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Konstanz, Germany
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McGregor D.,Toxicity Evaluation Consultants | Boobis A.,Imperial College London | Binaglia M.,Solvay Group | Botham P.,Syngenta | And 6 more authors.
Critical Reviews in Toxicology | Year: 2010

The United Nations Conference on Environment and Development (UNCED) has developed criteria for a globally harmonised system of classification and labelling of chemicals (GHS). With regard to carcinogenicity, GHS distinguishes between Category 1 ('known or presumed human carcinogens') and Category 2 ('suspected human carcinogens'). Category 1 carcinogens are divided into Category 1A ('known to have carcinogenic potential for humans'), based largely on human evidence, and 1B ('presumed to have carcinogenic potential for humans'), based largely on experimental animal data. Concerns have been raised that the criteria for applying these carcinogenicity classifications are not sufficiently well defined and potentially allow different conclusions to be drawn. The current document describes an attempt to reduce the potential for diverse conclusions resulting from the GHS classification system through the application of a series of questions during the evaluation of data from experiments with rodents; epidemiological data, which could lead to Category 1A, have not been considered. Answers to each question can lead either to a classification decision or to the next question, but this process should only be implemented in an environment of informed scientific opinion. The scheme is illustrated with five case studies. These questions are: (1) Has a relevant form of the substance been tested (2) Is the study design relevant to human exposure (3) Is there a substance-related response (4) Is the target tissue exposure relevant to humans (5) Can a mode of action be established (6) Is the mode of action relevant to humans (7) What is the potency © 2010 Informa UK Ltd.


Buenestado A.,University of Versailles | Grassin-Delyle S.,University of Versailles | Guitard F.,University of Versailles | Naline E.,University of Versailles | And 7 more authors.
British Journal of Pharmacology | Year: 2012

Background and purpose: Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS. Experimental approach: Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE 2, the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE 2 and 6-keto PGF 1α were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates. Key results: Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration- dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE 2 (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE 2(10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE 2and 6-keto PGF 1α release from lung macrophages which was associated with an up-regulation of COX-2 mRNA. Conclusions and implications: Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages. © 2011 The British Pharmacological Society.


Brown M.B.,MedPharm Ltd | Brown M.B.,University of Hertfordshire | Lau C.-H.,MedPharm Ltd | Lim S.T.,MedPharm Ltd | And 5 more authors.
Journal of Pharmacy and Pharmacology | Year: 2012

Objectives The developments in combinatorial chemistry have led to a rapid increase in drug design and discovery and, ultimately, the production of many potential molecules that require evaluation. Hence, there has been much interest in the use of mathematical models to predict dermal absorption. Therefore, the aim of this study was to test the performance of both linear and nonlinear models to predict the skin permeation of a series of 11 compounds. Methods The modelling in this study was carried out by the application of both quantitative structure permeability relationships and Gaussian process-based machine learning methods to predict the flux and permeability coefficient of the 11 compounds. The actual permeation of these compounds across human skin was measured using Franz cells and a standard protocol with high performance liquid chromatography analysis. Statistical comparison between the predicted and experimentally- derived values was performed using mean squared error and the Pearson sample correlation coefficient. Key findings The findings of this study would suggest that the models failed to accurately predict permeation and in some cases were not within two- or three-orders of magnitude of the experimentally-derived values. However, with this set of compounds the models were able to effectively rank the permeants. Conclusions Although not suitable for accurately predicting permeation the models may be suitable for determining a rank order of permeation, which may help to select candidate molecules for in-vitro screening. However, it is important to note that such predictions need to take into account actual relative drug candidate potencies. © 2012 Royal Pharmaceutical Society.


