Pharmacokinetic and Pharmacodynamic Comparison of Fluticasone Propionate/Formoterol Fumarate Administered via a Pressurized Metered-Dose Inhaler and a Novel Breath-Actuated Inhaler in Healthy Volunteers.

Introduction: Fluticasone propionate/formoterol fumarate (fluticasone/formoterol) exposures, following administration of Flutiform® K-haler®, a breath-actuated inhaler (BAI), were compared with the Flutiform pressurized metered-dose inhaler (pMDI) with/without spacer in two healthy volunteer studies. In addition, formoterol-induced systemic pharmacodynamic (PD) effects were examined in the second study. Methods: Study 1: single-dose, three-period, crossover pharmacokinetic (PK) study with oral charcoal administration. Fluticasone/formoterol 250/10 µg was administered via BAI, pMDI, or pMDI with spacer (pMDI+S). Pulmonary exposure for BAI was deemed no less than for pMDI (primary comparator) if the lower limit of 94.12% confidence intervals (CIs) for BAI:pMDI maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCt) ratios was ≥80%. Study 2: two-stage adaptive design, both stages being single-dose, crossover without charcoal administration. The PK stage compared fluticasone/formoterol 250/10 µg via BAI, pMDI, or pMDI+S. The primary comparisons were as follows: BAI versus pMDI+S for fluticasone and BAI versus pMDI for formoterol. Systemic safety with BAI was deemed no worse than primary comparator if the upper limit of 94.12% CIs for Cmax and AUCt ratios was ≤125%. PD assessment was to be conducted if BAI safety was not confirmed in the PK stage. Based on PK results, only formoterol PD effects were evaluated. The PD stage compared fluticasone/formoterol 1500/60 µg via BAI, pMDI, or pMDI+S; fluticasone/formoterol 500/20 µg pMDI; and formoterol 60 µg pMDI. The primary endpoint was maximum reduction in serum potassium within 4 hours postdose. Equivalence was defined as 95% CIs for BAI versus pMDI+S and pMDI ratios within 0.5-2.0. Results: Study 1: lower limit of 94.12% CIs for BAI:pMDI ratios >80%. Study 2, PK stage: upper limit of 94.12% CIs for fluticasone (BAI:pMDI+S) ratios <125%; upper limit of 94.12% CIs for formoterol (BAI:pMDI) ratios >125% (for Cmax, not AUCt). Study 2, PD stage: 95% CIs for serum potassium ratios 0.7-1.3 (BAI:pMDI+S) and 0.4-1.5 (BAI:pMDI). Conclusions: Fluticasone/formoterol BAI performance was within the range observed for the pMDI with/without a spacer. Sponsor: Mundipharma Research Ltd. EudraCT 2012-003728-19 (Study 1) and 2013-000045-39 (Study 2).

Pulmonary deposition of fluticasone propionate/formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler.

INTRODUCTION: A combination of fluticasone propionate/formoterol fumarate (FP/FORM) has been incorporated within a novel, breath-triggered device, named K-haler®. This low resistance device requires a gentle inspiratory effort to actuate it, triggering at an inspiratory flow rate of approximately 30 L/min; thus avoiding the need for coordination of inhalation with manual canister depression. The aim of the study was to evaluate total and regional pulmonary deposition of FP/FORM when administered via the K-haler device. MATERIALS AND METHODS: Twelve healthy subjects, 12 asthmatics, and 12 COPD patients each received a single dose of 2 puffs 99mtechnetium-labelled FP/FORM 125/5 µg. A gamma camera was used to obtain anterior and posterior two-dimensional images of drug deposition. Prior transmission scans (using a99mtechnetium flood source) allowed the definition of regions of interest and calculation of attenuation correction factors. Image analysis was performed per standardised methods. RESULTS: Of 36 subjects, 35 provided evaluable post-dose scintigraphic data. Mean subject ages were 35.7 (healthy), 44.5 (asthma) and 61.7 years (COPD); mean FEV1% predicted values were 109.8%, 77.4% and 43.2%, respectively. Mean pulmonary deposition was 26.6% (healthy), 44.7% (asthma), 39.0% (COPD) of the delivered dose. The respective mean penetration indices (peripheral:central ratio normalised to a transmission lung scan) were 0.44, 0.31 and 0.30. CONCLUSION: FP/FORM administration via the K-haler device resulted in high lung deposition in patients with obstructive lung disease but somewhat lesser deposition in healthy subjects. Regional deposition data demonstrated drug deposition in both the central and peripheral regions in all subject populations. EUDRACT NUMBER: 2015-000744-42.

