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Rowley H.L.,RenaSci Ltd. | Kulkarni R.S.,RenaSci Ltd. | Gosden J.,RenaSci Ltd. | Brammer R.J.,RenaSci Ltd. | And 2 more authors.
Journal of Psychopharmacology | Year: 2014

Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects. © 2014 The Author(s).


Grant
Agency: Cordis | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-2013-IAPP | Award Amount: 1.66M | Year: 2013

Age-related macular degeneration, diabetic retinopathy, and corneal inflammation are significant causes of irreversible blindness with increasing prevalence as the EU population ages and the diabetes epidemic expands. There is an unmet clinical need for more effective treatments to halt or reverse these diseases. Many EU pharmaceutical and biotechnology companies, with established processes for the synthesis and physiochemical characterisation of drugs, have bespoke chemical libraries and lead drugs with potential to treat ocular disease, but lack the expertise and infrastructure to test these drugs in relevant pre-clinical models. In parallel, academic labs with excellent infrastructure to study ocular disease, lack the industry expertise to appropriately develop drugs to enter clinical trials. Thus, clinical development of ocular therapeutics is impeded in the EU due to poor collaboration among academic and industry scientists. 3D-NET establishes a network of industry (Gadea, KalVista & RenaSci) and academic partners (UCD & UVA), who exchange knowledge and people, and whos combined S&T expertise will enhance the discovery and development of drugs that target ocular pathologies (retinal vessel permeability, unwanted blood vessel growth, inflammation and cell degeneration). Novel ophthalmic drugs will be discovered from unbiased screens of small molecules and developed from hits/leads and selected compounds (PI3K-inhs, lipoxins, Kallikrein-inhs, HDAC-inhs, serotonin agonists), on a set of in silico/in vitro/in vivo/ex vivo preclinical models. Expected outputs are: a) enhancing intersectoral training, career development and trans-national mobility of EU researchers, b) high impact publications/priority patent applications and c) overcoming barriers that impede industry-academia partnership in the EU inhibiting the discovery/development of new-cheaper and more effective drugs for ocular disease.


Freeman K.B.,University of Mississippi Medical Center | Heal D.J.,RenaSci Ltd | McCreary A.C.,Brains On Line | Woolverton W.L.,University of Mississippi Medical Center
Drug and Alcohol Dependence | Year: 2012

Background: Ropinirole, a D2/D3/5-HT1A agonist, is used for the treatment of Parkinson's disease and restless leg syndrome, and is currently being evaluated as a treatment for cocaine dependence. However, there is little information available on ropinirole's reinforcing effects. Methods: The current study tested ropinirole in monkeys (n= 7) trained to self administer cocaine on a fixed-ratio 25 (FR 25) schedule of reinforcement to determine if it would function as a reinforcer. In addition, a behavioral economics approach was used in four monkeys to compare the reinforcing effectiveness of ropinirole to cocaine. Results: Cocaine (0.01-0.3. mg/kg/injection) functioned as a reinforcer in all monkeys under the FR 25 schedule, and ropinirole (0.01-0.1. mg/kg/injection) functioned as a reinforcer in all but one. Furthermore, cocaine was a more effective reinforcer than ropinirole as indexed by demand functions. Conclusion: The current data indicate that ropinirole has reinforcing effects in monkeys, although its effectiveness as a reinforcer is relatively weak. © 2012 .


Pillidge K.,University College London | Porter A.J.,University College London | Vasili T.,University College London | Heal D.J.,RenaSci Ltd | Stanford S.C.,University College London
Pharmacology Biochemistry and Behavior | Year: 2014

Background Mice with functional ablation of the neurokinin-1 receptor gene (NK1R-/-) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT).Methods Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10 mg/kg; LDEB: 1, 3 or 10 mg/kg).Results Atomoxetine reduced the hyperactivity displayed by NK1R-/- mice in the LDEB at a dose (3 mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10 mg/kg) also reduced impulsivity in NK1R-/- mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. Conclusions This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R-/- mice consolidates the validity of using NK1R-/- mice in research of the aetiology and treatment of ADHD. © 2014 The Authors. Published by Elsevier Inc.


The abnormal behaviour of NK1R-/- mice (locomotor hyperactivity, inattentiveness and impulsivity in the 5-Choice Serial Reaction-Time Test) is arguably analogous to that of patients with attention deficit hyperactivity disorder (ADHD). Evidence suggests that small body size and increased body weight are risk factors for ADHD. Here, we compared the body size, body mass and body composition of Male and feMale NK1R-/- mice and their wildtypes that had been fed either standard laboratory chow or a high-fat (45%: 'Western') diet. Male NK1R-/- mice from both cohorts were approximately 7% shorter than wildtypes. A similar trend was evident in feMales. Male NK1R-/- mice fed the normal diet weighed less than wildtypes but the 'body mass index' ('mBMI': weight (mg)/length (cm)2) of feMale NK1R-/- mice was higher than wildtypes. When given the high-fat diet, the mBMI of both Male and feMale NK1R-/- mice was higher than wildtypes. There were no consistent genotype or sex differences in protein, ash or water content of mice from the two cohorts. However, the fat content of Male NK1R-/- mice on the Western diet was considerably (35%) higher than wildtypes and resembled that of feMales from both genotypes. We conclude that a lack of functional NK1R is associated with small body size but increases vulnerability to an increase in mBMI and fat content, especially in Males. This phenotype could also be evident in ADHD patients with polymorphism(s) of the TACR1 gene (the human equivalent of Nk1r). © British Association for Psychopharmacology.


