Salbutamol Easyhaler provides non-inferior relief of methacholine induced bronchoconstriction in comparison to Ventoline Evohaler with spacer: A randomized trial.

BACKGROUND: Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event. OBJECTIVE: We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed. METHODS: This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV1) were randomized to receive Salbutamol Easyhaler (2 × 200 µg), Ventoline Evohaler with spacer (4 × 100 µg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 µg) as a reliever. The treatment was repeated if FEV1 did not recover to at least -10 % of baseline. RESULTS: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV1%pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV1 between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose. CONCLUSION: The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks.

Effect of Carbidopa Dose on Levodopa Pharmacokinetics With and Without Catechol-O-Methyltransferase Inhibition in Healthy Subjects.

BACKGROUND AND OBJECTIVES: The treatment of Parkinson's disease (PD) is still symptomatic since disease-modifying treatments for PD are not available. Oral levodopa is the gold standard for the treatment of PD motor symptoms. However, incomplete and fluctuating plasma exposure of levodopa leads to suboptimal treatment of the symptoms. The main objective of this study was to investigate to what extent increased carbidopa doses (50 and 100 mg) increase the plasma levels of 100-mg immediate-release (IR) levodopa compared to a 25-mg carbidopa dose with and without co-administration of 200 mg entacapone. METHODS: A double-blind, placebo-controlled, randomized, crossover, phase I, pharmacokinetic study with 25 healthy volunteers was conducted. In addition, a semi-mechanistic pharmacokinetic model was built to theoretically evaluate the effect of inhibiting aromatic amino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) mediated metabolism of levodopa on the exposure of levodopa. RESULTS: The effect of increased carbidopa doses 50 and 100 mg on the total exposure (AUC) of 100 mg IR levodopa was +29% and +36%, respectively, when entacapone was co-administered. Without entacapone, the corresponding increases were +13% and +17%. With entacapone co-administration, the increased carbidopa dose also clearly increased levodopa trough concentration. There was no significant effect on the peak concentrations of levodopa. CONCLUSIONS: Increasing carbidopa doses significantly increased the exposure and reduced the fluctuation of IR levodopa in plasma during simultaneous COMT inhibition with entacapone. Theoretical pharmacokinetic simulations suggested that the plasma profile of oral IR levodopa can be even further improved by optimizing AADC and COMT inhibition.

Effectiveness and Treatment Compliance of Salmeterol-Fluticasone Easyhaler® Among Patients with Asthma, COPD, or Asthma-COPD Overlap Syndrome: Real-World Study Findings.

INTRODUCTION: For inhalation therapies to be effective, it is crucial that patients manage inhaler use correctly in their everyday life and achieve treatment compliance. We investigated the effectiveness of the salmeterol-fluticasone propionate Easyhaler® (SF EH) device-metered dry powder inhaler in a real-world setting in Hungary among adult patients with asthma, chronic obstructive pulmonary disease (COPD), or asthma-COPD overlap syndrome (ACO). METHODS: A prospective, open-label, multicenter, noninterventional, investigator-sponsored study was conducted in outpatient pneumonology centers. Eligible patients were aged ≥ 18 years with either a new diagnosis of asthma, COPD, or ACO, or whose disease was not controlled with preexisting medication. Data were collected at baseline and 12 + 4 weeks, including the asthma control test (ACT), COPD assessment test (CAT), spirometry parameters [including forced expiratory volume for 1 s (FEV1)], and physician- and patient-reported outcomes. RESULTS: Five hundred sixteen patients were recruited from 103 centers: 376 with asthma; 104 with COPD; and 36 with ACO. At week 12, there were significant improvements from baseline in both mean ACT score in patients with asthma (14.4 ± 4.2 versus 21.4 ± 2.8; P < 0.001) and mean CAT score in patients with COPD (24.0 ± 6.1 versus 16.0 ± 5.8; P < 0.001). Significant improvement was observed when the switch from the most frequently used previous inhalers was analyzed separately. Mean FEV1 improved from 76.0% ± 17.2 to 84.7% ± 16.1 (P < 0.001) and from 53.8% ± 15.0 to 59.9% ± 15.0 (P < 0.001) in patients with asthma or COPD, respectively. The study demonstrated improved physician-rated overall treatment compliance and patient preference for the SF EH over 3 months use compared with previous inhaler treatment, with patients effectively adopting the SF EH into everyday life. CONCLUSIONS: Treatment with SF EH significantly improved patients' lung function parameters and disease control.

A non-interventional switch study in adult patients with asthma or COPD on clinical effectiveness of salmeterol/fluticasone Easyhaler® in routine clinical practice.