Rhodium-Catalyzed Regioselective Synthesis of Isocoumarins through Benzothiadiazine-Fused Frameworks.

An unprecedented two-step, one-pot synthesis of benzimidazothiadiazine 5,5-dioxides is presented. Reaction condition based regioselectivity has been achieved where fused benzimidazo[1,2-b][1,2,4]thiadiazines are exclusively formed under thermal conditions, whereas benzimidazo[2,1-c][1,2,4]thiadiazines were created only under microwave irradiation. The salient features of this protocol include a regioselective sulfonylation of 2-aminobenzimidazole with o-halo sulfonyl chlorides followed by N-C bond formation. The acid forms of these fused regioisomers have been used to introduce novel guanidine-containing isocoumarin frameworks.

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.

OBJECTIVES: The present study was conducted to assess the efficacy, safety and tolerability of fluticasone propionate/formoterol fumarate combination therapy (FP/FORM; Flutiform®) compared with fluticasone propionate/salmeterol xinafoate (FP/SAL; Seretide® Evohaler®) in children with asthma. METHODS: This was an open-label, randomized, controlled, phase III trial and extension. Patients aged 4-12 years with reversible asthma [% predicted forced expiratory volume in 1 second (FEV1) 60-100%; documented reversibility of ⩾15% in FEV1] were randomized to receive FP/FORM (100/10 µg b.i.d.) or FP/SAL (100/50 µg b.i.d.) for 12 weeks. Eligible patients completing the 12-week core phase entered a 24-week extension phase with FP/FORM (100/10 µg b.i.d.). The primary efficacy endpoint was the change in predose FEV1 from day 0 to day 84. Secondary efficacy endpoints included change in predose to 2-hours postdose FEV1 from day 0 to day 84, peak expiratory flow rate (PEFR), patient-reported outcomes, rescue-medication use and asthma exacerbations. RESULTS: In total, 211 patients were randomized and 210 completed the core phase; of these patients, 208 entered and 205 completed the extension phase of the study. Predose FEV1 increased from day 0 to day 84 [FP/FORM, 182 ml; 95% confidence interval (CI), 127, 236; FP/SAL, 212 ml, 95% CI, 160, 265] and FP/FORM was noninferior to FP/SAL: least squares (LS) mean treatment difference: -0.031 (95% CI, -0.093, 0.031; p = 0.026). Secondary efficacy analyses indicated similar efficacy with both therapies. There were no notable differences observed in the safety and tolerability profile between treatments. No safety concerns were identified with long-term FP/FORM therapy, and there was no evidence of an effect of FP/FORM on plasma cortisol. CONCLUSIONS: FP/FORM improved lung function and measures of asthma control with comparable efficacy to FP/SAL, and demonstrated a favourable safety and tolerability profile in children aged 4-12 years.

The EFFECT trial: evaluating exacerbations, biomarkers, and safety outcomes with two dose levels of fluticasone propionate/formoterol in COPD.

Inhaled corticosteroid/long-acting ß2-agonist combination therapy is recommended in chronic obstructive pulmonary disease (COPD) patients at high risk of exacerbations. The EFFECT (Efficacy of Fluticasone propionate/FormotErol in COPD Treatment) trial is a Phase III, 52-week, randomized, double-blind study to evaluate the efficacy and safety of two doses of fluticasone propionate/formoterol compared to formoterol monotherapy in COPD patients with FEV1 ≥50% predicted and a history of exacerbations. The primary endpoint is the annualized rate of moderate and severe exacerbations. Secondary endpoints include pre-dose FEV1, EXACT-PRO (EXAcerbations of Chronic pulmonary disease Tool - Patient-Reported Outcome)-defined exacerbations, St George's Respiratory Questionnaire for COPD, COPD Assessment Test, and EXACT-Respiratory Symptoms total score. Lung-specific biomarkers (surfactant protein D and CC chemokine ligand-18) will be measured in a subset of patients to explore their relationship to other clinical indices in COPD and their predictive utility. Pneumonia will be diagnosed per criteria defined by the British Thoracic Society community acquired pneumonia guideline, primarily by radiological confirmation and, additionally, using clinical criteria when a chest radiograph cannot be obtained. Serial measurements of serum potassium, vital signs and electrocardiograms, 24-hour Holter monitoring, and 24-hour urinary cortisol measurement will be performed in a subset of patients in addition to conventional safety assessments.

Microwave-Assisted Multicomponent Synthesis of Dihydroquinoxalinones on Soluble Polymer Support.

