Fenoterol 100micrograms/dose / Ipratropium bromide 40micrograms/dose breath actuated inhaler

BackgroundBronchodilators (BDs) have been used therapeutically to improve exercise capacity in patients with other chronic respiratory diseases. However, the effect of BDs on the exercise capacity of individuals with non-cystic fibrosis bronchiectasis (NCFB) is poorly understood.ObjectiveThe aim of this study was to evaluate the effects of BDs on exercise capacity and thoracoabdominal kinematics in patients with NCFB.MethodsThis crossover randomized controlled trial will involve 45 outpatients with NCFB aged 18 to 59 years. They will be evaluated in 3 visits. On day 1, the maximal exercise capacity (cardiopulmonary exercise test; peak work rate [Wpeak]) will be assessed. On day 2, individuals will be randomized to receive either BD (ipratropium bromide 160 µg and fenoterol hydrobromide 400 µg) or a placebo and then undergo simultaneous endurance exercise capacity (constant work-rate exercise test) and thoracoabdominal kinematics (optoelectronic plethysmography) assessments. After at least 1-week washout (day 3), the individuals will repeat the same assessments as on day 2 in the reverse order. The time to the limit of tolerance will be obtained in both groups (BD and placebo groups) as the primary outcome. Thoracoabdominal kinematics will be assessed at 3 time points: at rest, during unloaded exercise, and at 75% Wpeak. The total chest wall and compartmental volumes as well as thoracoabdominal asynchrony will be assessed. The assessors and patients will be blinded to the interventions (BDs or placebo). Data will be compared using 1-sided t tests or Wilcoxon tests and repeated-measures analysis of variance or Friedman tests. Categorical data will be analyzed using the chi-square test or Fisher test. The associations among variables will be analyzed using Pearson or Spearman correlation. The significance level will be set at 5% (PResultsThe ethics approval was granted in November 2018, and a pilot study was commenced in April 2019 but was interrupted due to the COVID-19 pandemic. The study restarted in April 2022, and data collection is anticipated to continue until November 2025. The publication of the results is anticipated to be in 2025 or 2026.ConclusionsThere is no evidence that BDs can improve the exercise capacity of patients with NCFB. This trial will compare the endurance exercise capacity of the same individual with and without dual bronchodilation. If successful, this study will demonstrate that exercise capacity can be improved with the use of BDs in adults with NCFB.Trial registrationClinicalTrials.gov NCT05183841; https://clinicaltrials.gov/study/NCT05183841.International registered report identifier (irrid)DERR1-10.2196/68582.

Abstract licence: CC BY

Background: The aim of the present study was to evaluate the effect of ipratropium bromide with violet flower extract, ipratropium bromide with budesonide, and ipratropium bromide alone on the cuff-leak of the endotracheal tube and changes in hemodynamic parameters in intubated patients admitted to the intensive care unit. Materials and Methods: The present randomized clinical trial study was performed on 195 intubated patients in three groups of 65 patients. The first group received nebulized ipratropium bromide with budesonide (I + B group), the second group in addition to ipratropium bromide, received one tablespoon of the violet flower extract syrup every 8 hours (I + V group), and the third group received nebulized ipratropium bromide alone (I group). Hemodynamic parameters and the cuff-leak ratio (CLR) of patients were evaluated up to 72 hours after intubation. Results: The results of the present study revealed that 12 hours after intubation, the mean of CLR was significantly lower in group I (with a mean of 0.14 ± 0.02) as compared with that of the I + V and I + B groups (with the means of 0.16 ± 0.05 and 0.23 ± 0.05, respectively) (P < 0.001). In addition, 24 hours after intubation, the mean of CLR in group I + V was higher than that of I + B and I groups (P < 0.05). Conclusion: According to the results of this study, the use of violet extract syrup in patients under intubation can significantly improve patients' ratio of cuff-leak and SpO2. It seems that the use of violet extract syrup is effective to prevent unwanted complications during intubation and to facilitate patients' breathing.

Abstract licence: CC BY-NC-SA

AbstractIpratropium bromide (IPR) and fenoterol hydrobromide (FEN) have recently been combined in a promising inhaler to treat two prevalent inflammatory illnesses of the airways: bronchial asthma and chronic obstructive pulmonary disease (COPD). The necessity for a single, sensitive, and trustworthy analytical approach to cover the diverse and necessary tests of in-vitro and in-vivo studies is greatly grown with the rising production of new fixed combinations. Two novel, selective and environmentally friendly LC techniques were developed in order to guarantee precise measurement of IPR and FEN in their challenging formulation. The initial technique involved high-performance thin-layer chromatography (HPTLC) in conjunction with densitometric quantification. Chromatographic separation was attained on HPTLC plates utilizing ethyl acetate - ethanol - acetic acid (5.0:5.0:0.1, by volume) as a developing system. Densitometric quantification of the separated bands was carried out at 220.0 nm over concentration ranges of 0.50–15.0 µg/band for IPR and 0.50–12.0 µg/band for FEN. High-performance liquid chromatography (HPLC) paired with diode array detection (DAD) was the core of the second technique. The optimized separation was achieved on a Zorbax SB C18 (150 × 4.6 mm, 5 μm) column with a combination of 10.0 mM potassium dihydrogen orthophosphate, pH 5.0 ± 0.1, adjusted with o-phosphoric acid and methanol (70:30, v/v) as the mobile phase and pumped at flow rate of 1.0 mL/min. The peaks were monitored at 220.0 nm using diode array detection, achieving linearity range of 5.0–200.0 µg/mL for both drugs. The ICH criteria have been verified and both methods have been confirmed to be valid, and successfully applied for assay the cited drugs in the Atrovent® comp HFA metered dose inhaler as well as delivered dose uniformity testing of the final product. Finally, whiteness appraisal and several state-of-the-art green evaluation metrics were applied to evaluate the sustainability of the proposed methods. The suggested approaches produced promising results and are the first simple and sustainable methodologies for the simultaneous quantification of both drugs in different real samples, all of which strongly suggest their application in quality control laboratories.

