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Hutcheson D.M.,Glaxosmithkline | Hutcheson D.M.,Maccine Pte Ltd. | Quarta D.,Glaxosmithkline | Quarta D.,Aptuit Verona S.r.l. | And 8 more authors.
Behavioural Pharmacology | Year: 2011

Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist SB-334867 on aspects of psychostimulant-conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Halbout B.,Neurosciences CEDD | Halbout B.,Central Institute of Mental Health | Quarta D.,Neurosciences CEDD | Valerio E.,Neurosciences CEDD | And 4 more authors.
Addiction Biology | Year: 2011

Baclofen, a γ-amino-butyric-acid (GABA) B receptor agonist, can reduce cue-enhanced cocaine-seeking in rats and attenuate cue-evoked craving in cocaine addicts. However, baclofen also has sedative effects that might interfere with its efficacy in reducing cocaine's rewarding effects. The present study aimed at comparing the effects of baclofen with the GABA B-receptor positive allosteric modulator GS39783 on psychostimulant conditioned cues. Two identically trained groups of male Lister-Hooded rats were baselined on a new responding for a light stimulus previously paired with cocaine self-administration. One group was treated with the GABA B-receptor positive allosteric modulator GS39783 (0, 10, 30, 100 mg/kg, i.p.), the other with baclofen (0, 0.6, 1.25, 1.9, 2.5 mg/kg, i.p.). In another series of experiments, male Wistar rats received GS39783 (0, 10, 30, 100 mg/kg, i.p.) or baclofen (1.25 mg/kg) prior to the expression of a conditioned place preference (CPP) to amphetamine (2 mg/kg i.p.). Both GS39783 (30 and 100 mg/kg) and baclofen (2.5 mg/kg) significantly decreased responding for the cocaine cue; however, only GS39783 (30 mg/kg) reduced lever pressing responding without interfering with locomotor activity. Both GS39783 (30 and 100 mg/kg) and baclofen (1.25 mg/kg), significantly blocked the expression of amphetamine CPP without affecting locomotor activity. These findings suggest that GABA B positive allosteric modulators can modulate discrete and contextual psychostimulant conditioned stimuli in a manner dissociable from unwanted sedative effects and may offer a novel therapeutic approach to treat cravings and relapse to drug-taking triggered by stimuli associated with psychostimulant use. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.


PubMed | Maccine Pte Ltd, National University of Singapore and Merck And Co.
Type: Journal Article | Journal: PloS one | Year: 2016

Approximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored.Here we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8). BOLD fMRI data were collected during thermal challenge (ON:20 s/42C; OFF:40 s/35C, 4-cycle) at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm) application. Tail withdrawal behavioral studies were also conducted in the same animals using 42C or 48C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail).Group comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the pain matrix, including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8), while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures.These findings provide insights into the specific brain regions involved with aversive, pain-like, responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain deeper understanding of pain processing and evaluate the preclinical efficacy of novel analgesics.


Sutcliffe J.S.,Maccine Pte Ltd | Beaumont V.,CHDI Foundation CHDI Management Inc. | Watson J.M.,Maccine Pte Ltd | Chew C.S.,Maccine Pte Ltd | And 4 more authors.
PLoS ONE | Year: 2014

Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline. © 2014 munoz-sanjuan et al.


Wang Z.,University of Pittsburgh | Wang Z.,Maccine Pte. Ltd. | Song Q.,Nanyang Technological University | Soh Y.C.,Nanyang Technological University | Sim K.,Woodbridge Hospital
Computer Vision and Image Understanding | Year: 2013

This paper presents an adaptive spatial information-theoretic fuzzy clustering algorithm to improve the robustness of the conventional fuzzy c-means (FCM) clustering algorithms for image segmentation. This is achieved through the incorporation of information-theoretic framework into the FCM-type algorithms. By combining these two concepts and modifying the objective function of the FCM algorithm, we are able to solve the problems of sensitivity to noisy data and the lack of spatial information, and improve the image segmentation results. The experimental results have shown that this robust clustering algorithm is useful for MRI brain image segmentation and it yields better segmentation results when compared to the conventional FCM approach. © 2013 Elsevier Inc. All rights reserved.


