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Michel A.,Neurosciences TA Biology | Downey P.,Neurosciences TA Biology | Nicolas J.-M.,Non Clinical Development | Scheller D.,Neurosciences TA Biology
PLoS ONE | Year: 2014

In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (addon therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch- 58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6- OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients. ©2014 Michel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Delaunois A.,Non Clinical Development | Colomar A.,Non Clinical Development | Depelchin B.O.,Non Clinical Development | Cornet M.,Non Clinical Development
Acta Neurologica Scandinavica | Year: 2015

Objectives: Lacosamide is indicated for the adjunctive treatment of partial-onset seizures in adult patients. Unlike other sodium channel-blocking antiepileptic drugs, lacosamide selectively enhances sodium channel slow inactivation. Potential effects of lacosamide on cardiac sodium channels and their cardiovascular consequences were comprehensively assessed. This manuscript presents the non-clinical cardiac safety profile of lacosamide. Methods: Lacosamide was tested in vitro on sodium and L-type calcium currents from isolated human atrial myocytes and on hERG-mediated potassium currents from stably transfected HEK293 cells. Cardiac action potentials were recorded in guinea pig ventricular myocytes. In vivo, hemodynamic and ECG parameters were evaluated in anesthetized dogs and monkeys receiving acute cumulative intravenous doses of lacosamide. Results: Following intravenous dosing with lacosamide, dose-dependent PR and QRS prolongation and ECG abnormalities (loss of P waves, atrioventricular and intraventricular blocks, junctional premature contractions) were observed in anesthetized dogs and monkeys. In vitro, lacosamide reduced human cardiac sodium currents in a concentration-, voltage- and state-dependent manner. Lacosamide reductions in Vmax in guinea pig myocytes were similar to lamotrigine and carbamazepine. Lacosamide showed no relevant inhibitory effects on hERG and L-type calcium channels and did not prolong QTc in vivo. Conclusions: ECG findings in anesthetized animals correlate well with in vitro sodium channel-related effects and are also consistent with those (PR prolongation, first-degree atrioventricular block) reported in healthy volunteers and patients with epilepsy. Both in vivo and in vitro effects were detected from exposure levels 1.5- to 2-fold above those achieved with the maximum-recommended human lacosamide dose (400 mg/day). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Silva J.-P.,Non Clinical Development | Silva J.-P.,UCB Pharma | Vetterlein O.,Non Clinical Development | Jose J.,Non Clinical Development | And 2 more authors.
Journal of Biological Chemistry | Year: 2015

Human immunoglobulin G isotype 4 (IgG4) antibodies (Abs) are potential candidates for immunotherapy when reduced effector functions are desirable. IgG4 Abs are dynamic molecules able to undergo a process known as Fab arm exchange (FAE). This results in functionally monovalent, bispecific antibodies (bsAbs) with unknown specificity and hence, potentially, reduced therapeutic efficacy. IgG4 FAE is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 Abs. To date, the mechanism of FAE is not entirely understood and studies measuring FAE in ex vivo matrices have been hampered by the presence and abundance of endogenous IgG4 wild-type (WT) Abs. Using representative humanized WT IgG4 monoclonal Abs, namely, anti-IL-6 and anti-TNF, and a core-hinge stabilized serine 228 to proline (S228P) anti-IL-6 IgG4 mutant, it is demonstrated for the first time how anti-IgG4 affinity chromatography can be used to prepare physiologically relevant matrices for assessing and quantifying FAE. A novel method for quantifying FAE using a single MSD immunoassay is also reported and confirms previous findings that, dependent on the redox conditions, the S228P mutation can prevent IgG4 FAE to undetectable levels both in vitro and in vivo. Together, the findings and novel methodologies will allow researchers to monitor and quantify FAE of their own IgG4 molecules in physiologically relevant matrices. © 2015 by The American Society for Biochemistry and Molecular Biology Inc.


Wolf J.,University of Kiel | Waetzig G.H.,CONARIS Research Institute AG | Reinheimer T.M.,Non Clinical Development | Scheller J.,Heinrich Heine University Düsseldorf | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2016