BACKGROUND: Selection of the most appropriate device for a switch from one inhaler to an equivalent product is known to have a major impact on clinical outcomes in patients with asthma or chronic obstructive pulmonary disease (COPD). Salmeterol/fluticasone propionate (S/F) Easyhaler® has been demonstrated to be therapeutically equivalent with a reference product. However, no data on real-life effectiveness are currently available for patients switching to S/F Easyhaler from another S/F inhaler. METHODS: The aim of this prospective, open, multicenter, non-interventional study was to assess clinical effectiveness of propionate S/F Easyhaler in adult asthma and COPD patients switched from another inhaler. The primary endpoints were Asthma Control Test (ACT) and COPD Assessment Test (CAT). Secondary endpoints included assessments of patient satisfaction and preference and physician/nurse perception on S/F Easyhaler use. The study included three visits during a 12-week follow-up. RESULTS: A total of 211 patients (160 with asthma; 51 with COPD) were included in the analyses. In patients with asthma, there was a statistically significant increase in the mean ACT score at week 12 (20.2 ± 3.9) compared with the baseline (18.6 ± 4.1), with a mean increase of 1.6 (±3.5) points (p < 0.0001). In patients with COPD, CAT score persisted from baseline (19.9 ± 8.6) to week 12 (19.6 ± 7.0). Patients were significantly more satisfied with Easyhaler and most patients preferred Easyhaler over their previous inhaler. The physicians/nurses reported that it was 'very easy' to teach the use of Easyhaler and the training took less than 5 minutes in most cases. CONCLUSION: The results from this prospective real-life clinical study indicate better or at least similar treatment control of asthma and COPD after switching to S/F Easyhaler from another S/F inhaler. This study also shows that S/F Easyhaler was favored by the patients and that it is easy to teach, learn and use in a real-life setting.The reviews of this paper are available via the supplemental material section.

Inspiratory Flow Parameters Through Dry Powder Inhalers in Healthy Volunteers and Patients with Chronic Obstructive Pulmonary Disease (COPD): Device Resistance Does Not Limit Use in COPD.

INTRODUCTION: Achieving correct inhalation technique through an inhaler to ensure effective drug delivery is key to managing symptoms in patients with chronic obstructive pulmonary disease (COPD). However, many patients struggle to use their inhalers correctly, with the resultant reduction in therapeutic benefit. Consequently, appropriate inhaler choice is important to maximize clinical benefit. The primary objective of this study was to characterize inspiratory flow parameters across two Easyhaler® inhalers and the HandiHaler® inhaler in patients with COPD and healthy volunteers. METHODS: In this randomized, open-label, crossover study, subjects (100 patients with COPD; 100 healthy volunteers) were trained to perform inhalations of placebo powder via two variants of Easyhaler and placebo capsules via the HandiHaler inhalers. Subjects then performed three placebo inhalations through each inhaler in a random sequence. Inspiratory flow parameters were assessed, including peak inspiratory flow (PIF), for each inhaler. A parallel sub-study was conducted in patients with COPD from the main study to assess correct use of the inhalers, patient's preference, ability to learn to use the inhalers, and the feasibility of the In-Check Dial device to measure PIF values. RESULTS: Mean PIF rates and inspiratory volumes through the three inhalers were similar between patients with COPD and healthy volunteers, and all subjects achieved the 30 L/min PIF required for effective use of Easyhaler. Almost 70% of the 88 patients enrolled in the sub-study used the Easyhaler and HandiHaler inhalers without errors. The Easyhaler was preferred by 51% of patients, while 25% favored the HandiHaler. Teaching the use of both inhalers to almost 70% of patients was very easy. The In-Check Dial PIF values and those obtained via spirometry were strongly correlated (p<0.0001) for all three inhalers. CONCLUSION: The respiratory performance of patients with COPD does not appear to be a limiting factor in the use of Easyhaler.

Patients with asthma or chronic obstructive pulmonary disease (COPD) can generate sufficient inspiratory flows via Easyhaler® dry powder inhaler: a pooled analysis of two randomized controlled trials.

