Bronchodilator response after two methods of salbutamol nebulization in asthmatic children.

Introduction: Salbutamol is used in bronchodilator response testing (BDRT), which is an important diagnostic tool in bronchial obstructive diseases. Most available studies compare the bronchodilator response of salbutamol administered with a pressurized metered-dose inhaler and salbutamol in a nebulization solution. Aim: The spirometric evaluation of the bronchodilator response of two methods of salbutamol nebulization in asthmatic children. Material and methods: A randomized, open, comparative study was conducted in which 132 children with partially controlled asthma and current bronchial obstruction determined by spirometry were enrolled. BDRT was conducted using salbutamol solution administered with either a continuous jet nebulizer (CON) or a breath-actuated jet nebulizer (BAN). The BAN group received half the dose of the drug compared to the CON group, i.e. 2.5 mg. Changes in FEV1 and FEF25-75 after drug administration were calculated in relation to the baseline values. Results: The change in FEV1 after salbutamol administration was 16.9 ±9.7% in the BAN group and was statistically significantly higher than in the CON group (12.6 ±8.8%) (p = 0.026). The change in FEF25-75 was 37.7 ±23.2% in the BAN group and 32.7 ±25.5% in the CON group (p = 0.061). There were no statistically significant differences in the frequency of adverse events between the compared groups. Conclusions: Salbutamol inhaled from BAN results in a better bronchodilator response than twice the nominal dose of this drug inhaled from CON, which is due to the absence of drug loss during the expiratory phase and therefore greater pulmonary deposition.

Interferon alpha as antiviral therapy in chronic active Epstein-Barr virus disease with interstitial pneumonia - case report.

BACKGROUND: Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is defined as a severe, progressive lymphoproliferative disorder associated with active EBV infection persisting longer than 6 months and developing in patients without recognised immunodeficiency. Rarely, interstitial pneumonitis (IP) occurs as a serious complication in CAEBV patients. The standard therapeutic regimen for IP in CAEBV has not yet been defined. Although interferon alpha (IFN-alpha) is known to suppress viral DNA replication by affecting its basal promoter activation process, it is rarely used in CAEBV patients. CASE PRESENTATION: A 22-year-old Caucasian woman, diagnosed with CAEBV 1.5 years earlier, was admitted to the Immunology Clinic due to a 4-week history of productive cough, fever and general weakness. Cultures of blood, urine and sputum were negative, but EBV DNA copies were found in the sputum, whole blood, isolated peripheral blood lymphocytes as well as in the blood plasma. Cytokine assessment in peripheral blood revealed the lack of IFN-alpha synthesis. Disseminated maculate infiltrative areas in both lungs were observed on a computed tomography (CT) chest scan. The patient was not qualified for the allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to the risk of immunosuppression-related complications of infectious IP. Inhaled (1.5 million units 3 times a day) and subcutaneous (6 million units 3 times a week) IFN-alpha was implemented. To the best of our knowledge, this was the first documented use of inhaled IFN-alpha in a patient with CAEBV and concomitant IP. Patient's status has improved, and she was eventually qualified to allo-HSCT with reduced conditioning. Currently, the patient feels well, no EBV was detected and further regression of pulmonary changes was documented. CONCLUSIONS: CAEBV should be considered in patients who present with interstitial lung infiltration and involvement of other organs. Although more promising results have been obtained with allo-HSCT, inhaled IFN-alpha may also be a therapeutic option in patients with CAEBV and a concomitant IP.

[New dry powder inhalers]. / Nowe inhalatory suchego proszku.

The most recently approved DPI's - Ellipta™ and NEXThaler® are the most modern inhalers on the market. Both are flow independent in the physiological range of flows seen in patients with asthma and/or COPD. Both require three actions (open-load -inhaler) for a successful inhalation. The Ellipta™ inhaler is the first DPI, which enables simultaneous delivery of two compounds without need for co-formulation. NEXThaler® is the only DPI on the market delivering extra fine aerosol (MMAD < 2 µm) of a combined inhalation product of inhaled corticosteroid and long-action b2-agonist. Both have been approved world wide for products used in treatment of asthma and COPD.

