólicas, éstas se manejaron clínicamente con facilidad y presentaban poco riesgo en el departamento de urgencias o en la unidad de cuidados intensivos pediátricos.

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Abstract

Objectives: The use of continuous intravenous terbutaline treatment in severe asthma attacks has been hampered by the lack of well-powered clinical trials where effects of such treatment are described in detail. Here, we aimed to provide a descriptive report on the largest cohort of severe pediatric asthma patients treated with terbutaline.

Methods: The study was conducted in a pediatric intensive care unit in a large metropolitan tertiary care university hospital on 124 patients receiving terbutaline infusion. To stratify the effect of, and determine any age-related differences of, terbutaline, the patients were divided into 3 age groups (0-6 years, 7-12 years, and 13-18 years). Clinical response and the potential harmful effects of terbutaline infusion were determined.

Results: There were significant reductions in systolic (varying between 86% and 93% of the baseline) and diastolic blood pressures (varying between 74% and 86% of the baseline level). However, the values returned to baseline level shortly after discontinuation of infusion. Terbutaline increased heart rates in all groups shortly after initiation (9%-13% above baseline), which returned to below baseline levels 1 hour after discontinuation. Serum potassium levels were also reduced in all patients compared to their baseline values after initiation of terbutaline infusion. However, none of the subjects required potassium replacement.

Conclusions: The results indicate that overall, terbutaline infusion was well tolerated without irreversible adverse effects of the treatment. Although hemodynamic and metabolic disturbances occurred, these were clinically easily managed and posed little risk in emergency department or pediatric intensive care unit.

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Aerosol inhalation of ambroxol hydrochloride combined with terbutaline can promote recovery of children with severe pneumonia.

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# data[].attributes.attachment_link.keywords[]
bronchodilator agents / adverse effects*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Safety of Terbutaline for Treatment of Acute Severe Pediatric Asthma - PubMed

# data[].attributes.attachment_link.description
The results indicate that overall, terbutaline infusion was well tolerated without irreversible adverse effects of the treatment. Although hemodynamic and metabolic disturbances occurred, these were clinically easily managed and posed little risk in emergency department or pediatric intensive care u ...

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TITULO: Corticosteroides inhalados y riesgo de infección del tracto respiratorio superior en pacientes con asma
AÑO: 2019
TIPO DE ESTUDIO: Metaanálisis
RESULTADOS: Se incluyeron diecisiete ensayos (15.336 sujetos). En comparación con el tratamiento sin CSI, los CSI se asociaron con un riesgo significativamente mayor de  infección del tracto respiratorio superior (URTI). Se realizaron análisis de subgrupos para diferentes dosis, tanto los CSI de dosis alta como baja se asociaron con un riesgo significativamente mayor de URTI. Además, se observó fluticasona con un mayor riesgo de IRA pero no con budesonida, el tratamiento con fluticasona en dosis bajas se asoció con un riesgo significativamente mayor de IRA pero no con dosis altas.
CONCLUSIONES: Este estudio plantea preocupaciones de seguridad sobre el riesgo de URTI asociado con el uso de CSI en pacientes con asma, pero debe investigarse más a fondo.

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Inhaled corticosteroids and risk of upper respiratory tract infection in patients with asthma: a meta-analysis - PubMed

# data[].attributes.attachment_link.description
This study raises safety concerns about the risk of URTI associated with ICS use in patients with asthma, but it should be further investigated.

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https://pubmed.ncbi.nlm.nih.gov/26959519/

Título:Seguridad de la terbutalina para el tratamiento del asma pediátrica aguda grave

Año: 2018
Objetivos: El uso del tratamiento continuo con terbutalina intravenosa en los ataques de asma graves se ha visto obstaculizado por la falta de ensayos clínicos bien desarrollados en los que se describan en detalle los efectos de dicho tratamiento. Aquí, nuestro objetivo era proporcionar un informe descriptivo sobre la cohorte más grande de pacientes pediátricos con asma grave tratados con terbutalina.

Métodos: El estudio se llevó a cabo en una unidad de cuidados intensivos pediátricos en un gran hospital universitario de atención terciaria metropolitana en 124 pacientes que recibieron infusión de terbutalina. Para estratificar el efecto y determinar las diferencias relacionadas con la edad de la terbutalina, los pacientes se dividieron en 3 grupos de edad (0-6 años, 7-12 años y 13-18 años). Se determinó la respuesta clínica y los posibles efectos nocivos de la infusión de terbutalina.

Resultados: Hubo reducciones significativas en la presión arterial sistólica (variando entre 86% y 93% de la línea de base) y diastólica (variando entre 74% y 86% de la línea de base). Sin embargo, los valores volvieron al nivel inicial poco después de la interrupción de la perfusión. La terbutalina aumentó la frecuencia cardíaca en todos los grupos poco después del inicio (9% -13% por encima de la línea de base), que volvió a niveles por debajo de la línea de base 1 hora después de la interrupción. Los niveles séricos de potasio también se redujeron en todos los pacientes en comparación con sus valores iniciales después del inicio de la infusión de terbutalina. Sin embargo, ninguno de los sujetos requirió reemplazo de potasio.

Conclusiones: Los resultados indican que, en general, la infusión de terbutalina fue bien tolerada sin efectos adversos irreversibles del tratamiento. Aunque se produjeron alteraciones hemodinámicas y metabólicas, éstas se manejaron clínicamente con facilidad y presentaban poco riesgo en el departamento de urgencias o en la unidad de cuidados intensivos pediátricos.

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Abstract

Objectives: The use of continuous intravenous terbutaline treatment in severe asthma attacks has been hampered by the lack of well-powered clinical trials where effects of such treatment are described in detail. Here, we aimed to provide a descriptive report on the largest cohort of severe pediatric asthma patients treated with terbutaline.

Methods: The study was conducted in a pediatric intensive care unit in a large metropolitan tertiary care university hospital on 124 patients receiving terbutaline infusion. To stratify the effect of, and determine any age-related differences of, terbutaline, the patients were divided into 3 age groups (0-6 years, 7-12 years, and 13-18 years). Clinical response and the potential harmful effects of terbutaline infusion were determined.

Results: There were significant reductions in systolic (varying between 86% and 93% of the baseline) and diastolic blood pressures (varying between 74% and 86% of the baseline level). However, the values returned to baseline level shortly after discontinuation of infusion. Terbutaline increased heart rates in all groups shortly after initiation (9%-13% above baseline), which returned to below baseline levels 1 hour after discontinuation. Serum potassium levels were also reduced in all patients compared to their baseline values after initiation of terbutaline infusion. However, none of the subjects required potassium replacement.

Conclusions: The results indicate that overall, terbutaline infusion was well tolerated without irreversible adverse effects of the treatment. Although hemodynamic and metabolic disturbances occurred, these were clinically easily managed and posed little risk in emergency department or pediatric intensive care unit.

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bronchodilator agents / adverse effects*

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national center for biotechnology information

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Safety of Terbutaline for Treatment of Acute Severe Pediatric Asthma - PubMed

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The results indicate that overall, terbutaline infusion was well tolerated without irreversible adverse effects of the treatment. Although hemodynamic and metabolic disturbances occurred, these were clinically easily managed and posed little risk in emergency department or pediatric intensive care u ...

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https://journals.sagepub.com/doi/10.1177/2042098613504124

TITULO: Seguridad de los agonistas beta de acción prolongada y los corticosteroides inhalados en niños y adolescentes con asma.

OBJETIVO: identificar y discutir los principales estudios de seguridad publicados sobre el uso de LABA, ICS y el uso combinado de LABA / ICS en niños.

TIPO DE ESTUDIO: Revisión

AÑO:2013

RESULTADOS: seis estudios relevantes para la seguridad de la monoterapia con LABA, Se identificaron y revisaron siete estudios relevantes para la monoterapia con CSI y cuatro estudios sobre el tema del uso de la combinación de LABA / CSI. Con base en la literatura revisada, la controversia que rodea a estos medicamentos contra el asma quedó claramente expuesta. Por un lado, existe alguna evidencia de que la monoterapia con LABA puede estar asociada con EAG y muerte relacionada con el asma, mientras que la monoterapia con ICS puede estar asociada con un mayor riesgo de supresión del crecimiento. Por otro lado, el uso concomitante de un LABA con un CSI se ha asociado con resultados positivos que incluyen la reducción de los síntomas y la reducción de la tasa y la gravedad de las exacerbaciones.

CONCLUSION: La monoterapia con los corticosteroides inhalados (ICS) puede estar asociada con un mayor riesgo de supresión del crecimiento y la monoterapia con LABA puede estar asociada con EAG y muerte relacionada con el asma. Por otro lado, el uso concomitante de un LABA con un CSI se ha asociado con resultados positivos que incluyen la reducción de los síntomas y la reducción de la tasa y la gravedad de las exacerbaciones.

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Abstract

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy for adult, as well as pediatric, patients with asthma. However, the use of LABAs has raised safety concerns, especially the potential for severe asthma exacerbations (SAEs) resulting in hospitalizations or even death. Meanwhile, the use of inhaled corticosteroids (ICSs), a cornerstone in the treatment of mild-to-severe persistent asthma, has been associated with growth suppression in children. The purpose of this review was to identify and discuss the major published safety studies surrounding LABA, ICS, and combined LABA/ICS usage in children. By way of a critical search for influential published clinical trials, meta-analyses, and observational studies, six studies relevant to the safety of LABA monotherapy, seven studies relevant to ICS monotherapy, and four studies on the subject of LABA/ICS combination usage were identified and reviewed. Based on the reviewed literature, the controversy surrounding these anti-asthma medications was clearly exposed. On the one hand, there is some evidence that LABA monotherapy may be associated with SAEs and asthma-related death, while ICS monotherapy may be associated with a higher risk of growth suppression. On the other hand, the concurrent use of a LABA with an ICS has been associated with positive outcomes including symptom reduction and reduced rate and severity of exacerbations. Further clinical research is warranted and has been called for by the US Food and Drug Administration.

Introduction

Asthma, a chronic inflammatory disorder associated with variable airflow obstruction and bronchial hyperresponsiveness, is the most common chronic lower respiratory disease in children worldwide. It presents with recurrent episodes of wheeze, cough, shortness of breath, and chest tightness [ Papadopoulos et al. 2012]. In the United States in 2011, there were an estimated 7.1 million pediatric patients suffering from asthma (representing a 9.5% prevalence rate) who accounted for 27.3% of the total asthma-patient population in the US [ Centers for Disease Control and Prevention, 2011].

Children with asthma are limited in their day-to-day activities such as sports, school, and playing with pets, significantly reducing quality of life. In addition, children with asthma can be distressed by asthma symptoms and can become frightened by asthma attacks or exacerbations [ Juniper, 1997]. Meanwhile, parents or caregivers of children with asthma are affected by both absenteeism from and lost productivity at work [ Wang et al. 2005]. Epidemiologic studies tend to show that children do not grow out of asthma. Even if the symptoms disappear, asthma tends to reappear in adulthood [ Braman, 2006]. Moreover, some children with mild asthma as children will have severe disease as adults [ Braman, 2006]. Pediatric asthma is estimated to be responsible for approximately 13 million missed school days annually in the US [ Akinbami et al. 2010]. In 2004, pediatric asthma was responsible for 7 million ambulatory visits (to either physician offices or hospital outpatient departments), 750,000 visits to emergency departments, 198,000 hospitalizations, and 186 deaths [ Akinbami, 2006]. The annual cost of pediatric asthma in the US has been estimated at US$3.2 billion [ Weiss et al. 2000]. The lifetime cost of pediatric asthma for a cohort of people born in the year 2000 in the US is estimated to be US$7.2 billion, including US$3.2 billion in medical costs and US$4 billion in work/productivity loss experienced by both the patients and their parents [ Corso and Fertig, 2009]. Asthma disproportionately impacts low-income children in the US relative to the pediatric population in general, partly because of the substantial exposure poor children have to asthma triggers, such as dust and dust reservoirs, dust mites, roaches, rodents, molds, and tobacco smoke, that could exacerbate their condition [ Krieger et al. 2000].

Pharmacotherapy is fundamental to the treatment of pediatric asthma. Its goal is the control of symptoms and the prevention of exacerbations with a minimum of drug-related side effects. Short-acting inhaled β ₂ agonists (SABAs) are the most commonly used reliever medications for pediatric patients with asthma for the treatment of intermittent and acute asthma episodes. For children with intermittent asthma, a SABA is the only asthma medication they may take. For children with persistent asthma, controller medications are used to reduce bronchial inflammation. Inhaled corticosteroids (ICSs) are used as first-line controller treatment. The patient is generally started at a low dose (200 µg BDP equivalent); if control is inadequate, the dose may be increased. Leukotriene receptor antagonists (LTRAs) are an alternative first-line therapy for pediatric patients between the ages of 5 and 11 years old with mild persistent asthma who cannot use ICSs or an add-on therapy for those children whose asthma is not adequately controlled with ICS treatment alone [ Bacharier et al. 2008]. The benefit of LTRAs has been shown in children as young as 10 months, although Singulair was approved for patients 12 months and older for asthma [ Straub et al. 2005]. For patients who remain uncontrolled, a long-acting β ₂ agonist (LABA) may be added; in step therapy, at an earlier step for children aged 5-11 years, and a later step for children 0-4 years old [ U.S. Department of Health and Human Services, 2007]. LABA/ICS combination drugs are also available and are an important treatment option at least for a subpopulation of older children [ Lemanske et al. 2010]. For a list of anti-asthma medications, categorized by drug class, see Table 1.

Anti-asthma medications by drug class.

In terms of pediatric asthma management, physicians face a delicate balance between drug safety and efficacy to achieve optimal therapeutic benefits for individual patients. Although there are side effects, such as tachycardia, dizziness, and jitteriness, associated with SABAs, these drugs tend to have generally favorable safety profiles, even in very young patients [ Bacharier et al. 2008]. LTRAs are also generally safe and well-tolerated with an overall incidence of adverse events similar to placebo [ Knorr et al. 2001]. The most commonly encountered side effects with LTRAs are headache and gastrointestinal upset [ Bacharier et al. 2008].The importance of LTRAs in the management of pediatric asthma as well as safety issues surrounding their use are discussed in a number of recent studies [ Montuschi et al. 2007; Montuschi, 2008, 2011; Montuschi and Peters-Golden, 2010; Montuschi and Barnes, 2011].

Since their introduction, however, LABAs have been associated with very serious safety issues. Several studies have presented evidence of significant risk of exacerbations and asthma-related death associated with LABA use. Meanwhile, although serious side effects are unusual, ICSs are associated with at least temporary growth suppression [ Bacharier et al. 2008]. This study describes and discusses the current state of the evidence regarding LABA and ICS safety in the pediatric patient population, by reviewing some of the most impactful clinical trials, meta-analyses, and observational studies. As will become clear from this review, some of the important studies included both adults and children, while some were pediatric-specific. None of the studies involved children younger than 4 years old, hence, safety evidence has been extrapolated to that very young patient population in various treatment guidelines. For a list of studies reviewed, see Table 2.

Summary of influential pediatric long-acting beta agonist ( LABA) and inhaled corticosteroid (ICS) safety studies.

LABA studies

In a randomized, double-blind, placebo-controlled, multinational, multicenter study, Bensch and colleagues examined the efficacy and safety of formoterol dry powder in pediatric asthma patients. A total of 518 children aged 5-12 years were randomly assigned to receive 12 or 24 µg of formoterol dry powder or placebo twice daily for 12 months. Results showed 68 (40%) patients in the formoterol 24 µg group, 67 (39%) patients in the formoterol 12 µg group, and 71 (41%) patients in the placebo group experienced asthma exacerbations. Again, there was no statistically significant difference in the number of asthma exacerbations across the treatment groups [ Bensch et al. 2002].

In a pediatric-specific meta-analysis, Bisgaard examined the asthma-related exacerbation rates of LABA drugs in pediatric asthma patients. Eight studies (including those by Bensch and colleagues and von Berg and colleagues mentioned above) were included, with a total of 2,401 patients 4-17 years old with mild-to-severe persistent asthma [ Bisgaard, 2003]. The conclusion was that LABA treatment with either salmeterol or formoterol, among children taking an ICS, provided no additional protection from asthma exacerbation compared to children receiving a SABA or placebo. A significant increase in asthma-related hospitalizations (the RR ranged from 3.3 to 21.6 across the three studies that included hospitalizations as study endpoints) was, however, observed for children taking a LABA.

In a large, retrospective, cohort, database study with close to 1 million Medicaid patients (out of which there were 767,715 children less than 18 years old) in 10 states over 6 years, Guo and colleagues came to a similar conclusion regarding hospitalizations. Compared with patients taking a SABA only, LABA use in patients with pre-existing asthma was found to be positively associated with hospitalizations and intubations. On the other hand, the estimated hazard ratio for emergency-department visits was 0.68 (95% CI 0.63-0.73) for those same patients with pre-existing asthma. After controlling to the greatest extent possible for patient severity, patients taking a LABA were less likely to go to the emergency room than those on a SABA only [ Guo et al. 2011].

ICS studies

A number of studies have reported a direct association between ICS use and short-term growth suppression. Simons and colleagues conducted a randomized, double-blind, placebo-controlled, parallel-group, 1-year study on the use of ICSs by 241 pediatric asthma patients. During the study period, height on average increased by 3.96 cm in the beclomethasone group (200 µg twice a day), which was significantly (at least statistically) less than both the average growth in the placebo group (5.04 cm, p = 0.018) and the average growth in the salmeterol group (5.40 cm, p = 0.004) [ Simons et al. 1997].

The Childhood Asthma Management Program Research Group found similar results through a double-blind, placebo-controlled study. A total of 1,041 children, aged 5-12 years old, with mild-to-moderate persistent asthma, were randomly assigned to receive budesonide (200 µg), nedocromil (8 µg, a mast cell stabilizer), or placebo twice daily. The study participants were treated for 4-6 years. The children taking budesonide grew on average 22.7 cm, statistically significantly ( p = 0.005) less than the average growth of 23.8 cm among the children assigned the placebo [ Childhood Asthma Management Program Research Group, 2000].

Garcia Garcia and colleagues examined the efficacy and safety of fluticasone versus montelukast in a 12-month, multicenter, randomized, double-blind, clinical trial. Out of a total of 994 patients with mild persistent asthma who were 6 to 14 years old, 499 were assigned fluticasone (100 µg, twice daily), and 495 received montelukast (5 µg, once daily). The results showed that the average growth was statistically significantly lower ( p = 0.018) in the fluticasone group (5.81 cm) than in the montelukast group (6.18 cm) over a year's time [ Garcia Garcia et al. 2005].

Finally, in a randomized, double-blind clinical trial, a total of 285 pediatric asthma patients were randomly assigned to receive either fluticasone (88 µg, twice daily) or placebo for 2 years, then were followed for an additional year without medication. Compared with the placebo group, patients in the fluticasone group grew an average of 1.1 cm less ( p < 0.001) over the first 24 months. However, the height increase was 0.7 cm less ( p = 0.008) by the end of study period [ Guilbert et al. 2006].

Other research has studied the association between ICSs and other adverse events. Nayak and colleagues examined the efficacy and safety of beclomethasone dipropionate, formulated as an extra fine aerosol (hydrofluoroalkane-134a [HFA]-BDP), in children with moderate persistent asthma. A 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group study was conducted, with 353 children aged 5-12 years with persistent asthma enrolled. After a 2-week run-in period, children were randomized to receive low-dose HFA-BDP (80 µg), high-dose HFA-BDP (160 µg), or HFA-placebo twice daily. No statistically significant difference in the rate of adverse events was found across the groups [ Nayak et al. 2002].

LABA/ICS combination studies

The meta-analysis by Rodrigo and colleagues also compared LABA/ICS combination therapy with ICS-only therapy. Their results showed that combination therapy could reduce exacerbations (RR = 0.73; 95% CI 0.67-0.79) compared with the ICS-only group. The results also showed there was no statistically significant difference between the LABA/ICS combination group and the ICS-only group (RR = 2.96; 95% CI 0.50-17.57) in asthma-related death [ Rodrigo et al. 2009].

Zimmerman and colleagues conducted a double-blind, placebo-controlled, randomized, parallel-group, multicenter study. A total of 302 Canadian asthmatic children, aged 6-11 years, already taking an ICS medication, were enrolled in a 12-week study. The children were randomly assigned to receive either formoterol 4.5 µg, formoterol 9 µg, or placebo twice daily. A total of 19 asthma exacerbations occurred during the study, with no statistically significant difference across the groups [ Zimmerman et al. 2004].

Malone and colleagues conducted a pediatric-specific randomized, double-blind, active-controlled, parallel-group study to compare the safety of inhaled fluticasone propionate with or without inhaled salmeterol. A total of 203 children aged 4-11 years were randomly assigned to receive salmeterol/fluticasone propionate (50/100 µg) or fluticasone propionate (100 µg) only twice daily for 12 weeks. The results showed that three (3%) patients in the salmeterol/fluticasone propionate group experienced asthma exacerbations, compared with eight (8%) patients in the fluticasone-propionate-only group [ Malone et al. 2005].

Tal and colleagues conducted a double-blind, randomized, parallel-group, multicenter study, with 286 enrolled children, age 4-17 years old, with asthma. The asthmatic children were randomized to receive formoterol/budesonide (4.5/80 µg, twice daily) or budesonide (100 µg, twice daily). There were eight (5.4%) children in the formoterol/budesonide group who had asthma exacerbations, compared with four (2.9%) patients in the budesonide-only group [ Tal et al. 2002], essentially the opposite of the result from the study by Malone and colleagues.

Discussion

Based on the results of the studies discussed in this article, as well as on its own research, the United States Food and Drug Administration (FDA) issued a safety announcement on February 18, 2010, regarding the use of LABAs in adults and children. The FDA's announcement included the following: 'Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications' [ Food and Drug Administration, 2010]. At that time, the FDA also required a Risk Evaluation and Mitigation Strategy (REMS) for these products, which included a revised Medication Guide for patients and class-labeling changes. Although LABAs remain on the market, the FDA encourages them to be used at the lowest possible doses, for the shortest amount of time, and only in combination with ICSs [ Food and Drug Administration, 2010].

Meanwhile, a number of studies have now been devoted to understanding the effect of ICS utilization on adult height, arguably a more important endpoint than a short-term growth rate. Doull summarized the results from a number of longitudinal studies, concluding that the vast majority of asthmatic children will attain a normal adult height [ Doull, 2004]. With few side effects at recommended dosages and growth suppression a temporary phenomenon, the benefits of ICS treatment seem to outweigh the costs.

In its February 2010 safety announcement, the FDA asked that the LABA manufacturers conduct additional clinical trials to evaluate further the safety of LABAs when used in combination with ICSs. It did not feel that there was enough known about their safety in children. This decision was consistent with the conclusion reached by Cates and colleagues in their recent review of reviews: 'Regular combination therapy is likely to be less risky than monotherapy in children with asthma, but we cannot say that combination therapy is risk free. There are probably an additional three children per 1000 who suffer a non-fatal serious adverse event on combination therapy in comparison to ICS over 3 months. This is currently our best estimate of the risk of using LABA combination therapy in children and has to be balanced against the symptomatic benefit obtained for each child.' [ Cates et al. 2012, p. 2].

Concerns over the safety of asthma medication obviously make treatment more difficult. Moreover, pediatric asthma can be hard to diagnose in the first place because a number of other childhood conditions, such as rhinitis, sinusitis, and respiratory tract infections, can have symptoms similar to those caused by asthma and can co-occur with asthma. In children aged 6 and older, physicians diagnose asthma using the same tests, including spirometry, used to diagnose the disease in adults [ Mayo Clinic, 2013]. For younger children, there is a focus on the frequency and severity of symptoms including wheeze, nocturnal cough, exercise-induced symptoms, persistence of cough with colds, and exposure to environmental factors including allergens [ Bacharier et al. 2008]. Because asthma is characterized by clinical variation in presentation throughout the course of the disease, there is a strong need for noninvasive assessment of airway inflammation. Progress is being made in researching the use of exhaled breath concentrate (EBC) to study concentration of leukotrienes and other biomarkers in asthma [ Montuschi, 2009]. However, EBC requires additional study before being introduced to everyday clinical practice.

