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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.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 2.79M | Year: 2015

Antimicrobial resistance is posing a continuously-rising threat to global health. Indeed, one key recommendation from the recent Action plan against the rising threats from Antimicrobial Resistance report (submitted by the Commission to the European Parliament and Council (15.11.2011)) is the development of effective antimicrobials or alternatives for treatment of human and animal infections. The INTEGRATE project is a direct response to this. We have assembled a team of 10 beneficiaries from eight EU member states, encompassing both academic and non-academic sectors and different disciplines, to form a consortium committed to training Early Stage Researchers (ESRs) in the discovery and preclinical validation of novel Gram-negative antibacterial agents and antibacterial targets. The principle aim of the consortium is to provide a training platform where students are exposed to every aspect of the antimicrobial discovery process, ranging from target identification and validation, through organic synthesis, in silico design and compound screening, to mode-of-action and possible resistance mechanisms. This exposure will be accomplished through a concrete secondment plan, coupled with a series of high-level consortium-wide training events and networking programmes. Our intention is to reverse the current fragmentation of approaches towards antibacterial discovery through mutual cooperation. The INTEGRATE training framework is built on an innovative research project aimed at targeting important but non-essential gene products as an effective means of reducing bacterial fitness, thereby facilitating clearance of the pathogen by the host immune system. To achieve this, the individual work programmes have been designed to seamlessly inter-mesh contributions from the fields of in silico design, organic synthesis, molecular biology and biochemistry, and the very latest in vitro and in vivo screening technologies.

Just-Baringo X.,University of Barcelona | Just-Baringo X.,CIBER ISCIII | Just-Baringo X.,University of Manchester | Bruno P.,University of Barcelona | And 9 more authors.
Journal of Medicinal Chemistry | Year: 2014

Several analogues of baringolin (1) were prepared to evaluate the role of its characteristic thiazoline ring and pentapeptidic tail with the aim of defining structure-activity relationships for these moieties. The thiazoline ring appeared as a crucial moiety to maintain a broad scope of activities against different Gram-positive bacteria. Further modifications were performed to simplify the structure of the natural product and assess the role of its tail, resulting in an enhanced in vitro performance. Analogue 25, with the thiazole-containing macrocycle and a 4-aminocyclohexane-1-carboxylic acid moiety in place of the pentapeptidic tail, was identified as a much more potent analogue, capable of overcoming the absence of the thiazoline ring and performing extraordinarily well against all strains tested. This is the first library of thiopeptide analogues produced by chemical synthesis alone, which demonstrates the robustness and convenience of the synthetic strategy used. © 2014 American Chemical Society.

Cervo L.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Di Clemente A.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Orru A.,Institute Of Translational Pharmacology Cnr | Moro F.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | And 5 more authors.
Addiction Biology | Year: 2013

Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (SDs) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, SDs and CSs. Re-exposure to nicotine or sucrose SD+/CS +, but not non-reward SD-/CS-, revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to SD +/CS+ reduced nicotine-seeking; however, this effect was transient, with return to SD+/CS+ responding at 72 hours. Full recovery to SD+/CS+ responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

According to ECDC, over 4 million healthcare-associated infections in the EU cause 37,000 deaths and cost EUR 7 billion/year. Half of them are related to medical devices (i.e., catheters, implants) and 80% of these are related to bacterial biofilms. A recent EC report highlighted the medical device sectors role in driving EU economic growth, employing 500k people in 25k companies (80% are SMEs) with annual sales of EUR 85 billion. The strategy to prevent medical device-infections is alteration of the devices surface with antimicrobials. However, current antimicrobial surfaces dont control bacterial growth in tissue surrounding implants, and only Sterilex has received regulatory approval in the US as anti-biofilm agent. Participants in this proposal have earlier demonstrated a dramatic in vitro inhibition of biofilm formation by 3D-printing surfaces with antibiotics incorporated into the carrier polymers. This discovery opens new possibilities for printed medical devices that better resist biofilms. Our objective is to set-up a new European education platform to guide and inspire young researchers in the intersectoral exploration of innovative routes to counteract microbial biofilms by fabricating anti-infective, tailored, 3D-printed medical devices. Current opportunities for young researchers to receive an structured, inter-sectoral and up-to-date education on personalized medicine and medical devices are marginal, and to our knowledge PRINT-AID is the first ETN set up for this purpose. State-of-the-art printing technologies will be combined with in vitro and in vivo biofilm models and novel tools for data integration/standardization. Doctoral training will be performed within a high-quality network of 12 participants (5 industrial) from the EU and US. It will include online and face-to-face courses taught by researchers with academic and industrial expertise in biofilms, 3D-printing research, antimicrobials, material science, and drug development.

