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Objective: To assess at 24 months corrected age (CA) the neurological, respiratory, and general health status of children born prematurely from 27 +0 to 33 +6 weeks’ gestation who were treated in a first-in-human study with a new fully synthetic surfactant (CHF5633) enriched with SP-B and SP-C proteins. Outcome measures: Children were assessed using Bayley Scales of Infant Development (BSID), with a score below normal defined as BSID-II Mental Development Index score

To investigate the efficacy and safety of nebulized poractant alfa (at 200 and 400 mg/kg doses) delivered in combination with nasal continuous positive airway pressure compared with nasal continuous positive airway pressure alone in premature infants with diagnosed respiratory distress syndrome.This randomized, controlled, multinational study was conducted in infants at 28In total, 129 infants were randomized. No significant differences were observed for the primary outcome: 24 (57%), 20 (49%), and 25 (58%) infants received endotracheal surfactant and/or mechanical ventilation within 72 hours in the poractant alfa 200 mg/kg, poractant alfa 400 mg/kg, and nasal continuous positive airway pressure groups, respectively. Similarly, secondary respiratory outcomes did not differ among groups. Enrollment was halted early owing to a change in the benefit-risk balance of the intervention. Nebulized poractant alfa was well-tolerated and safe, and no serious adverse events were related to the study treatment.The intervention did not decrease the likelihood of respiratory failure within the first 72 hours of life.ClinicalTrials.gov: NCT03235986.

Aims: To demonstrate the noninferiority of extrafine beclomethasone/formoterol fumarate (BDP/FF) dry powder inhaler (DPI) vs. extrafine BDP/FF pressurized metered dose inhaler (pMDI; Foster® 100/6 μg NEXThaler and pMDI, respectively) in the onset of reliever effect after methacholine induced bronchospasm in asthmatic patients, evaluated in terms of forced expiratory volume in 1 s (FEV1) at 5 min postdose. The DPI provides an alternative device option for patients who cannot use a pMDI properly during an acute asthma attack. Methods: Sixty-five patients received one inhalation of BDP/FF DPI, BDP/FF pMDI or placebo after methacholine challenge, according to a double-blind, double-dummy, cross-over design. Lung function and Borg dyspnoea score were assessed up to 30 min postdose. Results: FEV1 adjusted mean difference between BDP/FF DPI and BDP/FF pMDI at 5 min postdose was 2 ml (95% confidence interval: –0.060; 0.065). A similar result was observed at the other time points. Median time to 85% recovery in FEV1 was 8 min for BDP/FF DPI, 7.5 min for BDP/FF pMDI and 28 min for placebo (P = 0.554 DPI vs. pMDI). The Borg score improved after treatment with both BDP/FF DPI and pMDI and the effect was greater than after placebo. Median time to reach 50% recovery was 4.2 min for BDP/FF DPI, 4.0 min for BDP/FF pMDI and 10.0 min for placebo (P = 0.609 DPI vs. pMDI). Conclusions: Extrafine Foster® NEXThaler, a flow-independent DPI, is comparable to extrafine Foster® pMDI when administered as reliever therapy after methacholine challenge, thus supporting the maintenance and reliever therapy approach also with Foster® NEXThaler.

Objective To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, poractant alfa, for the treatment of respiratory distress syndrome in infants born preterm. Study design Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or poractant alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. Results Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and poractant alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P Conclusions Treatment with CHF5633 showed similar efficacy and safety as poractant alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. Trial registration ClinicalTrials.gov : NCT02452476 .

INTRODUCTION: An extrafine combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo.METHODS: Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40-75 years; moderate to severe COPD (post-bronchodilator FEV1 40-80% predicted, FEV1/FVC PRIMARY OBJECTIVE: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR0-4h) at each dose level. Secondary variables included: HR0-12h, HR peak and individual timepoint; QTcF interval; SBP and DBP AUC0-12h; and potassium and glucose AUC0-4h. Adverse events (AEs) were collected.RESULTS: Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (-0.2 bpm [95% CI -1.3, 0.9] for 200/12 μg and 0.6 bpm [-0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo.CONCLUSIONS: Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.

