Fluticasone Propionate Research Articles

Serum Inhaled Corticosteroid Detection for Monitoring Adherence in Severe Asthma

Daily inhaled corticosteroids (ICSs) are fundamental to asthma management, but adherence is low. To investigate (1) whether LC-MS/MS could be used to detect ICSs in serum and (2) whether serum levels related to markers of disease severity. We collected blood samples over an 8-hour period from patients with severe asthma prescribed at least 1000 μg daily of beclomethasone dipropionate equivalent. Following baseline sampling, patients were observed taking their usual morning dose. Subsequent blood samples were obtained 1, 2, 4, and 8 hours postinhalation and analyzed by LC-MS/MS. Correlations between serum ICS levels and severity markers were investigated. A total of 60 patients were recruited (41 females; 39 prescribed maintenance prednisolone; mean age, 49 ± 12 years; FEV1, 63 ± 20 %predicted). Eight hours postinhalation, all patients using budesonide (n= 10) and beclomethasone dipropionate (15), and all but 1 using fluticasone propionate (28), had detectable serum drug levels. Fluticasone furorate was detected in 2 patients (of 4), ciclesonide in none (of 7). Low adherence by repeat prescription records (<80%) was identified in 43%. Blood ICS levels correlated negatively with exacerbation rate, and (for fluticasone propionate only) positively with FEV1 %predicted. Commonly used ICSs can be reliably detected in the blood at least 8 hours after dosing, and could therefore be used as a measure of adherence in severe asthma. Higher exacerbation rates and poorer lung function (for fluticasone propionate) were associated with lower blood levels.

Fluticasone propionate for external use: pharmacological properties and clinical effectiveness

Topical corticosteroids are first-line medications in the treatment of an overwhelming number of both acute and chronic inflammatory noninfectious skin diseases. These drugs can be characterized as the drugs of choice in dermatological practice, which is determined by anti-inflammatory, immunosuppressive and antiproliferative effects of corticosteroids. Nevertheless, the use of these drugs in some cases may be limited by the potential risk of adverse side effects, which, in turn, determines a rather widespread corticophobia among patients, as well as among some doctors. In this regard, the current efforts of pharmaceutical companies are focused on the development of topical corticosteroids with the least number of side effects without loss of clinical efficacy. The synthetic carbothioate corticosteroid fluticasone propionate (FP) is a medium strength (class III) synthetic fluorinated corticosteroid for topical treatment of skin conditions. Its molecule has a high degree of lipophilicity, which allows it to be actively absorbed into the skin. The drug has a high affinity to glucocorticoid receptors against the background of the absence of mineralcorticoid activity. In addition, FP is relatively quickly subjected to enzymatic hydrolysis to inactive metabolites. This determines the high clinical efficacy of this drug with minimal risk of both local and systemic adverse events. It is available as cream and ointment with the same efficacy, but with different concentrations (0.05 or 0.005%) of the active substance. This article reviews the pharmacology and safety profile as well as the use of topical FP in clinical practice.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

Multidisciplinary consensus on a stepwise treatment algorithm for management of chronic rhinosinusitis with nasal polyps.

Multidisciplinary consensus on a stepwise treatment algorithm for management of chronic rhinosinusitis with nasal polyps.

Efficacy and safety of single-inhaler triple therapy of glycopyrronium, formoterol and fluticasone in patients with COPD: a double-blind, randomised controlled trial.

