RenaSci Consultancy Ltd

Nottingham, United Kingdom

RenaSci Consultancy Ltd

Nottingham, United Kingdom
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Vickers S.P.,RenaSci Consultancy Ltd. | Clifton P.G.,University of Sussex
Neuropharmacology | Year: 2012

Obesity has reached epidemic proportions globally with an increasing incidence not just in Western cultures but also Mexico, Brazil, China and parts of Africa. In terms of pharmacological intervention, the track record of drug treatments for obesity is poor, especially in the case of centrally acting medicines, and there remains an unmet need for the development of safer compounds delivering superior efficacy. Animal models are of importance not only in detecting changes in food intake, energy expenditure and body weight but also providing confidence that these changes are behaviourally specific and not a result of drug-induced side effects. We review animal models of feeding behaviour that are used to aid our understanding of the control of body weight and energy regulation with special reference to CNS-acting drugs. The use of such models in the discovery of new drugs for the treatment of obesity is given particular emphasis. This article is part of a Special Issue entitled 'Central Control of Food Intake'. © 2012 Elsevier Ltd. All rights reserved.


Kennett A.,University of Bath | Heal D.J.,RenaSci Consultancy Ltd. | Wonnacott S.,University of Bath
Nicotine and Tobacco Research | Year: 2012

Introduction: Noradrenergic mechanisms in frontal cortex and hippocampus are relevant to attentional and stress-related aspects of addiction, respectively. Nicotinic receptors (nAChRs) modulate the release of noradrenaline (NA) in these tissues. This study determined if similar subtypes of nAChR regulate NA release in rat frontal cortex and hippocampus. Methods: The release of [3H]-NA from rat tissue prisms was characterized in a 96-well plate assay. In vivo microdialysis was used to monitor NA overflow from rat frontal cortex and hippocampus in conscious freely moving rats. Results: [3H]-NA release from frontal cortex prisms was more sensitive to nicotinic agonists than release from hippocampal prisms. The β2-selective agonist 5-iodo-A-85380 was 1000-fold more potent in frontal cortex compared with hippocampus. Agonist-evoked [3H]-NA release was inhibited by the β2-selective antagonist dihydro-beta-erythroidine (DHβE) in frontal cortex, whereas in hippocampal tissue, DHβE had no effect. In vivo, 5-iodo-A-85380 (1, 100 μM) applied locally via the dialysis probe, significantly increased NA overflow, compared with basal release, in frontal cortex but not in hippocampus. Conclusions: These data support the modulation of NA release by different nAChR subtypes in frontal cortex and hippocampus. The pharmacological profile for rat hippocampus is consistent with previous studies, implicating α3β4* nAChRs in the modulation of NA release in this tissue. nAChRs having this function in frontal cortex are pharmacologically distinct and correspond to β2-containing nAChRs. © The Author 2012. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.


Heal D.J.,RenaSci Consultancy Ltd | Smith S.L.,RenaSci Consultancy Ltd | Findling R.L.,Case Western Reserve University
Current Topics in Behavioral Neurosciences | Year: 2012

The stimulants, amphetamine and methylphenidate, have long been the mainstay of attention-deficit hyperactivity disorder (ADHD) therapy. They are rapidly effective and are generally the first medications selected by physicians. In the development of alternative pharmacological approaches, drug candidates have been evaluated with a wide diversity of mechanisms. All of these developments have contributed real progress in the field, but there is still much room for improvement and unmet clinical need in ADHD pharmacotherapy. The availability of a wide range of compounds with a high degree of specificity for individual monoamines (dopamine and noradrenaline) and/or different pharmacological mechanisms has refined our understanding of the essential elements for optimum pharmacological effect in managing ADHD. In this chapter, we review the pharmacology of the different classes of drug used to treat ADHD and provide a neurochemical rationale, predominantly from the use of in vivo microdialysis experiments, to explain their relative efficacy and potential to elicit side effects. In addition, we will consider how predictions based on results from animal models translate into clinical outcomes. The treatment of ADHD is also described from the perspective of the physician. Finally, the new research development for drugs to treat ADHD is discussed. © Springer-Verlag Berlin Heidelberg 2011.


Heal D.J.,RenaSci Consultancy Ltd | Gosden J.,RenaSci Consultancy Ltd | Smith S.L.,RenaSci Consultancy Ltd
International Journal of Obesity | Year: 2013

Obesity is an important causative factor in morbidity, disability and premature death. Increasing levels of obesity will impose enormous health, financial and social burdens on worldwide society unless effective interventions are implemented. For many obese individuals, diet and behavioural modification need to be supplemented by pharmacotherapy. Preclinical research has revealed a greater understanding of the complex nature of the hypothalamic regulation of food intake and has generated a wide range of new molecular targets for the development of drug candidates for obesity treatment. As shown by the clinical results that have been obtained with this next generation of therapies, some approaches, for example, fixed-dose drug combinations, have already demonstrated an ability to deliver levels of efficacy that are not achievable with the current antiobesity drug therapies. The regulatory and marketing landscape for development, registration and commercialisation of novel centrally acting drugs for treatment of obesity and related metabolic disorders has changed substantially in recent years. Now a much greater emphasis is placed on tolerability and safety, as well as efficacy. In this review we briefly describe the therapeutic approaches to tackle obesity that are in late-stage clinical development. We then discuss drugs in late-stage development for the treatment of obesity and also future directions. © 2013 Macmillan Publishers Limited. All rights reserved.