[Influence of inhaler and fine particle on efficacy of inhalation therapy in COPD]. / Wplyw doboru inhalatora i czastki na skutecznosc terapii wziewnej w POChP.

Orally inhaled products delivered via inhalation exert their effect directly to the target organ. This allows to administer a very low dose of a drug compared with an oral route with similar clinical effect and significantly reduced toxicity. However inhalation therapy is also limited by several factors. Delivery of the desired dose of the drug to the airways depends on a type of the inhaler - pressurised metered-dose inhaler (pMDI) or dry powder inhaler (DPI), inhaler characteristics (low or high internal resistance, diameter of particles and distribution of the generated aerosol fine particles), thermal conditions of air, and ability of patient to generate sufficient inspiratory flow (for DPI) or to coordinate actuation with inhalation (for pMDI). Unlike pMDIs, DPIs are breath- -actuated, hence avoiding the need for the patient to coordinate actuation with inspiration. Furthermore, DPIs are propellant-free and do not produce the cold sensation on inhalation. Currently available DPIs vary widely in design, operating characteristics and performance. And poor inhalation technique may compromise treatment efficacy. Hence, there is a clear need for a careful selection of DPIs for different patient groups, including children, elderly patients and those with severe airway obstruction.

Influence of Physicochemical Properties of Budesonide Micro-Suspensions on Their Expected Lung Delivery Using a Vibrating Mesh Nebulizer.

The efficiency of lung drug delivery of nebulized drugs is governed by aerosol quality, which depends both on the aerosolization process itself but also on the properties of aerosol precursors. This paper determines physicochemical properties of four analogous micro-suspensions of a micronized steroid (budesonide, BUD) and seeks relationships between these properties and the quality of the aerosol emitted from a vibrating mesh nebulizer (VMN). Despite the same BUD content in all tested pharmaceutical products, their physicochemical characteristics (liquid surface tension, viscosity, electric conductivity, BUD crystal size, suspension stability, etc.) are not identical. The differences have a weak influence on droplet size distribution in the mists emitted from the VMN and on theoretical (calculated) regional aerosol deposition in the respiratory system but, simultaneously, there is an influence on the amount of BUD converted by the nebulizer to aerosol available for inhalation. It is demonstrated that the maximum inhaled BUD dose is below 80-90% of the label dose, depending on the nebulized formulation. It shows that nebulization of BUD suspensions in VMN is sensitive to minor dissimilarities among analogous (generic) pharmaceutics. The potential clinical relevance of these findings is discussed.

Where is industry getting it wrong? A review of quality concerns raised at Day 120 by the Committee For Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products.

PURPOSE: The aim of this study was to identify common trends in the deficiencies identified in the quality part of the dossier during the evaluation of marketing authorisation applications for medicinal products for human use submitted through the EU's centralised procedure. METHODS: We analysed all the adopted Day 120 list of questions on the quality module of 52 marketing authorisation applications for chemical entity medicinal products submitted to the European Medicines Agency and evaluated by the Committee for Medicinal Products for Human Use (CHMP), during 12 consecutive plenary meetings held in 2007 and 2008. Subsequently we calculated the frequency of common deficiencies identified across these applications. RESULTS: Frequencies and trends on quality deficiencies have been recorded and presented for 52 marketing authorisation applications. 32 "Major Objections" originated from 13 marketing authorisation applications. 13 concerned were raised regarding drug substances and 19 for drug products. Furthermore, 905 concerns on drug substance and 1,054 on drug product were also adopted. CONCLUSIONS: The impact of the frequencies and trends in quality deficiencies that were identified are discussed from a regulatory point of view. It is expected that the results of this study will not only be of interest to pharmaceutical companies but will also aid regulators' in obtaining consistent information on drug products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products.

Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients.