BackgroundThe aim of this work was to investigate the safety and efficacy of single-inhaler triple therapy with 12.5 μg glycopyrronium (GB)/12 μg formoterol fumarate (FF)/250 μg fluticasone propionate (FP), compared to 50 μg GB co-administered with a fixed dose of 12 μg FF/250 μg FP in subjects with COPD.MethodsThis was a phase 3, randomised, double-blind, active-control, parallel-group, noninferiority study conducted at 20 sites across India. COPD patients aged ≥40 to ≤75 years, with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70, using mono/dual therapy with inhaled corticosteroids (ICSs), long-acting muscarinic antagonists (LAMAs), or long-acting β-agonists (LABAs) for ≥1 month, were included. Subjects were randomised 1:1 to GB/FF/FP or GB+FF/FP for 12 weeks. The primary efficacy end-point was the change from baseline in trough FEV1 at the end of 12 weeks. The study is registered with the Clinical Trials Registry of India (identifier number: CTRI/2019/01/017156).ResultsBetween 23 March 2019 and 14 February 2020, 396 subjects were enrolled, with 198 patients each in the fixed-triple (GB/FF/FP) and open-triple (GB+FF/FP) groups. The difference in least-square mean (LSM) changes in pre-dose FEV1 from baseline at 12 weeks was noninferior between the groups (p<0.05). The LSM change from baseline in post-dose FEV1 was comparable (p=0.38). A superiority test showed comparable efficacy (p=0.12) for the difference in mean change from baseline in trough FEV1 between the groups. Adverse events (mild or moderate) were recorded in 25.3% and 24.9% of subjects in the GB/FF/FP and GB+FF/FP groups.ConclusionsFixed triple therapy with GB/FF/FP provides comparable bronchodilation and lung function improvement as open-triple therapy. It is safe and well tolerated in symptomatic COPD patients with a history of exacerbations.

Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting β2-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting β2-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study

Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting β2-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects. Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD? We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vsthree commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively. Patients with COPD initiating IND/GLY and VI/UMEC showed an 11%(incidence rate ratio [IRR], 0.89; 95%CI, 0.80-0.98) and 20%(IRR, 0.80; 95%CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vsFF/BDP, were associated with a 27%(hazard ratio [HR], 0.73; 95%CI, 0.59-0.90) to 42%(HR, 0.58; 95%CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs. Both LABA/LAMAs vsSAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.

Statistical Optimization Amalgamated Approach on Formulation Development of Nano Lipid Carrier Loaded Hydrophilic Gel of Fluticasone Propionate

Abstract: Introduction: Formulation of a nano lipid carrier loaded hydrophilic gel of a corticosteroid, fluticasone propionate (FP) was investigated systemically with response surface model (RSM) for promising dermal delivery of the drug. Objectives: To achieve a better penetration of the drug and to overcome the generally associated adverse reactions of corticosteroids, the present study, explored the formulation and evaluation of nano lipid carriers (NLCs) of FP in a hydrophilic gel base. Methods: A central composite design was proposed to study the effect of processing materials on the physicochemical properties of the NLC. High shear homogenization method with stearic acid, isopropyl myristate and poloxamer 407 was used to make different batches of FP-NLCs. The model was optimized at a significance level of P<0.05. FTIR, DSC and surface morphology studies were carried out for the optimized product. The optimized product was incorporated in the Carbopol P940 gel base and was evaluated for its mechanical and rheological properties, ex-vivo permeation and skin irritation study. Results: It was observed that using the proposed model, a nano size (179 nm) stable (Zeta potential -26 mV) optimized product of FP-NLC with 85% entrapment efficiency was achieved. The nanogel exhibited a spreadability of 4.2 gm.cm/sec and a viscosity of 92.6 cp. Approximately 3.5 times improvement in ex-vivo permeation and no skin irritations on animals were reported on application of the nanogel of FP. Conclusion: Hence the investigation created a paradigm to explore the efficacy of nanogel of FP for dermal application with improved permeation and promising therapy for dermatitis. Key words: Fluticasone propionate, Niosome, Central composite design, Gel, Ex-vivo permeation.

A real world retrospective analysis of comparison of effectiveness and safety of mometasone furoate and fluticasone propionate in the management of eczema and dermatitis

Contact dermatitis is one the commonest dermatological condition which is managed by topical corticosteroids. Mid potent topical corticosteroids are commonly prescribed but there is no any comparative data between mometasone furoate and fluticasone propionate in the management of dermatitis.A real world retrospective study was conducted across India to compare the clinical assessment of mometasone 0.1% cream and fluticasone 0.005% cream in the management of contact dermatitis at 236 dermatology clinics.A data of 1106 patients were included in this analysis in which 598 were included in mometasone group while 508 in fluticasone group. At the end of 2 weeks, 216 patients (36.1%) in mometasone and 129 patients (25.4%) in fluticasone group achieved complete clearance of symptoms (p&amp;#60;0.05). Additionally, in mometasone group, 354 patients (59.2%) were found to achieve improvement whereas 293 patients (57.7%) achieved the same in fluticasone group. On further sub group analysis on aggravating factors, it was found that, mometasone was statistically significant in relieving symptoms of dermatitis due to artificial jewellery, detergent and occlusive foot ware than fluticasone. Moreover, mometasone demonstrated significant results in physician and patient global assessment as well. Patients in both groups tolerated therapy well.Both, mometasone furoate and fluticasone propionate were effective and safe in treatment of eczema/dermatitis. But mometasone furoate had shown significantly better effectiveness as compared to fluticasone in all predisposing factors for the disease.