BACKGROUND: To evaluate whether patients of varying ages and lung function with asthma or those with chronic obstructive pulmonary disease (COPD) can achieve sufficient inspiratory flows for effective use of the fixed-dose combination of salmeterol-fluticasone propionate and budesonide-formoterol dispensed with the Easyhaler® (EH) device-metered, multi-dose dry powder inhaler (DPI). METHODS: A pooled analysis of two randomized, multicenter, crossover, open-label studies (NCT01424137; NCT009849061) was conducted to characterize inspiratory flow parameters across the EH, Seretide Diskus (DI) and Symbicort Turbuhaler (TH) inhalers in patients with asthma and/or COPD of varying severity. The primary endpoint was peak inspiratory flow (PIF) rate through the EH. RESULTS: The intent-to-treat population comprised 397 patients; 383 patients were included in the per-protocol (PP) population. The mean PIF (standard deviation) values through the EH in patients <18 and ≥18 years of age with asthma and in those with COPD, were similar: 61.4 (11.5), 69.7 (13.5), and 61.9 (13.2) L/min, respectively. These flow rates correspond to pressure drops of 5.05 (1.80), 6.52 (2.34) and 5.19 (2.07) kPa, respectively. In total, 380 (99.2%) of patients in the PP population were able to generate a PIF rate through the EH of ≥30 L/min, which is required to enable consistent dose delivery from the DPI; there was a moderate direct association between age and PIF in younger patients with asthma, but this was inverse and less apparent in adult patients with asthma and/or those with COPD. Height and weight were also moderately correlated with PIF. Stronger associations with PIF were observed for some lung function parameters, particularly native PIF and forced inspiratory vital capacity. CONCLUSIONS: Over 99% of patients with asthma and/or COPD were able to inhale through the EH with an adequate PIF rate, irrespective of age, or severity of airway obstruction. This confirms that patients with asthma and/or COPD can achieve inspiratory flows via the EH DPI that are sufficient for its effective use.

Patient Inspiratory Maneuver Performance; Peak Lungpower, Acceleration and Volume.

Background: Use of drug delivery devices between nebulizers, dry powder inhalers (DPIs), or metered dose inhalers (MDIs), for treating patients with asthma and chronic obstructive pulmonary disease (COPD), is based on patients' capability of coordinating the inhalation maneuver and achieving sufficient airflow. There are limited data available with regard to how patients meet the requirements of successful inhalation performance, and how the concept of inspiratory lungpower could be applied. The aim of this work was to study the patient inspiratory airflow profile performance in large data sets. We analyzed how the Kamin-Haidl inhalation criteria were met by patients with DPIs such as Easyhaler for combination therapy (EH-combi), Easyhaler for monotherapy (EH-mono), Diskus, and Turbuhaler (TH), and applied peak lungpower instead of peak inspiratory flow rate as an indicator of patient performance. Materials and Methods: Data sets gathered in two previous studies for DPIs, that is, EH-combi, EH-mono, Diskus, and TH, were used to analyze how inspiratory lungpower representing inspiratory muscle power, flow acceleration, and volume after peak met the inhalation criteria. The measured patient airflow profiles through inhalers were assessed for patients with asthma or COPD. Results: Based on the Kamin-Haidl inhalation criteria, successful inhalation requirements were met with EH-combi in 96.1% and with EH-mono in 92.6% of patients. The success rates were 89.5% and 84.6% with Diskus and TH, respectively, (p < 0.0001 between devices). In patients with asthma or COPD, the mean lungpower was 7.51 and 6.15 W for EH-combi, 8.79 and 6.88 W for EH-mono, 7.18 and 4.36 W for Diskus, and 9.65 and 6.86 W for TH, respectively, when patients followed the manufacturer's written instructions. Conclusions: Lungpower applied to the Kamin-Haidl inhalation criteria concept could be an applicable method for reviewing patient performance for different DPIs despite DPIs' characteristic differences in airflow resistance. In light of these results, DPIs provide a feasible treatment option for a large majority of respiratory patients.

Correction to: A Multicenter, Observational, Prospective Study of the Effectiveness of Switching from Budesonide/Formoterol Turbuhaler® to Budesonide/Formoterol Easyhaler®.

Unfortunately, the mean difference in change from baseline ACT was incorrectly reported in the abstract as 19.0 vs. 20.8 instead of 18.9 vs. 20.7.

A Multicenter, Observational, Prospective Study of the Effectiveness of Switching from Budesonide/Formoterol Turbuhaler® to Budesonide/Formoterol Easyhaler®.