In order to improve targeted therapeutic approaches for asthma patients, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as obese asthmatics or severe asthmatics, are required. Here we report immunological and microbiome alterations in obese asthmatics (n = 50, mean age = 45), non-obese asthmatics (n = 53, mean age = 40), obese non-asthmatics (n = 51, mean age = 44) and their healthy counterparts (n = 48, mean age = 39). Obesity is associated with elevated proinflammatory signatures, which are enhanced in the presence of asthma. Similarly, obesity or asthma induced changes in the composition of the microbiota, while an additive effect is observed in obese asthma patients. Asthma disease severity is negatively correlated with fecal Akkermansia muciniphila levels. Administration of A. muciniphila to murine models significantly reduces airway hyper-reactivity and airway inflammation. Changes in immunological processes and microbiota composition are accentuated in obese asthma patients due to the additive effects of both disease states, while A. muciniphila may play a non-redundant role in patients with a severe asthma phenotype.

Gabapentin before laparoscopic sleeve gastrectomy reduces postoperative oxycodone consumption in obese patients: a randomized double-blind placebo-controlled trial.

BACKGROUND: Postoperative pain can be prevented. Gabapentin may be effective in this role. Our primary objective was to test the hypothesis that a prophylactic administration of gabapentin in obese patients before surgery has an opioid-sparing effect and reduces postoperative oxycodone consumption more efficiently than placebo. METHODS: The study enrolled 113 patients undergoing laparoscopic sleeve-gastrectomy under general anesthesia. The patients were randomly allocated to the control or gabapentin group and received a single oral dose of gabapentin 1200 mg or a matching placebo 1 h before surgery. RESULTS: The mean time from the end of anesthesia to the commencement of analgesic therapy was 74.3±37.8 minutes in the placebo group and 110.4±65.4 minutes with gabapentin (mean difference: -36, 95% CI: 12 to 40, P=0.0004). The mean 12-hour oxycodone consumption was 31.5±10 mg with placebo and 26.3±10 mg with gabapentin (mean difference: -5.2 mg, 95% CI: -9.08 to -1.35, P=0.0085). The mean NRS pain intensity at 12 hours was 2±0.9 in the placebo group and 1.5±0.9 with gabapentin (mean difference: -0.5, 95% CI: 0.15 to 0.81, P=0.003). CONCLUSIONS: The demand for oxycodone was delayed in the gabapentin group; also, the total 12-hour dose requirement of oxycodone was lower in the gabapentin group.

Evaluation of the Efficiency of Single-Inhaler Combination Therapy with Budesonide/Formoterol Fumarate in Patients with Bronchial Asthma in Daily Clinical Practice.

INTRODUCTION: The effectiveness of single-inhaler budesonide/formoterol fumarate combination therapy for asthma has been previously shown for the original product. The aim of this nonrandomized, open-label, postauthorization efficacy study (PAES) real-life clinical assessment was to evaluate the clinical effectiveness of a second product (Bufomix Easyhaler®) in the daily clinical practice of asthma therapy. METHODS: This multicenter PAES was conducted by 220 unselected allergologists and pulmonologists who enrolled 2200 adult outpatients (age 49.8 ± 17.9 years) with asthma treated with Bufomix Easyhaler® for at least 14 days before enrolment. Asthma control was assessed during three subsequent visits with 8-12-week intervals on the basis of the Asthma Control Test (ACT). Adherence was assessed with the Medication Adherence Questionnaire. In addition, patient satisfaction with Bufomix Easyhaler® was scored, and adverse drug reactions were recorded. RESULTS: The percentage of patients with well-controlled asthma or total control of asthma (ACT score 20-25 points) increased from 46.6% at the first visit to 90.8% at the third visit (p < 0.001). In addition, the percentage of patients with poor control of asthma (ACT score less than 15 points) decreased from 14.9% to 1.2% (p < 0.001). The adherence rate increased from 88% at the first visit to 95.3% at the third visit. Patient satisfaction with the use of this dry powder inhaler increased with the duration of its use. Only one adverse drug reaction was reported. CONCLUSION: The results obtained confirm the effectiveness of Bufomix Easyhaler® in the treatment of asthma in outpatient adults in daily clinical practice. FUNDING: Orion Corporation.

Inhalation devices: from basic science to practical use, innovative vs generic products.

