A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients

CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. We investigated the efficacy and safety of CHF6001 using the allergen challenge model in a double blind, placebo controlled, 3-way cross-over study. Thirty six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 μg or 1200 μg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks. Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 μg and 1200 μg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.2). Compared with placebo, CHF 6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma

Interspecific Germline Transmission of Cultured Primordial Germ Cells

In birds, the primordial germ cell (PGC) lineage separates from the soma within 24 h following fertilization. Here we show that the endogenous population of about 200 PGCs from a single chicken embryo can be expanded one million fold in culture. When cultured PGCs are injected into a xenogeneic embryo at an equivalent stage of development, they colonize the testis. At sexual maturity, these donor PGCs undergo spermatogenesis in the xenogeneic host and become functional sperm. Insemination of semen from the xenogeneic host into females from the donor species produces normal offspring from the donor species. In our model system, the donor species is chicken (Gallus domesticus) and the recipient species is guinea fowl (Numida meleagris), a member of a different avian family, suggesting that the mechanisms controlling proliferation of the germline are highly conserved within birds. From a pragmatic perspective, these data are the basis of a novel strategy to produce endangered species of birds using domesticated hosts that are both tractable and fecund

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.</p> <p>Methods</p> <p>Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV₁, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV₁area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV₁and analysis of variance for AMP challenge.</p> <p>Results</p> <p>Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV₁was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response.</p> <p>Conclusions</p> <p>The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01343745">NCT01343745</a></p

Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study

Dave Singh,1 Mario Scuri,2 Sara Collarini,2 Stefano Vezzoli,2 Fabrizia Mariotti,2 Annamaria Muraro,2 Daniela Acerbi2 1Medicines Evaluation, University Of Manchester, University Hospital of South Manchester, Manchester, UK; 2Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy Abstract: An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate &ndash; a &ldquo;fixed triple&rdquo;. This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 &micro;g versus placebo; Part&nbsp;2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 &micro;g twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 &micro;g once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 &micro;g. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV1) area under the curve (AUC0&ndash;12h) and peak FEV1, with a trend toward greater efficacy with higher GB dose. All adverse events were mild&ndash;moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose&ndash;response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV1 on Day 7 (primary) were 115, 142 and 136&nbsp;mL for GB 12.5, 25 and 50 &micro;g BID, respectively (all P&lt;0.001). GB 25 and 50 &micro;g BID were superior (P&lt;0.05) to GB 12.5 &micro;g BID for pre-dose morning FEV1 on Day 8. For this endpoint, GB 25 and 50 &micro;g BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV1 peak and AUC0&ndash;12h with all GB doses and placebo (all&nbsp;P&lt;0.001). All adverse events were mild&ndash;moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 &micro;g BID is the optimal dose in patients with COPD. Keywords: glycopyrronium, COPD, bronchodilator, dose-rangin

Sequence treatment with Intragastric Balloon BIB (R)

Background: Since 1998, we adopted the BioEnterics Intragastric Balloon (BIB®) in our clinical practice for treatment of obesity and morbid obesity. Aim of this work is to evaluate the efficacy of a second balloon to continue weight loss or to produce better weight loss. Methods: Since March 1998, 522 BIB® were inserted in 480 obese and morbidly obese patients (124 male and 356 female). 38 patients (15 male and 23 female) had two balloons and four (1 male and 3 female) underwent three balloon insertions. At first insertion mean age was 40 years (21-65); mean weight was 126 kg (82-229), mean BMI was 43.2 kg/m2 (29-81.1), and mean initial % excess weight was 76% (13.3-216.3). The patients were given a balanced diet of 1000 kcal/day with temporary addition of omeprazole, vitamins and oligoelements. Results: When the first BIB was removed, the mean weight loss was 19.9 kg (8-50), the mean reduction in BMI was 6.6 kg/m2 (2.7- 15.9) and the mean %EWL was 25.7%. At the second balloon removal, the mean weight loss was 7 kg (from +11 kg to -33 kg), the mean reduction in BMI was 2.6 kg/m2 (from +3.9 to -8.6) and the mean %EWL was 10.1%. Only with second balloon we observed six cases of intolerance with removal before the due date. Conclusion: Our experience shows that second balloon insertion is less effective in terms of weight loss and %EWL than the first balloon and that the incidence of complications is greate

Affinity-Purified Respiratory Syncytial Virus Antibodies from Intravenous Immunoglobulin Exert Potent Antibody-Dependent Cellular Cytotoxicity

Mixed infections are one of the major therapeutic challenges, as the current strategies have had limited success. One of the most common and widespread conditions of mixed infection is respiratory syncytial virus-mediated pathology of the respiratory tract in children. There is a dire need for the development of novel therapeutic approaches during mixed infections. Therapeutic intravenous immunoglobulin preparations, obtained from plasma pools of healthy donors have been used in immune deficiencies. This study was thus designed to characterize the functional efficacy of RSV-specific antibodies in IVIg. To explore the functional ability of these affinity-purified RSV-specific antibodies, the antibody-dependent and complement dependent cytotoxicity was determined using peripheral cells of healthy donors. This study demonstrates the existence of highly potent RSV-specific antibodies in IVIg preparations and provides the basis for the use of IVIg as broad-spectrum protective shield to RSV-infected children during mixed infections