Comparative nasal airflow with loratadine-pseudoephedrine and fluticasone nasal spray for allergic rhinitis

BackgroundAlthough it is known that oral antihistamine-pseudoephedrine combination tablets have a faster onset than intranasal corticosteroid sprays in the treatment of allergic rhinitis after the first dose, the magnitude of change has not been measured in a comparative manner. Furthermore, the sensation of sprayed liquid in the nose may lead patients to mistakenly believe that intranasal steroid sprays work instantly. ObjectiveTo evaluate, numerically, nasal airflow changes provided by a single dose of loratadine-pseudoephedrine tablet (LP) and fluticasone propionate nasal spray (FP) in participants experiencing allergic rhinitis symptoms, including nasal congestion. MethodsThis single-center, double-blinded, placebo-controlled, crossover study evaluated objective nasal airflow changes in patients with a documented sensitivity to ragweed pollen. Participants were randomized to receive 1 of 4 treatment sequences, and their peak nasal inspiratory flow (PNIF) was measured in a span of 4 hours after pollen exposure in an environmental exposure unit. ResultsAverage change in PNIF was 31% with LP in the course of the study, significantly greater than with placebo and FP (12% and 15%, respectively; P < .001). Nevertheless, FP did not produce a significant change compared with its placebo. At hour one post-dose, LP had a clinically significant 31% increase in PNIF, whereas FP only yielded an 8.6% increase (P < .001). Measurable nasal airflow improvements are associated with the opening of nasal passages, allowing congested patients to breathe more freely. ConclusionA single dose of LP quickly and significantly (P < .001) improved nasal airflow after ragweed pollen challenge in an environmental exposure unit. Comparatively, FP did not display this same benefit. Trial RegistrationClinicalTrials.gov Identifier: NCT03443843.

Comparisons of Efficacy and Safety between Triple (Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting Beta-Agonist) Therapies in Chronic Obstructive Pulmonary Disease: Systematic Review and Bayesian Network Meta-Analysis

Background: Various combinations of inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA), and long-acting beta-agonist (LABA) have been used as triple therapy for stable chronic obstructive pulmonary disease (COPD). Objective: Our study was conducted to answer whether there were significant differences among various combinations in efficacy, for reducing exacerbation or mortality, and in safety, for increasing cardiovascular events or pneumonia. Method: We searched parallel-group randomized controlled trials (RCTs) comparing ICS/LAMA/LABA with other inhaled drugs in patients with stable COPD for at least 12 weeks in PubMed, EMBASE, the Cochrane Library, and clinical trial registries from inception to December 31, 2019. We conducted a network meta-analysis with Bayesian statistics using a random-effects model with heterogeneous variance structure (PROSPERO, CRD42019126757). Results: Nine different combinations of ICS/LAMA/LABA were identified in 21 RCTs containing 29,892 patients with moderate to very severe COPD. We could not find any significant evidence suggesting a better treatment for reducing total exacerbations or all-cause mortality among ICS/LAMA/LABA combinations. There were also no significant differences in moderate to severe exacerbation, COPD-related mortality, or cardiovascular disease-related mortality among ICS/LAMA/LABA combinations, and the risk of major adverse cardiovascular events was not different. A significantly lower risk of pneumonia was found in fluticasone propionate (FP)/glycopyrrolate/salmeterol (SAL) than FP/tiotropium/SAL {median odds ratio [OR] (95% credible interval [CrI]) = 0 [0–0.72]} and FP/umeclidinium/SAL {median OR (95% Crl) = 0 [0–0.97]}. Conclusion: There were no significant differences in clinical outcomes, including acute exacerbation and all-cause mortality among various ICS/LAMA/LABA combinations in patients with moderate to very severe COPD.