Dahiya P.,Food and Veterinary Administration | Ogden B.E.,Maccine Pte. Ltd.
Frontiers in Bioscience - Scholar | Year: 2010

It is well recognized that animals play a vital role and are indispensable to scientific and medical research. Over the years, a number of non-animal procedures have been developed. However, despite all the advances in science, as yet, no system has been evolved which can completely replace a living system to conduct basic research. There is still a need to test food, drugs, medical devices, treatment regimes etc. on some animals before they can be tested and used (if found suitable) in human beings. Even the most sophisticated technology models have failed to mimic completely the complex cellular interactions occurring in a living system. The search for a complete alternative to animal research is still on and in the mean time we can all help play our part by conducting animal research in a humane and responsible fashion. This chapter discusses the ethical issues in animal research highlighting the need to use animals conscientiously.


Connolly B.M.,Merck And Co. | Vanko A.,Merck And Co. | McQuade P.,Merck And Co. | Guenther I.,Merck And Co. | And 8 more authors.
Molecular Imaging and Biology | Year: 2012

Purpose: The purpose of this study was to evaluate the binding specificity of the radiolabeled glucagon-like peptide 1 receptor (GLP-1R) agonist (Lys 40(DOTA)NH 2)Exendin-4 in the pancreas using a combination of ex vivo autoradiography and immunohistochemistry. Procedures: Sprague-Dawley rats were administered [ 64Cu](Lys 40(DOTA)NH 2)Exendin-4 i.v. with or without unlabeled Exendin (9-39) to determine binding specificity. Similar experiments were performed using Zucker diabetic fatty (ZDF) and Zucker lean (ZLC) rats. Animals were euthanized and the pancreas was extracted, immediately frozen, and sectioned. The sections were apposed to phosphor imaging plates, scanned, and immunostained for insulin. Results: Co-registration of the autoradiographic and immunohistochemical images revealed that [ 64Cu] (Lys 40(DOTA)NH 2)Exendin-4 specific binding was restricted to islet cells. This binding was blocked by the co-administration of Exendin(9-39) indicating that the radiotracer uptake is mediated by GLP-1R. Uptake of [ 64Cu](Lys 40(DOTA)NH 2)Exendin-4 was greatly decreased in the pancreas of ZDF rats. Conclusions: Ex vivo autoradiography results using [ 64Cu](Lys 40(DOTA)NH 2)Exendin-4 suggest that GLP-1R agonists based on Exendin-4 are attractive PET ligands for the in vivo determination of β-cell mass. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011.


Sutcliffe J.S.,Maccine Pte Ltd
Current Topics in Behavioral Neurosciences | Year: 2011

Interest in the influence of sex hormones within the central nervous system is a rapidly expanding area of research. A considerable amount of evidence has recently been obtained to support an important role of the gonadal steroids in cognitive processing. Not only are distinct and complementary behavioural phenotypes evident for each gender, in the case of the female but they are also reliant upon hormonal status. Gender influences and hormonal status are thus paramount and should encourage the development of more hypothesis-driven research strategies to understand gender differences in both normal behaviour and where this is altered in neuropsychiatric disorders. © Springer-Verlag Berlin Heidelberg 2011.