Catalani M.P.,Glaxosmithkline | Catalani M.P.,Aptuit Verona Srl | Alvaro G.,Glaxosmithkline | Bernasconi G.,Glaxosmithkline | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

During the lead optimization of NK1/NK3 receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK1 and NK3 receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK 1/NK3 activity, were reported in this paper. © 2011 Elsevier Ltd. All rights reserved.

Dopamine (DA) D3 receptor antagonism might play a significant role in different therapeutic areas. A high number of preclinical studies on DA D3 receptor antagonists have shown efficacy in animal models of Parkinson's disease, schizophrenia and drug dependence. This Review covers the activities of medicinal chemists in this field over the last ten years towards the identification of truly selective compounds. Both primary and patent literature is reviewed here. Since the original discoveries, a clear trend towards the optimization of the developability properties of the new scaffold has clearly emerged with time, from both academic and industrial researchers. Examples of advanced leads from academia and industry are described. The latest potential therapeutic applications are reported too. Through the looking glass: A large number of dopamine D3receptor antagonist have shown efficacy in animal models of Parkinson's disease, schizophrenia and drug dependence. Medicinal chemistry research over the past decade aimed at the identification of selective compounds in this field, both in academia and in industry, is reviewed. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dallow N.,Glaxosmithkline | Fina P.,Aptuit Verona Srl
Pharmaceutical Statistics | Year: 2011

In early drug development, especially when studying new mechanisms of action or in new disease areas, little is known about the targeted or anticipated treatment effect or variability estimates. Adaptive designs that allow for early stopping but also use interim data to adapt the sample size have been proposed as a practical way of dealing with these uncertainties. Predictive power and conditional power are two commonly mentioned techniques that allow predictions of what will happen at the end of the trial based on the interim data. Decisions about stopping or continuing the trial can then be based on these predictions. However, unless the user of these statistics has a deep understanding of their characteristics important pitfalls may be encountered, especially with the use of predictive power. The aim of this paper is to highlight these potential pitfalls. It is critical that statisticians understand the fundamental differences between predictive power and conditional power as they can have dramatic effects on decision making at the interim stage, especially if used to re-evaluate the sample size. The use of predictive power can lead to much larger sample sizes than either conditional power or standard sample size calculations. One crucial difference is that predictive power takes account of all uncertainty, parts of which are ignored by standard sample size calculations and conditional power. By comparing the characteristics of each of these statistics we highlight important characteristics of predictive power that experimenters need to be aware of when using this approach. © 2010 John Wiley & Sons, Ltd.

Perdona' E.,Glaxosmithkline | Perdona' E.,Aptuit Verona S.r.l | Costantini V.J.A.,Glaxosmithkline | Tessari M.,Glaxosmithkline | And 11 more authors.
Neuropharmacology | Year: 2011

There is preclinical evidence supporting the finding that the GABA B receptor orthosteric agonist, baclofen, has significant effects on eating behavior suggesting the potential therapeutic application of this compound for the treatment of eating related disorders. However, the wide clinical use of baclofen might be limited by the appearance of sedative and motor impairment effects. The identification of positive allosteric modulators (PAMs) of GABA B receptors represents a novel therapeutic approach to reduce the centrally-mediated adverse effects typical of the GABA B receptor orthosteric agonist. In the present work, we report the in vitro profile of a novel chemical structure, 2-{1-[2-(4-chlorophenyl)-5- methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE) identified by screening the GSK compound collection. CMPPE potentiates GABA-stimulated [ 35S]GTPγS binding to membranes of human recombinant cell line and of rat brain cortex. GABA concentration-response curves (CRC) in the presence of fixed concentrations of CMPPE, in rat native tissue, revealed an increase of both the potency and maximal efficacy of GABA. A similar modulatory effect was observed in GABA B receptor-mediated activation of inwardly rectifying potassium channels in hippocampal neurons. CMPPE (30-100 mg/kg) and GS39783 (100 mg/kg) significantly decreased food consumption in rat without impairment on the animal locomotor activity. On the contrary, baclofen (2.5 mg/kg) decreased both food intake and motor performance. All together these findings confirm the role of GABA B system in controlling animal food intake and for the first time demonstrate that GABA B receptor PAMs may represent a novel pharmacological approach to treat eating disorders without unwanted sedative effects. © 2011 Elsevier Ltd. All rights reserved.

PubMed | Aptuit Verona s.r.l.
Type: Journal Article | Journal: ChemMedChem | Year: 2011

Dopamine (DA) D(3) receptor antagonism might play a significant role in different therapeutic areas. A high number of preclinical studies on DA D(3) receptor antagonists have shown efficacy in animal models of Parkinsons disease, schizophrenia and drug dependence. This Review covers the activities of medicinal chemists in this field over the last ten years towards the identification of truly selective compounds. Both primary and patent literature is reviewed here. Since the original discoveries, a clear trend towards the optimization of the developability properties of the new scaffold has clearly emerged with time, from both academic and industrial researchers. Examples of advanced leads from academia and industry are described. The latest potential therapeutic applications are reported too.

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