Jeppesen P.B.,Rigshospitalet |
Messing B.,Hopital Beaujon Service de Gastroenterologie et Assistance Nutritive |
Iyer K.,Mount Sinai Medical Center |
Seidner D.L.,Vanderbilt University |
And 4 more authors.
Gastroenterology | Year: 2012
Background & Aims: Teduglutide, a glucagon-like peptide 2 analogue, might restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion. These factors could increase fluid and nutrient absorption in patients with short bowel syndrome with intestinal failure (SBS-IF). We performed a prospective study to determine whether teduglutide reduces parenteral support in patients with SBS-IF. Methods: We performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/d; n = 43) or placebo (n = 43) once daily. Parenteral support was reduced if 48-hour urine volumes exceeded baseline values by <10%. The primary efficacy end point was number of responders (patients with >20% reduction in parenteral support volume from baseline at weeks 20 and 24). Results: There were significantly more responders in the teduglutide group (27/43 [63%]) than the placebo group (13/43 [30%]; P =.002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 ± 3.8 L/wk (baseline 12.9 ± 7.8 L/wk) compared with 2.3 ± 2.7 L/wk (baseline 13.2 ± 7.4 L/wk) in the placebo group (P <.001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54%]) than in the placebo group (9/39 [23%]; P =.005). Teduglutide increased plasma concentrations of citrulline, a biomarker of mucosal mass. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3). Conclusions: Twenty-four weeks of teduglutide treatment was generally well tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF; ClinicalTrials.gov Number, NCT00798967. © 2012 AGA Institute.
Keith P.K.,McMaster University |
Desrosiers M.,Hotel Dieu de Montreal |
Laister T.,Nycomed A Takeda Company |
Schellenberg R.R.,St Pauls Hospital |
Waserman S.,McMaster University
Allergy, Asthma and Clinical Immunology | Year: 2012
Background: Allergic rhinitis (AR) is a common problem and we sought to examine the burden of disease and its management in Canada from the perspectives of patients and physicians.Methods: Two parallel, Canadawide structured telephone interviews surveyed 1,001 AR patients and 160 physicians in July 2006.Results: 44% of patients had experienced nasal symptoms unrelated to a cold and 20% had a physician diagnosis of AR. At screening 27% reported asthma, 15% chronic or recurrent sinusitis and 5% nasal polyps. With attacks nasal congestion and runny nose were the most bothersome symptoms. Other problems experienced were fatigue (46%), poor concentration (32%), and reduced productivity (23%). Most (77%) had not seen a physician in the past year. Physicians estimated they prescribed intranasal cortico steroids (INCS) to most AR patients (77%) consistent with guidelines but only 19% of patients had used one in the last month. Only 48% of patients were very satisfied with their current INCS. 41% of AR patients reported discontinuing their INCS with the most common reason being a perceived lack of long-lasting symptom relief (44%). 52% of patients felt that their current INCS lost effectiveness over 24 h. The most common INCS side effects included dripping down the throat, bad taste, and dryness. Most AR patients reported lifestyle limitations despite treatment (66%). 61% of patients felt that their symptoms were only somewhat controlled or poorly/not controlled during their worst month in the past year.Conclusions: AR symptoms are common and many patients experience inadequate control. Physicians report they commonly prescribe intranasal corticosteroids, but patient's perceived loss of efficacy and side effects lead to their discontinuation. Persistent relief of allergic rhinitis symptoms remains a major unmet need. Better treatments and education are required. © 2012 Keith et al.; licensee BioMed Central Ltd.
White W.B.,University of Connecticut |
Cooke G.E.,Ohio State University |
Kowey P.R.,Lankenau Medical Center |
Calverley P.M.A.,University of Liverpool |
And 7 more authors.
Chest | Year: 2013
Background: Evaluation of cardiovascular safety for new therapies for COPD is important because of a high prevalence of cardiac comorbidities in the COPD population. Hence, we evaluated the effects of rofl umilast, a novel oral phosphodiesterase 4 inhibitor developed for the treatment and prevention of COPD exacerbations, on major adverse cardiovascular events (MACEs). Methods: Intermediate-and long-term placebo-controlled clinical trials of rofl umilast in COPD were pooled and assessed for potential cardiovascular events. Studies comprised 14 12-to 52-week placebo-controlled trials in patients with moderate to very severe COPD. All deaths and serious nonfatal cardiovascular events were evaluated by an independent adjudication committee blinded to study and treatment. The MACE composite of cardiovascular death, nonfatal myocardial infarction, and stroke was analyzed according to treatment group. Results: Of 6,563 patients receiving rofl umilast, 52 experienced MACEs (14.3 per 1,000 patient-years), and of 5,491 patients receiving placebo, 76 experienced MACEs (22.3 per 1,000 patient-years). The MACE composite rate was signifi cantly lower for rofl umilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P = .019). Conclusions: A lower rate of cardiovascular events was observed with rofl umilast than with placebo in patients with COPD, indicating the lack of a cardiovascular safety signal when treating patients with COPD. Potential cardiovascular benefi ts of rofl umilast should be evaluated in future controlled clinical trials.
