Early bioavailability of inhaled salbutamol reflects lung dose in children.
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ABSTRACT:
SUBMITTER: Bonnelykke K
PROVIDER: S-EPMC2561100 | biostudies-literature | 2008 Oct
REPOSITORIES: biostudies-literature
Publications
Early bioavailability of inhaled salbutamol reflects lung dose in children.
Bønnelykke Klaus K Jespersen Jacob J JJ Bisgaard Hans H
British journal of clinical pharmacology 20080410 4
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Project description:ObjectiveTo compare the effectiveness of inhaled Magnesium Sulfate associated with Salbutamol versus Inhaled Salbutamol alone in patients with moderate and severe asthma exacerbations.MethodClinical, prospective and randomized study with patients between 3 and 14 years of age divided into two groups: one to receive inhaled salbutamol associated with magnesium sulfate (GSM), the other to receive inhaled salbutamol alone (GS). The sample consisted of 40 patients, 20 patients in each group. Severity was classified using the modified Wood-Downes score, with values between 4 and 7 classified as moderate and 8 or more classified as severe.ResultsPost-inhalation scores decreased both in patients who received salbutamol and magnesium and in those who received salbutamol alone, with no statistically significant difference between the groups.ConclusionsDespite the benefits when administered intravenously, inhalation of the drug alone or in combination did not reduce the severity of the exacerbation.
| S-EPMC11361882 | biostudies-literature
Project description:BACKGROUND:Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF). METHODS:The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99mTechnetium-labelled monodisperse salbutamol (1.5 μm or 6 μm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 μg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4). RESULTS:Small monodisperse particles (1.5 μm) achieved significantly better total lung deposition (TLD, mean % ± SD) than larger particles (6 μm), where polydisperse nebulisation was poor; (TLD, 64.93 ± 10.72; 50.46 ± 17.04; 8.19 ± 7.72, respectively). Small monodisperse particles (1.5 μm) achieved significantly better lung penetration (mean % ± SD) than larger particles (6 μm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean ± SD) 0.8 ± 0.16, 0.49 ± 0.21, and 0.73 ± 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 μm and 6 μm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation. CONCLUSION:Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF. TRIAL REGISTRATION:This trial was registered on clinicaltrials.gov ( NCT01457261 ).
| S-EPMC5801831 | biostudies-literature
Project description:This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the ?2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10(-6) and MA 10(-3) M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle.
| S-EPMC3933573 | biostudies-literature
Project description:BackgroundHigh prevalence rates of β2-agonist use among athletes in competitive sports makes it tempting to speculate that illegitimate use of β2-agonists boosts performance. However, data regarding the potential performance-enhancing effects of inhaled β2-agonists and its underlying molecular basis are scarce.MethodsIn total, 24 competitive endurance athletes (12f/12m) participated in a clinical double-blinded balanced four-way block cross-over trial to investigate single versus combined effects of β2-agonists salbutamol (SAL) and formoterol (FOR), to evaluate the potential performance enhancement of SAL (1200 µg, Cyclocaps, Pb Pharma GmbH), FOR (36 µg, Sandoz, HEXAL AG) and SAL + FOR (1200 µg + 36 µg) compared to placebo (PLA, Gelatine capsules containing lactose monohydrate, Pharmacy of the University Hospital Ulm). Measurements included skeletal muscle gene and protein expression, endocrine regulation, urinary/serum β2-agonist concentrations, cardiac markers, cardiopulmonary and lung function testing and the 10-min time trial (TT) performance on a bicycle ergometer as outcome variables. Blood and urine samples were collected pre-, post-, 3 h post- and 24 h post-TT.ResultsMean power output during TT was not different between study arms. Treatment effects regarding lung function (p < 0.001), echocardiographic (left ventricular end-systolic volume p = 0.037; endocardial global longitudinal strain p < 0.001) and metabolic variables (e.g. NR4A2 and ATF3 pathway) were observed without any influence on performance. In female athletes, total serum β2-agonist concentrations for SAL and FOR were higher. Microarray muscle gene analysis showed a treatment effect for target genes in energy metabolism with strongest effect by SAL + FOR (NR4A2; p = 0.001). Of endocrine variables, follicle-stimulating hormone (3 h Post-Post-TT), luteinizing hormone (3 h Post-Pre-TT) and insulin (Post-Pre-TT) concentrations showed a treatment effect (all p < 0.05).ConclusionsNo endurance performance-enhancing effect for SAL, FOR or SAL + FOR within the permitted dosages compared to PLA was found despite an acute effect on lung and cardiac function as well as endocrine and metabolic variables in healthy participants. The impact of combined β2-agonists on performance and sex-specific thresholds on the molecular and cardiac level and their potential long-term performance enhancing or health effects have still to be determined.Trial registrationRegistered at Eudra CT with the number: 2015-005598-19 (09.12.2015) and DRKS with number DRKS00010574 (16.11.2021, retrospectively registered).