Extrafine beclometasone dipropionate (BDP; 100 μg/actuation) and formoterol fumarate (F; 6 μg/actuation) as pMDI formulation (Foster ® ) is already approved for maintenance and reliever regimen in asthma. Since some patient may still prefer using a DPI, we evaluated the reliever effect of BDP (100 μg/actuation) and F (6 μg/actuation) DPI (NEXThaler ® ), known to be flow independent, as compared to Foster ® pMDI in asthmatics. Methods: In a double blind, randomised, 3-way crossover, placebo-controlled study, after methacholine challenge, patients took a single dose (1 puff) of BDP/F 100/6 µg either as Foster ® DPI or Foster ® pMDI or placebo. Primary objective was to show the non-inferiority (NI) of DPI vs pMDI in the onset of reliever effect after methacholine-induced bronchospasm, as measured by FEV 1 at 5 min post-dose. Lung function at other time points, dyspnoea Borg score and time to recovery were also assessed. Results: Adjusted mean difference between treatments on FEV 1 at 5 min post-dose (per protocol) was 10 mL and the lower 95% CI was -56 ml, above the pre-specified NI limit (-120 mL), thus demonstrating the NI between DPI and pMDI. Median time to recovery of FEV 1 to 85% of baseline was similar for DPI and pMDI (8 vs 7.5 min, respectively), but significantly longer for placebo (28 min). Both active treatments were superior to placebo, thus confirming assay sensitivity. Similar results were obtained for the secondary efficacy parameters. Conclusions: Foster ® 100/6 µg NEXThaler ® , a flow independent DPI, is comparable to Foster ® pMDI when administered as a reliever therapy after methacholine challenge, thus supporting the Maintenance And Reliever Therapy (MART) indication also with the DPI.

Objective CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy. Design Multicentre cohort study. Patients Forty infants from 27 +0 to 33 +6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO 2 ) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg. Outcome measures Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO 2 after dosing and need for poractant-alfa rescue. Results Rapid and sustained improvements in FiO 2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viralbronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected. Conclusions Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials. Trial registration number ClinicalTrials.gov NCT01651637.

Summary Aim Prescription of inhaled corticosteroids to children with asthma is recommended at half the nominal dose of adults in order to reduce the risk of systemic side effects. However, there is a lack of pharmacokinetic trials supporting such dose reduction regimens. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed dose combination of beclometasone-dipropionate (BDP) and formoterol after dry powder inhaler (DPI) administration in children, adolescents and adults. Methods The pharmacokinetic profiles of formoterol and beclometasone-17-monopropionate (B17MP; active metabolite of BDP) were evaluated over 8 h from two independent studies comprising children (6–11yrs, n = 27), adolescents (12–17 yrs, n = 28) and adults (≥18 yrs, n = 30) receiving a single, fixed dose of BDP/formoterol (children: 200 μg/24 μg, adolescents and adults: 400 μg/24 μg) via DPI. Results The systemic exposure (AUC) for children versus adults was almost doubled for formoterol and similar for B17MP despite the halved BDP dose administered in children. In adolescents the AUC for formoterol and B17MP were approximately one third higher than in adults for both compounds. Upon normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration ( C max ) correlated inversely with age and body surface area of the patients ( r ≤ −0.53; p Conclusion The systemic exposure to the active ingredients of BDP/formoterol administered as DPI correlates inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children.

Aim The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 μg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 μg vs. the free combination of BDP and formoterol pMDIs in asthmatic children.