INTRODUCTION: In real-life practice, asthma remains poorly controlled, with a considerable burden on patients' quality of life. Budesonide/formoterol (B/F) Easyhaler® has demonstrated similar dose consistency, therapeutic equivalence, and equivalent bronchodilator efficacy to B/F Turbuhaler®, but no real-life comparisons are yet available in patients switching from B/F Turbuhaler® to B/F Easyhaler®. METHODS: The primary objective of this real-life, non-interventional, observational study was to show non-inferiority of asthma control when adult patients in Swedish primary care with persistent asthma switched from B/F Turbuhaler® to B/F Easyhaler®. At visit 1, baseline demographic and endpoint data were recorded, and eligible patients switched to B/F Easyhaler®. The study comprised a control visit (visit 2) and a concluding examination (visit 3) after 12 weeks. Asthma control was assessed using the Asthma Control Test (ACT). The mini-Asthma Quality of Life Questionnaire (AQLQ) and lung function test were performed, and participants and investigators answered questionnaires about ease-of-use and teaching. RESULTS: A total of 117 patients were enrolled in the on-treatment population; 81 (64.8%) were female. At visit 3, B/F Easyhaler® demonstrated non-inferiority to B/F Turbuhaler®; the mean difference in change from baseline ACT was statistically significant (18.9 vs. 20.7, respectively; p < 0.0001) and met the non-inferiority criteria of B/F Easyhaler® being greater than - 1.5 points versus the reference product. Asthma was well controlled in 62 (53.0%) patients at baseline, increasing to 83 patients (70.9%) at visit 3. Patients experienced statistically significant improvements in mini-AQLQ score after B/F Easyhaler® treatment and lung function remained stable across the treatment period. B/F Easyhaler® was easy to learn and prepare for use. CONCLUSION: This real-life, non-interventional, non-inferiority study in adults with persist asthma demonstrates equivalent or better disease control when patients switch from B/F Turbuhaler® to B/F Easyhaler®. A further study with direct comparison between treatments could add to the understanding of inhaler switch. FUNDING: Orion Corporation, Orion Pharma.

Increased dose of carbidopa with levodopa and entacapone improves "off" time in a randomized trial.

OBJECTIVE: To investigate whether increased fixed carbidopa doses of 65 or 105 mg (ODM-101/65 and ODM-101/105) in combination with 75, 100, 125, or 150 mg of levodopa and 200 mg of entacapone might improve "off" time in fluctuating Parkinson disease (PD) compared to the standard combination of 4:1 levodopa/carbidopa with the usual 200 mg of entacapone (LCE) during a 4-week treatment period. METHODS: This was a randomized, double-blind, double-dummy, active-controlled, crossover, multicenter, phase II, proof-of-concept study in patients with fluctuating PD. RESULTS: One hundred seventeen patients were randomized into the study (mean age 67.0 years; daily "off" time 5.3 hours; mean daily levodopa dose 610 mg). Carryover-adjusted mean changes from baseline "off" times were during ODM-101/65, -1.53 hours (p = 0.02 vs LCE), during ODM-101/105, -1.57 hours (p = 0.01 vs LCE), and during LCE -0.91 hours. Changes in daily "on" time without dyskinesia were 1.54 hours (p = 0.005 vs LCE), 1.38 hours (p = 0.0214 vs LCE), and 0.69 hours, respectively. Changes in "on" time with troublesome dyskinesia were <0.1 hours and not significantly different between treatments. In patients with high-activity COMT genotypes Val/Met or Val/Val, "off" time was reduced more with ODM-101/65 and ODM-101/105 than with LCE (p = 0.015 and p = 0.006). No difference between the treatments was seen in safety and tolerability. The most common treatment-related adverse effects were nausea, dizziness, drug-effect decrease, and dyskinesia, which were in most cases mild or moderate in severity. Treatment-related serious adverse events were diarrhea (ODM-101/105 and LCE), and myocardial ischemia and blood creatine kinase increase (LCE). CONCLUSION: Increasing the dose of carbidopa in combination with levodopa and entacapone should be considered in the treatment of fluctuating PD to improve daily "off" times. Genotyping patients with PD according to COMT activity may improve individual treatment strategies. CLINICALTRIALSGOV IDENTIFIER: NCT01766258. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that an increased dose of carbidopa improves motor fluctuations when administered with levodopa and entacapone.

In Vitro Flow Rate Dependency of Delivered Dose and Fine Particle Dose of Salmeterol/Fluticasone Propionate Easyhaler and Seretide Diskus with Patient Flow Rates Collected in a Randomized Controlled Trial.