Abstract licence: CC BY 4.0

AbstractAsthma and chronic obstructive pulmonary disease (COPD) are the most common diagnoses for adults and children with respiratory tract inflammation. Recently, a novel fixed dose combination consisting of Ipratropium and Fenoterol has been released for the management and control of the symptoms of such disorders. The current research has newly developed and optimized three smart, accurate, simple, cost-effective, and eco-friendly spectrophotometric methods that enabled the simultaneous determination of the drugs under study in their combined inhaler dosage form, without the need for any previous separation steps, using water as a green solvent. The strategy employed was based on calculating one or two factors as a numerical spectrum or constant, which provided the complete removal of any component in the mixture that might overlap and the mathematical filtration of the targeted analyte. The methods developed could be classified into two types of spectrophotometric windows. Window I; involved absorption spectrum in their original zero-order forms (°D), which included recently designed methods named induced concentration subtraction (ICS) and induced dual wavelength (IDW). While window III focused on the ratio spectrum as the induced amplitude modulation (IAM) method. The extremely low absorptivity and lack of distinct absorption maximum in the zero-order absorption spectrum of Ipratropium were two intrinsic challenges that were better overcome by the proposed spectrophotometric methods than by the conventionally used ones. According to ICH guidelines, the proposed methods were validated using unified regression over range 2.0–40.0 µg/mL in the ICS method, while the linearity ranges for the IDW and IAM methods were 5.0–40.0 µg/mL of Ipratropium and 2.0–40.0 µg/mL of Fenoterol. Moreover, the three proposed methods were effectively used to assay the co-formulated marketed inhaler and further expanded to confirm the delivered dose uniformity in compliance with the USP guidelines. Finally, the established methods were evaluated for their greenness and blueness, in comparison to the official and reported analysis methods, using advanced cutting edge software metrics. Furthermore, the suggested techniques adhered well to the white analytical chemistry postulates that were recently published.

Abstract licence: CC BY 4.0

Transporters of the SLC22 family, such as organic cation transporter 1 (OCT1), possess very broad substrate specificity. It is unclear to what extent the inhibitory potencies of OCT1 depend on the substrate used. Here, we describe a multisubstrate drug cocktail that allows for the simultaneous testing of drug-drug interactions using 8 different victim drugs: fenoterol, salbutamol, sumatriptan, zolmitriptan, ipratropium, trospium, methylnaltrexone, and metformin. There were no significant differences in Michaelis constant (KM) and vmax of the OCT1-mediated uptake of the substrates alone or in the cocktail. Depending on the victim drug analyzed, we observed 6.7-fold differences in the inhibitory potency of fenoterol (IC50 of 0.75 μM for metformin and 5.1 μM for sumatriptan). Similarly, the inhibitory potency of verapamil varied 6.7-fold (IC50 of 1.3 μM for zolmitriptan and 8.7 μM for ipratropium). Two groups of inhibitors showed strong correlations in their victim-dependent inhibitory potencies. Group 1 comprised verapamil, quinidine, fenoterol, and ipratropium, and group 2 comprised metformin, sumatriptan, and trimethoprim. By comparing OCT1 paralogs and orthologs, the broadest substrate spectra were observed for OCT1 and multidrug and toxin extrusion 1, followed by OCT2, multidrug and toxin extrusion 2-K, and OCT3. In contrast, organic cation transporters novel 1 and organic cation transporters novel 2 exhibited very narrow substrate specificity, transporting only L-carnitine and L-ergothioneine, respectively. In conclusion, OCT1 demonstrates substantial differences in inhibitory potencies, depending on the victim drug used. We developed a cocktail approach that enables rapid screening for such differences, facilitating the identification of drug-drug interactions at the early stages of drug development. This approach can be extended to other transporters with broad substrate specificity. SIGNIFICANCE STATEMENT: Polyspecific transporters have a broad substrate-binding cavity with no defined single binding position. Consequently, inhibitors may exhibit different inhibitory potencies depending on the victim drug used for testing. Here, we demonstrate this for organic cation transporter 1 (OCT1, SLC22A1) and presents a drug cocktail designed to identify varying inhibitory potencies in vitro and prevent false-negative drug-drug interaction results during early drug development. This approach can be extended to other polyspecific drug transporters.