Introduction: CHF 5993 pMDI is a new fixed triple combination of extrafine Beclomethasone Dipropionate (BDP), Formoterol Fumarate (FF) and Glycopyrronium Bromide (GB) being developed in asthma as medium strength, 100/6/12.5µg/actuation (MS), and a high strength, 200/6/12.5 µg/actuation(HS) formulation. Objective: To assess the proportionality of BDP/B17MP (active metabolite of BDP) and the equivalence of FF and GB in terms of systemic and lung exposure, between the two strengths. Methods: Open label, randomized, single-dose, five-way crossover study in 47 healthy volunteers. Subjects received four inhalations of each strength with charcoal block (to assess the lung exposure) and without charcoal block (to assess the systemic exposure) and placebo. Pharmacokinetics of BDP/B17MP, FF and GB, as well as cardiovascular and systemic effects were studied Results: BDP and B17MP systemic and lung exposure were dose-proportional between HS and MS. GB and FF systemic and lung exposure were equivalent between the two strengths. After administration of HS, GB C max increased by 22% and 13% with and without charcoal block, respectively, compared to MS. However, this increase did not result in any clinically relevant change in cardiac and systemic effects or a higher incidence of AEs. No clinically relevant effects on heart rate, ECG parameters, vital signs, potassium, and glucose levels was observed after administration of either strength compared to placebo with no difference between HS and MS. Conclusions: Total systemic exposure and lung bioavailability of BDP/B17MP were proportional between the two strengths. FF and GB exposure was equivalent for the two strengths.

Introduction: CHF 5259 pMDI is an extrafine formulation of Glycopyrronium Bromide (GB; 12.5 µg/actuation) to be combined with a fixed dose combination of Beclometasone Dipropionate and Formoterol Fumarate (Foster ® 100/6 µg/actuation)as a two inhalations b.i.d. treatment in asthma and COPD. Main Objectives: To demonstrate the superiority of CHF 5259 pMDI vs. placebo in pre-dose morning FEV 1 and to assess safety and tolerability. Methods: Double-blind, randomised, 2-way crossover, placebo-controlled study. One hundred moderate/very severe COPD patients were randomised to receive either GB 12.5 µg 2 puffs b.i.d. or placebo over 4 weeks, with a 1-week wash-out period. The primary efficacy variable was change from baseline in pre-dose morning FEV 1 on Day 28. The key secondary efficacy variable was FEV 1 AUC 0-12h on Day 28. TDI and SGRQ score at Day 28 were included as secondary variables. Results: Pre-dose morning FEV 1 on Day 28 was higher in the treated group compared to placebo, with an adjusted mean difference (95% CI) between treatments of 0.088 L (0.039; 0.137) (p 1 AUC 0-12h on Day 28, with an adjusted mean difference of 0.121 L (0.079; 0.162) (p Conclusion: CHF 5259 pMDI provides superior clinical benefits compared to placebo in COPD patients with moderate/very severe lung function impairment over 4 weeks of treatment with a good safety profile.

