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Bateman E.D.,University of Cape Town | Goehring U.-M.,Takeda Pharmaceuticals International GmbH | Richard F.,Boehringer Ingelheim | Watz H.,Pulmonary Research Institute at Lung Clinic Grosshansdorf
Journal of Allergy and Clinical Immunology | Year: 2016

Background: Roflumilast, a selective phosphodiesterase 4 inhibitor, has been shown to provide modest improvements in lung function in patients with mild-to-moderate asthma, but its efficacy in patients with moderate-to-severe asthma has not been assessed. We hypothesized that this drug might provide benefit if combined with montelukast, a leukotriene receptor antagonist, in patients whose symptoms are uncontrolled by inhaled corticosteroids and long-acting β-agonists. Objective: We sought to examine the efficacy, safety, and mode of action of the addition of roflumilast and montelukast versus montelukast alone in patients with moderate-to-severe asthma. Methods: In a phase 2, randomized, double-blind, placebo-controlled, multiple-dose, 2-sequence, crossover study, 64 patients were randomized to receive 500 μg of roflumilast plus montelukast followed by placebo plus 10 mg of montelukast (sequence AB) or placebo plus 10 mg of montelukast followed by 500 μg of roflumilast plus 10 mg of montelukast (sequence BA). All patients had a diagnosis of bronchial asthma inadequately controlled by at least a medium-dose inhaled corticosteroid plus a long-acting β-agonist. Results: The analysis of FEV1 change from baseline to week 4 showed a statistically significant and clinically meaningful treatment difference of 100 mL for roflumilast plus montelukast versus placebo plus montelukast. Also, improvements in patient-reported outcomes and a reduction in urinary leukotriene E4 levels were observed during roflumilast plus montelukast treatment compared with placebo plus montelukast treatment. Adverse events were consistent with the known safety profile of roflumilast. Conclusion: The combination of roflumilast with montelukast compared with montelukast alone improved lung function and asthma control in patients with moderate-to-severe asthma and deserves further study for this indication. © 2016 The Authors. Source


Millier A.,Creativ Ceutical | Schmidt U.,Creativ Ceutical | Angermeyer M.C.,Center for Public Mental Health | Angermeyer M.C.,University of Cagliari | And 4 more authors.
Journal of Psychiatric Research | Year: 2014

Objectives of the study and background: Schizophrenia is a complex disease that affects 1% of the population. This disease has a considerable impact not only on patients' health and well-being but also on their surrounding environment. The costs of the disease's management remain large for individuals and society. While literature on the economic impact of schizophrenia is abundant, few studies have focused on its humanistic burden. This does not only concern patients, but also caregivers, relatives, neighbours and others in a patient's daily life. This burden appears through several dimensions, including treatment side effects and the impact on caregivers and features of the patient's environment. The aim of this review is to consider, compile and describe the humanistic burden of schizophrenia as documented in the literature. Materials and methods: We conducted a literature review assessing the worldwide disease burden of schizophrenia, taking into account all humanistic burden topics. The search considered several databases, including Embase, Medline, Cochrane Library, The German Institute of Medical Documentation and Information (DIMDI) and the ISPOR conference websites. Results: The search identified 200 literature reviews, covering several dimensions of humanistic burden and documenting many issues. Main findings included the high death rates that may be explained by long-lasting negative health habits, disease- and treatment-related metabolic disorders, and consequent increased frequencies of cardiovascular diseases. Co-existing depression was found to have adverse consequence on the course of schizophrenia progression, morbidity and mortality. Cognitive impairment also adds to the burden of schizophrenia. Social impairment is worsened by underestimated stigmatisation and lack of corresponding awareness within the professional and social spheres. Finally, caregiver burden was found to be considerable. Discussion: Humanistic burden among patients with schizophrenia is substantial potentially impacted by co-morbid depressive symptoms, caregiver burden and cognitive impairment. Effects of treatment on humanistic burden in addition to economic burden need to be explored in future trials. © 2014 The Authors. Source


Meilin S.,MD Biosciences Ltd | Machicao F.,University of Tubingen | Elmlinger M.,Takeda Pharmaceuticals International GmbH
Journal of Cellular and Molecular Medicine | Year: 2014

This study aimed to investigate whether Actovegin, which is a deproteinized ultrafiltrate derived from calf blood, demonstrates neuroprotective effects in a rat model of transient global cerebral ischaemia. Forty Sprague Dawley rats were subjected to four-vessel occlusion to induce transient global cerebral ischaemia followed by either saline or Actovegin treatment. Sham operations were performed on 15 rats. Actovegin (200 mg/kg) or saline was administered 6 hrs after carotid artery occlusion and then daily until Day 40. Learning and memory were evaluated using the Morris water maze test over two different 5-day periods, and grip strength testing was also performed to control for potential motor impairments. Rat brains were harvested for histological analysis on Day 68. In comparison to controls, Actovegin-treated rats exhibited a decreased latency to reach the hidden platform on the second learning trial of water maze testing (46.82 ± 6.18 versus 27.64 ± 4.53 sec., P < 0.05; 38.3 ± 8.23 versus 13.37 ± 2.73 sec., P < 0.01 for the first and second 5-day testing periods, respectively). In addition, Actovegin-treated rats spent more time in the platform quadrant than saline-treated rats during memory trials (P < 0.05). No differences in grip strength were detected. Histological analyses demonstrated increased cell survival in the CA1 region of the hippocampus following Actovegin treatment (left hemisphere, 166 ± 50 versus 332 ± 27 cells, P < 0.05; right hemisphere, 170 ± 45 versus 307 ± 28 cells, P < 0.05, in saline- versus Actovegin-treated rats, respectively). In rats, Actovegin treatment improves spatial learning and memory following cerebral ischaemia, which may be related to hippocampal CA1 neuroprotection. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Source