Although we have focused on asthma treatment in developed countries, asthma is a common disease in both high- and low-income countries, with prevalence increasing rapidly in the latter. Although prevalence may be leveling off somewhat in the former, this is a recent event after decades of rising prevalence and severity [ Greenwood, 2011]. In a large, global, multicenter study, the highest prevalence was found in the United Kingdom, Australia, New Zealand, and the Republic of Ireland, followed by countries in North, Central, and South America. The lowest prevalence was found in Eastern Europe, Albania, Greece, China, Taiwan, Uzbekistan, India, Indonesia, and Ethiopia [ Pearce et al. 2007]. The high cost of ICSs is a major barrier to persistent asthma management in low- and middle-income countries [ International Union Against Tuberculosis and Lung Disease and the International Study of Asthma and Allergies in Childhood, 2011].

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Safety of long-acting beta agonists and inhaled corticosteroids in children and adolescents with asthma - Ying Xia, Christina M. L. Kelton, Liang Xue, Jeff J. Guo, Boyang Bian, Patricia R. Wigle, 2013

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Abstract The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy for adult, as well as pediatric, patients with asthma. However, the use of LABAs has raised safety concerns, especially the potential for severe asthma exacerbations (SAEs) resulting in hospitalizations or even death.

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https://pubmed.ncbi.nlm.nih.gov/27578478/
Autor: Dahl R. y Col.
Año: 2016
Titulo:  Seguridad y tolerabilidad de tiotropio Respimat (®) una vez al día como complemento de al menos corticosteroides inhalados en pacientes adultos con asma sintomática: un análisis de seguridad combinado.
Objetivo: Evaluar la seguridad y tolerabilidad del tiotropio administrado a través del dispositivo Respimat (®), en comparación con placebo
Resultado:  De 3474 pacientes analizados, 2157 recibieron tiotropio.
El porcentaje de pacientes con efectos adversos fue comparable entre los grupos de tratamiento: tiotropio 5 μg, 60,8%; grupo placebo de 5 μg, 62,5%; tiotropio 2,5 µg, 57,1%; grupo placebo de 2,5 μg, 55,1%. De acuerdo con el perfil de la enfermedad, los efectos adversos más frecuentes en general fueron el asma, la disminución del flujo espiratorio máximo (ambos menos frecuentes con tiotropio) y la nasofaringitis. En conclusión los pacientes medicados con Tiotropium Respimat (®) demostraron seguridad y tolerabilidad comparables con las del placebo, como complemento de al menos la terapia con corticosteroides inhalados, en diferentes pasos de tratamiento en adultos con asma sintomática.

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doi: 10.1016/j.rmed.2016.07.001.

Affiliations

¹ Odense University Hospital, University of Southern Denmark, Sdr Boulevard, DK 5000, Odense C, Denmark. Electronic address: ronald.dahl2@rsyd.dk.

² TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany.

³ Pulmonary Department and Adult Cystic Fibrosis Center, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, 27 Rue du Fg St Jacques, 75014, Paris, France.

⁴ Royal Devon & Exeter Hospital, Barrack Rd, Exeter, Devon, EX2 5DW, UK.

⁵ University of Groningen, Department of Pulmonary Medicine, and Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Postbox 30.001, 9700 RB, Groningen, The Netherlands.

⁶ Global Biometrics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany.

⁷ TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany; Boehringer Ingelheim Pty Limited, Level 1, 78 Waterloo Rd, North Ryde, NSW 2113, Australia.

⁸ University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI 53792, Wisconsin, USA.

⁹ Department of Medicine, University of Cape Town, Mowbray, 7700, Cape Town, South Africa.

Free article

Free article

doi: 10.1016/j.rmed.2016.07.001.

Affiliations

¹ Odense University Hospital, University of Southern Denmark, Sdr Boulevard, DK 5000, Odense C, Denmark. Electronic address: ronald.dahl2@rsyd.dk.

² TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany.

³ Pulmonary Department and Adult Cystic Fibrosis Center, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, 27 Rue du Fg St Jacques, 75014, Paris, France.

⁴ Royal Devon & Exeter Hospital, Barrack Rd, Exeter, Devon, EX2 5DW, UK.

⁵ University of Groningen, Department of Pulmonary Medicine, and Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Postbox 30.001, 9700 RB, Groningen, The Netherlands.

⁶ Global Biometrics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany.

⁷ TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany; Boehringer Ingelheim Pty Limited, Level 1, 78 Waterloo Rd, North Ryde, NSW 2113, Australia.

⁸ University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI 53792, Wisconsin, USA.

⁹ Department of Medicine, University of Cape Town, Mowbray, 7700, Cape Town, South Africa.

Abstract

Background: Tiotropium, a long-acting anticholinergic bronchodilator, has demonstrated efficacy and safety as add-on therapy to inhaled corticosteroids (ICS), with or without other maintenance therapies, in patients with symptomatic asthma.

Objective: To evaluate safety and tolerability of tiotropium delivered via the Respimat(®) device, compared with placebo, each as add-on to at least ICS therapy, in a pooled sample of adults with symptomatic asthma at different treatment steps.

Methods: Data were pooled from seven Phase II and III, randomised, double-blind, parallel-group trials of 12-52 weeks' treatment duration, which investigated once-daily tiotropium Respimat(®) (5 μg, 2.5 μg) versus placebo as add-on to different background maintenance therapy including at least ICS. Adverse events (AEs) including serious AEs were assessed throughout treatment + 30 days after the last dose of trial medication.

Results: Of 3474 patients analysed, 2157 received tiotropium. The percentage of patients with AEs was comparable between treatment groups: tiotropium 5 μg, 60.8%; placebo 5 μg pool, 62.5%; tiotropium 2.5 μg, 57.1%; placebo 2.5 μg pool, 55.1%. Consistent with the disease profile, the most frequent AEs overall were asthma, decreased peak expiratory flow rate (both less frequent with tiotropium) and nasopharyngitis. Overall incidence of dry mouth, commonly associated with use of anticholinergics, was low: tiotropium 5 μg, 1.0%; placebo 5 μg pool, 0.5%; tiotropium 2.5 μg, 0.4%; placebo 2.5 μg pool, 0.5%. The percentage of cardiac disorder AEs was comparable between tiotropium and placebo: tiotropium 5 μg, 1.4%; placebo 5 μg pool, 1.4%; tiotropium 2.5 μg, 1.4%; placebo 2.5 μg pool, 1.1%. The proportions of patients with serious AEs were balanced across groups: tiotropium 5 μg, 4.0%; placebo 5 μg pool, 4.9%; tiotropium 2.5 μg, 2.0%; placebo 2.5 μg pool, 3.3%.

Conclusion: Tiotropium Respimat(®) demonstrated safety and tolerability comparable with those of placebo, as add-on to at least ICS therapy, at different treatment steps in adults with symptomatic asthma.

Keywords: Asthma; Respimat(®); Safety; Tiotropium; Tolerability.

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / administration & dosage

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / adverse effects

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / therapeutic use*

# data[].attributes.attachment_link.keywords[]
adrenergic beta-2 receptor agonists / administration & dosage

# data[].attributes.attachment_link.keywords[]
adrenergic beta-2 receptor agonists / therapeutic use

# data[].attributes.attachment_link.keywords[]
cholinergic antagonists / therapeutic use

# data[].attributes.attachment_link.keywords[]
nebulizers and vaporizers / statistics & numerical data

# data[].attributes.attachment_link.keywords[]
peak expiratory flow rate / drug effects

# data[].attributes.attachment_link.keywords[]
tiotropium bromide / administration & dosage

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Safety and tolerability of once-daily tiotropium Respimat(®) as add-on to at least inhaled corticosteroids in adult patients with symptomatic asthma: A pooled safety analysis - PubMed

# data[].attributes.attachment_link.description
doi: 10.1016/j.rmed.2016.07.001. 1 Odense University Hospital, University of Southern Denmark, Sdr Boulevard, DK 5000, Odense C, Denmark. Electronic address: ronald.dahl2@rsyd.dk. 2 TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany. 3 Pulmonary Department and Adult Cystic Fibrosis Center, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, 27 Rue du Fg St Jacques, 75014, Paris, France.

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Link: https://pubmed.ncbi.nlm.nih.gov/16203672/

TÍTULO:

Seguridad de la terbutalina intravenosa en el asma aguda grave: un estudio retrospectivo

AÑO: 2005
TIPO DE ESTUDIO: estudio retrospectivo
RESULTADOS: La aplicación de terbutalina intravenosa generó un aumento significativo en la frecuencia cardíaca y una caída significativa en la presión arterial diastólica. Ninguno de los pacientes presentó arritmias cardíacas. Sin embargo, todos los pacientes mejoraron y ninguno requirió el inicio de la ventilación después de comenzar con terbutalina.

CONCLUSIONES:  Se encontró que la terbutalina es segura para su uso en este grupo de pacientes en dosis que oscilan entre 1 y 5 microg / kg / min. Se encontró que la terbutalina intravenosa es un complemento útil en aquellos que no respondieron a la terapia inicial estándar.

# data[].attributes.attachment_link.title
Safety of intravenous terbutaline in acute severe asthma: a retrospective study - PubMed

# data[].attributes.attachment_link.description
Terbutaline was found to be safe for use in this patient group in doses ranging between 1 and 5 microg/kg/min. Intravenous terbutaline was found to be a useful adjunct in those who failed to respond to standard initial therapy.

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TITULO: Seguridad y tolerabilidad de tiotropio Respimat (®) una vez al día como complemento de al menos corticosteroides inhalados en pacientes adultos con asma sintomática: un análisis de seguridad combinado.

TIPO DE ESTUDIO Y AÑO: Ensayo clínico - 2016

OBJETIVO: Evaluar la seguridad y tolerabilidad del tiotropio administrado a través del dispositivo Respimat (®), en comparación con placebo, cada uno como complemento de al menos la terapia con CSI, en una muestra combinada de adultos con asma sintomática en diferentes etapas de tratamiento.

RESULTADOS:  El porcentaje de pacientes con efectos adversos  fue comparable entre los grupos de tratamiento: tiotropio 5 μg, 60,8%; grupo placebo de 5 μg, 62,5%; tiotropio 2,5 µg, 57,1%; grupo placebo de 2,5 μg, 55,1%. De acuerdo con el perfil de la enfermedad, los efectos adversos  más frecuentes en general fueron el asma, la disminución del flujo espiratorio máximo (ambos menos frecuentes con tiotropio) y la nasofaringitis. La incidencia global de boca seca, comúnmente asociada con el uso de anticolinérgicos, fue baja: tiotropio 5 μg, 1,0%; grupo placebo de 5 µg, 0,5%; tiotropio 2,5 µg, 0,4%; grupo placebo de 2,5 μg, 0,5%. El porcentaje de efectos adverso de trastornos cardíacos fue comparable entre tiotropio y placebo: tiotropio 5 μg, 1,4%; grupo placebo de 5 μg, 1,4%; tiotropio 2,5 µg, 1,4%; grupo placebo de 2,5 μg, 1,1%.

CONCLUSIÓN: tiotropium Respimat (®) demostró seguridad y tolerabilidad comparables con las del placebo, como complemento de al menos la terapia corticosteroides inhalados (CSI), en diferentes pasos de tratamiento en adultos con asma sintomática.
https://pubmed.ncbi.nlm.nih.gov/27578478/

# data[].attributes.attachment_link.readable_text
doi: 10.1016/j.rmed.2016.07.001.

Affiliations

¹ Odense University Hospital, University of Southern Denmark, Sdr Boulevard, DK 5000, Odense C, Denmark. Electronic address: ronald.dahl2@rsyd.dk.

² TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany.

³ Pulmonary Department and Adult Cystic Fibrosis Center, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, 27 Rue du Fg St Jacques, 75014, Paris, France.

⁴ Royal Devon & Exeter Hospital, Barrack Rd, Exeter, Devon, EX2 5DW, UK.

⁵ University of Groningen, Department of Pulmonary Medicine, and Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Postbox 30.001, 9700 RB, Groningen, The Netherlands.

⁶ Global Biometrics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany.

⁷ TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany; Boehringer Ingelheim Pty Limited, Level 1, 78 Waterloo Rd, North Ryde, NSW 2113, Australia.

⁸ University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI 53792, Wisconsin, USA.

⁹ Department of Medicine, University of Cape Town, Mowbray, 7700, Cape Town, South Africa.

Free article

Free article

doi: 10.1016/j.rmed.2016.07.001.

Affiliations

¹ Odense University Hospital, University of Southern Denmark, Sdr Boulevard, DK 5000, Odense C, Denmark. Electronic address: ronald.dahl2@rsyd.dk.

² TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany.

³ Pulmonary Department and Adult Cystic Fibrosis Center, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, 27 Rue du Fg St Jacques, 75014, Paris, France.

⁴ Royal Devon & Exeter Hospital, Barrack Rd, Exeter, Devon, EX2 5DW, UK.

⁵ University of Groningen, Department of Pulmonary Medicine, and Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Postbox 30.001, 9700 RB, Groningen, The Netherlands.

⁶ Global Biometrics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany.

⁷ TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany; Boehringer Ingelheim Pty Limited, Level 1, 78 Waterloo Rd, North Ryde, NSW 2113, Australia.

⁸ University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI 53792, Wisconsin, USA.

⁹ Department of Medicine, University of Cape Town, Mowbray, 7700, Cape Town, South Africa.

Abstract

Background: Tiotropium, a long-acting anticholinergic bronchodilator, has demonstrated efficacy and safety as add-on therapy to inhaled corticosteroids (ICS), with or without other maintenance therapies, in patients with symptomatic asthma.

Objective: To evaluate safety and tolerability of tiotropium delivered via the Respimat(®) device, compared with placebo, each as add-on to at least ICS therapy, in a pooled sample of adults with symptomatic asthma at different treatment steps.

Methods: Data were pooled from seven Phase II and III, randomised, double-blind, parallel-group trials of 12-52 weeks' treatment duration, which investigated once-daily tiotropium Respimat(®) (5 μg, 2.5 μg) versus placebo as add-on to different background maintenance therapy including at least ICS. Adverse events (AEs) including serious AEs were assessed throughout treatment + 30 days after the last dose of trial medication.

Results: Of 3474 patients analysed, 2157 received tiotropium. The percentage of patients with AEs was comparable between treatment groups: tiotropium 5 μg, 60.8%; placebo 5 μg pool, 62.5%; tiotropium 2.5 μg, 57.1%; placebo 2.5 μg pool, 55.1%. Consistent with the disease profile, the most frequent AEs overall were asthma, decreased peak expiratory flow rate (both less frequent with tiotropium) and nasopharyngitis. Overall incidence of dry mouth, commonly associated with use of anticholinergics, was low: tiotropium 5 μg, 1.0%; placebo 5 μg pool, 0.5%; tiotropium 2.5 μg, 0.4%; placebo 2.5 μg pool, 0.5%. The percentage of cardiac disorder AEs was comparable between tiotropium and placebo: tiotropium 5 μg, 1.4%; placebo 5 μg pool, 1.4%; tiotropium 2.5 μg, 1.4%; placebo 2.5 μg pool, 1.1%. The proportions of patients with serious AEs were balanced across groups: tiotropium 5 μg, 4.0%; placebo 5 μg pool, 4.9%; tiotropium 2.5 μg, 2.0%; placebo 2.5 μg pool, 3.3%.

Conclusion: Tiotropium Respimat(®) demonstrated safety and tolerability comparable with those of placebo, as add-on to at least ICS therapy, at different treatment steps in adults with symptomatic asthma.

Keywords: Asthma; Respimat(®); Safety; Tiotropium; Tolerability.

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / administration & dosage

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / adverse effects

# data[].attributes.attachment_link.keywords[]
adrenal cortex hormones / therapeutic use*

# data[].attributes.attachment_link.keywords[]
adrenergic beta-2 receptor agonists / administration & dosage

# data[].attributes.attachment_link.keywords[]
adrenergic beta-2 receptor agonists / therapeutic use

# data[].attributes.attachment_link.keywords[]
cholinergic antagonists / therapeutic use

# data[].attributes.attachment_link.keywords[]
nebulizers and vaporizers / statistics & numerical data

# data[].attributes.attachment_link.keywords[]
peak expiratory flow rate / drug effects

# data[].attributes.attachment_link.keywords[]
tiotropium bromide / administration & dosage

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Safety and tolerability of once-daily tiotropium Respimat(®) as add-on to at least inhaled corticosteroids in adult patients with symptomatic asthma: A pooled safety analysis - PubMed

# data[].attributes.attachment_link.description
doi: 10.1016/j.rmed.2016.07.001. 1 Odense University Hospital, University of Southern Denmark, Sdr Boulevard, DK 5000, Odense C, Denmark. Electronic address: ronald.dahl2@rsyd.dk. 2 TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim, Germany. 3 Pulmonary Department and Adult Cystic Fibrosis Center, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, 27 Rue du Fg St Jacques, 75014, Paris, France.

# data[].attributes.body
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713104/

TITULO:  Seguridad de los agonistas beta-2-adrenérgicos inhalados: ¿qué aporta la notificación espontánea?

TIPO DE ESTUDIO: Revisión sistemática

OBJETIVO:  El objetivo de este estudio fue analizar la seguridad de los agonistas beta2-adrenérgicos inhalados en las condiciones habituales de uso

RESULTADOS:  Los órganos y sistemas afectados con más frecuencia fueron el sistema nervioso central y periférico, la piel y anejos, los trastornos cardiovasculares y las alteraciones psiquiátricas, siendo el temblor, el prurito, la taquicardia y el nerviosismo las reacciones adversas más frecuentes. En la comparación de la distribución por órganos y sistemas se observó una frecuencia mayor de los trastornos de la piel y anejos  (odds ratio [OR], intervalo de confianza [IC] del 95%, 1,8 [1,1-2,9]) para salbutamol, y de alteraciones respiratorias para salmeterol (OR, IC del 95%, 3,0 [1,7-5,3])

CONCLUSIÓN:  Nuestros resultados sugieren la existencia de un patrón común de reacciones adversas para los agonistas beta-2-adrenérgicos, con algunas diferencias entre salbutamol y salmeterol.

# data[].attributes.attachment_link.title
Seguridad de los agonistas beta-2-adrenérgicos inhalados: ¿qué aporta la notificación espontánea?

# data[].attributes.body
Eficacia y seguridad de los corticosteroides inhalados en relación con el propionato de fluticasona: una revisión sistemática de ensayos controlados aleatorios en el asma

AÑO: 2017

Resultados: esta revisión sistemática evaluó ensayos controlados aleatorios (ECA) que compararon la eficacia y seguridad del propionato de fluticasona inhalado (FP) con otros CSI, incluidos dipropionato de beclometasona (BDP), budesonida (BUD) y ciclesonida (CIC). Se realizaron búsquedas en PubMed y se incluyeron 54 ECA que se ajustaban a criterios predeterminados. Los criterios de valoración evaluados incluyeron la función pulmonar, el control de los síntomas del asma, la frecuencia de las exacerbaciones, el uso de analgésicos, la calidad de vida y los efectos secundarios relacionados con los esteroides.

# data[].attributes.attachment_link.title
Efficacy and safety of inhaled corticosteroids relative to fluticasone propionate: a systematic review of randomized controlled trials in asthma - PubMed

# data[].attributes.attachment_link.description
Many trials have been published comparing inhaled corticosteroid (ICS) treatments in asthma. However, mixed results necessitate the summarization of available evidence to aid in decision-making. Areas covered: This systematic review evaluated randomized controlled trials (RCTs) that compared the eff…

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TITULO:

Eficacia y seguridad de salmeterol / fluticasona en comparación con montelukast solo (o terapia adicional a fluticasona) en el tratamiento del asma bronquial en niños y adolescentes: revisión sistemática y metanálisis

TIPO DE ESTUDIO: revisión sistemática y metanálisis
AÑO: 2021
RESULTADOS:
De los 1006 artículos identificados, 21 estudios cumplieron los criterios de inclusión con 2643 personas; dos tenían bajo riesgo de sesgo. En cuanto al resultado secundario, SFC mostró una mejora significativa del flujo espiratorio máximo (PEF)% pred después de 4 semanas en comparación con MFC (diferencia media [DM]: 5,45; intervalo de confianza [IC] del 95%: 1,57-9,34; I ² = 95 %; P = 0,006). En cuanto al nivel de control del asma, SFC también mostró un nivel de control total más alto (razón de riesgo [RR]: 1,51; IC del 95%: 1,24-1,85; I ² = 0; P<0,001) y una puntuación más alta en la prueba de control del asma infantil después de 4 semanas de tratamiento (DM: 2,30; IC del 95%: 1,39–3,21; I ² = 72%; P <0,001) en comparación con MFC.
CONCLUSIÓN:
El SFC puede ser más eficaz que el MFC para el tratamiento del asma en niños y adolescentes, especialmente para mejorar el nivel de control del asma.
https://journals.lww.com/cmj/Fulltext/2021/12200/Efficacy_and_safety_of_salmeterol_fluticasone.7.aspx

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Titulo:

Seguridad de la terbutalina para el tratamiento del asma pediátrica aguda grave

Autor: Doymaz, S. y Schneider, J.
Año: (2018)
Tipo de estudio: Revisión sistemática
Resultados: Hubo reducciones significativas en la presión arterial sistólica (variando entre el 86% y el 93% del valor inicial) y diastólica (variando entre el 74% y el 86% del nivel basal). Sin embargo, los valores volvieron al nivel inicial poco después de la interrupción de la perfusión. La terbutalina aumentó la frecuencia cardíaca en todos los grupos poco después del inicio (9% -13% por encima de la línea de base), que volvió a los niveles por debajo de la línea de base 1 hora después de la interrupción. Los niveles séricos de potasio también se redujeron en todos los pacientes en comparación con sus valores iniciales después del inicio de la infusión de terbutalina. Sin embargo, ninguno de los sujetos requirió reemplazo de potasio.
Conclusiones: Los resultados indican que, en general, la infusión de terbutalina fue bien tolerada sin efectos adversos irreversibles del tratamiento. Aunque se produjeron alteraciones hemodinámicas y metabólicas, éstas se manejaron clínicamente con facilidad y presentaban poco riesgo en el departamento de urgencias o en la unidad de cuidados intensivos pediátricos.
https://journals.lww.com/pec-online/Abstract/2018/05000/Safety_of_Terbutaline_for_Treatment_of_Acute.1.aspx

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https://pubmed.ncbi.nlm.nih.gov/30905424/
TITULO:

Montelukast y eventos neuropsiquiátricos en niños con asma: un estudio de casos y controles anidado

AÑO: 2019
TIPO DE ESTUDIO:

estudio de casos y controles

OBJETIVO: Examinar la asociación entre la prescripción de montelukast y los eventos neuropsiquiátricos en niños con asma.
RESULTADOS: Los niños que experimentaron un evento neuropsiquiátrico de nueva aparición tenían casi 2 veces más probabilidades de que se les prescribiera montelukast, en comparación con los controles (OR 1,91; IC del 95%: 1,15-3,18; p = 0,01). La mayoría de los casos se presentaron por ansiedad (48,6%) y / o alteración del sueño (26,1%).
CONCLUSIÓN: Los niños con asma que experimentaron un evento neuropsiquiátrico de nueva aparición tenían casi el doble de probabilidades de que se les prescribiera montelukast en el año anterior al evento. Los médicos deben conocer la asociación entre montelukast y los eventos neuropsiquiátricos en niños con asma, para informar las prácticas de prescripción y el seguimiento clínico.

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Affiliations

¹ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario.

² Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Division of Emergency Medicine, The Hospital for Sick Children, Toronto, Ontario; Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario; Paediatrics, Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario.

³ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario.

⁴ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario. Electronic address: teresa.to@sickkids.ca.

Affiliations

¹ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario.

² Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Division of Emergency Medicine, The Hospital for Sick Children, Toronto, Ontario; Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario; Paediatrics, Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario.

³ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario.

⁴ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario. Electronic address: teresa.to@sickkids.ca.

Abstract

Objective: To examine the association between montelukast prescription and neuropsychiatric events in children with asthma.

Study design: A matched, nested case-control design was used to identify cases and controls from a cohort of children aged 5-18 years with physician-diagnosed asthma from 2004 to 2015, in Ontario, Canada, prescribed an asthma maintenance medication. Cases were children with a hospitalization or emergency department visit for a neuropsychiatric event. Cases were matched to up to 4 controls on birth year, year of asthma diagnosis, and sex. The exposures were dispensed prescriptions for montelukast (yes/no) and number of dispensed montelukast prescriptions in the year before the index date. Conditional logistic regression was used to measure the unadjusted OR and aOR and 95% CIs for montelukast prescription and neuropsychiatric events. Covariates in the adjusted model included sociodemographic factors and measures of asthma severity.

