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di Cantogno E.V.,Merck Serono S.A. Geneva | Russell S.,Merck Serono S.A. | Snow T.,Merck Serono S.A.
Patient Preference and Adherence | Year: 2011

Background: All established disease-modifying drugs for multiple sclerosis require parenteral administration, which can cause difficulties for some patients, sometimes leading to suboptimal adherence. A new electronic autoinjection device has been designed to address these issues. Methods: Patients with relapsing multiple sclerosis currently receiving subcutaneous or intramuscular interferon beta-1a, interferon beta-1b, or glatiramer acetate completed an online questionnaire (July 4-25, 2008) that surveyed current injection practices, experiences with current injection methods, and impressions and appeal of the new device. Results: In total, 422 patients completed the survey, of whom 44% used autoinjectors, 43% prefilled syringes, and 13% syringes and vials; overall, 66% currently self-injected. Physical and psychological barriers to self-injection included difficulty with injections, needle phobia, and concerns over correct injection technique. Only 40% of respondents were "very satisfied" with their current injection method. The new electronic autoinjector was rated as "very appealing" by 65% of patients. The benefits of the new device included the ability to customize injection settings and to review dosing history. Conclusion: New technologies may help patients overcome physical and psychological barriers to self-injection. The combination of a reliable and flexible autoinjection device with dose-monitoring technology may improve communication between health care professionals and patients, and improve treatment adherence. © 2011 Gonzalez et al, publisher and licensee Dove Medical Press Ltd.


Podurgiel S.,University of Connecticut | Collins-Praino L.E.,University of Connecticut | Yohn S.,University of Connecticut | Randall P.A.,University of Connecticut | And 3 more authors.
Pharmacology Biochemistry and Behavior | Year: 2013

Safinamide is an α-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0 mg/kg IP), the muscarinic agonist pilocarpine (0.5 mg/kg IP), and the dopamine D2 antagonist pimozide (1.0 mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0 mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor. © 2013 Elsevier Inc.


Sormani M.P.,University of Genoa | Li D.K.,University of British Columbia | Bruzzi P.,Italian National Cancer Institute | Stubinski B.,Merck Serono S.A. Geneva | And 3 more authors.
Neurology | Year: 2011

Objective: In multiple sclerosis (MS), the aim of therapies is to prevent the accumulation of irreversible disability. This is difficult to assess given the short time course of clinical trials. MRI markers and relapses are often used as surrogate of disability in MS studies, but their validity remains controversial. We sought to validate, at the individual patient level, MRI lesions and relapses as surrogates for disability progression over the course of MS trials. Methods: Individual patient data from a large, placebo-controlled trial of interferon -1a in relapsing-remitting MS (RRMS) were analyzed. The Prentice criteria were applied to evaluate surrogacy of 1-year MRI active lesions and relapses for disability worsening (Expanded Disability Status Scale [EDSS]) over the 2-year follow-up. Results: All Prentice criteria were satisfied. Treatment reduced by 31% the odds of having EDSS worsening over 2 years, reducing the mean number of MRI lesions by 61% and the mean number of relapses by 36% over 1 year. Both 1-year MRI lesion activity and relapses, when considered independently, accounted for more than 60% of the treatment effect on 2-year EDSS worsening. A combination of 1-year MRI lesion activity and relapses explained 100% of the treatment effect on EDSS worsening over 2 years. Conclusions: A combined measure of 1-year changes in MRI lesions and relapses after interferon therapy fully estimated the corresponding effect on 2-year EDSS worsening. This short-term combined measure appears to be a surrogate for disability progression over a longer term when evaluating the effect of interferon in RRMS. Copyright © 2011 by AAN Enterprises, Inc.


