Vectura (United Kingdom)

<b>Introduction:</b> It is perceived that young children have difficulty inhaling with a mouthpiece. The VR647 inhalation system (VR647IS) is a breath-actuated device for paediatric patients that guides inhalation flow rate and volume to improve delivery to the lung and provides real-time feedback to improve the patient’s inhalation technique. <b>Aims:</b> To assess if young children could use the VR647IS with a mouthpiece. <b>Methods:</b> Children aged 1–4 years with cough and/or recurrent wheeze in the past year, and who had used either a MDI with a spacer or a nebulizer, were included in this open-label study. Patients inhaled isotonic saline for nebulization using VR647IS with a mouthpiece, during two clinic visits (V1/V2), 4–8 days apart. Inhalation success was assessed at the third attempt at each visit. In a human factors study use of VR647IS with a mouthpiece and a face mask was also assessed in 15 children aged 1-8 years. <b>Results:</b> Overall, 40/41 patients attempted at least one inhalation. Most patients used VR467IS with a mouthpiece successfully (65% and 70% at V1 and V2, respectively); 90% of patients aged 3–4 years, 64% aged 2 years and 17% aged 1 year were successful at using VR647IS with a mouthpiece at V2. Most patients (89%) aged 4 years inhaled with a mouthpiece without hands-on assistance at V2 and 43% of children aged 2 years could use it without assistance. In the human factors study 80% of all participants and 83% of children aged 1-2 years were able to use VR647IS with the mouthpiece. <b>Conclusions:</b> 90% of children aged &gt; 2 years were able to use VR647IS with a mouthpiece, and 89% of children aged 4 years could use VR647IS, without assistance.

Dysfunktion und Entzündung der kleinen Atemwege in der Lungenperipherie tragen wesentlich zur Atemflusslimitierung bei Asthma bei (Burgel et al. 2011). Glukokortikoidrezeptoren sind im ganzen Respirationstrakt verteilt. Ihre Dichte nimmt in den peripheren Atemwegen zu (Adcock et al. 1996). Eine Verabreichung in die Peripherie der Lunge ist deshalb sinnvoll. Mit dem In-silico -Lungendepositionsmodell mit numerischer Strömungsmechanik kann die Wirkstoffdeposition von Inhalationsgeräten untersucht werden. Das Ziel dieser Studie war die Beurteilung der Lungendeposition nach Inhalation von Budesonid mit verschiedenen Inhalationssystemen bei Patienten mit schwerem Asthma.

Incorrect inhaler use and poor adherence are the most common reasons for patients failing to achieve good asthma control¹. The AKITA JET nebuliser system employs flow- and volume-controlled inhalation technology (FAVORITE^TM) to guide the patient in the correct inhalation technique. Data on adherence for review by the treating physician is collected by a smart card. <b>Aim:</b> To assess treatment adherence in a study comparing the steroid-sparring effect of budesonide inhalation suspension administered using the AKITA JET nebuliser system in adult patients with severe asthma². <b>Methods:</b> Daily use of the AKITA JET smart nebuliser was recorded in a randomised, placebo-controlled study of 158 subjects with severe asthma comparing the steroid-sparing effect of budesonide (1mg and 0.5mg) with that of placebo administered BID for 18 weeks. A smart card attached to the device recorded each treatment, duration and breathing manoeuvers performed during inhalation. Dose compliance was expressed as % of successful / expected doses. <b>Results:</b> Treatment compliance was 82% for all patients. 84% of patients inhaled an aerosol volume ≥ 1 L/breath and 35% achieved the maximum aerosol inhalation volume of 1.4 L/breath. The average time to complete treatment was 13 min 33 sec. <b>Conclusions:</b> Treatment with smart nebulisers such as Akita JET help patients achieve the correct inhalation technique, deliver drug more efficiently to the lungs, as well as monitor treatment compliance. These attributes could improve patient outcomes in severe asthma, leading to improved patient satisfaction and adherence in a real world setting. ¹ 2017 GINA Report; http://ginasthma.org ² Vogelmeier et al, Eur Resp Jour 2014; DOI: 10.1183/09031936.00152014