Inhaled corticosteroids and long-acting β2-agonists are medications taken daily on a long-term basis to keep asthma under clinical control. Studies have shown that delivering this therapy in a combination inhaler is as effective as giving each drug separately, but fixed combination inhalers are more convenient for adolescents with asthma, increasing treatment adherence and ensuring that long-acting β2-agonists are always accompanied by inhaled corticosteroids [1,2]. An extrafine fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) is marketed both as a pressurized metered dose inhaler (pMDI) and as a dry powder inhaler (DPI), as Foster® and Foster® Nexthaler® (Chiesi Farmaceutici S.p.A., Parma, Italy) [3], respectively, at the dose strength of 100/6 μg for patients with asthma ≥18 years of age. The same dose strength is currently being developed in asthmatic adolescents aged 12–17 years. The purpose of this study was to investigate the systemic availability of B17MP (active metabolite of BDP) and formoterol after inhalation of an extrafine fixed combination of BDP/FF 100/6 μg via the NEXThaler® DPI in comparison to the free combination of BDP (Clenil® Pulvinal® 100 μg) and FF (Foradil® Aerolizer® 12 μg) DPIs (Novartis Pharmaceuticals Ltd, Frimley, UK) at a total single dose of 400/24 μg in asthmatic adolescents. Adolescents aged 12–17 years with mild-to-moderate asthma in a stable state participated in this randomized, crossover, single-dose study with two active treatment periods conducted at the Children's Asthma Clinic, Copenhagen, Denmark (ClinicalTrials.gov Identifier: NCT01191424). On each treatment day, blood was sampled for pharmacokinetic and pharmacodynamic assessments before and 5, 15 and 30 min and 1, 2, 4, 6 and 8 h after actuation of the DPIs [4]. Lung function [forced expiratory volume in 1 s (FEV1)] and heart rate were assessed concomitantly and adverse events recorded (see Appendix S1 for details). Pharmacokinetic end-points were as follows: area under the plasma drug concentration–time curve (AUC0–t), maximal plasma concentration (Cmax) and terminal half-life (t1/2) for B17MP and formoterol. The AUC0–t for B17MP was the primary end-point. Pharmacodynamic end-points were as follows: plasma potassium and plasma cortisol minimum plasma concentration (Cmin) and AUC0–t, plasma glucose Cmax and AUC0–2h, time-averaged FEV1 (AUC0–8h/8h) and heart rate (AUC0–8h/8h). All variables were log-transformed and treatment comparisons made using ANOVA models estimating the ratio of the adjusted geometric means test/reference (fixed/free combination) with the corresponding 90% confidence interval (CI) for the pharmacokinetic variables and 95% CI for the pharmacodynamic variables. Bioequivalence for the variables between treatments was demonstrated if the CIs were within the 0.8–1.25 acceptance region [5]. The study design had 90% power to reject the null hypothesis that the upper limit of the 90% CI for the ratio of test/reference means above 1.25 for B17MP AUC0–t. Twenty-seven adolescents [55% males; mean age (SD), 14 years (1.7)] completed the study. The B17MP AUC0–t was slightly higher following BDP/FF NEXThaler® vs. BDP and FF DPIs: test/reference ratio 1.14 (90% CI, 1.03–1.28; Table 1). The plasma cortisol test/reference ratio lower 90% CI bound was just below 0.8 [AUC0–t ratio, 0.92 (0.79–1.06)], but no plasma cortisol levels were below the lower clinical normal limit (5 ng ml−1) in either treatment group. Formoterol AUC0–t was higher following test vs. reference treatment [ratio, 1.46 (1.36–1.56)] and Cmax significantly increased [ratio, 2.83 (2.56–3.13)], but time to Cmax was the same for both treatments (median, 0.08 h). The plasma potassium [AUC0–t test/reference ratio, 0.98 (0.95–1.00)], plasma glucose [AUC0–2h ratio, 1.02 (0.99–1.05)] and heart rate [AUC0–8h/8h ratio, 1.05 (1.01–1.09)] were all within the predefined bioequivalence limit. The treatment effects on FEV1 were similar, and no notable differences in adverse events were observed (see Appendix S1). Table 1 Pharmacokinetic and pharmacodynamic comparison of BDP/FF 400/24 μg inhaled from the fixed BDP/FF 100/6 μg NEXThaler® DPI vs. BDP (Clenil® Pulvinal® 100 μg) and FF ... In adolescents with asthma, the systemic exposure to B17MP following four actuations of BDP/FF 100/6 μg NEXThaler® DPI compared with four actuations of BDP (Clenil® Pulvinal® 100 μg) and two actuations of FF (Foradil® Aerolizer® 12 μg) DPIs was slightly above the 125% bioequivalence limit, with a minor suppression of plasma cortisol levels. The clinical relevance of such suppression should be assessed after repeated administration according to European Medicines Agency guidelines [5]. Formoterol exposure was higher after administration of the fixed vs. free combination, but with comparable systemic effect in terms of heart rate, plasma glucose and plasma potassium. The FEV1 and safety profiles were also comparable. Potassium AUC0–t and Cmin were not affected by the increased formoterol exposure, which may be due to the transient formoterol peak concentration and the time delay between concentration and response or, alternatively, assay insensitivity. We speculate that the increased systemic exposure to formoterol and the slightly increased exposure to B17MP following the fixed BDP/FF NEXThaler® is caused by device-dependent different lung deposition. The BDP/FF NEXThaler® is an extrafine particle DPI with a low minimal inhalation flow threshold [6] in comparison to the Foradil® Aerolizer®, which requires a flow >60 l min−1, below which deagglomeration may be inefficient, resulting in a reduced emitted dose with larger particles and reduced lung deposition. In conclusion, inhalation from BDP/FF 100/6 μg NEXThaler® DPI resulted in a very similar exposure to B17MP but a greater exposure to formoterol compared with the licensed free combination in asthmatic adolescents. However, the greater bioavailability of formoterol following dosing with NEXThaler® had no systemic impact and did not affect the safety profile. For conduction of future bioequivalence trials, we highly recommend usage of devices with comparable lung deposition characteristics, because systemic absorption in adolescents seems to differ according to the device, which may have safety implications.

