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.
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.
Micheli F.,Aptuit Verona Srl
ChemMedChem | Year: 2011
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.
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.,Istituto di Ricerche Farmacologiche Mario Negri |
Di Clemente A.,Istituto di Ricerche Farmacologiche Mario Negri |
Orru A.,Institute Of Translational Pharmacology Cnr |
Moro F.,Istituto di 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.