Ash E.S.,University College London | Heal D.J.,RenaSci Ltd. | Clare Stanford S.,University College London
Neuropharmacology | Year: 2014

There is evidence for functional specificity of subregions along the rostrocaudal axis of the anterior cingulate cortex (ACC). The subregion-specific distribution of dopaminergic afferents and glutamatergic efferents along the ACC make these obvious candidates for coding such regional responses. We investigated this possibility using microdialysis in freely-moving rats to compare changes in extracellular dopamine and glutamate in the rostral ('rACC': Cg1 and Cg3 (prelimbic area)) and caudal ('cACC': Cg1 and Cg2) ACC induced by systemic or local administration of d-amphetamine. Systemic administration of d-amphetamine (3 mg/kg, i.p.) caused a transient increase in extracellular dopamine in the rACC, but an apparent increase in the cACC of the same animals was less clearly defined. Local infusion of d-amphetamine increased dopamine efflux in the rACC, only. Glutamate efflux in the rACC was increased by local infusion of dopamine (5-50 μM), which had negligible effect in the cACC, but only systemic administration of d-amphetamine increased glutamate efflux and only in the cACC. The asymmetry in the neurochemical responses within the rACC and cACC, to the same experimental challenges, could help explain why different subregions are recruited in the response to specific environmental and somatosensory stimuli and should be taken into account when studying the regulation of neurotransmission in the ACC. This article is part of the Special Issue entitled 'CNS Stimulants'. © 2014 The Authors.


Jones R.B.,RenaSci Ltd | Vickers S.P.,RenaSci Ltd | Cheetham S.C.,RenaSci Ltd | Headland K.R.,RenaSci Ltd | And 2 more authors.
European Journal of Pharmacology | Year: 2014

The effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, alone and in combination with voglibose or exendin-4, on glycaemic control and body weight were assessed in an animal model of type 2 diabetes. Voglibose is an α-glucosidase inhibitor but also increases glucagon-like peptide 1 (GLP-1). Exendin-4 is a GLP-1 receptor agonist. Male Zucker Diabetic Fatty (ZDF) rats were dosed for 3 days, fasted overnight and a sucrose/glucose tolerance test was performed. Linagliptin (1 mg/kg po) improved glucose tolerance by increasing plasma GLP-1 (active) and insulin secretion, whilst having no effect on body weight. Voglibose (1 and 10 mg/kg po) reduced body weight, improved glycaemic control, reduced plasma insulin and increased total but not active GLP-1. The combination of linagliptin and voglibose significantly reduced body weight, improved glycaemic control and reduced plasma insulin compared to linagliptin alone. Furthermore, linagliptin plus voglibose produced a marked increase in GLP-1 (active) at 5 min post-sucrose, compared to linagliptin, possibly because linagliptin prevented the degradation of GLP-1 secreted in response to voglibose. Exendin-4 (10 μg/kg sc) significantly reduced body weight, improved glucose tolerance but reduced GLP-1 (active). The combination of linagliptin and exendin-4 significantly reduced body weight and improved glycaemic control but had no effect on plasma GLP-1. Overall it did not markedly improve glycaemic control compared to the individual drugs. The improved glucose control, reduced body weight and markedly increased plasma GLP-1 levels in animals given linagliptin with voglibose, suggests that this combination may be particularly beneficial in the treatment of type 2 diabetes. © 2014 The Authors. Published by Elsevier B.V.


Heal D.J.,RenaSci Ltd | Smith S.L.,RenaSci Ltd | Gosden J.,RenaSci Ltd | Nutt D.J.,Imperial College London
Journal of Psychopharmacology | Year: 2013

Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine's diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine's distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed. © The Author(s) 2013.


Heal D.J.,RenaSci Ltd | Gosden J.,RenaSci Ltd | Jackson H.C.,RenaSci Ltd | Cheetham S.C.,RenaSci Ltd | Smith S.L.,RenaSci Ltd
Handbook of Experimental Pharmacology | Year: 2012

Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic side effects. We discuss the adverse metabolic consequences of schizophrenia, its exacerbation by a lack of social care, and the additional burden placed on patients by their medication. A critical evaluation of the animal models of antipsychotic-induced metabolic disturbances is provided with observations on their strengths and limitations. Finally, we discuss novel antipsychotic drugs with a lower propensity to increase metabolic risk and adjunctive medications to mitigate the adverse metabolic actions of the current generation of antipsychotics. © 2012 Springer-Verlag Berlin Heidelberg.


Heal D.J.,RenaSci Ltd | Gosden J.,RenaSci Ltd | Smith S.L.,RenaSci Ltd
Neuropharmacology | Year: 2014

The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable subjective effects such as drug "highs" or euphoria in drug-experienced human volunteers. Moreover they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to conclude that the highly unusual stimulant profile of cocaine and related compounds, eg methylphenidate, is not mediated by monoamine reuptake inhibition alone. We describe the experimental findings which suggest cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. This results in a firing-dependent, retro-transport of dopamine into the synaptic cleft. The proposed mechanism of cocaine is, therefore, different from other small molecule negative allostereric modulators of the monoamine reuptake transporters, eg SoRI-6238, which merely reduce the rate of inward transport. Because the physiological role of DAT is to remove dopamine from the synapse and the action of cocaine is the opposite of this, we have postulated that cocaine's effect is analogous to an inverse agonist. If this hypothesis is validated then cocaine is the prototypical compound that exemplifies a new class of monoaminergic drugs; DAT "inverse agonists". This article is part of the Special Issue entitled 'CNS Stimulants'. © 2014 Elsevier Ltd. All rights reserved.

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