Viborg Mortensen F.,University Hospital | Birth M.,Klinik fur Allgemein | Gunther K.,Hauptabteilung fur Allgemein und Viszeralchirurgie | Habicht A.,Signifikans ApS | And 2 more authors.
Gesundheitsokonomie und Qualitatsmanagement | Year: 2012

Aim: The aim of this study was to evaluate treatments for haemostasis and the potential hospital resource use implications of these treatments by way of expert assessment. Methods: This analysis was based on data from a non-interventional surveillance study, which enrolled 3098 patients at 227 centres in 12 European countries. All patients received a haemostatic sealing patch (TachoSil®, Nycomed GmbH, Zurich, Switzerland), with the decision to use TachoSil made by the surgeon. Data on duration of surgery, hospital length of stay (LOS) and use of blood products were collected. Surgeons were asked to compare TachoSil with products or procedures they would otherwise have used. Results: Mean duration of surgery was 192.1 minutes and mean hospital LOS was 17.5 days. According to surgeons, operating time would have been significantly reduced with TachoSil versus the potential alternative in 55.5% of patients (p<0.001). Surgeons predicted that the use of TachoSil would reduce duration of surgery by 12.2 minutes. Choice of alternative treatment, type of surgery and country had a significant effect on surgeons assessment. TachoSil was thought to offer greater benefits in anti-coagulated patients with a normal pre-operative coagulation test and in emergency surgery. Conclusion: The use of topical haemostatic agents such as TachoSil may offer benefits with regard to hospital resource use. copy; Georg Thieme Verlag KG · Stuttgart · New York.


Marta G.M.,Vienna University Hospital | Facciolo F.,Italian National Cancer Institute | Ladegaard L.,University of Southern Denmark | Dienemann H.,University of Heidelberg | And 6 more authors.
European Journal of Cardio-thoracic Surgery | Year: 2010

Objectives: Alveolar air leakage remains a serious problem in lung surgery, being associated with increased postoperative morbidity, prolonged hospital stay and greater health-care costs. The aim of this study was to evaluate the sealing efficacy and safety of the surgical patch, TachoSil®, in lung surgery. Methods: Patients undergoing elective pulmonary lobectomy who had grade 1 or 2 air leakage (evaluated by the water submersion test) after primary stapling and limited suturing were randomised at 12 European centres to open-label treatment with TachoSil® or standard surgical treatment (resuturing, stapling or no further treatment at the surgeons' discretion). Randomisation was performed during surgery using a centralised interactive voice response system. Duration of postoperative air leakage (primary end point), reduction of intra-operative air leakage intensity (secondary end point) and adverse events (AEs), including postoperative complications, were assessed. Results: A total of 486 patients were screened and 299 received trial treatment (intent-to-treat (ITT) population: TachoSil®, n=148; standard treatment, n=151). TachoSil® resulted in a reduction in the duration of postoperative air leakage (p=0.030). Patients in the TachoSil® group also experienced a greater reduction in intra-operative air leakage intensity (p=0.042). Median time until chest drain removal was 4 days with TachoSil® and 5 days in the standard group (p=0.054). There was no difference between groups in hospital length of stay. AEs were generally similar in both groups, including postoperative complications. Conclusions: TachoSil® was superior to standard surgical treatment in reducing both postoperative air leakage duration and intra-operative air leakage intensity in patients undergoing elective pulmonary lobectomy. © 2010 European Association for Cardio-Thoracic Surgery.


Vissers D.,Mapi Values | Stam W.,Mapi Values | Nolte T.,Schmerz und Palliativzentrum | Lenre M.,Nycomed | Jansen J.,Mapi Values
Current Medical Research and Opinion | Year: 2010