Chronomodulated Drug Delivery System of Salmeterol Fluticasone Nlcs Loaded Tablets: Preparation, Characterization, Stability and Drug Release Studies for Management of Asthma

Objective: The purpose of this study was to develop salmeterol, fluticasone nano-lipid carriers to estimate as potentials of oral delivery system for poorly water soluble drugs. Nano-lipid carriers applied to chronomodulated pulsatile drug delivery system maintain the concentration level by releasing the drug at predetermined time interval throughout the management of asthma. Method: The particle size analysis revealed that all the formulations were within the nanometer range of 150.0±2.4nm. Percentage of entrapment efficiency and drug loading were found to be 69.5±4.4 - 85.3±1.3 and 9.358±2.2-10.45±8.1, respectively. The SLM-FCN nano-lipid carrier’s optimized formulation showed spherical morphology with smooth surface under the transmission electron microscope (TEM), the crystalline characterization of drug in NLC was investigated by X-ray diffraction and differential scanning calorimetric (DSC). The ex-vivo permeation study showed many folds increment in the SLM-FCN NLCs compared to powder SLM-FCN 96.0±2.55 and pulsing plugs in-vivo drug released effectively in pre-determine time intervals. Conclusion: The progression concludes that chronomodulated programming pulsatile release was achieved with modified pulsing bilayerd plugged of salmeterol, fluticasone propionate NLCs, formulation remarkably improved oral bioavailability. we promise that finding in this investigations suggest practicability of the dosage form system can be taken after at bedtime then it will be delivered in the early morning which maintains the drug concentration throughout to control asthma.

Cannabis and its cannabinoids analysis by gas chromatography-mass spectrometry with Cold EI.

Cannabis extracts and products were analyzed by gas chromatography-mass spectrometry (GC-MS) with Cold EI for their full content including terpenes, sesquiterpenes, sesquiterpinols, fatty acids, delta 9-tetrahydrocannabinol (THC), cannabidiol (CBD), other cannabinoids, hydrocarbons, sterols, diglycerides, triglycerides, and impurities. GC-MS with Cold EI is based on interfacing GC and MS with supersonic molecular beams (SMB) along with electron ionization of vibrationally cold sample compounds in the SMB in a fly-through ion source (hence the name Cold EI). GC-MS with Cold EI improves all the performance aspects of GC-MS, enables the analysis of Cannabinoids with OH groups without derivatization, while providing enhanced molecular ions for improved identification, and enables internal quantitation without calibration. We found over 50 cannabinoid compounds including a new one with a Cold EI mass spectrum very similar to delta 9-THC as well as relatively large cannabinoids with molecular weight above m/z = 400. Because the analysis was universal in full scan and not targeted, we found impurities such as bromo CBD and fluticasone propionate and could monitor the formation of oxidized CBD during decarboxylation. In addition, GC-MS with Cold EI enabled nontargeted full analysis of terpenes, sesquiterpenes, and sesquiterpinols in cannabis extracts with good internal quantitation. GC-MS with Cold EI further served with very good sensitivity for the concentration determination of delta 9-THC in CBD-related products. Finally, cannabis drugs such as EP-1 used in Israel for treatment of epilepsy and for children with autism spectrum disorder (ASD) were analyzed for their full cannabinoids content for learning on the entourage effect and for drug activity optimization.

Prevalence of Suppressed Morning Serum Cortisol and Its Relationship With Cumulative Glucocorticoid Exposure in a Moderate-Severe Asthma Patient Cohort