Black D.M.,University of California at San Francisco |
Bilezikian J.P.,Columbia University |
Greenspan S.L.,University of Pittsburgh |
Wuster C.,Clinic for Endocrinology and Osteology |
And 5 more authors.
Osteoporosis International | Year: 2013
Summary: The purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy. Introduction: There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. Methods: Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. Results: PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8 % above baseline (p < 0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2 % above baseline. Larger increases in spine BMD were observed in participants with ≥80 % adherence to daily injections of PTH(1-84) (8.3 % in adherent vs 4.9 % in poorly adherent patients). Total hip BMD gains were 1.7 % in adherent vs 0.6 % in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. Conclusions: PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy. © 2012 International Osteoporosis Foundation and National Osteoporosis Foundation.
Wedzicha J.A.,University College London |
Rabe K.F.,University of Kiel |
Rabe K.F.,Center for Pulmonology and Thoracic Surgery |
Rabe K.F.,Leiden University |
And 5 more authors.
Chest | Year: 2013
Background: COPD exacerbations are associated with increased morbidity and mortality and can accelerate disease progression. The best predictor of future exacerbations is a history of previous exacerbations, which helps identify a frequent exacerbator phenotype. This post hoc analysis evaluated the effect of roflumilast, a drug known to reduce the COPD exacerbation rate, on exacerbation status. Methods: Pooled data from two 1-year, placebo-controlled, roflumilast (500 μg once daily) studies in patients with symptomatic COPD and severe airflow obstruction were evaluated (studies M2-124 and M2-125, ClinicalTrials.gov identifiers NCT00297102 and NCT00297115). A total of 3,091 patients were included in this analysis (62.5% with GOLD [Global Initiative for Chronic Obstructive Lung Disease] III COPD and 29.2% with GOLD 4 COPD). Based on their exacerbation frequency status in the previous year, patients were classified as frequent (two or more events) or infrequent (fewer than two events) exacerbators. Exacerbation frequency was analyzed at baseline and at year 1. Results: Among frequent exacerbators treated with roflumilast, 32.0% still had frequent exacerbations at year 1 compared with 40.8% of placebo-treated patients (risk ratio, 0.799; P = .0148). Among infrequent exacerbators, 17.5% of roflumilast-treated patients became frequent exacerbators at year 1 compared with 22.9% of those taking placebo (risk ratio, 0.768; P = .0018). The reduction in severe exacerbations leading to hospitalization/death was similar between subgroups and occurred independently of concomitant long-acting β2-agonists or previous inhaled corticosteroid treatment. When analyzed by severity of airflow limitation, 26.4% of roflumilast-treated frequent exacerbators with GOLD III COPD remained frequent exacerbators at year 1 compared with 38.9% of those taking placebo (P = .0042). Conclusions: Treatment with roflumilast shifts patients from the frequent to the more stable infrequent exacerbator state. Trial registry: ClinicalTrials.gov; No.: NCT00297102 and NCT00297115; URL: www.clinicaltrials.gov ©2013 American College of Chest Physicians.
Vollert S.,Nycomed A Takeda Company |
Kaessner N.,Nycomed |
Heuser A.,Nycomed A Takeda Company |
Hanauer G.,Nycomed |
And 5 more authors.
Diabetologia | Year: 2012
Aims/hypothesis: The cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects. Methods: Plasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA1c, blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets. Results: Single treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5- and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA1c by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolin-induced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling. Conclusions/interpretation: Our results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities. © 2012 Springer-Verlag.
Nave R.,Nycomed a Takeda Company |
Muller H.,Nycomed a Takeda Company
International Journal of General Medicine | Year: 2013
Asthma continues to be a global health problem and currently available treatments such as corticosteroids can cause unwanted side effects. Inhaled corticosteroids (ICS) are recommended as first-line therapy for reducing airway inflammation and have a distinct advantage over oral preparations as they provide a direct route of delivery to the lungs. However, local deposition of ICS in the oropharynx can lead to oral candidiasis, dysphonia, and pharyngitis. The pharmaceutical quality is a primary concern of any ICS asthma treatment, with a higher quality product resulting in improved efficacy and safety profiles. The particle size distribution and the spray force velocity of an ICS may directly influence lung deposition, and the spray duration of a device is another important factor when coordinating inhalation. Recent advances in ICS device and formulation technology have resulted in significant improvements in the efficacy of available asthma treatments. In particular, hydrofluoroalkane (HFA) solution technology and the development of smaller particle sizes have resulted in the production of new ICS formulations that have the ability to directly target drug delivery to the site of airway inflammation. Both the ICS formulation and the pressurized metered-dose inhaler device used to administer ciclesonide (CIC) HFA have been developed to treat the underlying chronic inflammation associated with asthma. CIC is administered as a prodrug which is activated in the lungs, leading to minimal oropharyngeal deposition. The small particle size of CIC results in the delivery of a high fraction of respirable particles to the small airways of the lungs, resulting in high lung deposition and continual dose consistency. This review summarizes how CIC administered as an HFA formulation is an effective treatment for asthma. © 2013 Nave and Mueller, publisher and licensee Dove Medical Press Ltd.