BACKGROUND: The Easyhaler® device-metered dry powder inhaler containing Salmeterol and Fluticasone propionate (S/F) has been developed for the treatment of patients with asthma and chronic obstructive pulmonary disease (COPD). We report two studies which evaluated the in vitro flow rate dependence of delivered dose (DD) and fine particle dose (FPD) of S/F Easyhaler versus Seretide Diskus®. METHODS: A randomized controlled trial (RCT) assessed inspiratory flow parameters of S/F Easyhaler and Seretide Diskus in subgroups of patients with asthma (children, adolescents and adults, and elderly) and in COPD patients. The 10th, 50th, and 90th percentile airflow rates were determined and utilized in vitro, to evaluate flow rate dependence of DD and FPD. Flow rate dependence was evaluated relative to the result obtained at the 50th percentile and any values deviating from 100% indicated flow rate dependence. The volumetric flow rate dependence (Q) index derived from FPD at 10th and 90th percentile airflows was also evaluated. RESULTS: Overall, 227 patients were enrolled and randomized; 216 completed the RCT. In total, 55.5% of patients were female, and the mean age was 46.3 years. Clinically relevant airflow rates (46, 68, and 85 L/min for S/F Easyhaler and 44, 71, and 96 L/min for Seretide Diskus) were carried forward into the in vitro study, which demonstrated similar flow rate dependence of DD and FPD for S/F Easyhaler compared with Seretide Diskus; all values were within ±15% limits across the 10th, 50th, and 90th percentile airflow rates. Q index results suggested that both S/F Easyhaler and Seretide Diskus are medium airflow-dependent products. CONCLUSIONS: Similar in vitro flow rate dependence of DD and FPD was demonstrated for S/F Easyhaler compared with Seretide Diskus, across a range of clinically relevant airflow rates, collected from patients with asthma and COPD.

Pharmacokinetics of Salmeterol and Fluticasone Propionate Delivered in Combination via Easyhaler and Diskus Dry Powder Inhalers in Healthy Subjects.

BACKGROUND: Easyhaler® dry powder inhaler (DPI) containing salmeterol and fluticasone propionate was developed for the treatment of asthma and chronic obstructive pulmonary disease. Three different Salmeterol/fluticasone Easyhaler test products (Orion Pharma, Finland) were compared against the reference product Seretide® Diskus® DPI (GlaxoSmithKline, United Kingdom) to study whether any of the test products are bioequivalent with the reference. METHODS: Open and randomized pharmacokinetic four-period crossover study on 65 healthy volunteers was performed in a single center to compare the lung deposition and total systemic exposure of salmeterol and fluticasone propionate after administration of single doses (two inhalations of 50/500 µg/inhalation strength) in fasting conditions. Blood samples were drawn before dosing and at frequent time points between 2 minutes and 34 hours after dosing for determination of drug concentrations. The primary variables for total systemic exposure and lung deposition of fluticasone propionate were maximum concentration of the concentration-time curve (Cmax) and area under the concentration-time curve from time zero to the last sample with quantifiable concentration (AUCt). For salmeterol, the primary variables for total systemic exposure were Cmax and AUCt and for lung deposition Cmax and AUC up to 30 minutes after study treatment administration (AUC30min). RESULTS: One of the Easyhaler test products met all the criteria for bioequivalence with the reference. The 96.7% confidence intervals (CIs) for the test/reference ratios of fluticasone propionate Cmax and AUCt were 0.9901-1.1336 and 0.9448-1.0542, respectively. Ninety percent CIs for salmeterol Cmax, AUC30min, and AUCt ratios were 1.0567-1.2012, 1.0989-1.2255, and 1.0769-1.1829, respectively. Median salmeterol time to maximum concentration (tmax) was 4.0 minutes. Median fluticasone propionate tmax was from 1.5 to 2.0 hours. Terminal elimination half-life was 11 hours for salmeterol and 9-10 hours for fluticasone propionate. CONCLUSIONS: Salmeterol/fluticasone Easyhaler was shown to be bioequivalent with the reference product.

Equivalent bronchodilation with budesonide/formoterol combination via Easyhaler and Turbuhaler in patients with asthma.

BACKGROUND: Therapeutic equivalence of Budesonide/formoterol Easyhaler compared to Symbicort Turbuhaler has been previously demonstrated with in vitro and pharmacokinetic studies. This study was performed to confirm equivalent bronchodilator efficacy of the products in asthmatic patients. METHODS: A randomised, single-dose, 4-period crossover study was carried out in a double-blind, double-dummy manner in 11 study sites. The studied doses were 320/9 µg and 1280/36 µg of budesonide/formoterol delivered by Easyhaler and Turbuhaler. Spirometry was performed before and 10 min, 20 min and 1, 2, 3, 4, 6, 8, 10 and 12 h after administration of the study treatments. The primary efficacy endpoint was average 12-h forced expiratory volume in 1 s (FEV1). The secondary efficacy endpoints were maximum FEV1 and FEV1 at 12 h post-dose. RESULTS: 72 asthma patients with reversible airway obstruction were randomised to receive study treatments. 53 patients completed all study periods according to the protocol and had sufficient data available to calculate the primary endpoint. They were included in the per-protocol analyses. The assay sensitivity of the study was shown as the common slope of average 12-h FEV1 between doses was 0.063 (95% CI 0.032-0.093) and showed statistical significance (p < 0.001). In equivalence testing, the difference in average 12-h FEV1 between the treatments (Easyhaler-Turbuhaler) was 0.013 l at the lower dose and -0.028 l at the higher dose, and their 95% confidence intervals (CIs) (-0.047 to 0.073 and -0.087 to 0.032, respectively) fell within the range of a clinically non-relevant difference. The results of the secondary efficacy endpoints were in line with the results of the primary endpoint. All treatments were well tolerated. CONCLUSIONS: The results confirm equivalent bronchodilator efficacy of Budesonide/formoterol Easyhaler compared to Symbicort Turbuhaler. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov, Identifier: NCT02308098.