Hadden M.,AMRI | Deering D.M.,AMRI | Henderson A.J.,AMRI | Surman M.D.,AMRI | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use as weight loss agents. © 2010 Elsevier Ltd. All rights reserved.


Bolea-Alamanac B.,University of Bristol | Nutt D.J.,Imperial College London | Adamou M.,South West Yorkshire Trust | Asherson P.,Institute of Psychiatry | And 9 more authors.
Journal of Psychopharmacology | Year: 2014

Attention deficit hyperactivity disorder (ADHD) is a common condition with a high societal burden. The present guidelines summarise current literature, generating expert consensus recommendations for the treatment of ADHD in children and adults. These guidelines also provide a review of recent research in the fields of neuroimaging, neuropsychology and genetics of ADHD. Novel discoveries in these areas have informed physiological models for the disease. Since the publication of the previous British Association for Psychopharmacology guidelines in 2008, new drugs have been licensed and further compounds are being investigated. The publication of randomised controlled trials of psychological interventions has contributed to the range of treatment options for ADHD. As the disorder has been diagnosed more frequently there has been greater focus on comorbid conditions and how they impact treatment. Services have continued to develop for the treatment of ADHD in adults and care agreements have been introduced to facilitate access to treatment. © 2014 The Author(s).


Klein T.,Boehringer Ingelheim | Niessen H.G.,Boehringer Ingelheim | Ittrich C.,Boehringer Ingelheim | Mayoux E.,Boehringer Ingelheim | And 5 more authors.
Diabetes, Obesity and Metabolism | Year: 2012

The effects of linagliptin on fat content in diet-induced obese rats were compared with those of the appetite suppressant sibutramine. Female Wistar rats fed a high-fat diet (HFD) for 3months received vehicle, linagliptin (10mg/kg) or sibutramine (5mg/kg) treatment orally, once daily for 6 additional weeks, while continuing the HFD. Magnetic resonance spectroscopy analysis of fat content was performed at baseline and at the end of the 6-week treatment period. Linagliptin treatment profoundly reduced hepatic fat compared with vehicle, with an effect comparable to that of sibutramine. The vehicle-corrected mean change (95% CI) from baseline in hepatic fat and intramyocellular lipid was -59.0% (-104.3%, -13.6%; p=0.015) and -62.1% (-131.6%, 7.4%; p=0.073), respectively, for linagliptin compared with -54.3% (-101.5%, -7.1%; p=0.027) and -72.4% (-142.4%, -2.4%; p=0.044), respectively, for sibutramine. © 2012 Blackwell Publishing Ltd.


Heal D.J.,RenaSci Consultancy Ltd | Gosden J.,RenaSci Consultancy Ltd | Smith S.L.,RenaSci Consultancy Ltd
Neuropharmacology | Year: 2012

Obesity is a global problem that is predominantly caused by the increasing adoption of a low-cost, Westernised diet that is rich in fat and sugar and a more sedentary lifestyle. The costs of this epidemic are substantial increases in Type 2 diabetes, cardiovascular disease and some types of cancer that are certain to place a huge burden on individuals, healthcare providers and society. In this review, we provide an overview of the chequered history of pharmacotherapy for the treatment of obesity and an analysis of the regulatory and commercial challenges for developing new centrally-acting drugs in this metabolic indication. The efficacy and safety of the drug candidates that are currently at the pre-registration phase, i.e., lorcaserin, Qnexa and Contrave, are critically assessed. The main focus, however, is to provide a comprehensive review of the wide range of novel CNS compounds that are in the discovery phase or early clinical development. The profiles of various clinical candidates in animal models of obesity predict that several new CNS approaches in the clinic have the potential to deliver greater weight-loss than existing agents. This article is part of a Special Issue entitled 'Central Control of Food Intake'. © 2012 Elsevier Ltd. All rights reserved.


Vickers S.P.,RenaSci Consultancy Ltd | Jackson H.C.,RenaSci Consultancy Ltd | Cheetham S.C.,RenaSci Consultancy Ltd
British Journal of Pharmacology | Year: 2011

The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic. © 2011 The British Pharmacological Society.


Gardiner J.V.,Imperial College London | Bataveljic A.,Imperial College London | Patel N.A.,Imperial College London | Bewick G.A.,Imperial College London | And 12 more authors.
Diabetes | Year: 2010

OBJECTIVE-Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis. RESEARCH DESIGN AND METHODS - We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebro-ventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanism of action by determining sites of neuronal activation after ICV injection of PK2, the hypothalamic site of action of PK2, and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2's potential as a therapeutic target, we investigated the effect of chronic administration in lean and obese mice. RESULTS - Hypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake, whereas anti-PK2 antibody increased food intake, suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of α-melanocyte-stimulating hormone (α-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the α-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight in lean and obese mice. CONCLUSIONS - This is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is mediated partly via the melanocortin system. © 2010 by the American Diabetes Association.

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