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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.

De Ron P.,Non Clinical Development | Dremier S.,Non Clinical Development | Winlow P.,Non Clinical Development | Winlow P.,University of Leeds | And 4 more authors.
European 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 (R2>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-γ (IFN-γ) 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-γ induced GTPases. In conclusion, these findings suggest a link between the behavioural and molecular events in the context of modafinil administration. © 2016 Elsevier B.V. and ECNP.

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

Al-Saffar A.,Uppsala University | Costa A.N.D.,Non Clinical Development | Delaunois A.,Non Clinical Development | Leishman D.J.,Eli Lilly and Company | And 3 more authors.
Handbook of Experimental Pharmacology | Year: 2015

Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and bio- chemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug- related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a- chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries. © Springer-Verlag Berlin Heidelberg 2015

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.

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