Usage and usability of one dry powder inhaler compared to other inhalers at therapy start: an open, non-interventional observational study in Poland and Germany.

INTRODUCTION: Inhalation is the preferred route of drug administration for patients with asthma or COPD. It is generally predicted that there is a high error rate in inhaler usage, especially at the therapy start. The primary objective of this study was the validation of a questionnaire that can be used for assessing a successful inhalation technique, patient satisfaction as well as the compliance in daily practice.The secondary objective was to examine the "real-life" usage of one inhalation device in comparison with other devices at the start of the therapy. MATERIAL AND METHODS: This open, multi centre and non-interventional study was designed to examine usage and usability of dry powder inhaler Easyhaler® (EH) (Orion Pharma, Finland) and other inhalers assessed by the physicians as well as by the patients. Inclusion criteria for patients were a physician-diagnosis of COPD or asthma or children with asthmatic disease, therapy start with an inhalation device and no or only few experiences with inhaler usage (inhaler usage for not more than 3 months). Each physician enrolled an equal number of patients in each group. RESULTS: 263 adult/adolescent patients with asthma and 115 with COPD as well as 164 children with asthmatic disease were enrolled. 49.4% of the adult/adolescent patients with asthma used an EH and 50.6% other inhalers. In the case of COPD, 47.8% were treated with an EH and 52.2% used other inhalation devices. Finally, 50.6% of the children with asthmatic disease used an EH and 49.4% were treated with other inhalers. Inhaler usage, patient satisfaction, compliance and patients assessments of usability were better when the patients used an EH. Inconvenient features were mainly documented for other inhalers. The analysis of Cronbachs alpha clearly showed the consistency of the received data from all patients. In addition, there was a large association between the assessment of the inhaler usage and the general assessment of the used inhaler in all patient groups. CONCLUSION: The results of this study show that investigators found EH easy to teach, the patients found it easy to use and their satisfaction with the device was high in comparison to other inhalation devices. Thus EH can be matched to many patients already at the therapy start. In addition, the high consistency of the received data and large association of the assessment of the inhaler usage and the general assessment of the inhaler indicate that the used questionnaires were appropriate tools to examine usage and usability of inhaler devices in adult patients and children.

Equivalent Lung Dose and Systemic Exposure of Budesonide/Formoterol Combination via Easyhaler and Turbuhaler.

BACKGROUND: Easyhaler(®) device-metered dry powder inhaler containing budesonide and formoterol fumarate dihydrate (hereafter formoterol) for the treatment of asthma and chronic obstructive pulmonary disease has been developed. The current approvals of the product in Europe were based on several pharmacokinetic (PK) bioequivalence (BE) studies, and in vitro-in vivo correlation (IVIVC) modeling. METHODS: Four PK studies were performed to compare the lung deposition and total systemic exposure of budesonide and formoterol after administration of budesonide/formoterol Easyhaler and the reference product, Symbicort Turbuhaler. The products were administered concomitantly with oral charcoal (lung deposition) and in two of the studies also without charcoal (total systemic exposure). Demonstration of BE for lung deposition (surrogate marker for efficacy) and non-inferiority for systemic exposure (surrogate marker for safety) were considered a proof of therapeutic equivalence. In addition, IVIVC models were constructed to predict study outcomes with different reference product fine particle doses (FPDs). RESULTS: In the first pivotal study, the exposure and lung dose via Easyhaler were higher compared to the reference product (mean comparison estimates between 1.07 and 1.28) as the FPDs of the reference product batch were low. In the following studies, reference product batches with higher FPDs were utilized. In the second pivotal study, non-inferiority of Easyhaler compared to Turbuhaler was shown in safety and BE in efficacy for all other parameters except the formoterol AUCt. In the fourth study where two reference batches were compared to each other and Easyhaler, budesonide/formoterol Easyhaler was bioequivalent with one reference batch but not with the other having the highest FPDs amongst the 28 reference batches studied. In the IVIVC based study outcome predictions, the test product was bioequivalent with great proportion of the reference batches. For the test product and the median FPD reference product BE was predicted. CONCLUSIONS: Equivalence regarding both safety and efficacy between budesonide/formoterol Easyhaler and Symbicort Turbuhaler was shown based on totality of evidence from the PK studies and IVIVC analyses, and therefore, therapeutic equivalence between the products can be concluded. The results of the PK studies are likely dependent on the variability of FPDs of the reference product batches.