The corticosteroid beclomethasone dipropionate (BDP) has been formulated with the long acting beta agonist formoterol (BDP/formoterol 100 microg/6 microg, Foster) in a single inhaler using Modulite technology. We have investigated the acute tolerability of high, cumulative doses of BDP/formoterol compared to formoterol alone and placebo. This was a double blind, 3-way cross-over comparison of 10 puffs of BDP/formoterol 100 microg/6 microg or formoterol 6 microg or placebo during maintenance treatment with BDP/formoterol two puffs per day. Pharmacokinetics over 12h during maintenance treatment was measured on day 7. High cumulative doses were then administered on three separated days. Eighteen patients with asthma were recruited (mean FEV(1) 65% predicted). The primary endpoint was serum potassium over the 12h period after high doses. QTc, blood pressure and heart rate over 12h, and plasma lactate and glucose over 3h following dosing were assessed. Formoterol caused a significantly greater decrease in serum potassium than BDP/formoterol or placebo (difference in mean minimum concentrations; 0.11 and -0.15 mmol/l, respectively, p0.05 for both comparisons). No significant differences in serum potassium parameters were found between BDP/formoterol and placebo. QTc, plasma lactate and vital signs values observed with the combination were not statistically different from those with formoterol alone. For glucose, the mean maximum increase after formoterol treatment was 0.4 mmol/l (p0.01 compared to placebo), while BDP/formoterol treatment caused a maximum increase of 0.7 mmol/l (p0.01 compared to formoterol and placebo). The active metabolite of BDP is beclomethasone-17-monopropriate (B17MP), which reached Cmax at 0.25 h, with an elimination half-life of 3.7 h. Formoterol also reached Cmax at 0.25 h, and concentrations were measurable up to 12 h. High doses of BDP/formoterol did not significantly reduce serum potassium, while formoterol alone did to a greater extent. The BDP/formoterol combination was well tolerated, and exhibited a safety profile generally similar to formoterol alone when administered in high doses to stable asthmatic patients.

We evaluated the cardiovascular effects of extrafine BDP/FF (100/6 µg/ actuation) at two dose levels delivered as dry powder (DPI) via NEXThaler ® or an approved pMDI (Foster ® ) in COPD patients. Methods: Forty-nine subjects with a post-bronchodilator FEV 1 ≥ 40 and ® NEXThaler ® or Foster ® pMDI at two dose levels (therapeutic: BDP 200 µg / FF 12 µg or supratherapeutic: BDP 800 µg / FF 48 µg) or Foster ® NEXThaler ® placebo. The main objective was to demonstrate the non-inferiority (NI) of the DPI vs the pMDI in terms of average heart rate (HR) in the interval 0-4 hours post-dose (NI limit= 5 bpm), at both dose levels. Secondary objectives were to evaluate the effects of study treatments on serum potassium, serum glucose, other cardiovascular parameters and to assess safety and tolerability. Results: The adjusted mean differences between treatments were -0.2 bpm (95% CI: -1.3; 0.9) for the lower dose and 0.6 bpm (95%CI: -0.5; 1.7) for the higher dose, well within the pre-defined limit of 5 bpm, thus demonstrating non-inferiority at both dose levels. At the therapeutic dose the change in HR 0-4h vs placebo is well below the clinical significance level of 5 bpm. The results for the secondary parameters further supported the therapeutic equivalence of the two treatments. Both treatments were safe and well tolerated. Conclusions: Extrafine BDP/FF administered via NEXThaler or pMDI did not result in a significantly different effect on HR 0-4h. , thus supporting the safe use of both formulations in COPD patients.