Gregoire L.,Molecular Endocrinology and Genomic Research Center | Jourdain V.A.,Molecular Endocrinology and Genomic Research Center | Jourdain V.A.,Laval University | Townsend M.,EMD Serono, Inc. | And 3 more authors.
Parkinsonism and Related Disorders | Year: 2013

Introduction: Safinamide is a compound under investigation for use in the treatment of Parkinson's disease for combination with pharmacological therapy currently available. The objective of this study was to test the effects of safinamide in an animal model of l-DOPA-induced dyskinesias (LID), the MPTP lesioned dyskinetic macaque monkey, in comparison to and in combination with amantadine. Methods: LID and parkinsonian symptoms were measured in dyskinetic monkeys treated with l-DOPA with and without several dose levels of safinamide, amantadine, and the two in combination. Safinamide plasma levels were monitored during the experiments. Results: Safinamide pre-treatment (3, 10, 20 and 30 mg/kg) dose-dependently reduced LID scores, in two acute and one semi-chronic experiment. Intensity and duration of LID were reduced and inversely correlated with safinamide blood levels. All doses of safinamide tested prolonged the duration of the beneficial antiparkinsonian effect of l-DOPA. Amantadine (5 and 20 mg/kg) reduced LID, but reduced duration of antiparkinsonian response to l-DOPA. When added to amantadine (5 mg/kg), safinamide showed no (3 mg/kg) or modest (20 mg/kg) additional beneficial effects on LID while the combined treatment prevented the reduction of the duration of the l-DOPA antiparkinsonian effect observed with amantadine only. Conclusions: Safinamide and amantadine reduced LID in this primate model while only safinamide increased the duration of the antiparkinsonian response of l-DOPA, suggesting that safinamide may have effects on LID that are pharmacologically distinct from amantadine, which is in current clinical use for control of LID. © 2013 Elsevier Ltd.


Dorner T.,Charite University Hospital Berlin and Deutsches Rheumaforschungszentrum | Kinnman N.,Merck Serono S.A. Geneva | Tak P.P.,University of Amsterdam
Pharmacology and Therapeutics | Year: 2010

B cell-depletion therapy, particularly using anti-CD20 treatment, has provided proof of concept that targeting B cells and the humoral response may result in clinical improvements in immune-mediated inflammatory disease. In this review, the mechanisms of action of B cell-targeting drugs are investigated, and potential biomarkers associated with response to treatment in patients with autoimmune diseases are identified. Most available data relate to B cell depletion using anti-CD20 therapy (rituximab) in patients with rheumatoid arthritis (RA). Treatment leads to significant clinical benefit, but apparently fails to deplete long-lived plasma cells, and discontinuation is associated with relapse. Biomarkers commonly used in studies of B cell-targeted therapies include rheumatoid factor, anti-citrullinated peptide antibodies, and immunoglobulin (Ig) levels. More recently, there has been interest in markers such as B cell phenotype analysis, and B lymphocyte stimulator (BLyS)/a proliferation-inducing ligand (APRIL), the latter particularly in studies of the IgG Fc-transmembrane activator and CAML interactor (TACI) fusion protein (atacicept) and anti-BLyS therapy (belimumab). Data from clinical trials of B cell-depleting agents in RA suggest that specific autoantibodies, BLyS, APRIL, and circulating and synovial B lineage cell levels may have potential as biomarkers predictive of response to treatment. Further trials validating these markers against clinical outcomes in RA are required. In patients with systemic lupus erythematosus, Fc receptors and levels of circulating immune cells (including B cells and natural killer cells) may be relevant markers. © 2010 Elsevier Inc. All rights reserved.


Broekmans F.J.M.,University Utrecht | De Ziegler D.,University of Paris Descartes | Howles C.M.,Merck Serono S.A. Geneva | Gougeon A.,French Institute of Health and Medical Research | And 2 more authors.
Fertility and Sterility | Year: 2010

Objective: To provide recommendations for the standardized use of the Antral follicle count (AFC) which is used to predict ovarian response to gonadotrophin stimulation during assisted reproductive technology treatment. However, the nature of the follicles that are visualized by ultrasound and the competence of the oocytes held within are largely unknown. In addition, there is considerable variability in the clinical definitions and technical methods used to count and measure antral follicles in both published studies and clinical practice. Design and Setting: In December 2007, specialist reproductive medicine clinicians and scientists attended a workshop in an effort to address these issues. Literature concerning the physiology and measurement of ovarian antral follicles was reviewed, clinical and technical considerations regarding antral follicle measurement were discussed, and an operational definition of AFC was developed. Patient(s): None. Intervention(s): None. Outcome Measures: Simple recommendations were established for the standardization of AFC assessment in routine clinical practice. The basic clinical and technical requirements required for AFC evaluation were agreed upon, and a systematic method of measuring and counting antral follicles in routine practice was proposed. Conclusion(s): The use of a standardized approach according to the practical recommendations for antral follicle counting as presented is encouraged in future clinical trials and routine practice. The authors also advocate a systematic evaluation of these recommendations as standardized study data become available. © 2010 by American Society for Reproductive Medicine.