Results: In total, 898 cases with a neuropsychiatric event and 3497 matched controls were included. Children who experienced a new-onset neuropsychiatric event had nearly 2 times the odds of having been prescribed montelukast, compared with controls (OR 1.91, 95% CI 1.15-3.18; P = .01). Most cases presented for anxiety (48.6%) and/or sleep disturbance (26.1%).

Conclusions: Children with asthma who experienced a new-onset neuropsychiatric event had nearly twice the odds of having been prescribed montelukast in the year before their event. Clinicians should be aware of the association between montelukast and neuropsychiatric events in children with asthma, to inform prescribing practices and clinical follow-up.

Keywords: asthma; children; drug safety; montelukast; neuropsychiatric events.

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# data[].attributes.attachment_link.keywords[]
anti-asthmatic agents / adverse effects*

# data[].attributes.attachment_link.keywords[]
nervous system diseases / chemically induced*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case-Control Study - PubMed

# data[].attributes.attachment_link.description
Children with asthma who experienced a new-onset neuropsychiatric event had nearly twice the odds of having been prescribed montelukast in the year before their event. Clinicians should be aware of the association between montelukast and neuropsychiatric events in children with asthma, to inform pre ...

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Los datos obtenidos de 696 pacientes asmáticos se extrajeron de 4 ensayos controlados aleatorios publicados entre 2015 y 2018. La doxofilina fue significativamente ( P <0,05) más eficaz que la teofilina para reducir los episodios de asma diarios (diferencia de medias - 0,14, IC del 95%: -0,27 - 0,00) y riesgo de EA (riesgo relativo 0,76; IC del 95%: 0,59-0,99). La doxofilina fue tan eficaz como la teofilina para mejorar el FEV ₁ , y se detectó una tendencia de superioridad ( P = 0,058) para la doxofilina sobre la teofilina con respecto a la reducción en el uso de salbutamol como medicación de rescate. El rango de efectividad fue doxofilina> teofilina>> placebo, y el rango de seguridad fue placebo> doxofilina>> teofilina.

Conclusiones: La doxofilina es una metilxantina eficaz y segura para el tratamiento del asma, con un perfil de eficacia / seguridad superior al de la teofilina.

# data[].attributes.attachment_link.readable_text
doi: 10.1186/s40248-019-0189-0.

Affiliations

¹ 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.

² 2Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy.

³ 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Free PMC article

Free PMC article

doi: 10.1186/s40248-019-0189-0.

Affiliations

¹ 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.

² 2Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy.

³ 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Abstract

Background: Oral methylxanthines are effective drugs for the treatment of chronic obstructive respiratory disorders. The novel methylxanthine doxofylline, that has bronchodilator and anti-inflammatory activities, is not affected by the major drawback of theophylline. Nowadays large-scale quantitative synthesis comparing the efficacy and safety profile of doxofylline vs. theophylline in the treatment of asthma is still lacking. Therefore, we performed a quantitative synthesis to compare the efficacy/safety profile of doxofylline and theophylline in asthma.

Methods: A pairwise and network meta-analyses were performed to assess the impact of doxofylline vs. theophylline and placebo on the change in asthma events, risk of adverse events (AEs), forced expiratory volume in 1 s (FEV ₁), and salbutamol use.

Results: Data obtained from 696 asthmatic patients were extracted from 4 randomized controlled trials published between 2015 and 2018. Doxofylline was significantly ( P < 0.05) more effective than theophylline in reducing the daily asthma events (mean difference - 0.14, 95%CI -0.27 - 0.00) and risk of AEs (relative risk 0.76, 95%CI 0.59-0.99). Doxofylline was as effective as theophylline in improving FEV ₁, and a trend of superiority ( P = 0.058) was detected for doxofylline over theophylline with respect to the reduction in the use of salbutamol as rescue medication. The rank of effectiveness was doxofylline>theophylline> > placebo, and the rank of safety was placebo>doxofylline> > theophylline.

Conclusions: Doxofylline is an effective and safe methylxanthine for the treatment of asthma, with an efficacy/safety profile greater than that of theophylline.

Trial registration: Meta-analysis registration: CRD42019119849.

Keywords: Asthma; Doxofylline; Meta-analysis; Theophylline.

Conflict of interest statement

Competing interestsPR has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; LC has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; he is or has been a consultant to ABC Farmaceutici; JO has no competing interests; MGM has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; MC has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; he is or has been a consultant to ABC Farmaceutici. MC is a member of the Editorial Board of Multidisciplinary Respiratory Medicine.

Similar articles

Impact of doxofylline compared to theophylline in asthma: A pooled analysis of functional and clinical outcomes from two multicentre, double-blind, randomized studies (DOROTHEO 1 and DOROTHEO 2).

Calzetta L, Hanania NA, Dini FL, Goldstein MF, Fairweather WR, Howard WW, Cazzola M. Calzetta L, et al. Pulm Pharmacol Ther. 2018 Dec;53:20-26. doi: 10.1016/j.pupt.2018.09.007. Epub 2018 Sep 13. Pulm Pharmacol Ther. 2018. PMID: 30219705

References

Page CP. Doxofylline: a "novofylline". Pulm Pharmacol Ther. 2010;23(4):231-234. doi: 10.1016/j.pupt.2010.04.002. - DOI - PubMed

Franzone JS, Cirillo R, Barone D. Doxofylline and theophylline are xanthines with partly different mechanisms of action in animals. Drugs Exp Clin Res. 1988;14(7):479-489. - PubMed

Cirillo R, Barone D, Franzone JS. Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors. Arch Int Pharmacodyn Ther. 1988;295:221-237. - PubMed

Dolcetti A, Osella D, De Filippis G, Carnuccio C, Grossi E. Comparison of intravenously administered doxofylline and placebo for the treatment of severe acute airways obstruction. J Int Med Res. 1988;16(4):264-269. doi: 10.1177/030006058801600403. - DOI - PubMed

Poggi R, Brandolese R, Bernasconi M, Manzin E, Rossi A. Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure. Chest. 1989;96(4):772-778. doi: 10.1378/chest.96.4.772. - DOI - PubMed

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national center for biotechnology information

# data[].attributes.attachment_link.title
Efficacy and safety profile of doxofylline compared to theophylline in asthma: a meta-analysis - PubMed

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doi: 10.1186/s40248-019-0189-0. 1 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy. 2 2Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy. 3 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768195/
TÍTULO:

Eficacia y efectos secundarios de la teofilina intravenosa en el asma aguda: revisión sistemática y metanálisis

TIPO DE ESTUDIO: Revisión sistemática y metanálisis.
AUTOR Y AÑO DE PUBLICACIÓN: Mahemuti G, et al; 2018.
RESULTADOS: La teofilina redujo significativamente la frecuencia cardíaca en comparación con el control activo ( p = 0,01) y la duración total de la estancia ( p = 0,002), pero los agonistas beta-2 fueron superiores a la teofilina para mejorar el volumen espiratorio forzado en un segundo (FEV1) ( p= 0,002). En comparación con el placebo, la teofilina intravenosa provocó más náuseas, vómitos y efectos adversos cardiovasculares (como palpitaciones y arritmias). No hubo diferencias en cuanto a dolor abdominal, efectos secundarios psicológicos, cefaleas, convulsiones o temblores.
CONCLUSIÓN: La teofilina, cuando se administra con broncodilatadores con o sin esteroides, es una opción rentable y segura para las exacerbaciones agudas del asma.

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Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis

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Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner’s formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, ...

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TITULO: Budesonida combinada inhalada-formoterol según sea necesario en el asma leve
AÑO: 2018
TIPO DE ESTUDIO: Estudio aleatorizado
RESULTADOS:Un total de 3849 pacientes fueron aleatorizados y 3836 (1277 en el grupo de terbutalina, 1277 en el grupo de budesonida-formoterol y 1282 en el grupo de mantenimiento con budesonida) se incluyeron en el análisis completo y conjuntos de datos de seguridad. Con respecto al porcentaje medio de semanas con asma bien controlada por paciente, budesonida-formoterol fue superior a terbutalina (34,4% frente a 31,1% de semanas; odds ratio, 1,14; intervalo de confianza [IC] del 95%, 1,00 a 1,30; P = 0,046) pero inferior a la terapia de mantenimiento con budesonida (34,4% y 44,4%, respectivamente; razón de posibilidades, 0,64; IC del 95%, 0,57 a 0,73). La tasa anual de exacerbaciones graves fue de 0,20 con terbutalina, 0,07 con budesonida-formoterol y 0,09 con terapia de mantenimiento con budesonida; la razón de tasas fue 0,36 (IC del 95%, 0,27 a 0,49) para budesonida-formoterol versus terbutalina y 0,83 (IC del 95%, 0,59 a 1,16) para la terapia de mantenimiento con budesonida-formoterol versus budesonida. La tasa de adherencia en el grupo de mantenimiento con budesonida fue del 78,9%. La mediana de la dosis diaria medida de glucocorticoide inhalado en el grupo de budesonida-formoterol (57 μg) fue del 17% de la dosis en el grupo de mantenimiento con budesonida (340 μg).
CONCLUSIONES: En pacientes con asma leve, la budesonida-formoterol según la necesidad proporcionó un control de los síntomas del asma superior a la terbutalina según la necesidad, evaluado según las semanas registradas electrónicamente con asma bien controlada, pero fue inferior a la terapia de mantenimiento con budesonida. Las tasas de exacerbación con los dos regímenes que contienen budesonida fueron similares y menores que las tasas con terbutalina. El uso de budesonida-formoterol según sea necesario dio como resultado una exposición a glucocorticoides sustancialmente menor que la terapia de mantenimiento con budesonida. (Financiado por AstraZeneca; número SYGMA 1 ClinicalTrials.gov, NCT02149199. Se abre en una nueva pestaña).
https://www.nejm.org/doi/10.1056/NEJMoa1715274?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov

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https://jamanetwork.com/journals/jama/article-abstract/1028648
Titulo: Anticolinérgicos inhalados y riesgo de eventos cardiovasculares adversos importantes en pacientes con enfermedad pulmonar obstructiva crónica

Tipo de estudio: Revisión sistemática y un metanálisis
Objetivo: Determinar los riesgos cardiovasculares de los anticolinérgicos inhalados, incluida la muerte cardiovascular, el infarto de miocardio (IM) y el accidente cerebrovascular.
Resultados: Después de una selección detallada de 103 artículos, se analizaron 17 ensayos que incluían a 14 783 pacientes. La duración del seguimiento osciló entre 6 semanas y 5 años. Se produjo muerte cardiovascular, infarto de miocardio o accidente cerebrovascular en 135 de 7472 pacientes (1,8%) que recibieron anticolinérgicos inhalados y 86 de 7311 pacientes (1,2%) que recibieron terapia de control (RR, 1,58 [intervalo de confianza del 95% {IC}, 1,21-2,06]; P  <0,001, I ²  = 0%). Entre los componentes individuales del criterio de valoración principal, los anticolinérgicos inhalados aumentaron significativamente el riesgo de infarto de miocardio (RR, 1,53 [IC 95% 1,05-2,23]; p  = 0,03, I ²  = 0%) y muerte cardiovascular (RR, 1,80 [95 % IC, 1,17-2,77]; P  = 0,008, I ² = 0%) sin un aumento estadísticamente significativo en el riesgo de accidente cerebrovascular (RR, 1,46 [IC del 95%,

Conclusiones: Los anticolinérgicos inhalados se asocian con un riesgo significativamente mayor de muerte cardiovascular, infarto de miocardio o accidente cerebrovascular entre los pacientes con EPOC.

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Título: Efecto terapéutico y seguridad de montelukast sódico combinado con budesonida en niños con asma variante de tos: un metanálisis.
Año: 2016
Autor: Wei Y, Li DS, Liu JJ, Zhang J, Zhao HE.
Tipo de estudio: Metaanálisis
Objetivo: Evaluar el efecto terapéutico y la seguridad de montelukast sódico combinado con budesonida en niños con asma variante de tos.
Resultados: Se incluyeron un total de 11 ECA con 1 097 pacientes. Los resultados del metanálisis mostraron que, en comparación con el grupo de control (inhalación de budesonida sola), el grupo de observación (inhalación de montelukast sódico combinado con budesonida) tuvo una tasa de respuesta general significativamente mayor y parámetros de función pulmonar más mejorados, incluido el volumen espiratorio forzado en el primer segundo, porcentaje de volumen espiratorio forzado en el primer segundo y flujo espiratorio máximo, así como una tasa de recurrencia significativamente menor (P <0,01). La incidencia de eventos adversos no mostró diferencias significativas entre los dos grupos.
Conclusión:  La inhalación de montelukast sódico combinado con budesonida tiene un efecto significativo en niños con asma variante de tos y no aumenta la incidencia de eventos adversos.
https://pubmed.ncbi.nlm.nih.gov/27817773/

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Objective: To evaluate the therapeutic effect and safety of montelukast sodium combined with budesonide in children with cough variant asthma.

Methods: The databases CNKI, Wanfang Data, VIP, PubMed, EMbase, and BioMed Central were searched for randomized controlled trials (RCTs) of montelukast sodium combined with budesonide in the treatment of children with cough variant asthma. Data extraction and quality assessment were performed for RCTs which met the inclusion criteria, and RevMan 5.3 software was used to perform quality assessment of the articles included and Meta analysis.

Results: A total of 11 RCTs involving 1 097 patients were included. The results of the Meta analysis showed that compared with the control group (inhalation of budesonide alone), the observation group (inhalation of montelukast sodium combined with budesonide) had significantly higher overall response rate and more improved pulmonary function parameters including forced expiratory volume in the first second, percentage of forced expiratory volume in the first second, and peak expiratory flow, as well as significantly lower recurrence rate (P<0.01). The incidence of adverse events showed no significant difference between the two groups.

Conclusions: Inhalation of montelukast sodium combined with budesonide has a significant effect in children with cough variant asthma and does not increase the incidence of adverse events.

目的: 评价孟鲁司特钠联合布地奈德治疗儿童咳嗽变异性哮喘的疗效和安全性。

方法: 计算机检索中国知网、万方、维普、PubMed、EMbase、BioMedCenral数据库等，纳入孟鲁司特钠联合布地奈德治疗儿童咳嗽变异性哮喘的随机对照试验，对符合纳入标准的临床研究进行资料提取和质量评价，采用RevMan5.3软件对纳入文献进行质量评价和Meta分析。

结果: 共纳入11篇中文文献，合计受试者1097例。Meta分析结果显示：观察组（孟鲁司特钠联合布地奈德吸入）的总有效率及肺功能指标第一秒用力呼气容积（FEV ₁）、第一秒用力呼气容积百分比（FEV ₁%）、呼气流量峰值（PEF）明显高于对照组（单用布地奈德吸入）（ P < 0.01）；观察组的复发率明显低于对照组（ P < 0.01）；不良反应发生率两组比较差异无统计学意义。

结论: 孟鲁司特钠联合布地奈德吸入治疗儿童咳嗽变异性哮喘临床治疗效果明显，且不增加不良反应的发生。

Similar articles

Montelukast and Budesonide for Childhood Cough Variant Asthma.

Sun W, Liu HY. Sun W, et al. J Coll Physicians Surg Pak. 2019 Apr;29(4):345-348. doi: 10.29271/jcpsp.2019.04.345. J Coll Physicians Surg Pak. 2019. PMID: 30925958

[Do fixed combinations increase effectiveness in asthma bronchiale?].

Vogelmeier C. Vogelmeier C. Dtsch Med Wochenschr. 2009 Dec;134 Suppl 10:S372-5. doi: 10.1055/s-0029-1243044. Epub 2009 Nov 25. Dtsch Med Wochenschr. 2009. PMID: 19941239 Review. German. No abstract available.

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anti-asthmatic agents / administration & dosage*

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bronchodilator agents / administration & dosage*

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national center for biotechnology information

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[Therapeutic effect and safety of montelukast sodium combined with budesonide in children with cough variant asthma: a Meta analysis] - PubMed

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Objective: To evaluate the therapeutic effect and safety of montelukast sodium combined with budesonide in children with cough variant asthma. Methods: The databases CNKI, Wanfang Data, VIP, PubMed, EMbase, and BioMed Central were searched for randomized controlled trials (RCTs) of montelukast sodium combined with budesonide in the treatment of children with cough variant asthma.

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TÍTULO:

Combinación de bromuro de ipratropio y salbutamol en niños y adolescentes con asma: un metanálisis

AÑO : 2021 , metanálisis
AUTORES: Hongzhen Xu , Lin Tong , Peng Gao , Yan Hu , Huijuan Wang,  Zhimin Chen , Luo Fang
RESULTADOS: De los 1061 estudios que se identificaron, 55 cumplieron con los criterios de inclusión e involucraron a 6396 participantes. IB + salbutamol redujo significativamente el riesgo de ingreso hospitalario en comparación con salbutamol solo (cociente de riesgo [RR] 0,79; IC del 95%: 0,66-0,95; p = 0,01; I2 = 40%). El análisis de subgrupos solo mostró una diferencia significativa en el riesgo de ingreso hospitalario en los participantes con exacerbación del asma grave (RR 0,73; IC del 95%: 0,60 a 0,88; p = 0,0009; I2 = 4%) y exacerbación de moderada a grave (RR 0,69; 95 % IC 0,50-0,96; p = 0,03; I2 = 3%). No hubo diferencias significativas en el riesgo de eventos adversos entre el grupo de IB + salbutamol y el grupo de salbutamol solo (RR 1,77; IC del 95%: 0,63 a 4,98).
CONCLUSIÓN: IB + salbutamol puede ser más seguro y eficaz que el salbutamol solo para el tratamiento del asma en niños y adolescentes, especialmente en aquellos con exacerbación del asma severa y moderada a severa. La evidencia de muy baja a alta calidad indicó que se necesitan futuros ECA doble ciego bien diseñados con una muestra grande para la investigación sobre la evaluación de la efectividad del tratamiento con IB + salbutamol para el asma en niños y adolescentes.

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Affiliations

¹ Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

² Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

Free PMC article

Free PMC article

Affiliations

¹ Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

² Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

Abstract

Background: A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice.

Objective: To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents.

Methods: The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the earliest record date to September 2020 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO.

Results: Of the 1061 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66-0.95; p = 0.01; I2 = 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.73; 95% CI 0.60-0.88; p = 0.0009; I2 = 4%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50-0.96; p = 0.03; I2 = 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63-4.98).

Conclusion: IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. The very low to high quality of evidence indicated that future well-designed double-blind RCTs with large sample are needed for research on evaluating the effectiveness of IB + salbutamol treatment for asthma in children and adolescents.

Conflict of interest statement

The authors have declared that no competing interests exist.

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Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma.

Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH. Kirkland SW, et al. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD001284. doi: 10.1002/14651858.CD001284.pub2. Cochrane Database Syst Rev. 2017. PMID: 28076656 Free PMC article. Review.

References

Masoli M, Fabian D, Holt S, Beasley R, Program GIfA. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59(5):469-78. 10.1111/j.1398-9995.2004.00526.x - DOI - PubMed

Zhou X, Hong J. Pediatric Asthma Management in China: Current and Future Challenges. Paediatr Drugs. 2018;20(2):105-10. 10.1007/s40272-017-0276-7 - DOI - PubMed

Kamble S, Bharmal M. Incremental direct expenditure of treating asthma in the United States. J Asthma. 2009;46(1):73-80. 10.1080/02770900802503107 - DOI - PubMed

Asher I, Pearce N. Global burden of asthma among children. Int J Tuberc Lung Dis. 2014;18(11):1269-78. 10.5588/ijtld.14.0170 - DOI - PubMed

Bao Y, Chen Z, Liu E, Xiang L, Zhao D, Hong J. Risk Factors in Preschool Children for Predicting Asthma During the Preschool Age and the Early School Age: a Systematic Review and Meta-Analysis. Curr Allergy Asthma Rep. 2017;17(12):85 10.1007/s11882-017-0753-7 - DOI - PubMed

Grant support

The author(s) received no specific funding for this work.

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national center for biotechnology information

# data[].attributes.attachment_link.title
Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: A meta-analysis - PubMed

# data[].attributes.attachment_link.description
IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. The very low to high quality of evidence indicated that future well-designed double-blind RCTs with large s ...

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Título: Eficacia y efectos secundarios de la teofilina intravenosa en el asma aguda
Año: 2018
Autor: Gulixian Mahemuti , Hui Zhang , Jing Li , Nueramina Tieliwaerdi ,y Lili Ren
Tipo de estudio:  Revisión sistemática y metanálisis
Objetivos: Cuantificar la utilidad y los efectos secundarios de la teofilina con o sin etilendiamina (aminofilina) en el asma aguda, con especial énfasis en los subgrupos de pacientes, como niños, adultos y medicamentos concomitantes.
Resultados: Se incluyeron 52 brazos de estudio de 42 ensayos individuales. De estos, 29 brazos del estudio incluyeron un control activo, como adrenalina, agonistas beta-2 o antagonistas del receptor de leucotrienos, y 23 brazos del estudio compararon teofilina (con o sin etilendiamina) con placebo o ningún fármaco. La teofilina redujo significativamente la frecuencia cardíaca en comparación con el control activo ( p = 0,01) y la duración total de la estancia ( p = 0,002), pero los agonistas beta-2 fueron superiores a la teofilina para mejorar el volumen espiratorio forzado en un segundo (FEV1) ( p= 0,002). La teofilina no fue significativamente diferente de otros fármacos en sus efectos sobre la frecuencia respiratoria, la capacidad vital forzada (FVC), la tasa de flujo espiratorio máximo, la tasa de admisión, el uso de medicación de rescate, la saturación de oxígeno o la puntuación de los síntomas. Un examen más detenido de los datos reveló que los medicamentos administrados además de la teofilina o el control cambiaron significativamente la eficacia de la teofilina (diferencia de subgrupos: p <0,00001).
Conclusiones: La teofilina, cuando se administra con broncodilatadores con o sin esteroides, es una opción rentable y segura para las exacerbaciones agudas del asma.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5768195/

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Abstract

Background and objective

Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner's formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, under which theophylline should be used for acute exacerbations of asthma. We aimed to quantify the usefulness and side effects of theophylline with or without ethylene diamine (aminophylline) in acute asthma, with particular emphasis on patient subgroups, such as children, adults, and concomitant medications.

Methods

We searched PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, and the WHO Clinical Trials Registry for randomized, controlled clinical trials. We planned a priori subgroup analyses by time post-medication, concomitant medication, control type, and age.

Results

We included 52 study arms from 42 individual trials. Of these, 29 study arms included an active control, such as adrenaline, beta-2 agonists, or leukotriene receptor antagonists, and 23 study arms compared theophylline (with or without ethylene diamine) with placebo or no drug. Theophylline significantly reduced heart rate when compared with active control ( p=0.01) and overall duration of stay ( p=0.002), but beta-2 agonists were superior to theophylline at improving forced expiratory volume in one second (FEV1) ( p=0.002). Theophylline was not significantly different from other drugs in its effects on respiratory rate, forced vital capacity (FVC), peak expiratory flow rate, admission rate, use of rescue medication, oxygen saturation, or symptom score. Closer examination of the data revealed that the medications given in addition to theophylline or control significantly changed the effectiveness of theophylline (subgroup difference: p<0.00001).

Conclusion

Given the low cost of theophylline, and its similar efficacy and rate of side effects compared with other drugs, we suggest that theophylline, when given with bronchodilators with or without steroids, is a cost-effective and safe choice for acute asthma exacerbations.

Keywords: theophylline, theophylline with ethylene diamine, aminophylline, asthma, bronchodilators, beta-2 agonists, adrenaline, FEV, PEFR, affordable drugs

Introduction

Acute asthma exacerbations are a frequent and serious reason for presentation to hospital emergency departments. Asthma prevalence in adults globally is estimated at 4.3%, with Australia, the UK, Sweden, and the Netherlands all exceeding 15%. 1 In children, the prevalence is even higher, with many countries reporting asthma rates in children over 20%. 2 In many parts of the world, asthma prevalence in increasing, although in some countries with high rates of asthma, the prevalence may now be levelling off. 3

Severe asthma exacerbations in children or adults are very serious and can be life-threatening. According to the World Health Organization, asthma causes ~250,000 deaths worldwide each year. 4 Despite a range of drugs for the treatment of asthma, 5 systematic evidence for the efficacy of these drugs is not universal. Thus, especially in developing countries, it is essential that the comparative effectiveness of all asthma treatments, including older and more affordable drugs, be available to health practitioners.