The aim of the study was to evaluate the effect on lung function of high dose BDP (200 μg/actuation) and formoterol fumarate (FF; 6 μg/actuation) compared to the BDP (100 µg) and the FF (6 μg) delivered with NEXThaler ® in asthmatic patients. Methods: In a double blind, randomised, 5-way crossover, placebo controlled study, single doses (1 or 4 inhalations) of NEXThaler ® 100/6 µg and 200/6 µg or placebo were administered to uncontrolled adult asthmatics with FEV 1 60% - 85% of predicted. The primary objective was to show the non-inferiority of NEXThaler ® 200/6 µg vs 100/6 µg at two dose levels in terms of FEV 1 over 12 hours post-dose (AUC 0-12h ). Secondary objectives included other pulmonary parameters and safety. Results: The lower limits of the 95% CIs for the adjusted mean difference between treatments on FEV 1 AUC 0-12h were well above the pre-specified non-inferiority limit (-0.12 L), thus demonstrating non-inferiority between NEXThaler ® 200/6 µg and 100/6 µg at both FF dose levels (6 and 24 µg). Superiority of active treatments vs placebo was demonstrated for both strengths at each dose level, as well as statistically significant differences between low and high dose level (6 and 24 µg), thus confirming assay-sensitivity and dose level effect. Similar results were obtained for the secondary efficacy parameters. The safety profile of the treatments was comparable and no serious adverse events were observed. Conclusions: The effect of FF on lung function is comparable between the two strengths of the NEXThaler ® formulation and not affected by the different strength of BDP.

CHF3381 (2-[(2,3-dihydro-1H-inden-2-yl)amino]acetamide monohydrochloride) is a new N-methyl-D-aspartate antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor in development for the treatment of neuropathic pain. This study developed a mechanistic model to describe the pharmacokinetics of CHF3381 and of its two metabolites, the relationship with MAO-A activity and heart rate. Doses of 100, 200, and 400 mg twice daily for 2 weeks were administered orally to 36 subjects. MAO-A activity was estimated by measuring concentrations of 3,4-dihydroxyphenylglycol (DHPG), a stable metabolite of norepinephrine. A multicompartment model with time-dependent clearance was used to describe the kinetics of CHF3381 and metabolite concentrations. Estimated pharmacokinetic parameters were CL (41.2 to 27.4 l/h over the study), V (131 liters), Q (1.7 l/h), V(p) (36 liters), and k(a) (1.85 h(-1)). The relationship between CHF3381 and DHPG or heart rate was described using an indirect or a direct linear model, respectively. The production rate of DHPG (k(in)) was 2540 ng . h(-1), reduced by 63% at maximal CHF3381 concentrations. EC(50) was 1670 mug/l, not significantly different from the in vitro IC(50). The increase in heart rate due to CHF3381 was 0.0055 bpm/micro(g l-1). CHF3381 produces a concentration-dependent decrease in DHPG plasma concentrations, whose magnitude increased after multiple twice-a-day regimens for 14 days.

BACKGROUND: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of beclometasone-dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults. METHODS: The pharmacokinetics of formoterol and beclometasone-17-monopropionate (active metabolite of beclometasone-dipropionate) was evaluated over 8�h from three studies, each performed in a different age and body size group. Children (7-11 years, n�=�20), adolescents (12-17 years, n�=�29) and adults (?18 years, n�=�24) received a single dose of beclometasone/formoterol (children: 200�?g/24�?g, adolescents and adults: 400�?g/24�?g) via pMDI with AeroChamber Plus?. RESULTS: The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for beclometasone-17-monopropionate in accordance with the halved dose of beclometasone administered in children (90% CIs within 0.8-1.25 for formoterol and 0.4-0.625 for beclometasone-17-monopropionate). The systemic exposure to beclometasone-17-monopropionate and formoterol was equivalent between adolescents and adults. CONCLUSIONS: The systemic exposure to the active ingredients of a fixed dose combination of beclometasone/formoterol administered via pMDI with AeroChamber Plus? correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.