Objective: To compare the efficacy of intranasal fentanyl spray (INFS), oral transmucosal fentanyl citrate (OTFC), fentanyl buccal tablet (FBT) and oral morphine (OM) for the treatment of breakthrough cancer pain (BTCP). Methods: A systematic literature review (Medline, EMBASE, BIOSIS; 19962007) identified six randomised controlled trials (RCTs) investigating the effects of INFS, OTFC, FBT and OM for the treatment of BTCP. The endpoint of interest was pain intensity difference (PID, reported on a 010 numeric rating scale [NRS]) up to 60 minutes after intake. Results of all trials were analysed simultaneously with a mixed treatment comparison (extended meta-analysis). MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics. Results: INFS provided the greatest reduction in pain relative to placebo: PID 1.7 points (95 CrI: 1.4; 1.9) at 15 minutes, 2.0 (1.6; 2.3) at 30 minutes, 2.0 (1.5; 2.4) at 45 minutes and 1.9 (1.5; 2.4) at 60 minutes. PID for OTFC and FBT relative to placebo were 0.4 (0.0; 0.8) and 0.5 (0.3; 0.7) at 15 minutes. Both treatments provided a reduction in pain superior to placebo at other time points. INFS displayed a more than 99 probability of providing the greatest pain reduction out of all interventions compared at 15 minutes after intake. This was maintained for any measured time point before 45 minutes when compared to FBT and for any measured time point before 60 minutes when compared to OTFC. Only from 45 minutes onwards did OM show a greater pain reduction than placebo. Conclusion: Based on currently available evidence, INFS is expected to provide the greatest improvement in the treatment of BTCP. Due to its slow onset to effect OM cannot be considered an efficacious treatment for BTCP. © 2010 Informa UK Ltd All rights reserved.


Zanchetta J.R.,Institute Investigaciones Metablicas | Bogado C.E.,Institute Investigaciones Metablicas | Cisari C.,University of Piemonte Orientale | Aslanidis S.,Hippokration General Hospital | And 3 more authors.
Current Medical Research and Opinion | Year: 2010

Objective: To determine the safety and efficacy of full-length parathyroid hormone, PTH(184), treatment for up to 36 months by evaluating bone mineral density (BMD) changes, bone histomorphometric indices, and clinical fracture incidence in postmenopausal women with osteoporosis. Background: The TOP trial demonstrated increased lumbar spine BMD (6.9) versus placebo after 18 months of PTH(184) treatment and reduced the incidence of new vertebral fractures (61; p0.001). The therapeutic benefits of long-term treatment of postmenopausal women with PTH(184) are unknown. Methods: The safety and efficacy of 36 months of once-daily dosing with 100g PTH(184) in postmenopausal women with osteoporosis were assessed. Women receiving placebo during the TOP trial were eligible for PTH(184) in the extension study. Clinical trial registration: NCT00172120. Results: Lumbar spine BMD increased by 8.5 above baseline (p<0.001) at 36 months of PTH(184) treatment, remaining stable during the last 12 months of treatment. Increases in total hip and femoral neck BMD occurred more slowly, reaching 3.2 and 3.4, respectively above baseline at 36 months (p<0.001). The total hip BMD showed no signs of reaching a limiting value although the femoral neck plateaued from months 24 to 36. Seven patients had vertebral fractures during the placebo phase of the TOP trial and before entering the extension study, but this rate decreased with the introduction of PTH(184) therapy, resulting in a single worsened vertebral fracture in the first 6 months and no further vertebral fractures from months 6 to 36. Treatment over 36 months with PTH(184) was well-tolerated and iliac crest biopsies showed no adverse effects on bone. Limitations: There was no placebo group for BMD comparisons. The number of patients assessed for fracture incidence was small. Conclusions: PTH(184) treatment for 36 months resulted in significant increases in BMD at the lumbar spine and hip, was associated with a lower incidence of vertebral fracture when compared to before therapy initiation, and was well-tolerated. The continuous increases in total hip BMD suggest that prolonged PTH(184) treatment may be beneficial for postmenopausal osteoporosis. Increased BMD at the femoral neck and lumbar spine also showed favourable changes but plateaued between 24 and 36 months. Long-term treatment was not associated with abnormalities in bone biopsies. © 2010 Informa UK Ltd All rights reserved.


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.

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