Theophylline, a methylxanthine, is a bronchodilator. When combined with ethylene diamine as "aminophylline", it is more soluble and is thus the more common form of theophylline used for intravenous (IV) administration. 6, 7 Available in generic form, theophylline with or without ethylene diamine is certainly affordable. However, its efficacy, especially in children, and the effective doses are a matter of dispute. We therefore undertook this study to compare the effectiveness of IV theophylline with all available comparators.

Methods

The current systematic review and meta-analysis was performed on the principles of the Cochrane Collaboration. 8

Data sources and search strategy

We searched PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov, and the WHO international clinical trials registry for relevant articles. Our search strategy used the following keywords, as full-text and MESH terms (where appropriate): (Theophylline OR 1,3-dimethylxanthine OR Elixophyllin OR Norphyl OR Phyllocontin OR Quibron-TSR OR Theo-24 OR TheoCap OR Theochron OR Theo-Dur OR Theo-Time OR Truxophyllin OR Uniphyl OR aminophylline) AND ("Short-acting beta2 agonist" OR "short-acting beta agonist" OR "beta* adrenergic receptor agonist" OR SABA OR salbutamol OR formoterol OR eformoterol OR "long-acting beta agonist" OR LABA OR albuterol OR levalbuterol OR betamethasone OR hydro-cortisone OR methylprednisolone OR prednisolone OR Ventolin OR Proventil OR Atock OR Atimos OR Foradil OR Oxis OR Perforomist OR salmeterol OR bambuterol OR fluticasone OR budesonide OR glucocorticoid OR Flixotide OR Flixonase OR Pulmicort OR Rhinocort OR anticholinergic OR ipratropium OR epinephrine OR beclamethasone OR montelukast OR zafirlukast OR "5-LOX inhibitor" OR cromolyn OR placebo OR no drug) AND Asthma AND (Intravenous OR IV OR iv) AND (RCT OR random OR randomised OR randomized OR groups OR "randomised controlled trial" OR "randomized controlled trial" OR "controlled clinical trial"). No date or language restrictions were applied. All citations were uploaded into EPPI-Reviewer 4 9 and were independently coded by two investigators. The date of the last search was 9 July 2017.

Inclusion criteria

Citations were included if they matched the following PICOTS: the population was children or adults presenting to an emergency department with an acute asthma exacerbation; the intervention was theophylline with or without ethylene diamine, administered intravenously; the control was placebo, no drug or active comparator; the outcomes were forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), symptom scores, admission rates, duration of stay, rescue medication use, oxygen saturation, pulse rate, respiratory rate, or adverse events; the time was between 15 minutes and 48 hours after administration of theophylline; the setting was acute, inpatient treatment in a hospital.

Study selection and study quality

Two authors independently assessed all citations at the title/abstract level in EPPI-Reviewer 4. Disagreements between the authors were resolved by consensus. Two authors then examined the full texts of all included abstracts in EPPI-Reviewer 4. In addition to the previously mentioned PICOTS criteria, studies were only included if they were randomized, controlled trials.

The Cochrane tool for assessing the risk of bias in RCTs 10 was used to assess study quality. Two investigators assessed the risk of bias according to random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, attrition, selective reporting, and other bias. We did not exclude studies if they were not blinded, but planned a sensitivity analysis to test the importance of blinding in assessing the outcomes.

Data extraction

One investigator extracted data from all included studies. A second investigator confirmed the data extraction. Data that were not given in the text or in tables were extracted using WebPlotDigitizer. 11 We extracted the data as given in the text. For the meta-analysis, we converted standard errors to standard deviations. Where more than one control was present, we extracted all study arms. If more than one study arm was used in an analysis, we avoided a unit of analysis error by dividing the number in the study arm by the number of study arms used in the analysis.

Statistical analysis

Meta-analysis was done using Review Manager (RevMan 5.3). 12 Mean differences and standardized mean differences with 95% confidence intervals (CIs) were calculated using an inverse variance model. 12 Odds ratios with 95% CI were calculated using the Mantel-Haenszel statistical method. 13 Because of differences in study design and participants, we used a random effects model for all analyses.

Results

All study results refer to "theophylline" whether or not it contained ethylene diamine. For a breakdown of which studies used which drug, please refer to the study characteristics given in the following section, as well as Table 1 .

Table 1

Study ID

Intervention
(N)

Control
(N)

Study type

Study length

Population

Age range, years

Average age, years

Inclusion (severity)

Intervention

Bolus dose

Ongoing dose

Control

Bolus dose

Ongoing dose

Background medication

Gender

Country

Blinding

Funding

NCT00442338 (2007) 28

31

30

P

60 minutes

Adults

No data

56

All

A

None

250 mg

Montelukast

None

14 mg

Inhaled beta-agonist or oxygen

Mixed

Multicenter

Unclear

Industry

Study characteristics

A total of 52 study arms from 42 individual trials were included in the meta-analysis ( Figure 1 , Table 1 ). Adults were studied in 29 study arms, 14- 36 with children the focus of 17 study arms. 37- 53 One study did not restrict the age of participants, 54 and one study did not report the age of participants. 55 Twenty-five study arms compared theophylline with an active control such as adrenaline, beta-2 agonists, or leukotriene receptor antagonists, 21 compared theophylline with placebo, and two studies compared theophylline with no drug. Forty-eight study arms used theophylline with ethylene diamine; and four used theophylline without ethylene diamine. Only two studies were funded or partly funded by industry. All other studies were funded and carried out by university or hospital clinical teams. Blinding of some kind took place in 37 study arms, with blinding being unclear in 11 arms. All studies were carried out in both males and females.

Quality of included studies

The quality of included studies is given in Figure 2 . In general, the risk of bias was unclear or low. Reporting of the method of randomization, allocation concealment, and study protocols was frequently missing. The lack of blinding in some studies led to an increase in the risk of bias to some degree.

FEV1/FVC

The FEV1 and FVC (after a full breath) are commonly measured outcomes for asthma studies. FEV1 can be measured in liters (L), or alternatively as a percent of the predicted value. In our analysis, the majority of the studies used liters to measure FEV1. We carried out a subgroup meta-analysis of FEV1 (L) by control type ( Figure 3A ). Intravenous (IV) theophylline was not significantly different from adrenaline ( p=0.12), a leukotriene receptor antagonist ( p=0.81), or placebo ( p=0.07) in increasing FEV1, but was significantly worse than beta-2 agonists (mean difference [MD] =−0.20 L [95% CI: −0.34, −0.07], p=0.002). A pooled analysis of all active controls, however, also showed a small but significantly improved FEV1 in the control compared with theophylline (MD =−0.14L [95% CI: −0.25, −0.02], p=0.001; Figure 3B ). Pooling of the six studies measuring FEV1 as a percent of predicted showed no difference between theophylline and control (MD =3.78 [95% CI: −1.08, 8.63], p=0.13, data not shown). Seven studies (nine study arms) reported on FVC ( Figure 3C ). There was no difference in FVC between theophylline and control groups ( p=0.73).

PEFR

PEFR is another common measurement of lung function in asthmatics. As for FEV1, PEFR can be measured in L or as a percent of the predicted value. A subgroup meta-analysis of PEFR (L) was performed to determine if theophylline was effective at increasing PEFR in the short-term (30 minutes-2 hours) or the longer-term (5 hours-24 hours) ( Figure 4A ). There were no significant differences between theophylline and control at either time point. A sensitivity analysis removing the placebo-controlled trials from this analysis did not alter the results (data not shown). When measured as a percent of predicted PEFR value ( Figure 4B ), neither the short-term studies (30 minutes-2 hours; p=0.56) nor the longer-term studies (5 hours-48 hours; p=0.44) showed any significant differences between theophylline and control groups.

Heart rate

During an asthma exacerbation, the heart rate increases to compensate for a reduction in oxygenation in the blood. Therefore, a lower heart rate, both immediately after the administration of medication as well as over the longer term, indicates that the medication is relieving the bronchoconstriction. In order to compare the effect of IV theophylline on heart rate, we undertook a subgroup meta-analysis by time after infusion ( Figure 5A ). In the short-term (30 minutes-3 hours post-infusion), theophylline lowered the heart rate by 4.17 beats per minute (bpm) compared with control therapy, which was significant ( p=0.02). At longer-term time points (24-36 hours post-infusion), the difference in heart rate between IV theophylline and control treatments was similar (−3.59 bpm), but failed to reach statistical significance ( p=0.32). In order to determine if theophylline was superior to other active therapies, we undertook a subgroup meta-analysis by control type ( Figure 5B ). In the active control studies, theophylline lowered the heart rate by 5.17 bpm more than active controls, and this difference was significant ( p=0.01). In the placebo-controlled trials, no significant difference was noted ( p=0.79).

Respiratory rate

An increased respiratory rate is, like heart rate, a sign of an ongoing asthma exacerbation. 56 Thus, a reduction in the respiratory rate should indicate an improvement in the status of a patient with acute asthma. We undertook a meta-analysis of the seven study arms measuring this outcome ( Figure 6 ). Theophylline was slightly less effective at lower respiratory rate, although this was not significant ( p=0.08).

Other outcomes

Other outcomes extracted were symptom scores, admission rate, duration of stay, use of rescue medication, and oxygen saturation ( Figure 7 ). In almost every case, there were no significant differences between theophylline and control. The exception was the duration of hospital stay ( Figure 7C ), with theophylline reducing the duration of stay by 0.23 hours (14 minutes) (95% CI: −0.37, −0.08 hours, p=0.002).

Subgroup analysis: background medication

Theophylline was neither more nor less effective than control treatments for almost all outcomes. This was true whether the control was an active comparator like salbutamol, or a placebo. We questioned whether the regimen of medications given to patients before or during the studies ("background medication") was responsible for the perceived lack of additional efficacy of theophylline over placebo.

In order to investigate this question, we undertook a subgroup analysis of FEV1 by background medication ( Figure 8 ). In studies where the background medication was oxygen only or no additional medication other than the study drug, the control drugs performed better than theophylline ( p<0.00001). Conversely, where patients were given bronchodilators with or without steroids, there was no significant differences between theophylline and control. Removal of the two studies comparing theophylline with placebo did not change the outcome.

Subgroup analysis: age of participants

As mentioned earlier, approximately two-thirds of the studies were conducted in adults, with one-third in children. In order to determine whether children responded differently to theophylline compared with adults, we intended to undertake a subgroup meta-analysis of FEV1 and PEFR by the age of participants. Unfortunately, these outcomes were rarely reported in children, as younger people can have great difficulty performing the necessary tests. Instead, we did a subgroup meta-analysis of symptom scores by age ( Figure 9 ). We found that there was no significant difference between adults and children in terms of symptoms ( p=0.38).

Subgroup analysis: blinded vs unblinded studies

In order to determine if blinding had any effect on the primary outcome (FEV1), we conducted a subgroup analysis of blinded vs unblinded studies. Studies that did not mention blinding were regarded as "unblinded". We found a slightly decreased efficacy for theophylline compared with controls in unblinded studies ( Figure 10 ), although the difference between blinded and unblinded studies was not significant ( p=0.18). Removal of placebo-controlled trials from the analysis did not change the results (data not shown).

Adverse events

Fortunately, many studies reported on adverse events ( Figure 11 ). Compared with placebo, IV theophylline caused more nausea, vomiting, and cardiovascular adverse events (such as palpitations and arrhythmias) ( Figure 11A ). There were no differences in abdominal pain, psychological side effects, headaches, seizures, or tremor. Compared with active comparators ( Figure 11B ), theophylline again caused more nausea and vomiting, but was not different from the active controls in terms of the frequency of psychological side effects, headaches, cardiovascular adverse events, tremor, CPK/CK elevation, or glucosuria/hyperglycemia.

Publication bias

In order to test for publication bias, we created funnel plots ( Figure 12 ). The funnel plot for FEV1 ( Figure 12A ) did not show significant asymmetry. This was true also for PEFR ( Figure 12B ), symptom scores ( Figure 12C ), or heart rate ( Figure 12D ).

Discussion

Our study has comprehensively reviewed the combined evidence for the efficacy and safety of IV theophylline in acute asthma. We found that theophylline somewhat reduced the heart rate and duration of stay, and was not significantly worse than adrenaline, beta-2 agonists, and leukotriene receptor antagonists. Furthermore, apart from an increase in nausea and vomiting, side effects from theophylline were not significantly different from other treatment regimes. That is, although theophylline was not clinically superior to other treatments, it was not significantly worse either.

However, of great importance was our subgroup analysis of FEV1 by the background medication given to patients ( Figure 8 ). Where the patients were given no medication, or oxygen alone, theophylline was inferior to subcutaneous epinephrine 15, 19, 30 and nebulized isoproterenol. 19, 30 However, in almost all circumstances, patients admitted to an emergency department for an acute asthma exacerbation are given nebulized beta-2 agonists and IV corticosteroids. 57- 59 If these treatments fail, additional treatments are then considered. Our data show that in the context of usual emergency department treatment, IV theophylline is at least as effective as montelukast 28 and IV salbutamol. 23, 34

Existing studies on theophylline point to inconsistencies. For example, Neame et al attempted to determine if salbutamol or theophylline should be used for acute severe asthma in children. 60 Despite a systematic search for articles, their qualitative analysis failed to draw any conclusions, due to "minimal and inconsistent" evidence.

A retrospective case-control study suggested that administration of theophylline increased hospital stay, compared with inhaled beta-2 agonists and corticosteroids. 61 A meta-analysis by Mitra et al found that, in children, addition of theophylline to nebulized short-acting beta-2 agonists and systemic steroids resulted in better lung function in the first 6 hours of treatment. 62 However, Mitra et al did not investigate the addition of other drugs to the same background therapy.

In contrast, a more recent meta-analysis analyzed trials directly comparing IV beta-2 agonists with IV theophylline in the treatment of acute asthma. 63 In this meta-analysis, Travers et al found no significant differences between IV beta-2 agonists and IV theophylline added to normal treatment in terms of hospital stay, PEFR, FEV1, heart rate, or clinical failure. In addition, Nair et al found that adding IV theophylline to inhaled beta-2 agonists did not provide additional benefit in adults with acute asthma. 64 None of these meta-analyses specifically investigated the role of background medication in the efficacy of theophylline, compared with other additional medications.

Recent data from the UK suggest that, at least in children, theophylline was the third most commonly administered drug in an acute setting, after salbutamol and magnesium sulfate. 65 However, different drugs, especially new, branded formulations of drugs, may differ in cost by a large degree. Indeed, a 2005 study included hospital cost in their analysis. 52 They found that treating their patients with theophylline was as effective as terbutaline, and the total treatment costs were less than a tenth of those with terbutaline.

Limitations of this analysis

We were fortunate to find a significant body of evidence testing the efficacy of theophylline. However, because asthma outcomes can be measured in a large number of different ways, we were limited in the investigations we could carry out. For example, we had planned to do meta-regression, but we felt there were insufficient studies in any one outcome to create a meaningful interpretation of the data. 8

Conclusion

Our data show that IV theophylline is superior to other treatments with regard to heart rate and duration of hospital stay, and equal to other treatments for almost all our other reported outcomes. Given the very low cost and similar safety profile of theophylline, it must surely be considered a cost-effective treatment for acute asthma exacerbations, especially for developing countries with restricted health budgets.

Acknowledgments

This study was supported by The Xinjiang Uygur Autonomous Region Natural Science Foundation Funded Projects (number: 2017D01C251).

Footnotes

Author contributions
GM developed and designed the concept for the systematic review and meta-analysis; she wrote the initial draft, did interpretation of the analyzed results, and finalized the manuscript. HZ, JL, NT, and LR did literature search, data collection, extraction, and analysis. GM, HZ, JL, NT, and LR wrote different sections of the manuscript. GM did the critical revision of the intellectual content of the article. All authors read and approved the final version of the manuscript.
Disclosure
The authors report no conflicts of interest in this work.

References

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28. NCT00442338 amp, Dohme Corp, editor. Study of MK0476 in Adult Patients With Acute Asthma (0476-334) 2007. [Accessed February 12, 2017]. Available from: http://clinicaltrials.gov/show/ NCT00442338.

42. Ibrahim SA, Elgurashi ED, Elkarim OA. Comparative study of intravenous aminophylline subcutaneous adrenaline and nebulised salbutamol in the treatment of acute asthma in children. Pediatr Rev Commun. 1993;7:175-182. [ Google Scholar]

54. Whig J, Puri S, Mahajan R, Chopra SC, Mittal N, Malhotra S. Placebo controlled evaluation of intravenous aminophylline in acute asthma. Lung India. 2001;19:97-100. [ Google Scholar]

Articles from Drug Design, Development and Therapy are provided here courtesy of Dove Press

# data[].attributes.attachment_link.title
Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis

# data[].attributes.attachment_link.description
Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner's formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, under which theophylline should be used for acute exacerbations of asthma.

# data[].attributes.body
TÍTULO: Efecto del tratamiento a largo plazo con budesonida inhalada sobre la altura adulta en niños con asma.

AÑO: 2000
TIPO DE ESTUDIO: Revisión Sistemática
RESULTADOS: La altura adulta dependió significativamente (P <0,001) de la altura del niño antes del tratamiento con budesonida. Aunque las tasas de crecimiento se redujeron significativamente durante los primeros años de tratamiento con budesonida.
CONCLUSIÓN: Los niños con asma que han recibido tratamiento a largo plazo con budesonida alcanzan una estatura adulta normal

# data[].attributes.attachment_link.readable_text
Abstract

Background: Short-term studies have shown that inhaled corticosteroids may reduce the growth of children with asthma. However, the effect of long-term treatment on adult height is uncertain.

Methods: We conducted a prospective study in children with asthma to examine the effect of long-term treatment with inhaled budesonide on adult height. We report on 211 children who have attained adult height: 142 budesonide-treated children with asthma, 18 control patients with asthma who have never received inhaled corticosteroids, and 51 healthy siblings of patients in the budesonide group, who also served as controls.

Results: The children in the budesonide group attained adult height after a mean of 9.2 years of budesonide treatment (range, 3 to 13) at a mean daily dose of 412 microg (range, 110 to 877). The mean cumulative dose of budesonide was 1.35 g (range, 0.41 to 3.99). The mean differences between the measured and target adult heights were +0.3 cm (95 percent confidence interval, -0.6 to + 1.2) for the budesonide-treated children, -0.2 cm (95 percent confidence interval, -2.4 to +2.1) for the control children with asthma, and +0.9 cm (95 percent confidence interval, -0.4 to +2.2) for the healthy siblings. The adult height depended significantly (P<0.001) on the child's height before budesonide treatment. Although growth rates were significantly reduced during the first years of budesonide treatment, these changes in growth rate were not significantly associated with adult height.

Conclusions: Children with asthma who have received long-term treatment with budesonide attain normal adult height.

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[Longitudinal growth in children with asthma treated with inhaled glucocorticoids].

Gradman J, Wolthers OD. Gradman J, et al. Ugeskr Laeger. 2006 Feb 27;168(9):885-9. Ugeskr Laeger. 2006. PMID: 16513049 Review. Danish.

[Inhalation corticosteroids and the growth of asthmatic children].

Brand PL, Hendriks JJ, Vaessen-Verberne AA. Brand PL, et al. Ned Tijdschr Geneeskd. 1999 Oct 9;143(41):2041-5. Ned Tijdschr Geneeskd. 1999. PMID: 10560544 Review. Dutch.

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Asma infantil y del lactante.

de Blic J, Scheinmann P. de Blic J, et al. EMC Pediatr. 2010;45(2):1-20. doi: 10.1016/S1245-1789(10)70178-5. Epub 2011 Aug 10. EMC Pediatr. 2010. PMID: 32308525 Free PMC article. Spanish.

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Effect of long-term treatment with inhaled budesonide on adult height in children with asthma - PubMed

# data[].attributes.attachment_link.description
Background: Short-term studies have shown that inhaled corticosteroids may reduce the growth of children with asthma. However, the effect of long-term treatment on adult height is uncertain. Methods: We conducted a prospective study in children with asthma to examine the effect of long-term treatment with inhaled budesonide on adult height.

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TITULO: Perfil de eficacia y seguridad de la doxofilina en comparación con la teofilina en el asma: un metanálisis

TIPO DE ESTUDIO Y AÑO: metaanálisis- 2019

OBJETIVO: evaluar el impacto de la doxofilina frente a la teofilina y el placebo en el cambio en los eventos de asma, el riesgo de eventos adversos (EA), el volumen espiratorio forzado en 1 s (FEV ₁ ) y el salbutamol.

RESULTADOS:  La doxofilina fue significativamente ( P <0,05) más eficaz que la teofilina para reducir los episodios de asma diarios (diferencia de medias - 0,14, IC del 95%: -0,27 - 0,00) y riesgo de efecto adverso (riesgo relativo 0,76; IC del 95%: 0,59-0,99). La doxofilina fue tan eficaz como la teofilina para mejorar el FEV ₁ , y se detectó una tendencia de superioridad ( P = 0,058) para la doxofilina sobre la teofilina con respecto a la reducción en el uso de salbutamol como medicación de rescate. El rango de efectividad fue doxofilina> teofilina>> placebo, y el rango de seguridad fue placebo> doxofilina>> teofilina.

CONCLUSIÓN: La doxofilina es una metilxantina eficaz y segura para el tratamiento del asma, con un perfil de eficacia / seguridad superior al de la teofilina.

https://pubmed.ncbi.nlm.nih.gov/31388422/

# data[].attributes.attachment_link.readable_text
doi: 10.1186/s40248-019-0189-0.

Affiliations

¹ 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.

² 2Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy.

³ 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Free PMC article

Free PMC article

doi: 10.1186/s40248-019-0189-0.

Affiliations

¹ 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.

² 2Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy.

³ 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Abstract

Background: Oral methylxanthines are effective drugs for the treatment of chronic obstructive respiratory disorders. The novel methylxanthine doxofylline, that has bronchodilator and anti-inflammatory activities, is not affected by the major drawback of theophylline. Nowadays large-scale quantitative synthesis comparing the efficacy and safety profile of doxofylline vs. theophylline in the treatment of asthma is still lacking. Therefore, we performed a quantitative synthesis to compare the efficacy/safety profile of doxofylline and theophylline in asthma.

Methods: A pairwise and network meta-analyses were performed to assess the impact of doxofylline vs. theophylline and placebo on the change in asthma events, risk of adverse events (AEs), forced expiratory volume in 1 s (FEV ₁), and salbutamol use.

Results: Data obtained from 696 asthmatic patients were extracted from 4 randomized controlled trials published between 2015 and 2018. Doxofylline was significantly ( P < 0.05) more effective than theophylline in reducing the daily asthma events (mean difference - 0.14, 95%CI -0.27 - 0.00) and risk of AEs (relative risk 0.76, 95%CI 0.59-0.99). Doxofylline was as effective as theophylline in improving FEV ₁, and a trend of superiority ( P = 0.058) was detected for doxofylline over theophylline with respect to the reduction in the use of salbutamol as rescue medication. The rank of effectiveness was doxofylline>theophylline> > placebo, and the rank of safety was placebo>doxofylline> > theophylline.

Conclusions: Doxofylline is an effective and safe methylxanthine for the treatment of asthma, with an efficacy/safety profile greater than that of theophylline.

Trial registration: Meta-analysis registration: CRD42019119849.

Keywords: Asthma; Doxofylline; Meta-analysis; Theophylline.

Conflict of interest statement

Competing interestsPR has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; LC has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; he is or has been a consultant to ABC Farmaceutici; JO has no competing interests; MGM has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; MC has participated as an advisor in scientific meetings the sponsorship of ABC Farmaceutici; he is or has been a consultant to ABC Farmaceutici. MC is a member of the Editorial Board of Multidisciplinary Respiratory Medicine.

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Impact of doxofylline compared to theophylline in asthma: A pooled analysis of functional and clinical outcomes from two multicentre, double-blind, randomized studies (DOROTHEO 1 and DOROTHEO 2).