Tchetchelnitski V.,University College London | Van den Eijnden M.,MERCK SERONO SA. Geneva | Schmidt F.,MERCK SERONO SA. Geneva | Stoker A.W.,University College London
International Journal of Developmental Neuroscience | Year: 2014

Receptor-type protein tyrosine phosphatases (RPTPs) have been implicated as direct or indirect regulators of neurotrophin receptors (TRKs). It remains less clear if and how such RPTPs might regulate TRK proteins in vivo during development. Here we present a comparative expression profile of RPTP genes and Trk genes during early stages of murine, dorsal root ganglion maturation. We find little if any specific, temporal mRNA co-regulation between individual RPTP and Ntrk genes between E12.5 and E14.5. Moreover, a double fluorescent in-situ hybridization and immunofluorescence study of seven Rptp genes with Ntrks revealed widespread co-expression of RPTPs in individual neurons, but no tight correlation with Trk expression profiles. No Rptp is expressed in 100% of Ntrk1-expressing neurons, whereas at least 6 RPTPs are expressed in 100% of Ntrk2- and Ntrk3-expressing neurons. An exception is Ptpro, which showed very selective expression. Short hairpin RNA suppression of Ptprf, Ptprs or Ptpro in primary, E13.5 DRG neurons did not alter TRK signalling. We therefore propose that TRK signalling may not be simply dependent on rate-limiting regulation by individual RPTP subtypes during sensory neuron development. Instead, TRK signalling has the potential to be buffered by concurrent inputs from several RPTPs in individual neurons. © 2014.


Exell S.,Merck Serono S.A. Geneva | Verdun E.,Merck Serono S.A. Geneva | Driebergen R.,Merck Serono S.A. Geneva
Expert Review of Medical Devices | Year: 2011

Disease-modifying drugs (DMDs) can provide important benefits for patients with multiple sclerosis (MS), but nonadherence to treatment is associated with an increased risk of relapse. All first-line DMDs used in MS require regular injection, but injection-related problems are common barriers to treatment adherence. Autoinjectors that allow automatic injection at the press of a button have increased the ease and convenience of injection, compared with manual injection. A new electronic autoinjector has recently been introduced for the administration of subcutaneous IFN-β-1a. This device is the first electronic autoinjector for use with any MS therapy, and includes several innovative features that may be advantageous to patients. One of these features is an accurate electronic dosing log, which can be viewed by the patient and the healthcare provider. This article discusses this new electronic device in the context of other autoinjectors currently used to self-inject first-line DMDs in MS. © 2011 Expert Reviews Ltd.


Bollin F.,Merck Serono S.A. Geneva | Dechavanne V.,Merck Serono S.A. Geneva | Chevalet L.,Merck Serono S.A. Geneva
Protein Expression and Purification | Year: 2011

Transient gene expression (TGE) is a well-established enabling technology for rapid generation of recombinant proteins, with Human Embryonic Kidney (HEK) and Chinese Hamster Ovary (CHO) cell lines and polyethyleneimine (PEI) as the transfection reagent being its most popular components. However, despite considerable progress made in the field, volumetric titers can still be a limiting factor causing the manipulation of increasing quantities of culture media and DNA. Here, we report a systematic analysis of TGE conditions and their influence on yields and protein quality. Guided by Design of Experiments (DoE), we conclude that TGE yields with one test antibody can be maximized by a parallel increase of cell density - 2.4 to 3.0 × 106 cells/mL - and PEI concentration - 24 to 30 mg/L - while maintaining a 1:1 ratio of heavy chain and light chain encoding plasmids. Interestingly, we also show that in these conditions, DNA concentration can be maintained in the 1 mg/L range, thereby limiting the need for large DNA preparations. Our optimized settings for PEI-mediated TGE in HEK and CHO cells evaluated on several proteins are generally applicable to recombinant antibodies and proteins. © 2011 Elsevier Inc. All rights reserved.


The present invention provides a new synthesis for preparing N-(3-amino-quinoxalin-2-yl)-sulfonamides of general formulae (I) or (I) and intermediates sulfonamides of formula (II) or (II):

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