PubMed | Merck And Co., Maccine Pte. Ltd. and Decision Research Inc.
Type: Journal Article | Journal: Journal of magnetic resonance imaging : JMRI | Year: 2016

To identify reproducible and reliable noninvasive regional imaging biomarkers of cardiac function and perfusion at rest and under stress in healthy nonhuman primates (NHPs) that may be used in the future for the early characterization of preclinical heart failure models, to evaluate therapy, and for clinical translation.Seven naive cynomolgus macaques underwent test-retest 3T cardiac MRI tagging and dual-bolus perfusion experiments. Regional cardiac function biomarkers, such as peak circumferential strain (CS), average diastolic strain-rate (DSR), contractile reserve (CR), diastolic reserve, peak torsion, and torsion reserve were quantified. Further, regional myocardial blood flow (MBF), myocardial perfusion reserve (MPR), and myocardial perfusion reserve-to-contractile reserve (MPR/CR) were also derived. Inter- and intraobserver reproducibility and test-retest reliability analyses were conducted using the reliability and generalizability coefficients including correlation coefficient (CC) and intraclass correlation coefficient (ICC).Overall, peak CS, DSR, and MBF are robust biomarkers at both rest and stress with moderate-good inter- and intraobserver reproducibility and test-retest reliability. At rest: intra-/interobserver reproducibility (CC): peak CS (0.81/0.81), DSR (0.81/0.81), MBF (0.72/0.57), peak torsion (0.79/0.79); test-retest reliability: (CC/ICC): peak CS (0.62/0.75), DSR (0.24/0.55), MBF (0.66/0.62), and peak torsion (0.79/0.78). Under stress: intra-/interobserver reproducibility (CC): peak CS (0.61/0.60), DSR (0.50/0.50), MBF (0.63/0.61), MPR (0.43/0.43), and peak torsion (0.38/0.38); test-retest reliability: (CC/ICC): peak CS (0.58/0.58), DSR (0.24/0.43), MBF (0.58/0.58), MPR (0.43/0.38), and peak torsion (0.38/0.38).We demonstrated the feasibility of using cardiac MRI to characterize left ventricular functional and perfusion responses to stress in an NHP species, and specific robust biomarkers such as peak CS, DSR, MBF, diastolic reserve, and MPR have been identified for clinical translation and drug research.1 J. Magn. Reson. Imaging 2017;45:556-569.


PubMed | Merck And Co., Maccine Pte. Ltd. and Decision Research Inc.
Type: Journal Article | Journal: PloS one | Year: 2015

Pre-clinical animal models are important to study the fundamental biological and functional mechanisms involved in the longitudinal evolution of heart failure (HF). Particularly, large animal models, like nonhuman primates (NHPs), that possess greater physiological, biochemical, and phylogenetic similarity to humans are gaining interest. To assess the translatability of these models into human diseases, imaging biomarkers play a significant role in non-invasive phenotyping, prediction of downstream remodeling, and evaluation of novel experimental therapeutics. This paper sheds insight into NHP cardiac function through the quantification of magnetic resonance (MR) imaging biomarkers that comprehensively characterize the spatiotemporal dynamics of left ventricular (LV) systolic pumping and LV diastolic relaxation. MR tagging and phase contrast (PC) imaging were used to quantify NHP cardiac strain and flow. Temporal inter-relationships between rotational mechanics, myocardial strain and LV chamber flow are presented, and functional biomarkers are evaluated through test-retest repeatability and inter subject variability analyses. The temporal trends observed in strain and flow was similar to published data in humans. Our results indicate a dominant dimension based pumping during early systole, followed by a torsion dominant pumping action during late systole. Early diastole is characterized by close to 65% of untwist, the remainder of which likely contributes to efficient filling during atrial kick. Our data reveal that moderate to good intra-subject repeatability was observed for peak strain, strain-rates, E/circumferential strain-rate (CSR) ratio, E/longitudinal strain-rate (LSR) ratio, and deceleration time. The inter-subject variability was high for strain dyssynchrony, diastolic strain-rates, peak torsion and peak untwist rate. We have successfully characterized cardiac function in NHPs using MR imaging. Peak strain, average systolic strain-rate, diastolic E/CSR and E/LSR ratios, and deceleration time were identified as robust biomarkers that could potentially be applied to future pre-clinical drug studies.

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