The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 μg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 μg vs. the free combination of BDP and formoterol pMDIs in asthmatic children.Children aged 5-11 years old inhaled BDP 200 μg and formoterol 24 μg as fixed vs. free combination in an open label, randomized, two way crossover single dose study. Blood was collected pre-dose up to 8 h post-dose for pharmacokinetic evaluation (AUC(0,t), AUC(0,∞), AUC(0,0.5 h, Cmax , tmax , t1/2 ). Pharmacodynamics included heart rate, plasma potassium, urinary glucose and cortisol excretion. Peak expiratory flow and adverse events were monitored.Twenty subjects were evaluable. The systemic exposure of B17MP and formoterol administered as fixed combination did not exceed the free combination: B17MP AUC(0,t) (pg ml(-1) h) ratio test : reference (90% CI), 0.81 (0.697, 0.948) and formoterol AUC(0,t) (pg ml(-1) h) ratio test : reference 0.97 (0.85, 1.10). All pharmacokinetic and pharmacodynamic end points showed non-superiority in favour of the test drug. One adverse event (vertigo) occurred but was not considered treatment-related.BDP and formoterol pharmacokinetic and pharmacodynamic effects are non-superior after administration of the two actives as fixed vs. the free combination in 5-11-year-old asthmatic children.

The aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of single administration of extrafine beclometasone (BDP)/formoterol hydrofluoroalkane (HFA) (Foster®, Chiesi Farmaceutici S.p.A., Italy) by pressurized metered dose inhaler (pMDI) in healthy volunteers, compared to the free combination of extrafine BDP pMDI (QVAR®, 3 M) and extrafine formoterol pMDI (Atimos®, Chiesi Farmaceutici S.p.A.) delivered via separate inhalers. Twelve healthy male volunteers completed this open label, randomized, single-dose, placebo-controlled, threeway cross-over study. Volunteers received (i) 4 inhalations of the fixed-combination of BDP/formoterol HFA (100/6 μg), (ii) 4 inhalations of BDP HFA (100 μg) and 2 inhalations of formoterol HFA (12 μg) administered separately or (iii) 4 inhalations of placebo HFA. There was a 7-day washout between treatment periods. PK parameters of BDP, FF, and of the main BDP metabolite (B17MP) were calculated. The systemic exposure to B17MP and formoterol after administration as a fixed combination or via separate inhalers was comparable. For B17MP, Cmax (794 ± 316 vs 663 ± 329 pg/mL), AUC0-t (3076 ± 1102 vs 2773 ± 833 pg.h/mL) and AUC0-30min (296 ± 11.7 vs 230 ± 13.3 pg.h/mL) were slightly higher, but not statistically significant, with the fixed than with the free combination. For formoterol, neither Cmax (27.6 ± 12.2 vs 28.7 ± 16.3 pg/mL) nor AUC0-t (69.3 ± 28.5 vs 67.4 ± 28.7 pg.h/mL) were significantly different between fixed and free combination. There was also no significant difference between the two combinations in serum cortisol levels, or cortisol urinary excretion adjusted for creatinine. Use of a single inhaler rather than separate inhalers to deliver extrafine drug particles of both BDP and formoterol to the lung does not modify relevant pharmacokinetics and pharmacodynamic parameters in healthy volunteers, therefore it may be considered as a therapeutic option to improve compliance in asthma patients who need chronic treatment.

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimer's disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.

A simple, efficient and environment-friendly procedure is developed for the condensation of malononitrile with aromatic, heteroaromatic and aliphatic aldehydes in water. The ylidenemalononitriles 3 are synthesised in high yields (84–98%) and selectivities (87–98%) in distilled water at 65 °C for 1 h, avoiding the addition of any catalyst.