| S-EPMC10462601 | biostudies-literature
Project description:Hydrogen sulfide (H2S) has emerged as an important physiological and pathophysiological signaling molecule in the cardiovascular system influencing vascular tone, cytoprotective responses, redox reactions, vascular adaptation, and mitochondrial respiration. However, bioavailable levels of H2S in its various biochemical metabolite forms during clinical cardiovascular disease remain poorly understood. We performed a case-controlled study to quantify and compare the bioavailability of various biochemical forms of H2S in patients with and without cardiovascular disease (CVD). In our study, we used the reverse-phase high performance liquid chromatography monobromobimane assay to analytically measure bioavailable pools of H2S. Single nucleotide polymorphisms (SNPs) were also identified using DNA Pyrosequencing. We found that plasma acid labile sulfide levels were significantly reduced in Caucasian females with CVD compared with those without the disease. Conversely, plasma bound sulfane sulfur levels were significantly reduced in Caucasian males with CVD compared with those without the disease. Surprisingly, gender differences of H2S bioavailability were not observed in African Americans, although H2S bioavailability was significantly lower overall in this ethnic group compared to Caucasians. We also performed SNP analysis of H2S synthesizing enzymes and found a significant increase in cystathionine gamma-lyase (CTH) 1364 G-T allele frequency in patients with CVD compared to controls. Lastly, plasma H2S bioavailability was found to be predictive for cardiovascular disease in Caucasian subjects as determined by receiver operator characteristic analysis. These findings reveal that plasma H2S bioavailability could be considered a biomarker for CVD in an ethnic and gender manner. Cystathionine gamma-lyase 1346 G-T SNP might also contribute to the risk of cardiovascular disease development.
| S-EPMC5975076 | biostudies-literature
Project description:RationaleLow vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control.ObjectivesTo assess the effect of vitamin D levels on prebronchodilator FEV(1), bronchodilator response, and responsiveness to methacholine (PC(20), provocative concentration of methacholine producing a 20% decline in FEV(1)) in patients with asthma treated with inhaled corticosteroids.MethodsWe measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20-30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV(1), bronchodilator response, and PC(20) from enrollment to 8-12 months.Measurements and main resultsOf the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D-deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D-sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV(1) increased from randomization to 12 months by 140 ml in the vitamin D-deficient group and prebronchodilator FEV(1) increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models.ConclusionsIn children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency.
| S-EPMC3480528 | biostudies-literature
Project description:The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children's hospitals included children (2-18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10-13) in the intervention group and 11 (9-12) in the control group (p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups (p = 0.508, β-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 μg/L (IQR 5-24) in the intervention group and 4 μg/L (IQR 0-7) in the control group (p = 0.001). Side effects were comparable between both groups.ConclusionWe found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered.What is known• Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled β2-agonists, and systemic steroids. • During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction.What is new• This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. • This study found no clinically significant side effects from the loading dose.
| S-EPMC9508206 | biostudies-literature
Project description:BackgroundThere are no published studies that have compared bronchodilatory effect of inhaled budesonide/formoterol combination with budesonide/salbutamol delivered by metered dose inhaler with a spacer in acute exacerbation of asthma in children. We, therefore, compared the bronchodilatory effects of inhaled budesonide/formoterol (dose: 200 μg and 12 μg respectively) combination with budesonide (200 μg)/salbutamol (200 μg) administered by metered dose inhaler and spacer in children of 5-15 years with mild acute exacerbation of asthma [Modified Pulmonary Index Score (MPIS) between 6-8] in this double-blind, randomized controlled trial. The primary outcome was FEV1 (% predicted) in the two groups at 1, 5, 15, 30, 60 min after administration of the study drug.ResultsWe did not observe any significant differences in the % predicted FEV1 and MPIS between formoterol and salbutamol at various time points from 1 min to 60 min post drug administration. There was significant improvement in FEV1 (% predicted) from baseline in both the groups as early as 1 min after drug administration.ConclusionsSalbutamol or formoterol delivered along with inhaled corticosteroid by metered dose inhaler with spacer in children between 5-15 years of age with mild acute exacerbation of asthma had similar bronchodilatory effects.Trial registrationClinicalTrials.gov: NCT00900874.
| S-EPMC3324377 | biostudies-literature
Project description:BackgroundSystemic corticosteroid use in acute respiratory failure has yielded uncertain benefits, partially because of off-target side effects. Inhaled corticosteroids (ICSs) confer localized antiinflammatory benefits and may protect adults with direct lung injury (DLI) from developing respiratory failure. To our knowledge, this relationship has not been studied in children.Research questionDo children with DLI who are prescribed ICSs before hospitalization have lower odds of progressing to respiratory failure?Study design and methodsThis retrospective, single-center cohort identified children seeking treatment at the ED with DLI and medication records before hospitalization. The primary outcome was intubation; secondary outcomes included noninvasive respiratory support (NRS). We tested the association of ICSs with intubation and NRS, adjusting for confounders. We stratified analyses on history of asthma and performed a sensitivity analysis adjusting for systemic corticosteroid use to account for status asthmaticus.ResultsOf 35,220 patients, 17,649 patients (50%) were prescribed ICSs. Intubation occurred in 169 patients (73 patients receiving ICSs) and NRS was used in 3,582 patients (1,336 patients receiving ICS). ICS use was associated with lower intubation (adjusted OR, 0.46; 95% CI, 0.31-0.67) and NRS (aOR, 0.45; 95% CI, 0.40-0.49). The association between ICS and NRS differed according to history of asthma (P = .04 for interaction), with ICS exposure remaining protective only for patients with a history of asthma. Results held true in sensitivity analyses.InterpretationICS use prior to hospitalization may protect children with DLI from progressing to respiratory failure, with possible differential efficacy according to history of asthma.
| S-EPMC11412107 | biostudies-literature
Project description:BackgroundIntravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer.ObjectiveOur aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose.MethodsFrom 19 children (median age 4.9 years [range 9 months-15.3 years], median weight 18 kg [range 7.8-70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R- and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients' clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose.ResultsA two-compartment model with separate clearance for R- and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol.ConclusionsThe pharmacokinetic model of intravenous R- and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic-pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma.
| S-EPMC7007440 | biostudies-literature