Samyshkin Y.,IMS Health | Kotchie R.W.,IMS Health | Mork A.-C.,Takeda Pharmaceuticals International GmbH | Briggs A.H.,University of Glasgow | Bateman E.D.,University of Cape Town
European Journal of Health Economics | Year: 2014

Objective To estimate the cost-effectiveness of adding a selective phosphodiesterase-4 inhibitor, roflumilast, to a long-acting bronchodilator therapy (LABA) for the treatment of patients with severe-to-very severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis with a history of frequent exacerbations from the UK payer perspective. Methods A Markov model was developed to predict the lifetime cost and outcomes [exacerbations rates, life expectancy, and quality-adjusted life years (QALY)] in patients treated with roflumilast, which showed a reduction in the exacerbation rates and lung function improvement in a pooled analysis from two clinical trials, M2-124 and M2-125. Sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness. Results The addition of roflumilast to concomitant LABA reduced the number of exacerbations from 15.6 to 12.7 [2.9 (95 % CI 0.88-4.92) exacerbations avoided] and increased QALYs from 5.45 to 5.61 [0.16 (95 %CI 0.02-0.31)QALYs gained], at an incremental cost of £3,197 (95 % CI £2,135-£4,253). Cost inLABAalone andLABA ? roflumilast were £16,161 and £19,358 respectively. The incremental costeffectiveness ratios in the base case were £19,505 (95 % CI £364-£38,646) per quality-adjusted life-year gained and 18,219 (95 % CI £12,697-£49,135) per life-year gained. Sensitivity analyses suggest that among the main determinants of cost-effectiveness are the reduction of exacerbations and the case fatality rate due to hospital-treated exacerbations. Probabilistic sensitivity analysis suggests that the probability of roflumilast being cost-effective is 82 % at willingness-to-pay £30,000 per QALY. Conclusions The addition of roflumilast to LABA in the treatment of patients with severe-to-very severe COPD reduces the rate of exacerbations and can be cost-effective in the UK setting. © The Author(s) 2013. Source


Craddy P.,Takeda Pharmaceuticals International GmbH | Palin H.-J.,McCann Complete Medical | Johnson K.I.,McCann Complete Medical
Diabetes Therapy | Year: 2014

Objective: To compare the safety and efficacy of the dipeptidylpeptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes and inadequate glycemic control.Design: Systematic review of randomized controlled trials (RCTs), health economic evaluation studies, systematic reviews, and meta-analyses, followed by primary Bayesian mixed treatment comparison meta-analyses (MTCs), and secondary frequentist direct-comparison meta-analyses using a random-effects model. Outcomes were reported as weighted mean change from baseline, or odds ratio (OR) with 95% credible interval.Data sources: MEDLINE, MEDLINE In-Process, EMBASE, and BIOSIS via Dialog ProQuest; Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews via EBSCO; four diabetes and two technical congress abstracts; and health technology assessment organization websites.Eligibility criteria: Patients with type 2 diabetes and inadequate glycemic control receiving any pharmacological anti-diabetic treatment.Data extraction and analysis: Title/abstracts were reviewed for eligibility, followed by full-text review of publications remaining after first pass. A three-person team filtered articles and an independent reviewer checked a random selection (10%) of filtered articles. Data extraction and quality assessment of studies were also independently reviewed. Five DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin) were compared via meta-analysis (where data were available) as monotherapy, dual therapy (plus metformin, sulfonylurea, pioglitazone, or insulin), and triple therapy (plus metformin/sulfonylurea).Results: The review identified 6,601 articles; 163 met inclusion criteria and 85 publications from 83 RCTs contained sufficient or appropriate data for analysis. MTCs demonstrated no differences between DPP-4 inhibitors in mean change from baseline in glycosylated hemoglobin (HbA1c) or body weight, or the proportions of patients achieving HbA1c <7% or experiencing a hypoglycemic event, apart from in patients on alogliptin plus metformin, who achieved HbA1c <7% more frequently than those treated with saxagliptin plus metformin [OR 6.41 (95% CI 3.15–11.98) versus 2.17 (95% CI 1.56–2.95)].Conclusions: This systematic review and MTC showed similar efficacy and safety for DPP-4 inhibitors as treatment for type 2 diabetes, either as monotherapy or combination therapy. © 2014, The Author(s). Source

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