INTRODUCTION: Inhalation therapy is a convenient method of treating respiratory diseases. The key factors required for inhalation are the preparation of drug carriers (aerosol particles) allowing reproducible dosing during administration. These technical challenges are accomplished with a variety of inhalation devices (inhalers) and medicinal formulations, which are optimized to be easily converted into inhalable aerosols. Areas covered: This review is focused on the most important, but often overlooked, effects, which are required for the reliable and reproducible inhalable drug administration. The effects of patient-related issues that influence inhalation therapy, such as proper selection of inhalers for specific cases is discussed. We also discuss factors that are the most essential if generic inhalation product should be considered equivalent to the drugs with the clinically confirmed efficacy. Expert opinion: Proper device selection is crucial in clinical results of inhalation therapy. The patients' ability to coordinate inhalation with actuation, generation of optimal flow through the device, use of optimal inspiratory volume, all produces crucial effects on disease control. Also the severity of the disease process effects proper use of inhalers. Interchanging of inhalers can produce potentially conflicting problem regarding efficacy and safety of inhalation therapy.

[The effect of fenspiride on the number of exacerbations and the time of first exacerbation in patients with chronic bronchitis]. / Wplyw fenspirydu na liczbe zaostrzen i czas ich wystapienia u chorych na przewlekle zapalenie oskrzeli.

UNLABELLED: The aim of the work was evaluation of efficacy of fenspiride b.i.d. on the number of exacerbations and the time to the first exacerbation in patients with chronic bronchitis. MATERIAL AND METHODS: Randomized, multicentre study controlled versus placebo was carried out in 12 centers in Poland. All patients, 89 females and 68 males aged between 20 and 74, were treated with fenspiride at the dose of 160 mg/day for a period of 6 months. The following symptoms were recorded every month in order to evaluate the therapeutic efficacy: sputum quality and quantity, cough intensity, dyspnea and bronchospasm. Based on these symptoms diagnosis of exacerbation was performed according to American Thoracic Society criteria. RESULTS: Quality and quantity of sputum and cough significantly improved in the fenspiride group (comparing to the placebo group p= 0.027 and p = 0.049 adequately for sputum and cough). A significant difference between groups was observed in the number of exacerbation episodes and their duration. In the fenspiride group there were 0.53 episodes of exacerbation compared with 1.12 episodes in the placebo group (p = 0.038). Mean duration of exacerbation was 3.3 days in the fenspiride group and 7.3 days in the placebo treated patients (p = 0.034). Time to the first exacerbation differed between groups, but this difference was not statistically significant. Number of side effects observed did not differ between groups. CONCLUSION: Fenspiride treatment was assessed as relatively effective in terms of influence on exacerbations, and well tolerated during six month therapy.

European Union pharmacovigilance capabilities: potential for the new legislation.

European Directives and Regulations introduced between late 2010 and 2012 have substantially overhauled pharmacovigilance processes across the European Union (EU). In this review, the implementation of the pharmacovigilance legislative framework by EU regulators is examined with the aim of mapping Directive 2010/84/EU and Regulation EC No. 1235/2010 against their aspired objectives of strengthening and rationalizing pharmacovigilance in the EU. A comprehensive review of the current state of affairs of the progress made by EU regulators is presented in this paper. Our review shows that intense efforts by regulators and industry to fulfil legislative obligations have resulted in major positive shifts in pharmacovigilance. Harmonized decision making, transparency in decision processes with patient involvement, information accessibility to the public, patient adverse drug reaction reporting, efforts in communication and enhanced cooperation between member states to maximize resource utilization and minimize duplication of efforts are observed.

Licensing of Generic Medicines: Are There Any Challenges Left? A Pharmaceutical Regulatory Perspective.

When an innovative product (innovator) is not covered anymore by intellectual property rights, cheaper equivalent medicinal products (generic products) may be marketed and used in clinical practice. The regulation of generic products is well-established, and is primarily based on standard rules for quality, therapeutic equivalence requirements (the latter in most instances proven through a bioequivalence study), and safety data for the innovator. The extensive experience from bringing generic products to the market over the last decades allows the conclusion that they are well-accepted and provide a useful alternative option for cost-effective pharmacotherapy. While supporting this conclusion, there are a number of issues to be considered during the assessment of a generic product application. Six scenarios are described in total, from an efficacy and a safety perspective, where potential concerns with the current regulatory standards could arise in the approval of generic products. We also propose solutions to these scenarios in order to foster debate on these issues.