Calzetta L, Hanania NA, Dini FL, Goldstein MF, Fairweather WR, Howard WW, Cazzola M. Calzetta L, et al. Pulm Pharmacol Ther. 2018 Dec;53:20-26. doi: 10.1016/j.pupt.2018.09.007. Epub 2018 Sep 13. Pulm Pharmacol Ther. 2018. PMID: 30219705

References

Page CP. Doxofylline: a "novofylline". Pulm Pharmacol Ther. 2010;23(4):231-234. doi: 10.1016/j.pupt.2010.04.002. - DOI - PubMed

Franzone JS, Cirillo R, Barone D. Doxofylline and theophylline are xanthines with partly different mechanisms of action in animals. Drugs Exp Clin Res. 1988;14(7):479-489. - PubMed

Cirillo R, Barone D, Franzone JS. Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors. Arch Int Pharmacodyn Ther. 1988;295:221-237. - PubMed

Dolcetti A, Osella D, De Filippis G, Carnuccio C, Grossi E. Comparison of intravenously administered doxofylline and placebo for the treatment of severe acute airways obstruction. J Int Med Res. 1988;16(4):264-269. doi: 10.1177/030006058801600403. - DOI - PubMed

Poggi R, Brandolese R, Bernasconi M, Manzin E, Rossi A. Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure. Chest. 1989;96(4):772-778. doi: 10.1378/chest.96.4.772. - DOI - PubMed

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national center for biotechnology information

# data[].attributes.attachment_link.title
Efficacy and safety profile of doxofylline compared to theophylline in asthma: a meta-analysis - PubMed

# data[].attributes.attachment_link.description
doi: 10.1186/s40248-019-0189-0. 1 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy. 2 2Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy. 3 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

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TÍTULO: Eficacia y seguridad del propionato de fluticasona / fumarato de formoterol en pacientes pediátricos con asma: un ensayo controlado aleatorizado
AÑO: 2018
TIPO DE ESTUDIO: Ensayo controlado aleatorio
MÉTODO: Los pacientes, de 5 <12 años con asma persistente ⩾ 6 meses y volumen espiratorio forzado en 1 s (FEV ₁ ) ⩽ 90% del pronóstico, se asignaron al azar a un tratamiento de 1: 1: 1 a 12 semanas. Los objetivos del estudio fueron demostrar la superioridad de fluticasona / formoterol frente a fluticasona y no inferioridad frente a fluticasona / salmeterol.
RESULTADOS: Se aleatorizó un total de 512 pacientes: fluticasona / formoterol, 169; fluticasona, 173; fluticasona / salmeterol, 170. La fluticasona / formoterol fue superior a la fluticasona para el criterio de valoración principal: cambio del FEV ₁ antes de la dosis al inicio a 2 h después de la dosis del FEV ₁ durante 12 semanas [diferencia media de mínimos cuadrados (LS) 0,07 l; Intervalo de confianza (IC) del 95% 0,03, 0,11; p <0,001]. Se observaron pocas exacerbaciones graves (fluticasona / formoterol: dos; fluticasona / salmeterol: dos).
CONCLUSIONES: Este estudio respalda la eficacia y seguridad de fluticasona / formoterol en una población pediátrica con asma y su superioridad a la fluticasona.

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Affiliations

¹ Prywatna Praktyka Lekarska, Gabinet Pediatryczno-Alergologiczny, Ul. Przejazd 2A, Białystok, Poland.

² University Hospital Plovdiv, Medical University of Plovdiv, Bulgaria.

³ Mundipharma Research Limited, Cambridge, UK.

Free PMC article

Randomized Controlled Trial

Free PMC article

Affiliations

¹ Prywatna Praktyka Lekarska, Gabinet Pediatryczno-Alergologiczny, Ul. Przejazd 2A, Białystok, Poland.

² University Hospital Plovdiv, Medical University of Plovdiv, Bulgaria.

³ Mundipharma Research Limited, Cambridge, UK.

Abstract

Background: The efficacy and safety of fluticasone propionate/formoterol fumarate pressurized metered-dose inhaler (pMDI) (fluticasone/formoterol; Flutiform ®; 100/10 µg b.i.d.) was compared with fluticasone propionate (Flixotide ® Evohaler ® pMDI; 100 µg b.i.d.) and fluticasone/salmeterol (Seretide ® Evohaler ® pMDI; 100/50 µg b.i.d.) in a pediatric asthma population (EudraCT number: 2010-024635-16).

Methods: A double-blind, double-dummy, parallel group, multicenter study. Patients, aged 5-<12 years with persistent asthma ⩾ 6 months and forced expiratory volume in 1 s (FEV ₁) ⩽ 90% predicted were randomized 1:1:1 to 12 weeks' treatment. The study objectives were to demonstrate superiority of fluticasone/formoterol to fluticasone and non-inferiority to fluticasone/salmeterol.

Results: A total of 512 patients were randomized: fluticasone/formoterol, 169; fluticasone, 173; fluticasone/salmeterol, 170. Fluticasone/formoterol was superior to fluticasone for the primary endpoint: change from predose FEV ₁ at baseline to 2 h postdose FEV ₁ over 12 weeks [least squares (LS) mean difference 0.07 l; 95% confidence interval (CI) 0.03, 0.11; p < 0.001] and the first key secondary endpoint, FEV ₁ area under the curve over 4 hours (AUC 0-4 h) at week 12 (LS mean difference 0.09 l; 95% CI: 0.04, 0.13; p < 0.001). Per a prespecified non-inferiority margin of -0.1 l, fluticasone/formoterol was non-inferior to fluticasone/salmeterol for the primary endpoint (LS mean difference 0.00 l; 95% CI -0.04, 0.04; p < 0.001) and first key secondary endpoint (LS mean difference 0.01; 95% CI -0.03, 0.06; p < 0.001). Fluticasone/formoterol was non-inferior to fluticasone/salmeterol for the second key secondary endpoint, change from predose FEV ₁ over 12 weeks (treatment difference -0.02 l; 95% CI -0.06, 0.02; p < 0.001), but was not superior to fluticasone for this endpoint (LS mean difference 0.03 l; 95% CI -0.01, 0.07; p = 0.091). All treatments elicited large improvements from baseline to week 12 for the Pediatric Asthma Quality of Life Questionnaire (LS mean change 0.76 to 0.85 units) and Asthma Control Questionnaire (LS mean change -1.03 to -1.13 units). Few severe exacerbations were seen (fluticasone/formoterol: two; fluticasone/salmeterol: two). All treatments were well tolerated.

Conclusions: This study supports the efficacy and safety of fluticasone/formoterol in a pediatric asthma population and its superiority to fluticasone.

Keywords: ICS/LABA; asthma; children; combination therapy; fluticasone propionate; formoterol fumarate.

Conflict of interest statement

Conflict of interest statement: Kay Spooner is an employee of the study sponsor, Mundipharma Research Limited. Tammy McIver and Sanjeeva Dissanayake were employees of the study sponsor at the time this study was conducted.

Anna Ploszczuk and Miroslava Bosheva have no conflicts of interest to disclose.

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A 12-week open-label, randomized, controlled trial and 24-week extension to assess the efficacy and safety of fluticasone propionate/formoterol in children with asthma.

Emeryk A, Klink R, McIver T, Dalvi P. Emeryk A, et al. Ther Adv Respir Dis. 2016 Aug;10(4):324-37. doi: 10.1177/1753465816646320. Epub 2016 May 16. Ther Adv Respir Dis. 2016. PMID: 27185164 Free PMC article. Clinical Trial.

Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study.

Bodzenta-Lukaszyk A, Dymek A, McAulay K, Mansikka H. Bodzenta-Lukaszyk A, et al. BMC Pulm Med. 2011 May 23;11:28. doi: 10.1186/1471-2466-11-28. BMC Pulm Med. 2011. PMID: 21605396 Free PMC article. Clinical Trial.

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.

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Comparing LAMA with LABA and LTRA as add-on therapies in primary care asthma management.

Kaplan A, FitzGerald JM, Buhl R, Vogelberg C, Hamelmann E. Kaplan A, et al. NPJ Prim Care Respir Med. 2020 Nov 11;30(1):50. doi: 10.1038/s41533-020-00205-9. NPJ Prim Care Respir Med. 2020. PMID: 33177503 Free PMC article. Review.

References

Global Initiative for Asthma. GINA Global Strategy for Asthma Management and Prevention, 2016; http://ginasthma.org/

Ni Chroinin M, Lasserson TJ, Greenstone I, et al. Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev 2009; 8: CD007949. - PMC - PubMed

Murphy K, Bender B. Treatment of moderate to severe asthma: patient perspectives on combination inhaler therapy and implications for adherence. J Asthma Allergy 2009; 2: 63-72. - PMC - PubMed

GlaxoSmithKline Briefing Document. Benefit risk assessment of salmeterol for the treatment of asthma in adults and children, 2008; https://wayback.archive-it.org/7993/20170405035641/https://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4398b1-04-GSK.pdf

Bodzenta-Lukaszyk A, Pulka G, Dymek A, et al. Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler. Respir Med 2011; 105: 674-682. - PubMed

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adrenergic beta-2 receptor agonists / administration & dosage*

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adrenergic beta-2 receptor agonists / adverse effects

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bronchodilator agents / administration & dosage*

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fluticasone-salmeterol drug combination / administration & dosage*

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fluticasone-salmeterol drug combination / adverse effects

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formoterol fumarate / administration & dosage*

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glucocorticoids / administration & dosage*

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national center for biotechnology information

# data[].attributes.attachment_link.title
Efficacy and safety of fluticasone propionate/formoterol fumarate in pediatric asthma patients: a randomized controlled trial - PubMed

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1 Prywatna Praktyka Lekarska, Gabinet Pediatryczno-Alergologiczny, Ul. Przejazd 2A, Białystok, Poland. 2 University Hospital Plovdiv, Medical University of Plovdiv, Bulgaria. 3 Mundipharma Research Limited, Cambridge, UK. Free PMC article Randomized Controlled Trial Free PMC article 1 Prywatna Praktyka Lekarska, Gabinet Pediatryczno-Alergologiczny, Ul. Przejazd 2A, Białystok, Poland.

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https://pubmed.ncbi.nlm.nih.gov/24153452/
TITULO:

Seguridad cardiovascular de los productos combinados de corticosteroides inhalados con agonistas beta de acción prolongada en pacientes adultos con asma: una revisión sistemática

AÑO: 2014
TIPO DE ESTUDIO: Revisión sistematica
RESULTADOS: Un total de 15 estudios (con 17 cohortes en LABA-ICS para comparar con un comparador o placebo) con un total de 5440 participantes del estudio cumplieron los criterios de inclusión. Dos estudios sobre budesonida-formoterol y uno sobre fluticasona-salmeterol informaron eventos adversos cardiovasculares emergentes del tratamiento, todos los cuales fueron arritmias. A modo de comparación, la estimación combinada de la razón de posibilidades de Peto (0,72; intervalo de confianza [IC] del 95%: 0,17-3; p = 0,65) y la razón de riesgo resumida (0,77; IC del 95%: 0,26-2,3; p = 0,64) indicó una Diferencia no significativa entre LABA-ICS y los grupos de comparación / placebo.
CONCLUSIÓN: Nuestra revisión sistemática encontró que pocos estudios y ensayos informaron eventos adversos cardiovasculares emergentes del tratamiento con LABA-ICS. Sin embargo, la razón de posibilidades de Peto y la razón de riesgo para estos resultados no fue estadísticamente significativa. Esto sugiere que los productos LABA-ICS pueden tener un perfil cardiovascular seguro en pacientes con asma.

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doi: 10.1007/s00408-013-9525-x.

Affiliation

¹ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of South Carolina, 1 Medical Park, Suite 300, Columbia, SC, 29203, USA, imran.iftikhar@uscmed.sc.edu.

doi: 10.1007/s00408-013-9525-x.

Affiliation

¹ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of South Carolina, 1 Medical Park, Suite 300, Columbia, SC, 29203, USA, imran.iftikhar@uscmed.sc.edu.

Abstract

Introduction: Long-acting beta agonists and inhaled corticosteroids combination products (LABA-ICS) are widely used in the treatment of asthma. However, there appears to be little data on their cardiovascular safety. The purpose of this study was to conduct a systematic review of the available studies and trials on the cardiovascular safety of LABA-ICS in adults with asthma.

Methods: Two independent reviewers screened citations from PubMed and National Clinical Trials registry to identify studies and trials on the cardiovascular effects of LABA-ICS in patients with asthma.

Results: A total of 15 studies (with 17 cohorts on LABA-ICS to compare with a comparator or placebo) with 5,440 total study participants met the inclusion criteria. Two studies on budesonide-formoterol and one on fluticasone-salmeterol reported treatment emergent cardiovascular adverse events, all of which were dysrhythmias. For comparison, the pooled estimate of the Peto odds ratio (0.72; 95 % confidence interval [CI] 0.17-3; p = 0.65) and the summary risk ratio (0.77; 95 % CI 0.26-2.3; p = 0.64) indicated a nonsignificant difference between LABA-ICS and comparator/placebo groups.

Conclusions: Our systematic review found that few studies and trials reported treatment emergent cardiovascular adverse events with LABA-ICS. However, the Peto odds ratio and risk ratio for these outcomes was statistically nonsignificant. This suggests that LABA-ICS products may have a safe cardiovascular profile in asthma patients.

Similar articles

Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease.

Nannini LJ, Lasserson TJ, Poole P. Nannini LJ, et al. Cochrane Database Syst Rev. 2012 Sep 12;2012(9):CD006829. doi: 10.1002/14651858.CD006829.pub2. Cochrane Database Syst Rev. 2012. PMID: 22972099 Free PMC article. Review.

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adrenal cortex hormones / administration & dosage

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adrenal cortex hormones / adverse effects*

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adrenergic beta-agonists / administration & dosage

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adrenergic beta-agonists / adverse effects*

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anti-asthmatic agents / administration & dosage

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anti-asthmatic agents / adverse effects*

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anti-inflammatory agents / administration & dosage

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anti-inflammatory agents / adverse effects*

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bronchodilator agents / administration & dosage

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bronchodilator agents / adverse effects*

# data[].attributes.attachment_link.keywords[]
cardiovascular diseases / chemically induced*

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national center for biotechnology information

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Cardiovascular safety of long acting beta agonist-inhaled corticosteroid combination products in adult patients with asthma: a systematic review - PubMed

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Our systematic review found that few studies and trials reported treatment emergent cardiovascular adverse events with LABA-ICS. However, the Peto odds ratio and risk ratio for these outcomes was statistically nonsignificant. This suggests that LABA-ICS products may have a safe cardiovascular profil ...

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Título:  Un ensayo aleatorizado de prednisolona versus prednisolona e itraconazol en la aspergilosis broncopulmonar alérgica en estadio agudo que complica el asma.

Año: 2021
Autor: Rites A, et al.
Objetivo: Comparar la eficacia y seguridad de la combinación de prednisolona-itraconazol versus Monoterapia con prednisolona en ABPA
Resultados: Los resultados primarios fueron las tasas de exacerbación a los 12 meses y la ABPA dependiente de glucocorticoides dentro de los 24 meses posteriores al inicio del tratamiento. Los resultados secundarios clave fueron las tasas de respuesta y el porcentaje de disminución de la IgE total sérica a las seis semanas, el tiempo hasta la primera exacerbación de ABPA y los efectos adversos (EA) emergentes del tratamiento. Aleatorizamos a 191 sujetos para recibir prednisolona (n = 94) o prednisolona- combinación de itraconazol (n = 97). La tasa de exacerbaciones a un año fue del 33% y 20,6% en los brazos de prednisolona y prednisolona-itraconazol, respectivamente (p = 0,054). Ninguno de los participantes progresó a ABPA dependiente de glucocorticoides. Todos los sujetos experimentaron una respuesta compuesta a las 6 semanas, junto con una disminución de la IgE total en suero (disminución media, 47,6%frente al 45,5%).
Conclusión: Hubo una tendencia hacia una disminución en las exacerbaciones de ABPA al año con la combinación de prednisolona-itraconazol que con la monoterapia con prednisolona. Se requiere un ensayo de tres brazos que compare las monoterapias de itraconazol y prednisolona con su combinación, preferiblemente en un diseño multicéntrico, para definir la mejor estrategia de tratamiento para la ABPA en estadio agudo.

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doi: 10.1183/13993003.01787-2021. Online ahead of print.

Affiliations

¹ Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India agarwal.ritesh@outlook.in.

² Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

³ Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

⁴ Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

doi: 10.1183/13993003.01787-2021. Online ahead of print.

Affiliations

¹ Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India agarwal.ritesh@outlook.in.

² Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

³ Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

⁴ Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Abstract

Whether a combination of glucocorticoid and antifungal triazole is superior to glucocorticoid alone, in reducing exacerbations, in patients with allergic bronchopulmonary aspergillosis (ABPA) remains unknown. We aimed to compare the efficacy and safety of prednisolone-itraconazole combination versus prednisolone monotherapy in ABPA.We randomised subjects with treatment-naïve acute-stage ABPA complicating asthma to receive either prednisolone alone (four months) or a combination of prednisolone and itraconazole (four and six months, respectively). The primary outcomes were exacerbation rates at 12 months and glucocorticoid-dependent ABPA within 24 months of initiating treatment. The key secondary outcomes were response rates and percentage decline in serum total IgE at six weeks, time to first ABPA exacerbation, and treatment-emergent adverse effects (AE).We randomised 191 subjects to receive either prednisolone (n=94) or prednisolone-itraconazole combination (n=97). The one-year exacerbation rate was 33% and 20.6% in the prednisolone and the prednisolone-itraconazole arms, respectively (p=0.054). None of the participants progressed to glucocorticoid-dependent ABPA. All the subjects experienced a composite response at 6-weeks, along with a decline in serum total IgE (mean decline, 47.6% versus 45.5%). The mean time to first ABPA exacerbation (417 days) was not different between the groups. None of the participants required modification of therapy due to AE.There was a trend towards a decline in ABPA exacerbations at 1-year with the prednisolone-itraconazole combination than prednisolone monotherapy. A three-arm trial comparing itraconazole and prednisolone monotherapies with their combination, preferably in a multicentric design, is required to define the best treatment strategy for acute-stage ABPA.

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Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, Behera D, Chakrabarti A. Agarwal R, et al. Chest. 2018 Mar;153(3):656-664. doi: 10.1016/j.chest.2018.01.005. Epub 2018 Jan 11. Chest. 2018. PMID: 29331473 Clinical Trial.

A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.

Agarwal R, Aggarwal AN, Dhooria S, Singh Sehgal I, Garg M, Saikia B, Behera D, Chakrabarti A. Agarwal R, et al. Eur Respir J. 2016 Feb;47(2):490-8. doi: 10.1183/13993003.01475-2015. Epub 2015 Nov 19. Eur Respir J. 2016. PMID: 26585431 Clinical Trial.

A randomised trial of vitamin D in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.

Dodamani MH, Muthu V, Thakur R, Pal A, Sehgal IS, Dhooria S, Aggarwal AN, Garg M, Chakrabarti A, Agarwal R. Dodamani MH, et al. Mycoses. 2019 Apr;62(4):320-327. doi: 10.1111/myc.12879. Epub 2019 Feb 5. Mycoses. 2019. PMID: 30561849 Clinical Trial.

Azoles for allergic bronchopulmonary aspergillosis associated with asthma.

Wark P, Wilson AW, Gibson PG. Wark P, et al. Cochrane Database Syst Rev. 2001;(4):CD001108. doi: 10.1002/14651858.CD001108. Cochrane Database Syst Rev. 2001. PMID: 11687098 Updated. Review.

Azoles for allergic bronchopulmonary aspergillosis.

Wark P, Wilson AW, Gibson PG. Wark P, et al. Cochrane Database Syst Rev. 2000;(3):CD001108. doi: 10.1002/14651858.CD001108. Cochrane Database Syst Rev. 2000. PMID: 10908485 Updated. Review.

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national center for biotechnology information

# data[].attributes.attachment_link.title
A randomised trial of prednisolone versus prednisolone and itraconazole in acute-stage allergic bronchopulmonary aspergillosis complicating asthma - PubMed

# data[].attributes.attachment_link.description
doi: 10.1183/13993003.01787-2021. Online ahead of print. 1 Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India agarwal.ritesh@outlook.in. 2 Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. 3 Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

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Titulo:

Seguridad del tiotropio en pacientes con asma

Resultados:
El perfil de seguridad de tiotropio, un LAMA, se utilizo  datos de la gran escala UniTinA-asma ®programa de ensayos clínicos, que investigó el uso de tiotropio en más de 6000 pacientes con asma que permanecieron sintomáticos a pesar de recibir terapia de mantenimiento con corticosteroides inhalados (CSI), con o sin otras terapias complementarias. El gran número de pacientes incluidos permite un análisis sólido de la seguridad y la tolerabilidad. En general, se observó una incidencia similar de pacientes que informaron cualquier evento adverso (EA) en los grupos de tiotropio (5 µg y 2,5 µg) y placebo. El empeoramiento del asma, la disminución del flujo espiratorio máximo y las infecciones del tracto respiratorio superior fueron los EA notificados con mayor frecuencia. Los EA graves (AAG) y los EA relacionados con el fármaco definidos por el investigador se informaron con poca frecuencia en todos los grupos de tratamiento, incluido el grupo de placebo, y no hubo muertes en ningún estudio. Informes de efectos secundarios típicamente asociados con fármacos anticolinérgicos, como sequedad de boca y retención urinaria, fueron infrecuentes o no se notificaron en niños, adolescentes o adultos. Las proporciones similares de pacientes tratados con tiotropio frente a los tratados con placebo que informan EA y AAG en poblaciones afroamericanas y japonesas, así como en pacientes de edad avanzada, contribuyen a la evidencia acumulada de la seguridad y tolerabilidad del tiotropio en una amplia población étnica y de edad.

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Affiliations

¹ Service de Pneumologie, Hôpital Cochin, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, Sorbonne Paris Cité, Paris, 75014, France.

² Departments of Pediatrics and of Social and Preventive Medicine, University of Montréal, Montréal, Canada Research Centre, CHU Sainte-Justine, Montréal, Canada.

Free PMC article

Free PMC article

Affiliations

¹ Service de Pneumologie, Hôpital Cochin, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, Sorbonne Paris Cité, Paris, 75014, France.

² Departments of Pediatrics and of Social and Preventive Medicine, University of Montréal, Montréal, Canada Research Centre, CHU Sainte-Justine, Montréal, Canada.

Abstract

Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma ® clinical trial program, which investigated the use of tiotropium in over 6000 patients with asthma who remained symptomatic despite receiving inhaled corticosteroids (ICS) maintenance therapy, with or without other adjunct therapies. The large number of patients included allows robust analysis of safety and tolerability. Overall, a similar incidence of patients reporting any adverse event (AE) was observed in the tiotropium (5 µg and 2.5 µg) and placebo groups. Asthma worsening, decreased peak expiratory flow, and upper respiratory tract infections were the most frequently reported AEs. Serious AEs (SAEs) and investigator-defined drug-related AEs were infrequently reported across all treatment groups, including the placebo group, and there were no deaths in any study. Reports of side effects typically associated with anticholinergic drugs, such as dry mouth and urinary retention, were either infrequent or not reported in children, adolescents or adults. The similar proportions of tiotropium- versus placebo-treated patients reporting AEs and SAEs in African-American and Japanese populations, as well as in elderly patients, contribute to the accumulating evidence of the safety and tolerability of tiotropium across broad ethnic and age populations.

Keywords: anticholinergics; asthma; long-acting muscarinic antagonists; safety; tiotropium.

Conflict of interest statement

Conflict of interest statement: DD reports receiving consulting fees, lecture fees and payment for the development of educational activities from Boehringer Ingelheim, Chiesi, Dey Pharma, Novartis, Nycomed and Pfizer.

FMD reports receiving unrestricted research funds from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Canada, Novartis and Trudell Medical; honorarium for consultancy work from Boehringer Ingelheim and Sanofi; and honorarium as speaker from Boehringer Ingelheim and AstraZeneca (China).

Oral health in asthmatic patients: a review : Asthma and its therapy may impact on oral health.

Gani F, Caminati M, Bellavia F, Baroso A, Faccioni P, Pancera P, Batani V, Senna G. Gani F, et al. Clin Mol Allergy. 2020 Nov 7;18(1):22. doi: 10.1186/s12948-020-00137-2. Clin Mol Allergy. 2020. PMID: 33292326 Free PMC article. Review.