Abstract licence: CC BY

Abstract Ipratropium bromide (IPR) and fenoterol hydrobromide (FEN) are well-known medications for treating asthma and chronic obstructive pulmonary disease (COPD). A simple, feasible, efficient, and cost-effective colorimetric assay has been established for determination of the newly introduced co-formulated metered dose inhaler (Atrovent® comp HFA). The developed method is based on the properly optimized reaction of drugs under study with the charge transfer reagent 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), resulting in orange-colored complexes measured at 464.3 and 514.0 nm for IPR and FEN, respectively. Smoothly applicable and easily manipulated resolution method, Vierordt’s method, based on straightforward mathematical equations that do not need complicated software was implemented for the simultaneous determination of IPR and FEN. The proposed methodology can be applied in routine analysis enabling fast and economical determination of the combined dosage form without the need for previous separation steps. The validity of the proposed colorimetric method was thoroughly assured as per ICH guidelines with acceptable accuracy and precision. The linearity ranges for IPR and FEN were 5.0–55.0 µg/mL and 10.0–40.0 µg/mL, respectively. Using cutting-edge software metric tools, namely the analytical greenness (AGREE), and complementary green analytical procedure index (ComplexGAPI), the greenness profile of the suggested method was clearly evaluated. The method also conformed well to the recently published blueness (BAGI tool) and whiteness (RGB12 tool) concepts.

Abstract licence: CC BY 4.0

BackgroundBronchodilator responsiveness (BDR) in asthma involves both the central and peripheral airways but is primarily relieved with beta-2-agonists and evaluated by spirometry. To date, antimuscarinics can be added as a reliever medication in more severe asthma. We hypothesize that combining both short-acting beta-2 agonist (SABA) and short-acting muscarinic antagonist (SAMA) could also improve the responsiveness in mild-moderate asthma. Therefore, we aimed to compare the direct effects of inhaling SABA alone, SAMA alone or combining both SABA and SAMA on the central and peripheral airways in asthma.MethodsTwenty-three patients with mild-moderate BDR in asthma performed dynamic spirometry and impulse oscillometry before (baseline) and multiple timepoints within an hour after inhalation of SABA (salbutamol), SAMA (ipratropium bromide), or both SABA and SAMA at three different visits.ResultsThe use of SAMA alone did not show any improvement compared to the use of SABA alone. Inhalation of SABA+SAMA, however, averaged either similar or better BDR than SABA alone in FEV1, MMEF, FVC, R5, R20 and R5-R20. Inhaling SABA+SAMA reached a stable BDR in more patients within 0-10 minutes and also reached the FEV1 (Δ%)>12% faster (3.5 minutes) than inhaling SABA alone (5.1 minutes). Inhaling SABA+SAMA was significantly better than SAMA alone in FEV1 (p = 0.015), MMEF (p = 0.0059) and R20 (p = 0.0049). Using these three variables highlighted a subgroup (30%, including more males) of patients that were more responsive to inhaling SABA+SAMA than SABA alone.ConclusionOverall, combining SAMA with SABA was faster and more consistent at increasing the lung function than SABA alone or SAMA alone, and the additive effect was best captured by incorporating peripheral-related variables. Therefore, SAMA should be considered as an add-on reliever for mild-moderate patients with BDR in asthma.

Abstract licence: CC BY-NC

Organic cation transporter 1 (OCT1) is located in the sinusoidal membrane of human hepatocytes. It mediates the uptake of hydrophilic organic cationic drugs in hepatocytes and thus determine their systemic concentrations. OCT1 has a broad spectrum of structurally diverse substrates like metformin, sumatriptan, trospium, and fenoterol. Recent cryo-EM data suggested that Y361 (tyrosine361), E386 (glutamate386), and R439 (arginine439), referred to as the YER motif, could be important for transport. Building on this, we used extensive functional analyses to investigate the general function and the substrate-specific effects of the YER motif. We determined the activity of the Y361A, E386A, and R439A mutants for 15 OCT1 substrates. Extended mutagenesis revealed the negative charge of E386 and the positive charge of R439 as essential for the transport of all substrates tested. Charge reversal mutants, E386R-R439E, did not restore transport activity, suggesting that at least one of the two amino acids is involved in additional interactions essential for transport. Y361 exhibited substrate-specific effects. The Y361A mutant transported fenoterol but not pirbuterol or other beta2-adrenergic drugs with only one aromatic ring. Molecular dynamics simulations suggested that substrates with aromatic or lipophilic characteristics may compensate for the missing aromatic ring at position 361. Only tryptophan at codon 361 efficiently rescued the transport of the Y361A mutant supporting hydrogen bound interaction with E386 and R439. Our study confirms that the YER motif is essential for OCT1 transport and points to Y361 as a lever that interacts with E386 and R439 to trigger the closing of the binding pocket of human OCT1.

Abstract licence: CC BY