NEXThaler, an innovative dry powder inhaler delivering an extrafine fixed combination of beclometasone and formoterol to treat large and small airways in asthma.

INTRODUCTION: Airway inflammation and remodelling in asthma occur in the large airways and also in the small airways. The small airways are those < 2 mm in diameter and are significant sites of chronic asthmatic inflammation. It is important, therefore, to target the small as well as the large airways in any strategy for effective treatment of this disease. AREAS COVERED: The present review deals with the recently developed fixed dose drug combination of beclometasone dipropionate/formoterol fumarate that emits extrafine particles when delivered from an innovative dry powder inhaler (DPI), NEXThaler®. The aim is to present the technical and clinical aspects of aerosolized drug delivery to the lungs. EXPERT OPINION: The data show that the NEXThaler DPI is an efficient device for the management of persistent asthma. The evaluation of the inhalation profiles through the NEXThaler DPI demonstrates that device activation and consistent dose delivery occurs at patient achievable inhalation flow rates, and supports the broad utility of the NEXThaler DPI in patients with asthma. Overall, all the effectiveness, efficiency and satisfaction outcomes demonstrate the NEXThaler DPI is easy to use.

Strengthening and rationalizing pharmacovigilance in the EU: where is Europe heading to? A review of the new EU legislation on pharmacovigilance.

Amendments to the European pharmacovigilance legislative framework are expected to come into force in 2011, following the adoption of the proposed amendments to Directive 2001/83/EC on the community code relating to medicinal products for human use (hereinafter referred to as the Directive) and to Regulation (EC) No. 726/2004 laying down community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (EMA) [hereinafter referred to as the Regulation]. The Regulation shall apply 18 months after publication in the Official Journal of the European Union. The amendments to the Directive and the Regulation will induce changes in the EU in terms of evaluation of risk associated with medicinal products as well as the framework on how the EU takes harmonized regulatory action on drug safety. In this review, the text agreed between the European Parliament and Council is examined and compared with the pharmacovigilance legislative framework currently in force. We argue that the new legislation has improved numerous uncertainties in current legislative framework and provides for the following: (i) clear roles, responsibilities and obligations for the key responsible parties; (ii) rationalization of EU decision making on drug safety issues in order to deliver measures that are equally and fully implemented for all relevant products across the community with a view to preventing unnecessary patient exposure to risks; (iii) strengthening medicine safety transparency and communication so that the understanding and trust of patients and health professionals in the safety of medicines will improve, as well as the penetration of key warnings; (iv) strengthening companies' pharmacovigilance systems, allowing companies to improve their systems constantly while reducing administrative burden; (v) ensuring the proactive and proportionate collection of high-quality data relevant to the safety of medicines through risk management and structured data collection in the form of Post-Authorization Safety Studies (PASS), together with rationalized single-case and periodic reporting of suspected adverse drug reactions (ADRs); (vi) involvement of stakeholders in pharmacovigilance through direct patient reporting of suspected ADRs and inclusion of patients and healthcare professionals in decision making; and (vii) simplification of the current community pharmacovigilance procedures with consequent efficiency gains for both the pharmaceutical industry and medicines regulators. For the first time, companies can be made legally liable to carry out PASS and Post-Authorization Efficacy Studies. The amendments to the Regulation and to the Directive will strengthen the European network on pharmacovigilance. A Pharmacovigilance Risk Assessment Committee (PRAC) based at the EMA will be set up, which will be responsible for all matters related to pharmacovigilance at an EU level. Three European databases will be strengthened (EudraVigilance, EudraPharm and the European Pharmacovigilance issues Tracking Tool) as well as the setting up of an EU safety portal to better inform the public on all safety issues being discussed at an EU level. Public hearings at the PRAC will improve transparency in the decision-making process, whilst details and results of all PASS agreed to by the PRAC will also be made publically available.