References

World Health Organization. Asthma Fact Sheet 307, http://www.who.int/mediacentre/factsheets/fs307/en/ (2017, accessed 24 January 2018).

Schmier JK, Manjunath R, Halpern MT, et al. The impact of inadequately controlled asthma in urban children on quality of life and productivity. Ann Allergy Asthma Immunol 2007; 98: 245-251. - PubMed

Asthma UK. Asthma Facts and FAQs, https://www.asthma.org.uk/about/media/facts-and-statistics/ (2016, accessed 24 January 2018).

Global Initiative for Asthma. GINA Report: Global Strategy for Asthma Management and Prevention, http://ginasthma.org/2018-gina-report-global-strategy-for-asthma-managem... (2018, accessed 22 October 2018).

Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med 2014; 24: 14009. - PMC - PubMed

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anti-asthmatic agents / administration & dosage

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bronchodilator agents / administration & dosage*

# data[].attributes.attachment_link.keywords[]
cholinergic antagonists / administration & dosage

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cholinergic antagonists / adverse effects

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glucocorticoids / administration & dosage

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tiotropium bromide / administration & dosage*

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national center for biotechnology information

# data[].attributes.attachment_link.title
Safety of tiotropium in patients with asthma - PubMed

# data[].attributes.attachment_link.description
Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, i ...

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TITULO:

Eficacia y efectos secundarios de la teofilina intravenosa en el asma aguda: revisión sistemática y metanálisis

TIPO DE ESTUDIO: Revisión sistemática y metanálisis
AÑO: 2018
RESULTADOS: Se incluyeron 52 brazos de estudio de 42 ensayos individuales. De estos, 29 brazos del estudio incluyeron un control activo, como adrenalina, agonistas beta-2 o antagonistas del receptor de leucotrienos, y 23 brazos del estudio compararon teofilina (con o sin etilendiamina) con placebo o ningún fármaco. La teofilina redujo significativamente la frecuencia cardíaca en comparación con el control activo ( p = 0,01) y la duración total de la estancia ( p = 0,002), pero los agonistas beta-2 fueron superiores a la teofilina para mejorar el volumen espiratorio forzado en un segundo (FEV1) ( p= 0,002).
CONCLUSIÓN:
Dado el bajo costo de la teofilina y su eficacia y tasa de efectos secundarios similares en comparación con otros medicamentos, se sugiere utilizar la teofilina, cuando se administra con broncodilatadores con o sin esteroides, ya que es una opción rentable y segura para las exacerbaciones agudas del asma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768195/

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Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis

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Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner’s formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, ...

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https://pubmed.ncbi.nlm.nih.gov/30905424/
TITULO: Montelukast y eventos neuropsiquiátricos en niños con asma: un estudio de casos y controles anidado.
AÑO: 2020
TIPO DE ESTUDIO: Estudio de casos y controles anidado.
RESULTADOS: En total, se incluyeron 898 casos con un evento neuropsiquiátrico y 3497 controles emparejados. Los niños que experimentaron un evento neuropsiquiátrico de nueva aparición tenían casi 2 veces más probabilidades de que se les prescribiera montelukast, en comparación con los controles (OR 1,91; IC del 95%: 1,15-3,18; p = 0,01). La mayoría de los casos se presentaron por ansiedad (48,6%) y / o alteración del sueño (26,1%).
CONCLUSIÓN: Los niños con asma que experimentaron un evento neuropsiquiátrico de nueva aparición tenían casi el doble de probabilidades de que se les prescribiera montelukast en el año anterior al evento. Los médicos deben conocer la asociación entre montelukast y los eventos neuropsiquiátricos en niños con asma, para informar las prácticas de prescripción y el seguimiento clínico.

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Affiliations

¹ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario.

² Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Division of Emergency Medicine, The Hospital for Sick Children, Toronto, Ontario; Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario; Paediatrics, Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario.

³ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario.

⁴ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario. Electronic address: teresa.to@sickkids.ca.

Affiliations

¹ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario.

² Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Division of Emergency Medicine, The Hospital for Sick Children, Toronto, Ontario; Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario; Paediatrics, Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario.

³ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario.

⁴ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario; Institute for Clinical Evaluative Sciences, Toronto, Ontario; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario. Electronic address: teresa.to@sickkids.ca.

Abstract

Objective: To examine the association between montelukast prescription and neuropsychiatric events in children with asthma.

Study design: A matched, nested case-control design was used to identify cases and controls from a cohort of children aged 5-18 years with physician-diagnosed asthma from 2004 to 2015, in Ontario, Canada, prescribed an asthma maintenance medication. Cases were children with a hospitalization or emergency department visit for a neuropsychiatric event. Cases were matched to up to 4 controls on birth year, year of asthma diagnosis, and sex. The exposures were dispensed prescriptions for montelukast (yes/no) and number of dispensed montelukast prescriptions in the year before the index date. Conditional logistic regression was used to measure the unadjusted OR and aOR and 95% CIs for montelukast prescription and neuropsychiatric events. Covariates in the adjusted model included sociodemographic factors and measures of asthma severity.

Results: In total, 898 cases with a neuropsychiatric event and 3497 matched controls were included. Children who experienced a new-onset neuropsychiatric event had nearly 2 times the odds of having been prescribed montelukast, compared with controls (OR 1.91, 95% CI 1.15-3.18; P = .01). Most cases presented for anxiety (48.6%) and/or sleep disturbance (26.1%).

Conclusions: Children with asthma who experienced a new-onset neuropsychiatric event had nearly twice the odds of having been prescribed montelukast in the year before their event. Clinicians should be aware of the association between montelukast and neuropsychiatric events in children with asthma, to inform prescribing practices and clinical follow-up.

Keywords: asthma; children; drug safety; montelukast; neuropsychiatric events.

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anti-asthmatic agents / adverse effects*

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nervous system diseases / chemically induced*

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national center for biotechnology information

# data[].attributes.attachment_link.title
Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case-Control Study - PubMed

# data[].attributes.attachment_link.description
Children with asthma who experienced a new-onset neuropsychiatric event had nearly twice the odds of having been prescribed montelukast in the year before their event. Clinicians should be aware of the association between montelukast and neuropsychiatric events in children with asthma, to inform pre ...

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TITULO:

Seguridad del tiotropio en pacientes con asma

AÑO Y TIPO DE ESTUDIO: 2019; Metaanálisis .
RESULTADOS: Se ha investigado la seguridad y tolerabilidad del tiotropio en más de 6000 pacientes con asma, incluidos adultos, adolescentes y niños. En general, los hallazgos demuestran una proporción similar de pacientes que informaron cualquier EA entre los grupos de tratamiento con tiotropio (5 µg y 2,5 µg) y placebo. De manera similar, la notificación de eventos adversos graves y eventos adversos relacionados con el fármaco definidos por el investigador fue baja y comparable entre los grupos de tratamiento, y no se informaron muertes en ningún ensayo.

CONCLUSIONES:  El tiotropio muestra un excelente perfil de seguridad, con proporciones comparables de pacientes que informan EA y AAG a los tratados con placebo. Los efectos secundarios típicos de la clase terapéutica anticolinérgica, como sequedad de boca y retención urinaria, fueron bajos o ausentes en todos los grupos de edad. Por lo tanto, el tiotropio proporciona una opción terapéutica adicional bien tolerada y eficaz para el tratamiento del asma en pacientes cuya enfermedad permanece mal controlada a pesar de los CSI más la terapia complementaria, o como una opción terapéutica alternativa en pacientes en los que los ABAP u otras opciones complementarias son inadecuados o ineficaces.

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Affiliations

¹ Service de Pneumologie, Hôpital Cochin, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, Sorbonne Paris Cité, Paris, 75014, France.

² Departments of Pediatrics and of Social and Preventive Medicine, University of Montréal, Montréal, Canada Research Centre, CHU Sainte-Justine, Montréal, Canada.

Free PMC article

Free PMC article

Affiliations

¹ Service de Pneumologie, Hôpital Cochin, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, Sorbonne Paris Cité, Paris, 75014, France.

² Departments of Pediatrics and of Social and Preventive Medicine, University of Montréal, Montréal, Canada Research Centre, CHU Sainte-Justine, Montréal, Canada.

Abstract

Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma ® clinical trial program, which investigated the use of tiotropium in over 6000 patients with asthma who remained symptomatic despite receiving inhaled corticosteroids (ICS) maintenance therapy, with or without other adjunct therapies. The large number of patients included allows robust analysis of safety and tolerability. Overall, a similar incidence of patients reporting any adverse event (AE) was observed in the tiotropium (5 µg and 2.5 µg) and placebo groups. Asthma worsening, decreased peak expiratory flow, and upper respiratory tract infections were the most frequently reported AEs. Serious AEs (SAEs) and investigator-defined drug-related AEs were infrequently reported across all treatment groups, including the placebo group, and there were no deaths in any study. Reports of side effects typically associated with anticholinergic drugs, such as dry mouth and urinary retention, were either infrequent or not reported in children, adolescents or adults. The similar proportions of tiotropium- versus placebo-treated patients reporting AEs and SAEs in African-American and Japanese populations, as well as in elderly patients, contribute to the accumulating evidence of the safety and tolerability of tiotropium across broad ethnic and age populations.

Keywords: anticholinergics; asthma; long-acting muscarinic antagonists; safety; tiotropium.

Conflict of interest statement

Conflict of interest statement: DD reports receiving consulting fees, lecture fees and payment for the development of educational activities from Boehringer Ingelheim, Chiesi, Dey Pharma, Novartis, Nycomed and Pfizer.

FMD reports receiving unrestricted research funds from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Canada, Novartis and Trudell Medical; honorarium for consultancy work from Boehringer Ingelheim and Sanofi; and honorarium as speaker from Boehringer Ingelheim and AstraZeneca (China).

Oral health in asthmatic patients: a review : Asthma and its therapy may impact on oral health.

Gani F, Caminati M, Bellavia F, Baroso A, Faccioni P, Pancera P, Batani V, Senna G. Gani F, et al. Clin Mol Allergy. 2020 Nov 7;18(1):22. doi: 10.1186/s12948-020-00137-2. Clin Mol Allergy. 2020. PMID: 33292326 Free PMC article. Review.

References

World Health Organization. Asthma Fact Sheet 307, http://www.who.int/mediacentre/factsheets/fs307/en/ (2017, accessed 24 January 2018).

Schmier JK, Manjunath R, Halpern MT, et al. The impact of inadequately controlled asthma in urban children on quality of life and productivity. Ann Allergy Asthma Immunol 2007; 98: 245-251. - PubMed

Asthma UK. Asthma Facts and FAQs, https://www.asthma.org.uk/about/media/facts-and-statistics/ (2016, accessed 24 January 2018).

Global Initiative for Asthma. GINA Report: Global Strategy for Asthma Management and Prevention, http://ginasthma.org/2018-gina-report-global-strategy-for-asthma-managem... (2018, accessed 22 October 2018).

Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med 2014; 24: 14009. - PMC - PubMed

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anti-asthmatic agents / administration & dosage

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bronchodilator agents / administration & dosage*

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cholinergic antagonists / administration & dosage

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cholinergic antagonists / adverse effects

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glucocorticoids / administration & dosage

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tiotropium bromide / administration & dosage*

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national center for biotechnology information

# data[].attributes.attachment_link.title
Safety of tiotropium in patients with asthma - PubMed

# data[].attributes.attachment_link.description
Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, i ...

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Título: Perfil de eficacia y seguridad de la doxofilina en comparación con la teofilina en el asma.

Tipo de estudio :  metanálisis

Autor : Paola Rogliani  y col.

Año : 2019

Resultados: Los datos obtenidos de 696 pacientes asmáticos se extrajeron de 4 ensayos controlados aleatorios publicados entre 2015 y 2018. La doxofilina fue significativamente ( P <0,05) más eficaz que la teofilina para reducir los episodios de asma diarios (diferencia de medias - 0,14, IC del 95%: -0,27 - 0,00) y riesgo de EA (riesgo relativo 0,76; IC del 95%: 0,59-0,99). La doxofilina fue tan eficaz como la teofilina para mejorar el FEV ₁ , y se detectó una tendencia de superioridad ( P = 0,058) para la doxofilina sobre la teofilina con respecto a la reducción en el uso de salbutamol como medicación de rescate. El rango de efectividad fue doxofilina> teofilina>> placebo, y el rango de seguridad fue placebo> doxofilina>> teofilina.

Conclusiones: La doxofilina es una metilxantina eficaz y segura para el tratamiento del asma, con un perfil de eficacia / seguridad superior al de la teofilina.

https://pubmed.ncbi.nlm.nih.gov/31388422/

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Título:

Nifedipino versus Terbutalina, Eficacia Tocolítica y Efectos Adversos Maternas y Neonatales: Un Ensayo Piloto Aleatorizado y Controlado

Autor y Año: Padovani, T; 2014
Tipo de estudio: ECA
Resultados: Aleatorizamos a 32 mujeres a nifedipino y 34 a terbutalina. No se produjeron efectos adversos maternos graves ni desenlaces adversos neonatales graves en ninguno de los grupos. La administración de terbutalina aumentó el temblor (76,4% frente a 0%), náuseas (58,8% frente a 9,4%) y mareos (29,4% frente a 6,25%).
Conclusiones: En este estudio, la terbutalina y el nifedipino tuvieron un rendimiento similar en sus efectos tocolíticos. Cada medicamento tiene efectos secundarios específicos, aunque en general, el nifedipino se asoció con menos efectos adversos.

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Tania Regina Padovani , Gordon Guyatt , Luciane Cruz Lopes ,

Corresponding Author

Luciane Cruz Lopes

Pharmaceutical Sciences Post graduate Course, University of Sorocaba, UNISO, Sorocaba, Brazil

Author for correspondence: Luciane Cruz Lopes, Pharmaceutical Sciences Post graduate Course, University of Sorocaba, UNISO, Rodovia Raposo Tavares, KM 92,5 Sorocaba, SP, Brasil CEP 18023-000, Brazil (e-mail luslopes@terra.com.br ). Search for more papers by this author

Gordon Guyatt

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
Search for more papers by this author

Tania Regina Padovani

Pharmaceutical Sciences Post graduate Course, University of Sorocaba, UNISO, Sorocaba, Brazil

Pontificia Universidade Católica São Paulo, São Paulo, Brazil
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First published:

Abstract

Although previous evidence suggests advantages of nifedipine over terbutaline as tocolytic agents, in some jurisdictions, terbutaline is approved for use and nifedipine is not. In women in preterm labour, we compared the impact of terbutaline versus nifedipine on inhibition of uterine contractions, preterm birth, neonatal sepsis, intracranial haemorrhage or necrotizing enterocolitis, death or admission to a neonatal intensive care unit and maternal adverse reactions. We randomized 32 women to nifedipine and 34 to terbutaline. We found no difference between groups in tocolysis or preterm birth. No serious maternal adverse effects or serious neonatal adverse outcome occurred in either group. Less serious maternal adverse effects less common with terbutaline included flushing (2.94% versus 43.7%) and headache (5.9% versus 31.2%). The administration of terbutaline increased tremor (76.4% versus 0%), nausea (58.8% versus 9.4%) and dizziness (29.4% versus 6.25%). The total number of side effects, and the proportion of women experiencing one or more side effects, proved greater with terbutaline. In this study, terbutaline and nifedipine performed similarly in their tocolytic effects. Each drug has specific side effects, although overall, nifedipine was associated with fewer adverse effects.

Premature birth is common (over 5% and, in some countries, over 10%) 1, 3, 5. 4. Preterm infants often require intensive care that is associated with emotional and economic costs to both the family and society 2 and is responsible for approximately 75% of all neonatal deaths and 50% of childhood neurological morbidities

Approximately 75% of preterm birth is attributable to spontaneous preterm labour 1. Delay in preterm labour therefore provides a potential opportunity for decreasing neonatal morbidity and mortality 6.

The optimal medical management of threatened preterm labour is controversial 7. Despite theoretical benefits of keeping the foetus in utero long enough to enable administration of a full course of corticosteroids to assist in foetal lung maturation, and to organize transfer to an appropriate neonatal care unit, no agent has been shown to improve neonatal outcome 2, 7. Thus, the choice of therapy has focused on delay in delivery and minimization of adverse effects.

The drugs registered for tocolysis include the β adrenoceptor agonist ritodrine (United States and Europe), terbutaline (Brazil) and the oxytocin receptor antagonist atosiban (Europe) 8. Calcium channel blockers (nifedipine) and cyclooxygenase inhibitors (indomethacin) are also used for inhibiting preterm labour although, in many countries, they are not currently registered for this indication 9.

Betamimetics (isoxsuprine, ritodrine, terbutaline, fenoterol and salbutamol) delay labour 10- 10, 15 and has advantages of oral administration and relatively low cost. Several randomized, controlled trials have compared the efficacy of calcium channel blockers, usually nifedipine and betamimetics. Although most trials had important methodological limitations, and conclusions varied regarding effectiveness (most reporting similar tocolysis 16- 21, 6, 21- 24. 22, all reported a better side effect profile with nifedipine with fewer women requiring cessation of therapy due to adverse events 20 and some suggesting the superiority of nifedipine 13, 14. Many centres use nifedipine, which also has established effectiveness in delaying labour 12, but their use has been limited by a high incidence of maternal adverse effects

Despite this evidence, sponsors have not sought regulatory approval for nifedipine as a tocolytic agent in many countries; its use is therefore off-label. Furthermore, hesitations about its use arise from reports of maternal hypotension 25 and concerns about placental perfusion 26. Finally, some have suggested that as calcium channel blockers are not licensed for tocolysis, under-reporting of adverse events may be occurring 8.

In the face of the current situation in which terbutaline remains the most common tocolytic used in many low- and middle-income and some high-income (e.g. Germany) countries and nifedipine is only being used off-label, we considered that an additional randomized trial comparing the efficacy of nifedipine with terbutaline on tocolytic and on maternal and neonatal outcome could help to inform optimal management of preterm labour.

Methods

The protocol for this trial and a CONSORT checklist are available as supporting information; see Data S1.

Ethics statement

This study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol and its amendments received independent ethics committee or institutional review board approval before site initiation and recruitment of patients. The protocol was approved by the Ethics Committee at University of Sorocaba (#2010-20), and the study protocol was registered in Platforms Brazil.

Participants

Eligible participants were Brazilian women aged 18-40 years, with singleton pregnancies, presenting to the labour ward with all of the following: at least four painful and regular uterine contractions in each 20-min. interval, cervical dilatation of 0-3 cm (for nulliparous) or 1-3 cm (for multiparae), cervical effacement of ≥50%, 24-33⁺⁶ weeks of gestation and intact membranes who were diagnosed as threatened preterm labour. Gestational age was confirmed by either a documented first-trimester ultrasound scan or a reliable menstrual date confirmed by ultrasonography performed before 20 weeks of gestation 27.

Exclusion criteria were maternal comorbidity including bronchial asthma, diabetes mellitus, cardiovascular diseases, severe anaemia, pregnancy-induced hypertension (>140/90 mmHg) and hypotension (<80/50 mmHg); complications at delivery (no reassuring foetal heart rate tracing, severe pre-eclampsia, placental abruption, antepartum haemorrhage, fever above 38°C); foetal complications (congenital anomaly, hydramnios and chorioamnionitis and intrauterine growth retardation < fifth percentile); contra-indication to the use of betamimetic or calcium blocker agents; previous treatment with tocolytics in current pregnancy; and refusal to give informed consent.

Study design

The trial was performed in three centres in Brazil between August 2010 and March 2012. Consecutive patients meeting eligibility criteria were randomized in a 1:1 ratio to oral nifedipine or intravenous terbutaline. At each centre, a pharmacist investigator created a computer-generated randomization schedule and, after confirming eligibility for each participant, informed the attending physician regarding allocation to terbutaline or nifedipine, thus ensuring concealment of allocation (those enrolling patients were unaware of the arm to which the patient would be allocated). The doctors and nurses were not blind to allocation. Data were collected by a physician in training, and outcome were adjudicated by one of two physicians blind to group assignment.

Intervention

The participants received terbutaline or nifedipine as follows:

1. Terbutaline (ampoule 0.5 mg/mL): intravenous infusion of 2.5 μg/min. followed by an increase of 2.5 μg/min. every 15 min. to a maximum of 20 μg/min. When the minimum dose capable of stopping contractions was established, this infusion was maintained for 24 hr. After 24 hr of drug administration, the dose was decreased by 2.5 μg/min. every 15 min. until full discontinuation 28.

2. Nifedipine (tablet 20 mg) given orally. If contractions did not cease after 30 min., a second dose was given. Once tocolysis was achieved, nifedipine 20 mg orally was administered every 8 hr for a period of 48 hr. The total dose administered during 48 hr was 120 mg.

Uterine contractions were monitored continuously by an external tocodynamometer for 2-4 hr after initiation of the study drug followed by two to three times a day for 30-60 min.

Tocolytic drugs were discontinued in the face of progression to a cervical dilatation of 4 cm or more or rupture of membranes, no decrease in contractions after 12 hr, or if there was a suspicion of chorioamnionitis. Recurrence of preterm labour during the first 48 hr after effective tocolysis was treated with the same agent as the initial tocolysis. Other tocolytic agents were not permitted concomitantly unless, after at least 1 hr of observation during treatment, there was an increase or no change in the frequency of the contractions, or an increase in cervical dilatation of 1 cm or more.

All patients were monitored throughout the intervention for haemodynamic and metabolic changes. Continuous cardiotocography was used to monitor foetal heart rate patterns. For both groups, monitoring of heart rate, blood pressure and contractions were monitored every 15 min. for the first hour, hourly for the next 24 hr, every 6 hr during the next 48 hr and thereafter daily when uterine quiescence had been achieved.

Prophylactic antibiotics for group B streptococcus and corticosteroids were administered according to standard clinical indications.

Outcome measures

The effectiveness outcome of interest were failure of tocolysis (continued uterine contractions 12 hr after drug initial administration or cervical dilatation to >4 cm); delivery prior to 48 hr from the initiation of contractions; delivery before 34 and 37 weeks' gestation; the interval between trial entry and delivery; and gestational age at delivery using the capurro method 29.

The outcome of interest related to adverse events were severe maternal adverse drug reactions, maternal less serious adverse events and discontinuation of treatment because of adverse events.

The neonatal outcome of interest were perinatal death or admission to neonatal intensive care unit, birth weight, Apgar score at 1 and 5 min., respiratory distress syndrome, need for oxygen, intubation, intraventricular or intracranial haemorrhage, necrotizing enterocolitis, retinopathy of prematurity, neonatal jaundice, neonatal sepsis, foetal death, neonatal death, length of stay in the neonatal intensive care unit blood pressure (hypertension ≥90/140 mmHg or hypotension ≤50/80 mmHg) and foetal tachycardia or bradycardia.

Outcome ascertainment was complete, and no patients were lost to follow-up.

Statistical analysis

We present patient characteristics using the arithmetic mean, standard deviation, median, minimum and maximum values, and frequencies as appropriate. The analyses were intention-to-treat. For conducting parametric tests of outcome, we confirmed data normality and homogeneity of variances, using histograms and the Levene test, respectively. We used the Student's t-test for independent samples when these assumptions were met, and otherwise used the Mann-Whitney U-test. We calculated risk ratios (RR) and associated 95% confidence intervals (95% CI). The criterion for statistical significance in all analyses was <5%. Data were analysed using the SPSS statistical feature, version 15.0 for Windows (Statistical Package for the Social Sciences, SPSS, Chicago, Illinois, USA), and Biostat V5, Analystsoftware, Sao Paulo, Brazil.

Results

Of 663 women presenting with preterm labour, 597 failed to meet eligibility criteria (fig. 1). Of the remaining 66, 34 were randomized to terbutaline and 32 to nifedipine (fig. 1). Baseline demographic and obstetric characteristics were similar in the two groups (table 1).

General characteristics of patients

Terbutaline (n = 34)

Nifedipine (n = 32)

Race n (%)

SBD, systolic blood pressor; DBP, diastolic blood pressure, bpm: beat per minute.

Values are mean ± S.D.