Interleukin-6 (IL-6) signaling can be divided into classic signaling (via the membrane-bound IL-6 receptor, IL-6R) and trans-signaling (via the soluble IL-6R, sIL-6R), and both modes of signaling activate cells via a homodimer of the ubiquitously expressed β-receptor glycoprotein 130 (gp130). IL-6 trans-signaling is responsible for most of the pro-inflammatory activities of IL-6 and plays a role in many inflammatory diseases including inflammation-driven cancers. IL-6 trans-signaling can be selectively inhibited by soluble forms of gp130. To date, three forms of sgp130 (full-length sgp130, sgp130-RAPS and sgp130-E10) with different molecular weight have been described, which originate from alternative splicing or alternative polyadenylation of the gp130 mRNA. All these proteins are capable of blocking signaling of the IL-6/sIL-6R complex, albeit with different efficacy. The full length form of sgp130 comprises the domains D1 to D6 and a short unique C-terminus which arises from alternative splicing. In the present study, we analyze the role of a unique cysteine residue (Cys-628) within this C-terminus, which is contained neither in the membrane-bound gp130 nor in the two other sgp130 forms. Full-length sgp130 can form a disulfide-linked dimer via this cysteine residue. These natural sgp130 dimers are absent under reducing conditions or in a sgp130 C628A mutant. Although the disulfide-dimerized sgp130 represents only a small fraction of the total amount of sgp130 and, thus, may appear to be dispensable for the global inhibitory activities of sgp130 in the circulation, it may represent a further possibility to modulate gradients of sgp130 with different properties depending on the local redox potential in a cell- or tissue-dependent manner. © 2016 Elsevier Inc. All rights reserved.


Benjamin A.,Astrazeneca | Costa A.N.D.,Non Clinical Development | Delaunois A.,Non Clinical Development | Rosseels M.-L.,Non Clinical Development | Valentin J.-P.,Non Clinical Development
Handbook of Experimental Pharmacology | Year: 2015

The kidney is a complex excretory organ playing a crucial role in various physiological processes such as fluid and electrolyte balance, control of blood pressure, removal of waste products, and drug disposition. Drug-induced kidney injury (DIKI) remains a significant cause of candidate drug attrition during drug development. However, the incidence of renal toxicities in preclinical studies is low, and the mechanisms by which drugs induce kidney injury are still poorly understood. Although some in vitro investigational tools have been developed, the in vivo assessment of renal function remains the most widely used methodology to identify DIKI. Stand-alone safety pharmacology studies usually include assessment of glomerular and hemodynamic function, coupled with urine and plasma analyses. However, as renal function is not part of the ICH S7A core battery, such studies are not routinely conducted by pharmaceutical companies. The most common approach consists in integrating renal/urinary measurements in repeat-dose toxicity studies. In addition to the standard analyses and histopathological examination of kidneys, novel promising urinary biomarkers have emerged over the last decade, offering greater sensitivity and specificity than traditional renal parameters. Seven of these biomarkers have been qualified by regulatory agencies for use in rat toxicity studies. © Springer-Verlag Berlin Heidelberg 2015


PubMed | Aarhus University Hospital, Charles III University of Madrid and Non Clinical Development
Type: Comparative Study | Journal: Journal of the American Heart Association | Year: 2016

Treatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin-releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested that not all means of ADT carry the same risk, raising the possibility of non-testosterone-mediated effects of different forms of ADT on atherosclerosis. Here we compared effects of ADT on atherosclerosis in intact and orchiectomized Apoe-deficient mice.Chow-fed Apoe-deficient mice were allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe-deficient mice, all types of ADT reduced testosterone production to castration levels. Although hypercholesterolemia was accentuated in leuprolide-treated mice, the amount and composition of atherosclerosis was not different between the different types of ADT. In orchiectomized Apoe-deficient mice, leuprolide, but not degarelix, augmented hypercholesterolemia, changed body, thymus, and spleen weights, and increased atherosclerosis in the aortic root. No direct effects of the drugs were detectable on cytokine secretion from murine bone marrow-derived macrophages or on splenocyte proliferation.No differences in the development of atherosclerosis were detected among groups of intact Apoe-deficient mice treated with different types of ADT. A pro-atherogenic, possibly cholesterol-mediated, effect of leuprolide was seen in orchiectomized mice that might be relevant for understanding the potential cardiovascular risk associated with GnRH agonist-based ADT.