The extent to which inhaled glucocorticoid exposure (ICS) contributes to risk of adrenal insufficiency (AI) is not fully understood. The aim of this study was to establish the relative contribution of both oral (OCS) and inhaled (ICS) glucocorticoid exposure to risk of AI.82 patients with severe asthma treated with fluticasone propionate (FP) who participated in a 32-week prospective randomised trial INCA SUN, (NCT02307669) were studied. Cumulative ICS exposure was calculated using a unique digital device, which creates an acoustic recording of inhaler adherence and technique. Analysis of this data provides an exact measure of the ICS dose received by each patient. Morning serum samples collected during the final study visit (week 32) were analysed for serum cortisol concentration (cortisol) using Roche Elecsys Cortisol II immunoassay. Participants were then stratified into three groups based on cortisol concentration to predict risk of AI; cortisol < 100nmol/l (high risk), 100–315 nmol/l (indeterminate risk) and > 315 nmol/l (low risk) based on locally derived reference ranges. 21% participants were classified as low risk, 18% as high risk and the remaining 61% at indeterminate risk of AI. Median morning cortisol in the low risk group was ten-fold higher than those in the high risk group (380 vs 38.5 nmol/l, p=0.001). OCS exposure was a significant predictor of risk of AI (OR 1.1 [1.03–1.17] per mg/kg increase in prednisolone exposure, p=0.004)). Participants at high risk were more likely to be on maintenance OCS (33% vs 0%, p=0.015) and had a greater median cumulative OCS exposure over the study period (7.55 vs 0.66 mg/kg prednisolone, p=0.002). ICS exposure was also associated with risk of AI. Participants at high risk AI had a greater adherence to ICS therapy (78% vs 62%, p=0.049) and greater cumulative received ICS dose over the study duration than those at low risk AI (178.2 vs 127.9 mg, p=0.036). ICS exposure remained a significant predictor of AI even when OCS exposure is controlled for (OR 2.49 [1.06–5.82] per 1mg/kg increase in FP exposure). Both the asthma control test (ACT) & asthma quality of life questionnaire (AQLQ) scores correlate with morning cortisol concentration (ACT r=0.2, p=0.068, AQLQ r=0.26, p=0.019). Interestingly, participants with cortisol < 100nmol/l reported worse asthma control (ACT score 16 vs 20, p=0.07) and a lower AQLQ score (4.1 vs 5.8, p=0.02) than the low risk group despite objectively better lung function (FEV1 90.6 vs 77.6% predicted). Our data suggests that both cumulative oral and inhaled glucocorticoid exposure contribute independently to cortisol suppression and risk of AI. The discrepancy between objective (FEV1) and more subjective measures of asthma control (ACT score) in the high risk group suggests that undiagnosed AI, as well as other non-airway co-morbidities, may contribute to the symptom burden experienced by these patients.

Antimicrobial Peptides SLPI and Beta Defensin-1 in Sputum are Negatively Correlated with FEV1.

BackgroundChronic obstructive pulmonary disease (COPD) and asthma have heterogeneous inflammation with inhaled corticosteroids (ICS) as a mainstay of treatment. There is increased prevalence of non-typeable Haemophilus influenzae (NTHi) persistence in airways of patients with neutrophilic airway inflammation, potentially due to suppressed host defence after corticosteroid treatment. Antimicrobial peptides (AMPs) have antimicrobial activity against pathogens and immunomodulatory effects. We investigated whether AMPs associate with NTHi presence in COPD and asthma, and whether ICS alter this.MethodsSecretory leukocyte protease inhibitor (SLPI), osteopontin, elafin and beta defensin-1 were measured in sputum supernatants from healthy donors (n=9), asthmatics (n=21) and patients with COPD (n=14). Elafin and beta defensin-1 were measured in a primary human bronchial epithelial cells (HBECs) from healthy and COPD donors infected with NTHi and pre-treated with fluticasone propionate (FP) and budesonide (BUD). Internalised NTHi was quantified by qPCR.ResultsSputum SLPI was negatively correlated with FEV1 (p<0.001, r=−0.610), FEV1% predicted (p<0.001, r=−0.583) and FEV1/FVC (p=0.001, r=−0.528). Sputum beta defensin-1 was negatively associated with FEV1 (p<0.001***r=−0.594). SLPI and beta defensin-1 levels in sputum were higher in the healthy controls and COPD group compared to the asthma group (p=0.001 and p=0.014) and (p<0.001 and p=0.007, respectively). ICS use was associated with higher sputum osteopontin compared to those with no ICS use. NTHi infection of COPD HBECs produced higher levels of beta defensin-1 compared to healthy donors (mean (SD) release: 45.1pg/mL (7.3) vs 21.2pg/mL (7.3) respectively, p=0.014). Elafin release from HBECs from COPD donors did not change following NTHi infection; however, elafin from healthy donors was significantly reduced (%mean reduction: 23.7%, 95% confidence intervals (CI) of reduction: 5.3–38.4%, p<0.01).ConclusionSputum SLPI and beta defensin-1 may be markers to identify those patients with declining lung function. ICS use was associated with higher sputum osteopontin compared to those with no ICS use.

Fluticasone Propionate Suppresses Poly(I:C)-Induced ACE2 in Primary Human Nasal Epithelial Cells.