Effectiveness outcome

Table 2 presents comparisons of the effect of terbutaline versus nifedipine on outcome related to tocolysis. Tocolytic drugs were discontinued in three patients in the terbutaline group (two because of progression to a cervical dilatation of >4 cm and one because of rupture membranes) and in three patients in the nifedipine group (one because of progression to a cervical dilatation of >4 cm and two because of rupture membranes). Time of tocoloysis in the terbutaline group (2.45 ± 1.67) was not different from the nifedipine group (2.78 ± 2.1); mean difference - 0.35 (95% CI −1.21 to 0.52, p = 0.2). Other results were also similar in the two groups, with generally good outcome for most of the women; we found no statistically significant differences. The confidence intervals around most estimates were, however, very wide.

Parameters of effectiveness

Terbutaline (n = 34)

Nifedipine (n = 32)

RR (95% CI)

p

RR, relative risk; CI 95%, confidence interval 95%.

Adverse effect associated with tocolytic therapy

We observed no serious adverse effects. No women in either group required cessation of therapy due to adverse events. Table 3 presents the pattern of less serious adverse effects. Flushing and headache were both frequent and occurred more often after the administration of nifedipine. The administration of terbutaline, however, increased the risk of other side effects, including tremor, nausea and dizziness. Most women in both groups experienced at least one adverse effect (94.1% terbutaline versus 71.9% nifedipine); more women in the terbutaline group experienced two or more side effects (84.8% terbutaline versus 33.3% nifedipine); and the total number of adverse effects was higher in the terbutaline group (78 events in terbutaline versus 35 in nifedipine).

Adverse effects

Terbutaline n = 34 (%)

Nifedipine n = 32 (%)

RR (CI 95%)

p-Value

32 (94.1)

23 (71.9)

1.39 (1.10-1.76)

0.01

RR, relative risk; CI 95%, confidence interval of 95%.

AE adverse effects.

Two hypotensive events that occurred with the use of nifedipine were controlled with the administration of volume (sodium chloride 9%) and placing the patient in the left lateral decubitus position.

Table 4 presents the impact of the two agents on foetal outcome. Outcome were similar between groups. No foetus experienced either bradycardia or tachycardia.

Neonatal outcome

Terbutaline n = 34 (%)

Nifedipine n = 32 (%)

RR or Mean difference (CI 95%)

p-Value

Neonatal sepsis

2 (5.8)

1 (3.1)

1.83 (0.17 to 19.30)

0.61 ⁶

RR, relative risk; CI 95%, confidence interval 95%.

Discussion

We found no significant differences between terbutaline and nifedipine and concerning effective tocolysis, the recurrence of preterm labour in the first 48 hr and the time of delivery (table 2). We observed no serious adverse effects in either treatment arm. The proportion of patients who experienced one or more less serious adverse effects during tocolytic therapy was greater in women who received terbutaline than in those who received nifedipine (table 3). Women who received terbutaline significantly more frequently developed tremors, nausea and dizziness (table 3). Headache and flushing, however, occurred significantly more frequently with nifedipine (table 3), and the only two important hypotensive events occurred in the nifedipine group.

Neonatal adverse outcome were similar in the two groups (table 4). Despite both agents proving effective in prolonging preterm labour up to 48 hr, allowing enough time for the administrations of corticosteroid and pulmonary maturation, and despite most deliveries occurring after 34 weeks of pregnancy, the number of newborn babies developed respiratory distress syndrome was still high in both groups (35.2% in terbutaline, 31.2% in nifedipine).

Strengths and weaknesses of this study

Strengths of this study include the careful confirmation of preterm labour 7, 27; the low risk of bias (concealed randomization, blinding of outcome assessment, no loss to follow-up, analyse as randomized); and the rigorous and comprehensive collection of data relevant to the efficacy of tocolysis, adverse effects on the mothers and neonatal outcome.

The trial's primary limitation is its small sample size and the resulting wide confidence intervals. Another limitation is that we did not follow infants beyond discharge from hospital. A third limitation is the relatively small number of women presenting with premature labour who proved eligible for this study. Unfortunately, the incidence of potential contra-indications to tocolytic therapy, in particular foetal and maternal abnormalities and complications, are frequent in women presenting in premature labour. For example, in another study of tocolytic therapy, of 566 potentially eligible women, only 64 proved eligible and were included 30.

Relation to previous work

The most compelling summary of results of previous trials thus far comes from a network meta-analysis examining all the randomized trials of all agents used for tocolysis 6. This meta-analysis found that, in comparison with terbutaline, calcium channel blockers have a higher probability of achieving delay in delivery beyond 48 hr. Our failure to replicate this finding may well be a result of our small sample size; the confidence interval includes the benefit of nifedipine seen in the meta-analysis. Two previous meta-analyses have suggested nifedipine is superior to terbutaline in terms of prevention of neonatal adverse events, although they failed to show a difference in these events between nifedipine and placebo 22, 6 failed to find differences in respiratory distress between agents. If there is indeed a difference between neonatal adverse events between the two agents, the small sample size in our study could once again be an explanation for our failure to detect the difference. 24 while the network meta-analysis

Our findings regarding adverse effects with terbutaline (in particular tremors and nausea) are similar to those reported in previous meta-analyses by Tsatsaris et al. 24 and King et al. 15 However, these authors also report a higher frequency of tachycardia, palpitations and chest pain, which our patients did not experience. Previous trials also reported treatment discontinuation because of side effects with terbutaline from 6% to 38%, whereas terbutaline adverse effects in our trial did not require discontinuation in any patient 31. In our trial, the dose of terbutaline was adjusted to a safe range according to guidance from Klasco 28, 33, 34. This may explain both our failure to observe either cardiovascular adverse events or the necessity to discontinue terbutaline because of adverse effects. 32; our doses were lower than in previous trials of this agent

We observed no serious adverse effects with terbutaline. This result is consistent with data suggesting that adverse effects are rare: acute pulmonary oedema, estimated from 1:350 to 1:400, which may result in the mother's death. Over 25 deaths related to the administration of terbutaline in order to inhibit preterm labour have been reported 24. Due to the risks involved, the FDA has warned about the use of this drug as a tocolytic agent 35.

We observed more frequent headaches with nifedipine than terbutaline, presumably secondary to nifedipine's vasodilatory effects 36- 10, 2, 42, 26. Considering possible under-reporting of adverse effects, authors recommend precaution, particularly in women with cardiovascular morbidity 2, 44, 45. 43, which causes concern about placental perfusion, excessive hypotension, myocardial infarction and heart failure. Two women receiving nifedipine in our study became hypotensive. In many countries, these considerations led to the withdrawal from the market of nifedipine's quick release presentation 21, 22, 31, 41 have reported that nifedipine generates fewer total adverse events than terbutaline, a finding that our study confirmed. On the other hand, anti-hypertensive drugs - as in the case of nifedipine - may produce maternal hypotension 39, 40. Overall, however, previous evidence summaries 38, a result consistent with previous studies

Implications for future research

Given nifedipine's toxicity advantages, such a study might appropriately use a non-inferiority design to ensure that an important outcome, such as failure to achieve tocolysis within 12 hr, was not appreciably higher with nifedipine than terbutaline. Given the rate of failure of tocolysis in the terbutaline group of approximately 9%, and assuming conventional values of type 1 and type 2 error, one would require 2547, 1140 and 647 participants per group to definitively demonstrate that nifedipine did not increase the frequency of failure of tocolysis in 12 hr by, respectively, 2%, 3% or 4%.

Conclusion

The results of this study support previous evidence suggesting that nifedipine is as effective as terbutaline in its impact on tocolysis and neonatal outcome with fewer maternal and foetal adverse effects. The oral administration of nifedipine, as well as its low cost (it does not involve skilled technicians for the administration and does not require parenteral application), further recommends the treatment.

Acknowledgements

Elton Luis Faggioni Trani and Victor Simezo for adjudications outcomes. No funding was received for this project.

Disclosure

The authors declare no conflict of interest.

Author contributions

All authors participated in the preparation of the manuscript and agreed to the submitted version of the paper. Tania Padovani and Luciane Lopes involved in the study concept and design. Tania Padovani participated in acquisition of data. Gordon Guyatt and Luciane Lopes analysed and interpreted the data. Gordon and Luciane Lopes drafted the manuscript. Tania Padovani, Luciane Lopes and Gordon Guyatt critically revised the manuscript for important intellectual content.

Abstract

Although previous evidence suggests advantages of nifedipine over terbutaline as tocolytic agents, in some jurisdictions, terbutaline is approved for use and nifedipine is not. In women in preterm labour, we compared the impact of terbutaline versus nifedipine on inhibition of uterine contractions, preterm birth, neonatal sepsis, intracranial haemorrhage or necrotizing enterocolitis, death or admission to a neonatal intensive care unit and maternal adverse reactions. We randomized 32 women to nifedipine and 34 to terbutaline. We found no difference between groups in tocolysis or preterm birth. No serious maternal adverse effects or serious neonatal adverse outcome occurred in either group. Less serious maternal adverse effects less common with terbutaline included flushing (2.94% versus 43.7%) and headache (5.9% versus 31.2%). The administration of terbutaline increased tremor (76.4% versus 0%), nausea (58.8% versus 9.4%) and dizziness (29.4% versus 6.25%). The total number of side effects, and the proportion of women experiencing one or more side effects, proved greater with terbutaline. In this study, terbutaline and nifedipine performed similarly in their tocolytic effects. Each drug has specific side effects, although overall, nifedipine was associated with fewer adverse effects.

Premature birth is common (over 5% and, in some countries, over 10%) 1, 3, 5. 4. Preterm infants often require intensive care that is associated with emotional and economic costs to both the family and society 2 and is responsible for approximately 75% of all neonatal deaths and 50% of childhood neurological morbidities

Approximately 75% of preterm birth is attributable to spontaneous preterm labour 1. Delay in preterm labour therefore provides a potential opportunity for decreasing neonatal morbidity and mortality 6.

The optimal medical management of threatened preterm labour is controversial 7. Despite theoretical benefits of keeping the foetus in utero long enough to enable administration of a full course of corticosteroids to assist in foetal lung maturation, and to organize transfer to an appropriate neonatal care unit, no agent has been shown to improve neonatal outcome 2, 7. Thus, the choice of therapy has focused on delay in delivery and minimization of adverse effects.

The drugs registered for tocolysis include the β adrenoceptor agonist ritodrine (United States and Europe), terbutaline (Brazil) and the oxytocin receptor antagonist atosiban (Europe) 8. Calcium channel blockers (nifedipine) and cyclooxygenase inhibitors (indomethacin) are also used for inhibiting preterm labour although, in many countries, they are not currently registered for this indication 9.

Betamimetics (isoxsuprine, ritodrine, terbutaline, fenoterol and salbutamol) delay labour 10- 10, 15 and has advantages of oral administration and relatively low cost. Several randomized, controlled trials have compared the efficacy of calcium channel blockers, usually nifedipine and betamimetics. Although most trials had important methodological limitations, and conclusions varied regarding effectiveness (most reporting similar tocolysis 16- 21, 6, 21- 24. 22, all reported a better side effect profile with nifedipine with fewer women requiring cessation of therapy due to adverse events 20 and some suggesting the superiority of nifedipine 13, 14. Many centres use nifedipine, which also has established effectiveness in delaying labour 12, but their use has been limited by a high incidence of maternal adverse effects

Despite this evidence, sponsors have not sought regulatory approval for nifedipine as a tocolytic agent in many countries; its use is therefore off-label. Furthermore, hesitations about its use arise from reports of maternal hypotension 25 and concerns about placental perfusion 26. Finally, some have suggested that as calcium channel blockers are not licensed for tocolysis, under-reporting of adverse events may be occurring 8.

In the face of the current situation in which terbutaline remains the most common tocolytic used in many low- and middle-income and some high-income (e.g. Germany) countries and nifedipine is only being used off-label, we considered that an additional randomized trial comparing the efficacy of nifedipine with terbutaline on tocolytic and on maternal and neonatal outcome could help to inform optimal management of preterm labour.

Methods

The protocol for this trial and a CONSORT checklist are available as supporting information; see Data S1.

Ethics statement

This study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol and its amendments received independent ethics committee or institutional review board approval before site initiation and recruitment of patients. The protocol was approved by the Ethics Committee at University of Sorocaba (#2010-20), and the study protocol was registered in Platforms Brazil.

Participants

Eligible participants were Brazilian women aged 18-40 years, with singleton pregnancies, presenting to the labour ward with all of the following: at least four painful and regular uterine contractions in each 20-min. interval, cervical dilatation of 0-3 cm (for nulliparous) or 1-3 cm (for multiparae), cervical effacement of ≥50%, 24-33⁺⁶ weeks of gestation and intact membranes who were diagnosed as threatened preterm labour. Gestational age was confirmed by either a documented first-trimester ultrasound scan or a reliable menstrual date confirmed by ultrasonography performed before 20 weeks of gestation 27.

Exclusion criteria were maternal comorbidity including bronchial asthma, diabetes mellitus, cardiovascular diseases, severe anaemia, pregnancy-induced hypertension (>140/90 mmHg) and hypotension (<80/50 mmHg); complications at delivery (no reassuring foetal heart rate tracing, severe pre-eclampsia, placental abruption, antepartum haemorrhage, fever above 38°C); foetal complications (congenital anomaly, hydramnios and chorioamnionitis and intrauterine growth retardation < fifth percentile); contra-indication to the use of betamimetic or calcium blocker agents; previous treatment with tocolytics in current pregnancy; and refusal to give informed consent.

Study design

The trial was performed in three centres in Brazil between August 2010 and March 2012. Consecutive patients meeting eligibility criteria were randomized in a 1:1 ratio to oral nifedipine or intravenous terbutaline. At each centre, a pharmacist investigator created a computer-generated randomization schedule and, after confirming eligibility for each participant, informed the attending physician regarding allocation to terbutaline or nifedipine, thus ensuring concealment of allocation (those enrolling patients were unaware of the arm to which the patient would be allocated). The doctors and nurses were not blind to allocation. Data were collected by a physician in training, and outcome were adjudicated by one of two physicians blind to group assignment.

Intervention

The participants received terbutaline or nifedipine as follows:

1. Terbutaline (ampoule 0.5 mg/mL): intravenous infusion of 2.5 μg/min. followed by an increase of 2.5 μg/min. every 15 min. to a maximum of 20 μg/min. When the minimum dose capable of stopping contractions was established, this infusion was maintained for 24 hr. After 24 hr of drug administration, the dose was decreased by 2.5 μg/min. every 15 min. until full discontinuation 28.

2. Nifedipine (tablet 20 mg) given orally. If contractions did not cease after 30 min., a second dose was given. Once tocolysis was achieved, nifedipine 20 mg orally was administered every 8 hr for a period of 48 hr. The total dose administered during 48 hr was 120 mg.

Uterine contractions were monitored continuously by an external tocodynamometer for 2-4 hr after initiation of the study drug followed by two to three times a day for 30-60 min.

Tocolytic drugs were discontinued in the face of progression to a cervical dilatation of 4 cm or more or rupture of membranes, no decrease in contractions after 12 hr, or if there was a suspicion of chorioamnionitis. Recurrence of preterm labour during the first 48 hr after effective tocolysis was treated with the same agent as the initial tocolysis. Other tocolytic agents were not permitted concomitantly unless, after at least 1 hr of observation during treatment, there was an increase or no change in the frequency of the contractions, or an increase in cervical dilatation of 1 cm or more.

All patients were monitored throughout the intervention for haemodynamic and metabolic changes. Continuous cardiotocography was used to monitor foetal heart rate patterns. For both groups, monitoring of heart rate, blood pressure and contractions were monitored every 15 min. for the first hour, hourly for the next 24 hr, every 6 hr during the next 48 hr and thereafter daily when uterine quiescence had been achieved.

Prophylactic antibiotics for group B streptococcus and corticosteroids were administered according to standard clinical indications.

Outcome measures

The effectiveness outcome of interest were failure of tocolysis (continued uterine contractions 12 hr after drug initial administration or cervical dilatation to >4 cm); delivery prior to 48 hr from the initiation of contractions; delivery before 34 and 37 weeks' gestation; the interval between trial entry and delivery; and gestational age at delivery using the capurro method 29.

The outcome of interest related to adverse events were severe maternal adverse drug reactions, maternal less serious adverse events and discontinuation of treatment because of adverse events.

The neonatal outcome of interest were perinatal death or admission to neonatal intensive care unit, birth weight, Apgar score at 1 and 5 min., respiratory distress syndrome, need for oxygen, intubation, intraventricular or intracranial haemorrhage, necrotizing enterocolitis, retinopathy of prematurity, neonatal jaundice, neonatal sepsis, foetal death, neonatal death, length of stay in the neonatal intensive care unit blood pressure (hypertension ≥90/140 mmHg or hypotension ≤50/80 mmHg) and foetal tachycardia or bradycardia.

Outcome ascertainment was complete, and no patients were lost to follow-up.

Statistical analysis

We present patient characteristics using the arithmetic mean, standard deviation, median, minimum and maximum values, and frequencies as appropriate. The analyses were intention-to-treat. For conducting parametric tests of outcome, we confirmed data normality and homogeneity of variances, using histograms and the Levene test, respectively. We used the Student's t-test for independent samples when these assumptions were met, and otherwise used the Mann-Whitney U-test. We calculated risk ratios (RR) and associated 95% confidence intervals (95% CI). The criterion for statistical significance in all analyses was <5%. Data were analysed using the SPSS statistical feature, version 15.0 for Windows (Statistical Package for the Social Sciences, SPSS, Chicago, Illinois, USA), and Biostat V5, Analystsoftware, Sao Paulo, Brazil.

Results

Of 663 women presenting with preterm labour, 597 failed to meet eligibility criteria (fig. 1). Of the remaining 66, 34 were randomized to terbutaline and 32 to nifedipine (fig. 1). Baseline demographic and obstetric characteristics were similar in the two groups (table 1).

General characteristics of patients

Terbutaline (n = 34)

Nifedipine (n = 32)

Race n (%)

SBD, systolic blood pressor; DBP, diastolic blood pressure, bpm: beat per minute.

Values are mean ± S.D.

Effectiveness outcome

Table 2 presents comparisons of the effect of terbutaline versus nifedipine on outcome related to tocolysis. Tocolytic drugs were discontinued in three patients in the terbutaline group (two because of progression to a cervical dilatation of >4 cm and one because of rupture membranes) and in three patients in the nifedipine group (one because of progression to a cervical dilatation of >4 cm and two because of rupture membranes). Time of tocoloysis in the terbutaline group (2.45 ± 1.67) was not different from the nifedipine group (2.78 ± 2.1); mean difference - 0.35 (95% CI −1.21 to 0.52, p = 0.2). Other results were also similar in the two groups, with generally good outcome for most of the women; we found no statistically significant differences. The confidence intervals around most estimates were, however, very wide.

Parameters of effectiveness

Terbutaline (n = 34)

Nifedipine (n = 32)

RR (95% CI)

p

RR, relative risk; CI 95%, confidence interval 95%.

Adverse effect associated with tocolytic therapy

We observed no serious adverse effects. No women in either group required cessation of therapy due to adverse events. Table 3 presents the pattern of less serious adverse effects. Flushing and headache were both frequent and occurred more often after the administration of nifedipine. The administration of terbutaline, however, increased the risk of other side effects, including tremor, nausea and dizziness. Most women in both groups experienced at least one adverse effect (94.1% terbutaline versus 71.9% nifedipine); more women in the terbutaline group experienced two or more side effects (84.8% terbutaline versus 33.3% nifedipine); and the total number of adverse effects was higher in the terbutaline group (78 events in terbutaline versus 35 in nifedipine).

Adverse effects

Terbutaline n = 34 (%)

Nifedipine n = 32 (%)

RR (CI 95%)

p-Value

32 (94.1)

23 (71.9)

1.39 (1.10-1.76)

0.01

RR, relative risk; CI 95%, confidence interval of 95%.

AE adverse effects.

Two hypotensive events that occurred with the use of nifedipine were controlled with the administration of volume (sodium chloride 9%) and placing the patient in the left lateral decubitus position.

Table 4 presents the impact of the two agents on foetal outcome. Outcome were similar between groups. No foetus experienced either bradycardia or tachycardia.

Neonatal outcome

Terbutaline n = 34 (%)

Nifedipine n = 32 (%)

RR or Mean difference (CI 95%)

p-Value

Neonatal sepsis

2 (5.8)

1 (3.1)

1.83 (0.17 to 19.30)

0.61 ⁶

RR, relative risk; CI 95%, confidence interval 95%.

Discussion

We found no significant differences between terbutaline and nifedipine and concerning effective tocolysis, the recurrence of preterm labour in the first 48 hr and the time of delivery (table 2). We observed no serious adverse effects in either treatment arm. The proportion of patients who experienced one or more less serious adverse effects during tocolytic therapy was greater in women who received terbutaline than in those who received nifedipine (table 3). Women who received terbutaline significantly more frequently developed tremors, nausea and dizziness (table 3). Headache and flushing, however, occurred significantly more frequently with nifedipine (table 3), and the only two important hypotensive events occurred in the nifedipine group.

Neonatal adverse outcome were similar in the two groups (table 4). Despite both agents proving effective in prolonging preterm labour up to 48 hr, allowing enough time for the administrations of corticosteroid and pulmonary maturation, and despite most deliveries occurring after 34 weeks of pregnancy, the number of newborn babies developed respiratory distress syndrome was still high in both groups (35.2% in terbutaline, 31.2% in nifedipine).

Strengths and weaknesses of this study

Strengths of this study include the careful confirmation of preterm labour 7, 27; the low risk of bias (concealed randomization, blinding of outcome assessment, no loss to follow-up, analyse as randomized); and the rigorous and comprehensive collection of data relevant to the efficacy of tocolysis, adverse effects on the mothers and neonatal outcome.

The trial's primary limitation is its small sample size and the resulting wide confidence intervals. Another limitation is that we did not follow infants beyond discharge from hospital. A third limitation is the relatively small number of women presenting with premature labour who proved eligible for this study. Unfortunately, the incidence of potential contra-indications to tocolytic therapy, in particular foetal and maternal abnormalities and complications, are frequent in women presenting in premature labour. For example, in another study of tocolytic therapy, of 566 potentially eligible women, only 64 proved eligible and were included 30.

Relation to previous work

The most compelling summary of results of previous trials thus far comes from a network meta-analysis examining all the randomized trials of all agents used for tocolysis 6. This meta-analysis found that, in comparison with terbutaline, calcium channel blockers have a higher probability of achieving delay in delivery beyond 48 hr. Our failure to replicate this finding may well be a result of our small sample size; the confidence interval includes the benefit of nifedipine seen in the meta-analysis. Two previous meta-analyses have suggested nifedipine is superior to terbutaline in terms of prevention of neonatal adverse events, although they failed to show a difference in these events between nifedipine and placebo 22, 6 failed to find differences in respiratory distress between agents. If there is indeed a difference between neonatal adverse events between the two agents, the small sample size in our study could once again be an explanation for our failure to detect the difference. 24 while the network meta-analysis

Our findings regarding adverse effects with terbutaline (in particular tremors and nausea) are similar to those reported in previous meta-analyses by Tsatsaris et al. 24 and King et al. 15 However, these authors also report a higher frequency of tachycardia, palpitations and chest pain, which our patients did not experience. Previous trials also reported treatment discontinuation because of side effects with terbutaline from 6% to 38%, whereas terbutaline adverse effects in our trial did not require discontinuation in any patient 31. In our trial, the dose of terbutaline was adjusted to a safe range according to guidance from Klasco 28, 33, 34. This may explain both our failure to observe either cardiovascular adverse events or the necessity to discontinue terbutaline because of adverse effects. 32; our doses were lower than in previous trials of this agent

We observed no serious adverse effects with terbutaline. This result is consistent with data suggesting that adverse effects are rare: acute pulmonary oedema, estimated from 1:350 to 1:400, which may result in the mother's death. Over 25 deaths related to the administration of terbutaline in order to inhibit preterm labour have been reported 24. Due to the risks involved, the FDA has warned about the use of this drug as a tocolytic agent 35.