Dunkern T.,Nycomed A Takeda Company
Journal of computer-aided molecular design | Year: 2012
IMPDH (Inosine 5'-monophosphate dehydrogenase) catalyzes a rate-limiting step in the de novo biosynthesis of guanine nucleotides. IMPDH inhibition in sensitive cell types (e.g., lymphocytes) blocks proliferation (by blocking RNA and DNA synthesis as a result of decreased cellular levels of guanine nucleotides). This makes it an interesting target for cancer and autoimmune disorders. Currently available IMPDH inhibitors such as mycophenolic acid (MPA, uncompetitive inhibitor) and nucleoside analogs (e.g., ribavirin, competitive inhibitor after intracellular activation by phosphorylation) have unfavorable tolerability profiles which limit their use. Hence, the quest for novel IMPDH inhibitors continues. In the present study, a ligand-based virtual screening using IMPDH inhibitor pharmacophore models was performed on in-house compound collection. A total of 50,000 virtual hits were selected for primary screen using in vitro IMPDH II inhibition up to 10 μM. The list of 2,500 hits (with >70 % inhibition) was further subjected to hit confirmation for the determination of IC(50) values. The hits obtained were further clustered using maximum common substructure based formalism resulting in 90 classes and 7 singletons. A thorough inspection of these yielded 7 interesting classes in terms of mini-SAR with IC(50) values ranging from 0.163 μM to little over 25 μM. The average ligand efficiency was found to be 0.3 for the best class. The classes thus discovered represent structurally novel chemotypes which can be taken up for further development.
Christensen N.P.A.,Copenhagen University |
Nielsen S.,Nycomed A Takeda Company |
Rantanen J.,Copenhagen University |
Cornett C.,Copenhagen University |
Bertelsen P.,Nycomed A Takeda Company
Powder Technology | Year: 2014
There is a growing need to increase our understanding of physicochemical stability of pharmaceuticals during manufacturing. The present study has investigated effects of excipients and processing conditions on the physicochemical properties of two weakly acidic model drugs (piroxicam and lornoxicam) in solid dosage pharmaceuticals. By means of solid-state analysis it was observed that basic excipients (sodium bicarbonate and dicalcium phosphate) may induce salt formation of these drug compounds during wet granulation, whereby the drug dissolution rate from formulations containing lornoxicam was significantly increased while the dissolution from piroxicam-containing formulations was unaffected. Following preparation of the solid drug formulations, chromatographic analysis demonstrated that the processing-induced sodium salt formation increase chemical degradation of both model drugs during storage. Hence, the present study illustrate that processing-induced transformations in the solid phase of drugs encountered during manufacture of solid dosage pharmaceuticals may significantly impact critical quality attributes of the final medicinal product. © 2014.
Sann H.,Nycomed A Takeda Company |
Erichsen J.V.,Nycomed A Takeda Company |
Hessmann M.,Nycomed A Takeda Company |
Pahl A.,Nycomed A Takeda Company |
Hoffmeyer A.,Nycomed A Takeda Company
Life Sciences | Year: 2013
Aims Although acute dextran sodium sulphate (DSS)-induced colitis in mice is frequently used as a preclinical model for testing drugs involved in inflammatory bowel disease (IBD), only limited data is available that compares the efficacy of established drug treatments and combinations employed in IBD. We have therefore compared the efficacy of aminosalicylates (mesalazine, olsalazine), corticosteroids (budesonide), thiopurines (6-thioguanine (6-TG)) and cyclosporine A (CsA) and combinations thereof as well as the EP4 agonist AGN205203 in the acute DSS-colitis model. Main methods Female BALB/c mice were challenged with 4% DSS in drinking water for 7 days to induce colitis and treated daily with different drugs/combinations orally. Disease scores (diarrhoea, bleeding, disease activity index), systemic (body weight loss, serum amyloid A levels) and colonic (myeloperoxidase activity, length and histopathology) inflammation parameters were analysed. Key findings Mesalazine, olsalazine (100 mg/kg) and budesonide (0.5 mg/kg) were only weakly active or even worsened colitis. 6-TG dose-dependently reduced systemic and colonic inflammation parameters with estimated ED50 values between 0.5-4 mg/kg. CsA (10, 25 and 50 mg/kg) dose-dependently reduced colitis with high efficacy on systemic inflammation. A combination of CsA 25 mg/kg + olsalazine 100 mg/kg produced a more pronounced anti-inflammatory effect than the compounds given alone. AGN205203 (3, 10 and 30 mg/kg BID) was the most efficacious compound and almost completely inhibited colitis. Significance 6-TG and CsA are suitable reference compounds in the DSS mouse model. CsA + olsalazine, as a combination, was more efficacious than the compounds given alone, supporting combination treatments in IBD. © 2013 Elsevier Inc.