BackgroundFrom the first detection in 2019, SARS-CoV-2 infections have spread rapidly worldwide and have been proven to cause an urgent and important health problem. SARS-CoV-2 cell entry depends on two proteins present on the surface of host cells, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). The nasal cavity is thought to be one of the initial sites of infection and a possible reservoir for dissemination within and between individuals. However, it is not known how the expression of these genes is regulated in the nasal mucosa.ObjectiveIn this study, we examined whether the expression of ACE2 and TMPRSS2 is affected by innate immune signals in the nasal mucosa. We also investigated how fluticasone propionate (FP), a corticosteroid used as an intranasal steroid spray, affects the gene expression.MethodsPrimary human nasal epithelial cells (HNECs) were collected from the nasal mucosa and incubated with Toll-like receptor (TLR) agonists and/or fluticasone propionate (FP), followed by quantitative PCR, immunofluorescence, and immunoblot analyses.ResultsAmong the TLR agonists, the TLR3 agonist Poly(I:C) significantly increased ACE2 and TMPRSS2 mRNA expression in HNECs (ACE2 36.212±11.600-fold change, p<0.0001; TMPRSS2 5.598±2.434-fold change, p=0.031). The ACE2 protein level was also increased with Poly(I:C) stimulation (2.884±0.505-fold change, p=0.003). The Poly(I:C)-induced ACE2 expression was suppressed by co-incubation with FP (0.405±0.312-fold change, p=0.044).ConclusionThe activation of innate immune signals via TLR3 promotes the expression of genes related to SARS-CoV2 cell entry in the nasal mucosa, although this expression is suppressed in the presence of FP. Further studies are required to evaluate whether FP suppresses SARS-CoV-2 viral cell entry.

Supercritical CO2 Extraction of Organic Solvents from Flunisolide and Fluticasone Propionate.

In this work, Class 2 and Class 3 solvents contained in two corticosteroids, flunisolide (Fluni) and fluticasone propionate (Fluti), were reduced to a few ppm by supercritical CO2 extraction. The process was carried out at pressures from 80 to 200 bar, temperatures of 40 °C and 80 °C, and at a fixed CO2 flow rate of 0.7 kg/h. The results demonstrated that CO2 density is the key parameter influencing the extraction kinetics and the solvent final residue. In particular, in the range investigated, optimal pressure and temperature conditions for the extraction of residual organic solvents were found working at 200 bar and 40 °C, which corresponds to a CO2 density of 0.840 g/cm3. Operating in this way, total organic solvent residues were reduced from 13,671 ppm and 326 ppm to 12 ppm and 10 ppm for Fluni and Fluti, respectively.

Determination of salmeterol, α-hydroxysalmeterol and fluticasone propionate in human urine and plasma for doping control using UHPLC-QTOF-MS.

Salmeterol and fluticasone are included in the Prohibited List annually issued by the World Anti-Doping Agency. While for other permitted beta-2 agonists a threshold has been established, above which any finding constitutes an Adverse Analytical Finding, this is not the case with salmeterol. The salmeterol metabolite, α-hydroxysalmeterol, has been described as a potentially more suitable biomarker for the misuse of inhaled salmeterol. In this study, a new and rapid UHPLC-QTOF-MS method was developed and validated for the simultaneous quantification of salmeterol, α-hydroxysalmeterol and fluticasone in human urine and plasma, which can be used for doping control. The analytes of interest were extracted by means of solid phase extraction and were separated on a Zorbax Eclipse Plus C18 column. Detection was performed in a quadrupole time-of-flight mass spectrometer equipped with an electrospray ionization source, in positive mode for the detection of salmeterol and its metabolite and in negative mode for the detection of fluticasone. Method was validated over a linear range from 0.10to 2.00 ng/ml for salmeterol and fluticasone, and from 1.00 to 20.0ng/ml for α-hydroxysalmeterol, in urine, whereas in plasma, the linear range was from 0.025 to 0.500 ng/ml for salmeterol and fluticasone, respectively.