Entacapone and prostate cancer risk in patients with Parkinson's disease.

BACKGROUND: The association between Parkinson's disease (PD) and prostate cancer, both common in elderly men, is disputable. In the STRIDE-PD study, prostate cancer developed in 9 patients (3.7%) receiving levodopa/carbidopa with entacapone, a catechol-O-methyltransferase inhibitor, versus 2 cases (0.9%) without entacapone. The current pharmacoepidemiological study aimed to determine whether entacapone increases prostate cancer incidence or mortality in PD patients and whether cumulative exposure affects these rates. METHODS: We performed a retrospective cohort study using population-wide health care registers with patient-level linkage. Prostate cancer incidence and mortality were modeled by Cox's proportional hazards models. RESULTS AND CONCLUSIONS: Use of entacapone with l-dopa/dopa decarboxylase inhibitor caused no increased risk of prostate cancer incidence (hazard ratio [HR]: 1.05; 95% confidence interval: 0.76-1.44) or mortality (0.93; 0.43-1.98). The HR for cumulative entacapone use of >360 days versus never-use was 0.82 (0.56-1.18) for prostate cancer incidence and 1.27 (0.60-2.72) for prostate cancer mortality.

The effect of different dosing regimens of levodopa/carbidopa/entacapone on plasma levodopa concentrations.

BACKGROUND: Repeated dosing of levodopa/carbidopa/entacapone (LCE) has shown a favourable pharmacokinetic (PK) profile compared with levodopa/carbidopa (LC), but increases maximum plasma levodopa concentrations (C(max)) during the day. High levodopa concentrations are associated with peak-dose dyskinesias. PURPOSE: To determine whether administering LCE 75/18.5/200 and 125/31.5/200 mg (LCE 75 and LCE 125) following a morning dose of LCE 100/25/200 and 150/37.5/200 mg (LCE 100 and LCE 150), respectively, would avoid the increase in levodopa C(max) values observed during multiple dosing of LCE 100 and LCE 150. METHODS: This was an open, randomized, three-period, crossover PK trial in healthy volunteers (n = 19). Subjects were randomized to Group 1 or 2. Group 1 received in random sequence: LCE 150 followed by LCE 125 three times daily (tid); LCE 150 four times daily (qid); LC 150 qid. Group 2 received in random sequence: LCE 100 followed by LCE 75 tid; LCE 100 qid; LC 100 qid. Levodopa C(max), minimum plasma concentration (C(min)), area under the curve (AUC(0-14)) and peak-trough fluctuation (PTF) were calculated up to 14 h after the first dose. RESULTS: Levodopa C(max) was not increased when the LCE dose was decreased by 25 mg after the morning dose. In comparison to LC, levodopa C(min) levels and AUC(0-14) values for LCE were significantly higher, while the levodopa PTF was significantly smaller. CONCLUSIONS: Reducing the dose of LCE by 25 mg following the first morning dose results in a more consistent levodopa C(max) profile, avoiding levodopa accumulation while maintaining significantly higher C(min) levels and AUC(0-14) values compared with LC.

Health risk assessment of indoor air pollution in Finnish ice arenas.

Poor indoor air quality and epidemic carbon monoxide (CO) and nitrogen dioxide (NO(2)) poisonings due to exhaust emissions from ice resurfacers have been continuously reported from enclosed ice arenas for over 30 years. The health risks in users of Finnish ice arenas were analysed in three ways: (1) evaluation of four cases of epidemic CO poisonings, (2) modelling the association between NO(2) exposure and respiratory symptoms among junior ice hockey players, and (3) estimation of the number of arena users at risk of breathing poor quality air due to non-compliance of ice arenas with recommended abatement measures. The common causes for the CO poisonings involving over 300 subjects were large emissions from propane-fuelled ice resurfacer, small arena volume, negligible ventilation, and very recent opening of the arena. Rhinitis (prevalence 18.3%) and cough (13.7%) during or after training or game were significantly associated with the estimated personal NO(2) exposure of young hockey players (n=793) to average concentrations ranging from 21 to 1176 microg/m(3) in their home arena. During a 6-year follow-up of an intensive information campaign the portion of electric resurfacers increased from 9% to 27%, and that of emission control technology on propane-fuelled resurfacers increased from 13% to 84%. The portion of inadequately ventilated arenas decreased from 34% to 25%. However, 48% of the investigated Finnish ice arenas (n=125) did not fully comply with the non-regulatory recommendations. Consequently, 20000 daily users of ice arenas were estimated to remain in 2001 at risk of breathing poor quality air. Modern small and inadequately ventilated ice arenas pose their users (mostly children and young adults) at risk of breathing poor quality air and suffering from acute adverse health effects. Governmental regulations are needed worldwide to ensure safe sports in enclosed ice arenas.