The performance of two quality control (QC) tests for aerodynamic particle size distributions (APSD) of orally inhaled drug products (OIPs) is compared. One of the tests is based on the fine particle dose (FPD) metric currently expected by the European regulators. The other test, called efficient data analysis (EDA), uses the ratio of large particle mass to small particle mass (LPM/SPM), along with impactor sized mass (ISM), to detect changes in APSD for QC purposes. The comparison is based on analysis of APSD data from four products (two different pressurized metered dose inhalers (MDIs) and two dry powder inhalers (DPIs)). It is demonstrated that in each case, EDA is able to detect shifts and abnormalities that FPD misses. The lack of sensitivity on the part of FPD is due to its "aggregate" nature, since FPD is a univariate measure of all particles less than about 5μm aerodynamic diameter, and shifts or changes within the range encompassed by this metric may go undetected. EDA is thus shown to be superior to FPD for routine control of OIP quality. This finding augments previously reported superiority of EDA compared with impactor stage groupings (favored by US regulators) for incorrect rejections (type I errors) when incorrect acceptances (type II errors) were adjusted to the same probability for both approaches. EDA is therefore proposed as a method of choice for routine quality control of OIPs in both European and US regulatory environments.

<b>Rationale:</b> Janus kinases (JAK) transduce multiple cytokine receptors reported to play an important role in asthma and COPD disease progression. VR588 is promising pan-JAK inhibitor suited to inhalation delivery. These studies were designed to characterise the <i>in-vitro</i> kinase inhibition profile of VR588 and to determine its selectivity versus non-JAK kinases. <b>Methods:</b> Kinase activity was assessed in a non-cell (Z9Lyte™ Florescence assay) and in cell based assays using stimulation of human whole blood (IL-2 stimulated INFγ production and JAK1/JAK3 and pSTATa/b activation and IL-6 stimulated pSTAT3 to assess JAK1, JAK2 and Tyk2 activity). In addition, the selectivity of VR588 (1mM) against a panel of 93 human kinases was assessed. <b>Results:</b> VR588 potently inhibited JAK1, 2, 3 and Tyk2 kinases (IC₅₀ 4.2, 0.7, 2.1 &amp; 6 nM respectively) in the non-cell based assay and showed poor inhibitory activity against non–JAK kinases FLT3, PDGFB, JNK2 and Syk (IC₅₀ 247, 2350,4000, 8900 nM respectively). This potent and broad JAK inhibition was confirmed in the cell based assays with inhibition of IL-2 stimulated INFγ, IL-2 stimulated pSTATa/b &amp; IL-6 stimulated pSTAT3 demonstrating IC₅₀ values of 209, 29 &amp; 62 nM respectively. Selectivity versus human kinases revealed no relevant off-target effects. <b>Conclusions:</b> VR588 represents a potent, selective and balanced pan-JAK inhibitor and the lack of off-target effects mitigates the potential for unwanted kinase activity. These results suggest VR588 may have utility as a pharmacological treatment for asthma and COPD and have prompted the characterisation of absorption, distribution, metabolism, and excretion (ADME) and in vivo efficacy via the inhaled route.

In this first study of inhaled apomorphine (VR040) in patients with Parkinson's disease, the primary objective was to find the minimum efficacious dose of apomorphine that was useful in rescuing patients during 'off' periods. Safety, tolerability and pharmacokinetics of inhaled apomorphine were assessed during the study. A double-blind, placebo-controlled, randomized trial of three escalating single doses of inhaled apomorphine (0.2, 0.5 and 0.8 mg fine particle dose) versus placebo (3 : 1 active:placebo) was performed. Parkinson's motor severity assessments by a clinician, and disease state assessment by the patient, were performed at baseline during an 'off' state, and at specified times after test drug administration. Safety assessments (including vital signs, electrocardiogram and forced expiratory volume) were performed, and plasma apomorphine levels measured. All 24 patients completed the study, and considering the three dose levels together, inhaled apomorphine did not significantly increase the proportion of patients switching from 'off' to 'on' (0/6 at 0.2 mg, 3/6 at 0.5 mg and 2/6 at 0.8 mg vs. 1/6 for placebo), or decrease the time from 'off' to 'on' post-treatment (10 min for 0.5 mg, 40 min for 0.8 mg, vs. 20 min for placebo). However, there was a suggestion of benefit at the higher doses (5/12 switched 'on' at the 0.5 or 0.8 mg doses, vs. 1/6 for placebo). There were no serious adverse events and treatment was well tolerated. Peak plasma concentration was 1-3 min post-dose, and plasma level dose proportionality was observed. Inhaled apomorphine was safe and well tolerated at the doses tested for an acute challenge to rescue 'off' periods, but efficacy at these doses was limited. A follow-up study at higher doses is appropriate given these initial findings.