Usability and Robustness of the Wixela Inhub Dry Powder Inhaler

Background: Wixela Inhub is a generic version of Advair Diskus recently approved by the U.S. Food and Drug Administration. The Inhub inhaler delivers fluticasone propionate (FP)/salmeterol in a dry powder formulation. The goals of our studies were to demonstrate that the Inhub inhaler can be used by representative end users and confirm the robustness of the Inhub inhaler.Methods: Study 1: A nondosing usability assessment, the device orientation study, confirmed that intended users (represented by patients diagnosed with asthma or chronic obstructive pulmonary disease [COPD] who were naive to dry powder inhalers and current Advair Diskus users) could use the Inhub inhaler safely and effectively. Subjects were provided with an Inhub inhaler in commercial packaging, including instructions for use, and were asked to undertake three dose simulations using the inhaler. Subjects were encouraged to interact with this new drug delivery device as they would at home. Subjects were not provided with training on the use of the device. Subjects were observed interacting with the Inhub inhaler, and those who currently use Diskus were also observed interacting with the Diskus to determine whether their mental model of the use of Diskus impacted their interaction with the Inhub device, this assessment was not a primary outcome of the study. Study 2: This is an open-label clinical study to confirm the robustness of the Inhub inhaler after at home patient use. Subjects diagnosed with asthma or COPD were provided Inhub inhaler training and subsequently self-administered 3 weeks of twice daily doses of Wixela Inhub 250 μg FP/50 μg salmeterol in the home environment. The Inhub inhalers were returned to the investigator after ∼3 weeks of outpatient use for in vitro tests on the drug remaining in each inhaler.Results: Study 1 enrolled 110 subjects, and all completed the study. Most subjects (100/110) held the Inhub inhaler in the correct orientation and of those who did not, 9 still achieved a peak inhalation flow rate of ≥30 L/min and a total inhaled volume of ≥1 L, thus meeting the requirements of the study success criteria. In Study 2, 111 pediatric, adult, and elderly subjects with asthma or COPD received the study drug. After ∼3 weeks of outpatient use of the Inhub inhaler by subjects, comprehensive in vitro testing demonstrated that the FP and salmeterol pharmaceutical performance in the Inhub inhaler was preserved.Conclusions: The majority of subjects demonstrated safe and effective use of the Inhub inhaler. In vitro testing and inspections confirmed the robustness of the Inhub inhaler after outpatient use.Clinical trial registration number: NCT02474017

Blood eosinophil count in patients with COPD on inhaled corticosteroids in comparison with healthy smoker and nonsmoker controls

Background Chronic obstructive pulmonary disease (COPD) is associated with acute and chronic pulmonary inflammation in the lung and as a systemic inflammation. The blood eosinophil counts are now recommended by the Global Initiative for the Management of Obstructive Lung Disease as a guide of inhaled corticosteroid use in clinical practice, as it can predict its effect on the rate of COPD exacerbation. The increasing peripheral blood eosinophilic count in patients with COPD could explain the systemic eosinophilia in COPD, which causes increased lung eosinophil count in these patients, especially those on inhaled corticosteroids (ICS). Patients and methods The study included 56 patients with COPD who were active smokers with pack-years beyond 10 as cases. The control group includes 60 patients as healthy nonsmokers (HNS) and 66 patients as healthy current smokers (HS), with pack-year beyond 10. Prebronchodilator and postbronchodilator spirometry was done in the pulmonary function unit of the Chest Department, Ain Shams University Hospital, to confirm or to exclude the COPD diagnosis. The COPD cases were categorized as per the Global Initiative for the Management of Obstructive Lung Disease severity assessment guideline and were receiving budesonide 800 μg/day and formoterol 24 μg/day or salmeterol 100 μg and fluticasone propionate 500 μg twice daily. Skin prick test and complete blood count for its differential and eosinophil count were done for all cases. Results The study included 56 patients with COPD who were active smokers and received ICS. The control group included 60 patients as HNS along with 66 patients as healthy current smokers. The HNS group showed the least total leukocytic count of 5588.33±1081.13/µl and the least eosinophilic count of 99.47±91.51/µl, whereas the COPD group showed the highest total leukocytic count. A statistically significant relation was found also between COPD patients’ eosinophil count and the use of ICS, with P value 0.000. Conclusion The peripheral blood eosinophil counts collected from patients with COPD on ICS are significantly higher than the patients with COPD who are not using ICS and the healthy smoker and nonsmoker control group.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 μm (A-4.5), 3.8 μm (B-3.8), and 3.7 μm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 μg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).