Entacapone prolongs the reduction of PLM by levodopa/carbidopa in restless legs syndrome.

OBJECTIVES: Levodopa is effective in the treatment of restless legs syndrome (RLS). However, due to the short duration of action of conventional levodopa/decarboxylase inhibitor formulations, multiple dosing may be required in individual patients with persisting symptoms. We assessed whether a new levodopa formulation containing levodopa, carbidopa, and entacapone (LCE) improves levodopa action in RLS. METHODS: Twenty-eight RLS patients with periodic limb movement (PLM) received single doses of Stalevo 50 (LCE50; 50/12.5/200 mg), Stalevo 100 (LCE100; 100/25/200 mg), Stalevo 150 (LCE150; 150/37.5/200 mg), Sinemet 100 (LC100; 100/25 mg), or placebo in a randomized, double-blind, crossover study with polysomnography. Periodic limb movements per hour (PLM/h) during total sleep time and PLM during total time in bed were the primary and secondary variables, respectively. RESULTS: Mean PLM/h during total sleep time after Stalevo 50 (12.6/h, P < 0.05), LCE100, LCE150, and LC100 (6.4/h, 3.5/h and 9.5/h, respectively; P < 0.01) were significantly reduced compared with placebo (25.7/h). Improvement was also observed in PLM/h during total time in bed for all treatments (P < 0.01) and a significant dose response observed between LCE doses (P < 0.05). Compared with LC100, LCE100 and LCE150 reduced PLMs during the second half (P = 0.06 and P < 0.001, respectively) or during the last 3 early morning hours (hours 5-7 from the start of recording) of the night (P < 0.05 and P < 0.01, respectively). All formulations were well tolerated. CONCLUSIONS: Single doses of LCE tablets decreased PLMs in a dose-related manner in RLS patients. Prolonged effects of levodopa on PLMs suggest that, compared with standard levodopa, this new levodopa formulation provides longer symptom control throughout the night in patients with previously untreated RLS.

Clinically equivalent bronchodilatation achieved with formoterol delivered via Easyhaler and Aerolizer.

BACKGROUND: User-friendly devices for the delivery of asthma drugs are needed to enhance treatment compliance. Formoterol inhalation powder has been developed to Easyhaler multidose powder inhaler to enable the treatment of all asthma severities with the same device. OBJECTIVES: This double-blind, double-dummy, single- dose, placebo-controlled, cross-over study aimed to demonstrate the non-inferiority of the bronchodilating effect of formoterol 12 microg delivered via Easyhaler versus via Aerolizer. In addition, dose responses following placebo, 12-microg and 48-microg doses of formoterol via Easyhaler were compared. Furthermore, onset and duration of action, and safety of formoterol inhaled using the two inhalers were compared. METHODS: Sixty-seven adult asthmatic subjects showing >or=15% increase in forced expiratory volume in 1 s (FEV(1)) after short-acting sympathomimetic inhalation were enrolled and completed the study. The study comprised screening and 4 treatment days, with each subject inhaling a single 12-mug dose of formoterol via Easyhaler, a 12-microg dose via Aerolizer, a 48-microg dose via Easyhaler or placebo. Repeat spirometry and vital sign measurements were performed for 12 h during treatment days. The primary efficacy variable was the area under the flow volume curve (AUC(0-12)) of FEV(1). Secondary efficacy variables comprised maximum FEV(1 )(FEV(1max)), forced vital capacity (FVC), and the need of rescue medication during the treatment days. Safety was evaluated by determining blood pressure, heart rate and the number of adverse events (AEs). RESULTS: Results showed the non-inferiority of the bronchodilating effect of 12 microg formoterol via Easyhaler compared to Aerolizer. The Easyhaler-Aerolizer ratio for AUC(0-12) of FEV(1 )was 0.991 (95% confidence interval from 0.969 to 1.013). No statistically significant differences emerged for secondary efficacy variables. A statistically significant dose response was seen following placebo, 12- and 48-microg doses in FEV(1). No safety differences emerged for the 12-microg dose inhaled via Easyhaler or Aerolizer, but the incidence of AEs was higher following formoterol 48 microg and placebo treatments. CONCLUSIONS: Formoterol delivered via Easyhaler was therapeutically equivalent to Aerolizerat the 12-microg dose. The 48-microg dose via Easyhaler demonstrated statistically significantly greater bronchodilation but showed an increased occurrence of AEs.