A one-pot and two-step reaction of four components, including aldehydes, Fmoc-protected α-amino acid, isocyanide, and soluble polymer-supported 4-fluoro-3-amino benzoate ester, was developed for an efficient synthesis of dihydroquinoxalinones under microwave irradiation. Fmoc deprotection followed by intramolecular cyclization of the diamide gave a facile access to novel bicyclic quinoxalin-2-ones. On the basis of this approach, a new route to synthesize this privileged scaffold from the diamide intermediate was designed and accomplished with high yields. Use of multicomponent reaction (MCR) has been shown to display a good functional group tolerance, while the product isolation and purification is straightforward by precipitation and washings. Current library discusses the synthesis and diversification of 21 compounds produced using this strategy.

Diastereoselective synthesis of bridged polycyclic alkaloids via tandem acylation/intramolecular Diels-Alder reaction.

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-ß-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron ß-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-ß-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

Effect of doxycycline in patients of moderate to severe chronic obstructive pulmonary disease with stable symptoms.

BACKGROUND: The protease-antiprotease hypothesis proposes that inflammatory cells and oxidative stress in chronic obstructive pulmonary disease (COPD) produce increased levels of proteolytic enzymes (neutrophil elastase, matrix metalloproteinases [MMP]) which contribute to destruction of parenchyma resulting in progressive decline in forced expiratory volume in one second. Doxycycline, a tetracycline analogue, possesses anti-inflammatory properties and inhibits MMP enzymes. OBJECTIVES: To assess the effect of 4 weeks doxycycline in a dose of 100 mg once a day in patients of moderate to severe COPD with stable symptoms. METHODS: In an interventional, randomized, observer-masked, parallel study design, the effect of doxycycline (100 mg once a day for 4 weeks) was assessed in patients of COPD having stable symptoms after a run-in period of 4 weeks. The study participants in reference group did not receive doxycycline. The parameters were pulmonary functions, systemic inflammation marker C-reactive protein (CRP), and medical research council (MRC) dyspnea scale. Use of systemic corticosteroids or antimicrobial agents was not allowed during the study period. RESULTS: A total of 61 patients completed the study (31 patients in doxycycline group and 30 patients in reference group). At 4 weeks, the pulmonary functions significantly improved in doxycycline group and the mean reduction in baseline serum CRP was significantly greater in doxycycline group as compared with reference group. There was no significant improvement in MRC dyspnea scale in both groups at 4 weeks. CONCLUSION: The anti-inflammatory and MMP-inhibiting property of doxycycline might have contributed to the improvement of parameters in this study.

Adverse drug reaction profile of oseltamivir in children.

AIM: To monitor and evaluate the pattern of ADRs to oseltamivir in pediatric population suffering from H1N1 influenza at a tertiary care hospital. MATERIALS AND METHODS: Children offered oseltamivir for treatment and chemoprophylaxis were monitored for adverse events by direct questioning for symptoms and clinical examination on day 5 and day 10. Assessment of neurological events was done by asking the parents or guardians regarding development of specific symptoms. Adverse events obtained were analyzed for severity, causality and age-group wise. RESULTS: Out of 191 children (median age, 3 years), 69 (36.1%) developed ADRs. Most common symptoms were vomiting (16.2%) followed by diarrhea (12.0%), ear disorders (8.9%), and insomnia (6.8%). The incidence of neuropsychiatric symptoms was 12.6% which were mild-to-moderate on severity scale. There was no significant difference in the incidence of adverse events between children less than 1 year and other age groups. CONCLUSION: Oseltamivir is well tolerated in Indian children with suspected or confirmed H1N1 influenza. Our study also indicates safety of oseltamivir in infants.

Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence.

Clopidogrel is a prodrug which requires cytochrome P450 2C19 (CYP 2C19) enzyme for its conversion to an active thiol metabolite. Proton pump inhibitors (PPIs) inhibits enzyme CYP 2C19 interfering with the conversion of clopidogrel into its active metabolite. Studies document the possible interaction of clopidogrel and PPIs leading to a decrease in the antiplatelet efficacy of clopidogrel. A PubMed/MEDLINE database literature search was carried out and the bibliographies of found articles were checked for other relevant literature. Most retrospective cohort studies and studies using platelet markers found a significant association between PPI use especially omeprazole and decreased efficacy of clopidogrel while few comparative trials using clinical outcomes found no association between the same. Pantoprazole was not associated with the decrease in the antiplatelet efficacy of clopidogrel. Patients on dual antiplatelet therapy and/or with a history of gastrointestinal bleed will require gastroprotection in the form of PPIs. In such cases, pantoprazole should be the preferred PPI. Rabeprazole can be used as an alternative.