We observed more frequent headaches with nifedipine than terbutaline, presumably secondary to nifedipine's vasodilatory effects 36- 10, 2, 42, 26. Considering possible under-reporting of adverse effects, authors recommend precaution, particularly in women with cardiovascular morbidity 2, 44, 45. 43, which causes concern about placental perfusion, excessive hypotension, myocardial infarction and heart failure. Two women receiving nifedipine in our study became hypotensive. In many countries, these considerations led to the withdrawal from the market of nifedipine's quick release presentation 21, 22, 31, 41 have reported that nifedipine generates fewer total adverse events than terbutaline, a finding that our study confirmed. On the other hand, anti-hypertensive drugs - as in the case of nifedipine - may produce maternal hypotension 39, 40. Overall, however, previous evidence summaries 38, a result consistent with previous studies

Implications for future research

Given nifedipine's toxicity advantages, such a study might appropriately use a non-inferiority design to ensure that an important outcome, such as failure to achieve tocolysis within 12 hr, was not appreciably higher with nifedipine than terbutaline. Given the rate of failure of tocolysis in the terbutaline group of approximately 9%, and assuming conventional values of type 1 and type 2 error, one would require 2547, 1140 and 647 participants per group to definitively demonstrate that nifedipine did not increase the frequency of failure of tocolysis in 12 hr by, respectively, 2%, 3% or 4%.

Conclusion

The results of this study support previous evidence suggesting that nifedipine is as effective as terbutaline in its impact on tocolysis and neonatal outcome with fewer maternal and foetal adverse effects. The oral administration of nifedipine, as well as its low cost (it does not involve skilled technicians for the administration and does not require parenteral application), further recommends the treatment.

Acknowledgements

Elton Luis Faggioni Trani and Victor Simezo for adjudications outcomes. No funding was received for this project.

Disclosure

The authors declare no conflict of interest.

Author contributions

All authors participated in the preparation of the manuscript and agreed to the submitted version of the paper. Tania Padovani and Luciane Lopes involved in the study concept and design. Tania Padovani participated in acquisition of data. Gordon Guyatt and Luciane Lopes analysed and interpreted the data. Gordon and Luciane Lopes drafted the manuscript. Tania Padovani, Luciane Lopes and Gordon Guyatt critically revised the manuscript for important intellectual content.

# data[].attributes.attachment_link.title
Nifedipine versus Terbutaline, Tocolytic Effectiveness and Maternal and Neonatal Adverse Effects: A Randomized, Controlled Pilot Trial

# data[].attributes.attachment_link.description
Tania Regina Padovani , Gordon Guyatt , Luciane Cruz Lopes , Corresponding Author Luciane Cruz Lopes Pharmaceutical Sciences Post graduate Course, University of Sorocaba, UNISO, Sorocaba, Brazil Author for correspondence: Luciane Cruz Lopes, Pharmaceutical Sciences Post graduate Course, University of Sorocaba, UNISO, Rodovia Raposo Tavares, KM 92,5 Sorocaba, SP, Brasil CEP 18023-000, Brazil (e-mail luslopes@terra.com.br ).

# data[].attributes.body
TÍTULO: Un ensayo clínico a largo plazo sobre el perfil de eficacia y seguridad de la doxofilina en el asma: el estudio LESDA
AÑO Y TIPO DE ESTUDIO: 2020 -ECA
RESULTADOS: Los EA más notificados
fueron náuseas (14,56%), dolor de cabeza (14,24%), insomnio (10,68%) y dispepsia (10,03%) y fueron de gravedad leve o moderada y, en general, bien tolerados.
Los EA fueron algunos de los motivos del retiro del estudio del 17,48% de los pacientes. Los EA que con mayor frecuencia llevaron a la interrupción del tratamiento fueron náuseas, dolor de cabeza e insomnio, y por lo general ocurrieron durante el primer mes de tratamiento. Ningún sujeto experimentó EA graves. Ningún sujeto murió durante o poco
después de finalizar el estudio.
CONCLUSIÓN: La doxofilina (metilxantina) es bien tolerada cuando se administra de forma crónica a pacientes con asma mal controlada.

# data[].attributes.attachment_link.title
A long-term clinical trial on the efficacy and safety profile of doxofylline in Asthma: The LESDA study - PubMed

# data[].attributes.attachment_link.description
Doxofylline, an oral methylxanthine with bronchodilator and anti-inflammatory activities, offers a promising alternative to theophylline due to its superior efficacy/safety profile. No long-term studies on the efficacy and safety of doxofylline are currently available in asthma. The aim of the Long-…

# data[].attributes.body
https://bmjopen.bmj.com/content/4/5/e004587.short
Titulo: Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis.
Año: 2014
Autor: Narum S., et al.
Tipo de Estudio: Meta-análisis
Objetivo: Evaluar si los corticosteroides se asocian con un mayor riesgo de hemorragia gastrointestinal o perforación.
Resultados: Se incluyeron 159 estudios (N=33 253). En total, 804 (2,4%) pacientes tuvieron una hemorragia o perforación gastrointestinal (2,9% y 2,0% para corticosteroides y placebo). Los corticosteroides aumentaron el riesgo de hemorragia gastrointestinal o perforación en un 40% (OR 1,43; IC del 95%: 1,22 a 1,66). El riesgo aumentó para los pacientes hospitalizados (OR 1,42; IC del 95%: 1,22 a 1,66). Para los pacientes en atención ambulatoria, el aumento del riesgo no fue estadísticamente significativo (OR 1,63; IC del 95%: 0,42 a 6,34). Sólo se produjeron 11 hemorragias o perforaciones gastrointestinales entre 8651 pacientes en atención ambulatoria (0,13%).
Conclusion: El uso de corticosteroides se asoció con un mayor riesgo de hemorragia gastrointestinal y perforación. El aumento del riesgo fue estadísticamente significativo solo para los pacientes hospitalizados. Para los pacientes en atención ambulatoria, la incidencia total de sangrado o perforación fue muy baja, y el aumento del riesgo no fue estadísticamente significativo.

# data[].attributes.attachment_link.title
Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis

# data[].attributes.attachment_link.description
Objective To assess whether corticosteroids are associated with increased risk of gastrointestinal bleeding or perforation. Design Systematic review and meta-analysis of randomised, double-blind, controlled trials comparing a corticosteroid to placebo for any medical condition or in healthy partici…

# data[].attributes.body
TITULO: Seguridad y efectos adversos de los corticosteroides inhalados en pacientes con asma.
AÑO: 2018
TIPO DE ESTUDIO: Revisión sistemática
OBJETIVO:  resumir la evidencia
con respecto a los principales efectos adversos de los CSI, particularmente en asmáticos y aquellos con el espectro más severo de la enfermedad.
CONCLUSIONES: El uso de Glucortiesteroides inhalatorios en niños y adultos con el asma se asocia con posibles efectos adversos. Los niños y adultos con asma grave tienen mayor riesgo de sufrir efectos adversos y el riesgo aumenta con la dosis administrada; esta es la razón por
muchos asmáticos graves pueden experimentar varios efectos adversos dañinos y efectos que afectan negativamente a su calidad de vida.

# data[].attributes.attachment_link.readable_text
Asthma is a common inflammatory airway disease for which the most commonly used controller medications are inhaled corticosteroids (ICS). Asthma control is difficult to achieve in individuals with severe asthma, which comprise 5% to 10% of individuals with asthma, even with high doses of ICS and other anti-inflammatory drugs. In this clinical context, the adverse effects of ICS (including hypothalamic-pituitary-adrenal axis suppression, reduction in growth velocity, osteoporosis, diabetes, and respiratory infections) become more probable and impacting on the quality of life of severe asthmatics. We here summarize the evidence of ICS-related adverse effects, particularly in patients with asthma. The possibility of using biologic agents earlier for severe asthma has the potential to prevent or reduce the occurrence of corticosteroid-related adverse effects, and also reduce corticosteroid-related costs.

View full text

# data[].attributes.attachment_link.title
Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma

# data[].attributes.attachment_link.description
Asthma is a common inflammatory airway disease for which the most commonly used controller medications are inhaled corticosteroids (ICS). Asthma control is difficult to achieve in individuals with severe asthma, which comprise 5% to 10% of individuals with asthma, even with high doses of ICS and other anti-inflammatory drugs.

# data[].attributes.body
Título: Análisis combinado de ensayos de seguridad para el asma de agonistas β2 de acción prolongada
Año: 2018
Tipo de estudio: Ensayo Clínico Aleatorizado
Resultados: Entre los 36.010 pacientes del estudio por intención de tratar, hubo tres intubaciones relacionadas con el asma (dos en el grupo de glucocorticoides inhalados y una en el grupo de terapia combinada) y dos muertes relacionadas con el asma (ambas en el grupo de terapia combinada)
Conclusiones: La terapia combinada con un agonista adrenérgico de acción larga más un glucocorticoide inhalado no resultó en un riesgo significativamente mayor de eventos graves relacionados con el asma que el tratamiento con un glucocorticoide inhalado solo

# data[].attributes.attachment_link.readable_text
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# data[].attributes.body
TITULO: Una revisión sistemática de los eventos adversos asociados con la administración de medicamentos comunes para el asma en niños.

TIPO DE ESTUDIO: revisión sistémica de ECA AÑO: 2017

Resultados: Se incluyeron 46 estudios: 24 ECA, 15 de cohorte, 4 análisis combinados de ECA, 1 de casos y controles, 1 ensayo de etiqueta abierta y 1 estudio cuasiexperimental. Los estudios examinaron las siguientes clases de fármacos: corticosteroides inhalados (ICS) (n = 24), beta-agonistas de acción corta (n = 10), beta-agonistas de acción prolongada (LABA) (n = 3), ICS + LABA (n = 3), antagonistas de los receptores de leucotrienos (n = 3) y otros (n = 3). Se realizaron 29 estudios en América del Norte y 29 fueron financiados por la industria. Presentamos un índice detallado de 406 descripciones y frecuencias de ADE organizadas por clase de fármaco. La mayoría de los datos se centran en los ICS, con 174 ADE que afectan a 13 sistemas de órganos, incluida la supresión del crecimiento y las suprarrenales. Observamos EAF graves, aunque raros, con una frecuencia que oscilaba entre el 0,9% y el 6% por fármaco. No hubo muertes confirmadas, excepto por 13 muertes potenciales en un estudio LABA que incluyó a participantes adultos y pediátricos combinados. Identificamos preocupaciones metodológicas sustanciales, particularmente con la identificación de ADE y la determinación de la gravedad. Ningún estudio utilizó evaluaciones estandarizadas disponibles de causalidad, gravedad o prevención.

Conclusiones: La mayoría de los estudios se centran en los CSI, y se describe la supresión del crecimiento y las suprarrenales. Los EA graves son relativamente poco frecuentes, sin muertes pediátricas confirmadas. Identificamos preocupaciones metodológicas sustanciales, destacando la necesidad de estandarización con investigaciones futuras que examinen la seguridad de los medicamentos pediátricos para el asma.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182738

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TITULO:

Perfil de eficacia y seguridad de la doxofilina en comparación con la teofilina en el asma: un metanálisis

TIPO DE ESTUDIO: metanálisis
AÑO: 2019
RESULTADOS: Los datos obtenidos de 696 pacientes asmáticos se extrajeron de 4 ensayos controlados aleatorios publicados entre 2015 y 2018. La doxofilina fue significativamente ( P <0,05) más eficaz que la teofilina para reducir los episodios de asma diarios (diferencia media - 0,14, IC del 95%: -0,27 - 0,00 ) y riesgo de EA (riesgo relativo 0,76; IC del 95%: 0,59-0,99). La doxofilina fue tan eficaz como la teofilina para mejorar el FEV ₁ , y  se detectó una tendencia de superioridad ( P = 0,058) para la doxofilina sobre la teofilina con respecto a la reducción en el uso de salbutamol como medicación de rescate. El rango de efectividad fue doxofilina> teofilina>> placebo, y el rango de seguridad fue placebo> doxofilina>> teofilina.
CONCLUSIÓN:
La doxofilina es una metilxantina eficaz y segura para el tratamiento del asma, con un perfil de eficacia / seguridad superior al de la teofilina.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679461/

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Efficacy and safety profile of doxofylline compared to theophylline in asthma: a meta-analysis

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Oral methylxanthines are effective drugs for the treatment of chronic obstructive respiratory disorders. The novel methylxanthine doxofylline, that has bronchodilator and anti-inflammatory activities, is not affected by the major drawback of theophylline. ...

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TÍTULO: Eficacia y seguridad de la budesonida administrada mediante inhalador de dosis medida presurizado en niños con asma

AÑO: 2015
TIPO DE ESTUDIO: Estudio de fase 2 multicéntrico doble ciego
RESULTADOS: El número de pacientes que experimentaron eventos adversos y suspensiones fue menor en el grupo de budesonida que en el grupo de placebo. No hubo eventos graves reportados.
CONCLUSIÓN: La budesonida a 160 μg dos veces al día a través de un inhalador de dosis medida presurizado fue generalmente bien tolerada y mejoró significativamente la función pulmonar, los síntomas, el uso de medicación de rescate y los despertares nocturnos en comparación con el placebo en niños de 6 a menos de 12 años con asma y una necesidad demostrada de corticosteroides inhalados.

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Affiliations

¹ Allergy and Asthma Medical Group and Research Center, San Diego, California. Electronic address: eliomeltzer@gmail.com.

² Colorado Allergy & Asthma Centers, Denver, Colorado.

³ AstraZeneca, Mölndal, Sweden.

⁴ T-STAT, LLC Statistical Consulting and Contracting, Downingtown, Pennsylvania.

⁵ AstraZeneca LP, Wilmington, Delaware.

Free article

Free article

Affiliations

¹ Allergy and Asthma Medical Group and Research Center, San Diego, California. Electronic address: eliomeltzer@gmail.com.

² Colorado Allergy & Asthma Centers, Denver, Colorado.

³ AstraZeneca, Mölndal, Sweden.

⁴ T-STAT, LLC Statistical Consulting and Contracting, Downingtown, Pennsylvania.

⁵ AstraZeneca LP, Wilmington, Delaware.

Abstract

Background: Budesonide is approved for delivery using a nebulized solution and dry-powder inhaler, but its use through a pressurized metered-dose inhaler (pMDI) in pediatric patients with asthma has not been determined.

Objective: To examine the efficacy and safety of 160 μg twice daily of budesonide through a pMDI vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.

Methods: A 6-week, international, multicenter, double-blinded, parallel-group, phase 2 study randomized 304 pediatric patients (mean age, 9 years; 21.7% <8 years) 1:1 to 160 μg (80 μg × 2 inhalations) twice daily of budesonide through a pMDI or placebo after a 7- to 21-day run-in period. The primary efficacy end point was change from baseline in morning peak expiratory flow (PEF); safety end points included adverse events, vital signs, and discontinuations.

Results: Budesonide treatment significantly improved morning PEF vs placebo; mean treatment effect (budesonide vs placebo) was 13.6 L/min (P < .0001). Budesonide also showed significant improvements vs placebo for forced expiratory volume in 1 second, evening PEF, forced expiratory flow at 25% to 75% of pulmonary volume, reliever medication use, nighttime awakenings, awakenings with reliever use, and percentage of patients with at least 15- and at least 30-L/min increase in morning PEF from baseline. The numbers of patients experiencing adverse events and discontinuations were smaller in the budesonide than in the placebo group. No serious adverse events were reported.

Conclusion: Budesonide at 160 μg twice daily through a pMDI was generally well tolerated and significantly improved lung function, symptoms, rescue medication use, and nighttime awakenings vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.

Trial registration: ClinicalTrials.gov NCT01136382.

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bronchodilator agents / administration & dosage*

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national center for biotechnology information

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Efficacy and safety of budesonide administered by pressurized metered-dose inhaler in children with asthma - PubMed

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Budesonide at 160 μg twice daily through a pMDI was generally well tolerated and significantly improved lung function, symptoms, rescue medication use, and nighttime awakenings vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.

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Titulo: Corticosteroides administrados por vía intranasal y alteraciones neuropsiquiátricas: una revisión del programa internacional de farmacovigilancia de la Organización Mundial de la Salud.
Tipo de Estudio: Metanalisis
Año:2008
Resultados: Se recibieron un total de 429 notificaciones de 16 países (1980-abril de 2006), de eventos neuropsiquiátricos ocurridos en pacientes que utilizan INC, lo que representa el 7,6% del total de notificaciones sobre estos fármacos en el mismo período. Los eventos notificados con frecuencia fueron nerviosismo, ansiedad, agitación, insomnio, labilidad emocional, depresión, somnolencia, confusión, convulsiones y migraña. La mayoría de los informes se referían a propionato de fluticasona, dipropionato de beclometasona, furoato de mometasona o budesonida. En 370 informes (86,2%), el INC fue la única droga sospechosa y en 220 (51,3%) fue la única droga utilizada. En 97 de 108 pacientes que habían interrumpido el uso del corticosteroide intranasal, la reacción disminuyó. De 41 pacientes, 32 tuvieron una recaída cuando se reintrodujo el fármaco.
Conclusiones: Los datos recopilados por el Programa Internacional de Farmacovigilancia sugieren que el uso intranasal de corticosteroides puede complicarse por reacciones adversas neuropsiquiátricas. Se necesitan más estudios para confirmar la conexión y determinar la frecuencia y los factores de riesgo de tales reacciones.

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doi: 10.1016/S1081-1206(10)60837-X.

Affiliation

¹ Department of Social and Clinical Pharmacy, Faculty of Pharmacy, Charles University in Prague, Hradec Kralove, Czech Republic. jitka.pokladnikova@faf.cuni.cz

doi: 10.1016/S1081-1206(10)60837-X.

Affiliation

¹ Department of Social and Clinical Pharmacy, Faculty of Pharmacy, Charles University in Prague, Hradec Kralove, Czech Republic. jitka.pokladnikova@faf.cuni.cz

Abstract

Background: The systemic use of corticosteroids is connected with a variety of psychiatric and neurologic effects. Corticosteroids for intranasal administration (INCs) are considered to act locally and to exert minimal systemic effects. An unexpected cluster of case reports of neuropsychiatric disorders during intranasal corticosteroid use was reported to the World Health Organization Uppsala Monitoring Centre.

Objective: To investigate the possible connection between intranasal corticosteroid use and the development of neuropsychiatric disorders, as reported to the International Pharmacovigilance Programme.

Methods: All reports containing adverse event terms indicating neuropsychiatric disturbances in suspected connection with intranasal corticosteroids were retrieved from Vigibase and evaluated (April 2006). The case reports are heterogeneous and vary regarding source, documentation quality, and relationship likelihood.

Results: A total of 429 reports were received from 16 countries (1980-April 2006), of neuropsychiatric events occurring in patients using INCs, representing 7.6% of the total of reports regarding these drugs in the same period. Frequently reported events were nervousness, anxiety, agitation, insomnia, emotional lability, depression, somnolence, confusion, convulsions, and migraine. Most reports concerned fluticasone propionate, beclometasone dipropionate, mometasone furoate, or budesonide. In 370 reports (86.2%), the INC was the sole suspect drug and in 220 (51.3%) it was the only drug used. In 97 of 108 patients who had discontinued use of the intranasal corticosteroid, the reaction abated. Of 41 patients, 32 had a relapse when the drug was reintroduced.

Conclusions: The data collected by the International Pharmacovigilance Programme suggest that the intranasal use of corticosteroids can be complicated by neuropsychiatric adverse reactions. Further study is needed to confirm the connection and to determine the frequency and risk factors of such reactions.

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adrenal cortex hormones / administration & dosage*

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adrenal cortex hormones / adverse effects*

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nervous system diseases / chemically induced*

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national center for biotechnology information

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Intranasally administered corticosteroids and neuropsychiatric disturbances: a review of the international pharmacovigilance programme of the World Health Organization - PubMed

# data[].attributes.attachment_link.description
The data collected by the International Pharmacovigilance Programme suggest that the intranasal use of corticosteroids can be complicated by neuropsychiatric adverse reactions. Further study is needed to confirm the connection and to determine the frequency and risk factors of such reactions.

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TITULO: Seguridad y eficacia de dupilumab en el asma no controlada: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados.
AÑO: 2019
TIPO DE ESTUDIO: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados.
RESULTADOS: Se incluyeron un total de cuatro ECA (2.992 pacientes), se mostró reducciones significativas de la tasa anualizada de exacerbación del asma grave en el grupo de dupilumab en comparación con placebo (RR 0,44; IC del 95%: 0,35 a 0,055; P <0,01; I2 = 42%). Además, los cambios en el volumen espiratorio forzado absoluto a 1 s (FEV1), se aumentaron significativamente para el grupo de dupilumab (DM 0,14; IC del 95%: 0,12–0,17; P <0,01; I2 = 0%). Finalmente, no hubo diferencias significativas entre ambos grupos en el desarrollo de cualquier evento adverso, eventos adversos graves, eventos adversos que llevaron a la muerte, suspensión de la medicación por evento adverso o la aparición de infecciones del tracto respiratorio superior, influenza o bronquitis. Sin embargo, dupilumab se asoció con un mayor riesgo de reacciones en el lugar de la inyección en comparación con placebo (RR 1,91; IC del 95% 1,41, 2,59; P <0,01; I2 = 24%).
CONCLUSION: entre los pacientes con asma no controlada, la adición de dupilumab se asoció con un riesgo reducido de exacerbaciones graves del asma y una mejoría en el FEV1 sin un mayor riesgo de eventos adversos aparte de las reacciones en el lugar de la inyección con dupilumab.

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Abstract
Objective: We aimed to perform a meta-analysis evaluating the efficacy and safety of dupilumab in patients with uncontrolled asthma. Data source: A search of electronic databases was performed using PubMed, Cochrane library and Embase. Study selection: The literature search was conducted independently by two reviewers. Only randomized controlled trials (RCTs) that compared between placebo and dupilumab in patients with uncontrolled asthma were included in this analysis. Pooled risk ratios (RRs) and mean differences (MDs) with their corresponding 95% confidence intervals (CIs) were calculated for dichotomous and continuous data, respectively. Results: A total of four RCTs representing 2,992 patients were included. Pooled analysis showed significant reductions of the annualized rate of severe asthma exacerbation in the dupilumab group compared with placebo (RR 0.44; 95% CI 0.35-0.055; P < 0.01; I2 = 42%). In addition, the absolute forced expiratory volume at 1 s (FEV1) changes were significantly increased for the dupilumab group (MD 0.14; 95% CI: 0.12-0.17; P < 0.01; I2 = 0%). Finally, there were no significant differences between both groups in the development of any adverse event, serious adverse events, adverse events leading to death, discontinuation of medication due to adverse event or the occurrence of upper respiratory tract, influenza or bronchitis infections. However, dupilumab was associated with an increased risk of injection site reactions compared with placebo (RR 1.91; 95% CI 1.41, 2.59; P < 0.01; I2 = 24%). Conclusion: Among patients with uncontrolled asthma, the addition of dupilumab was associated with a reduced risk of severe asthma exacerbations and improvement in FEV1 without an increased risk of adverse events apart from injection site reactions with dupilumab.

Disclosure statement

No conflicts of interests.

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Dupilumab safety and efficacy in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials

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Abstract Objective: We aimed to perform a meta-analysis evaluating the efficacy and safety of dupilumab in patients with uncontrolled asthma. Data source: A search of electronic databases was performed using PubMed, Cochrane library and Embase. Study selection: The literature search was conducted independently by two reviewers.

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TÍTULO:  Reacciones adversas por salbutamol en pacientes asmáticos: reflexiones acerca del uso en las exacerbaciones.
TIPO DE ESTUDIO: Artículo de revisión
AÑO:2021
CONCLUSIONES: Salbutamol presenta un buen perfil de seguridad, de leve a moderada; siendo una buena opción para tratar el asma.

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https://pubmed.ncbi.nlm.nih.gov/31884206/
TÍTULO: Un ensayo clínico a largo plazo sobre el perfil de eficacia y seguridad de la doxofilina en el asma: el estudio LESDA

TIPO DE ESTUDIO: Artículo de revisión
AÑO:2020
CONCLUSIONES: La doxofilina mejorA significativamente la tasa de eventos de asma (eventos / día: -0,57 ± 0,18, P <0,05 frente al valor inicial) y el uso de salbutamol como medicación de rescate (inhalaciones / día: -1,48 ± 0,25, P <0,01 frente al valor inicial ).

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A long-term clinical trial on the efficacy and safety profile of doxofylline in Asthma: The LESDA study - PubMed

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Doxofylline, an oral methylxanthine with bronchodilator and anti-inflammatory activities, offers a promising alternative to theophylline due to its superior efficacy/safety profile. No long-term studies on the efficacy and safety of doxofylline are currently available in asthma. The aim of the Long-…