PubMed | CONARIS Research Institute AG, University of Kiel, Heinrich Heine University Düsseldorf and Non Clinical Development
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2016

Interleukin-6 (IL-6) signaling can be divided into classic signaling (via the membrane-bound IL-6 receptor, IL-6R) and trans-signaling (via the soluble IL-6R, sIL-6R), and both modes of signaling activate cells via a homodimer of the ubiquitously expressed -receptor glycoprotein 130 (gp130). IL-6 trans-signaling is responsible for most of the pro-inflammatory activities of IL-6 and plays a role in many inflammatory diseases including inflammation-driven cancers. IL-6 trans-signaling can be selectively inhibited by soluble forms of gp130. To date, three forms of sgp130 (full-length sgp130, sgp130-RAPS and sgp130-E10) with different molecular weight have been described, which originate from alternative splicing or alternative polyadenylation of the gp130 mRNA. All these proteins are capable of blocking signaling of the IL-6/sIL-6R complex, albeit with different efficacy. The full length form of sgp130 comprises the domains D1 to D6 and a short unique C-terminus which arises from alternative splicing. In the present study, we analyze the role of a unique cysteine residue (Cys-628) within this C-terminus, which is contained neither in the membrane-bound gp130 nor in the two other sgp130 forms. Full-length sgp130 can form a disulfide-linked dimer via this cysteine residue. These natural sgp130 dimers are absent under reducing conditions or in a sgp130 C628A mutant. Although the disulfide-dimerized sgp130 represents only a small fraction of the total amount of sgp130 and, thus, may appear to be dispensable for the global inhibitory activities of sgp130 in the circulation, it may represent a further possibility to modulate gradients of sgp130 with different properties depending on the local redox potential in a cell- or tissue-dependent manner.


PubMed | Neurosciences TA Biology and Non Clinical Development
Type: Journal Article | Journal: PloS one | Year: 2014

In Parkinsons disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients.


PubMed | CNS Research and Non Clinical Development
Type: Journal Article | Journal: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology | Year: 2016

The mechanisms of action of modafinil continue to be poorly characterised and its potential for abuse in preclinical models remains controverted. The aim of this study was to further elucidate the mechanism of action of modafinil, through a potential behavioural and molecular association in the mouse. A conditioned place preference (CPP) paradigm was implemented to investigate the rewarding properties of modafinil. Whole genome expression and qRT-PCR analysis were performed on the ventral tegmental area (VTA), nucleus accumbens (NAC) and prefrontal cortex (PFC) of modafinil-treated and control animals. Modafinil administration (65 mg/kg) induced an increase in locomotor activity, an increase in the change of preference for the drug paired side after a conditioning period as well as changes to gene expression profiles in the VTA (120 genes), NAC (23 genes) and PFC (19 genes). A molecular signature consisting of twelve up-regulated genes was identified as common to the three brain regions. Multiple linear correlation analysis showed a strong correlation (R(2)>0.70) between the behavioural and molecular endpoints in the three brain regions. We show that modafinil had a concomitant effect on CPP, locomotor activity, and up-regulation of interferon- (IFN-) regulated genes (Gbp2, Gbp3, Gbp10, Cd274, Igtp), while correlating the latter set of genes with behaviour changes evaluated through the CPP. A potential association can be proposed based on the dysregulation of p47 family genes and Gbp family of IFN- induced GTPases. In conclusion, these findings suggest a link between the behavioural and molecular events in the context of modafinil administration.


PubMed | Non Clinical Development
Type: Journal Article | Journal: Acta neurologica Scandinavica | Year: 2015

Lacosamide is indicated for the adjunctive treatment of partial-onset seizures in adult patients. Unlike other sodium channel-blocking antiepileptic drugs, lacosamide selectively enhances sodium channel slow inactivation. Potential effects of lacosamide on cardiac sodium channels and their cardiovascular consequences were comprehensively assessed. This manuscript presents the non-clinical cardiac safety profile of lacosamide.Lacosamide was tested in vitro on sodium and L-type calcium currents from isolated human atrial myocytes and on hERG-mediated potassium currents from stably transfected HEK293 cells. Cardiac action potentials were recorded in guinea pig ventricular myocytes. In vivo, hemodynamic and ECG parameters were evaluated in anesthetized dogs and monkeys receiving acute cumulative intravenous doses of lacosamide.Following intravenous dosing with lacosamide, dose-dependent PR and QRS prolongation and ECG abnormalities (loss of P waves, atrioventricular and intraventricular blocks, junctional premature contractions) were observed in anesthetized dogs and monkeys. In vitro, lacosamide reduced human cardiac sodium currents in a concentration-, voltage- and state-dependent manner. Lacosamide reductions in Vmax in guinea pig myocytes were similar to lamotrigine and carbamazepine. Lacosamide showed no relevant inhibitory effects on hERG and L-type calcium channels and did not prolong QTc in vivo.ECG findings in anesthetized animals correlate well with in vitro sodium channel-related effects and are also consistent with those (PR prolongation, first-degree atrioventricular block) reported in healthy volunteers and patients with epilepsy. Both in vivo and in vitro effects were detected from exposure levels 1.5- to 2-fold above those achieved with the maximum-recommended human lacosamide dose (400 mg/day).

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