The forthcoming implementation of the European Clinical Trial Regulation (Regulation (EU) No. 536/2014), which is expected to facilitate the conduct of clinical trials across the European Union, will require National Authorities to create the best conditions for the implementation of the new Regulation through national guidelines, so that sponsors may reconsider Europe as a prime location for planning clinical trials. During a meeting titled "Innovation in Clinical Research", an expert panel discussed potential local advances fostering competitiveness of European clinical research with representatives of the pharmaceutical industry, patient organisations and Italian regulatory agency in view of the forthcoming implementation of (EU) No. 536/2014 on clinical trials of medicinal products. In this article we summarise the findings of the meeting, describe features characterising clinical research patterns and offer some suggestions on the possible involvement of all stakeholders in order to foster research innovation and allow the timely access to novel medicines for patients.

Page 1. Annali dell'Istituto Superiore di Sanità Vol. 53, No. 2 2017 Contents EDITORIAL On transparency in health care guidelines Carlo Petrini and Enrico Alleva COMMENTARIES Patient-physician alliance: from Hippocrates to Post-Genomic Era Simonetta Pulciani and Domenica Taruscio The emerging role of the human bone marrow as a privileged developmental niche for the transmission stages of the malaria parasite Plasmodium falciparum Pietro Alano Pertussis in infants and the resurgence of a vaccine preventable disease: what to do? Giorgio Fedele and Paola Stefanelli A harmonized and efficient clinical research environment would benefit patients and enhance European competitiveness Antonino Amato, Eugenio Aringhieri, Stefania Boccia, Filippo Buccella, Barbara Gorini, Donatella Gramaglia, Riccardo Masetti, Paolo Rossi and Pier Giuseppe Pelicci ORIGINAL ARTICLES AND REVIEWS …

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or= 80, and CGI-S score >or= 4. Patients were randomized to ziprasidone (80-160 mg/day, n = 73) or clozapine (250-600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (- 25.0 +/- 22.0, 95% CI - 30.2 to - 19.8) and clozapine (- 24.5 +/- 22.5, 95% CI - 29.7 to - 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

a Chair of Psychiatry, Brescia University School of Medicine, Brescia, Italy b University Psychiatric Unit, Brescia University School of Medicine and Brescia Spedali Civili, Brescia, Italy c Department of Mental Health, Brescia Spedali Civili, Brescia, Italy d Center of Behavioral and Neurodegenerative Disorders, Brescia University and EULO, Brescia, Italy e Medical Department, Pfizer Italia, Rome, Italy f Pfizer Inc, New York, NY, USA

Background: Recent data have suggested few differences in the cognitive effects of antipsychotic medications. However, assessment of such effects can be complex, due to a number of factors. Clozapine has previously shown greater clinical and lesser cognitive benefits than other atypicals. This study compared the cognitive benefits of clozapine and ziprasidone in schizophrenia patients (n = 130) with a history of either failure to respond to or intolerance of previous adequate antipsychotic treatments.Methods: Patients were randomized (double-blind) to either clozapine or ziprasidone in a single country (Italy), multi-site trial. The cognitive assessments examined episodic memory (RAVLT), executive functioning (Stroop test), and processing speed (Trail-making test (TMT) Parts A and B).Results: Analyses found statistically significant within-group improvements for ziprasidone in learning and delayed recall on the RAVLT and on TMT Parts A and B. Clozapine-treated patients improved on the RAVLT, but not on the TMT. A composite cognitive score improved from baseline in both groups, but the improvements were significantly larger in the ziprasidone group (p=.029).Implications: These results indicated that cognitive functioning improved following treatment with ziprasidone in patients with a history of either treatment resistance or intolerance, and that the effects are comparable or greater than those observed with clozapine. One interpretation of these findings is that clozapine treatment interferes with the performance benefits associated with practice. (c) 2007 Elsevier B.V. All rights reserved.

The Crimean region is unique in the abundance of Palaeolithic sites, particularly numerous in mountain parts of the peninsula. Most are attributed to the Middle Palaeolithic. During recent decades, the sites have been investigated by the Ukrainian archeologists V.P. Chabai, A.I. Yevtushenko, Yu.E. Demidenko, A.P. Veselsky, and others. Integrated studies performed by a large group of specialists included assessment of the geological and geomorphological setting of every site, and analysis of paleontological remains recovered from cultural layers (large and small mammals, birds, molluscs, as well as pollen and spores). Cultural layers of the sites have been dated using various methods (14C, TL, ESR).Studies have included several thousand small mammal bone remains recovered from seven multi-layered Palaeolithic sites in the Crimea, providing the basis for reconstructions of environments at different stages of human habitation. The oldest finds of small mammals are attributed to the last interglacial, and the youngest to the Denekamp (Bryansk) interstadial. More than 20 species of small mammals have been identified, which permitted recognition of specific features of faunal assemblages differing in age. The faunas display a certain stability of species composition over a period of almost 100,000 years. No species typical of cold environments have been found, and the faunas are dominated by open landscape dwellers. Forest and near water species are present in small quantities. Some mammals identified in the sites do not occur in the Crimea at present. On the other hand, a number of species inhabiting the Crimea today have not been found in the fossil assemblages. On the whole, the Mountain Crimea was a refugium for mammals, and possibly also for other organisms, during the last glaciation. Due to its southern position, the Crimea retained rather comfortable environmental and climate conditions throughout the Late Pleistocene. Similarly, the environments were undoubtedly hospitable for humans.

Two diastereomeric furan-2-carbonylamino-3-oxohexahydroindolizino[8,7-b]indole carboxylates, highly constrained analogues of endogenous pyroglutamyl tripeptide inhibitors of snake venom endopeptidases, have been prepared as potential inhibitors of adamalysin II and matrix metalloproteinases. They proved to be inactive against adamalysin II and weak inhibitors of gelatinase A, gelatinase B, stromelysin 1 and human neutrophil collagenase. Evaluation of the mode of binding of the (2R,5S,11bR) isomer in the active site of adamalysin II suggests that the decrease of potency may be due to the reorientation of the acylamino chain in three of the heterocyclic nucleus, to a short contact at the entrance of the S'(1) hydrophobic cleft and to the loss of flexibility of the tetracyclic nucleus in the P'(1), P'(2) region of the inhibitor, which prevents optimal arrangement in the S'(1) specificity subsite.

Two crystal structures of human neutrophil collagenase (HNC, MMP-8), one complexed with a primed- and the other with an unprimed-side inhibitor, were determined using synchrotron radiation at 100 K. Both inhibitors contain non-hydroxamate zinc-binding functions. The Pro-Leu-L-Trp(P)(OH)(2) occupies the unprimed region of the active site, furnishes new structural information regarding interaction between the catalytic zinc ion and the phosphonate group, and is the only example of occupation of the S(1) subsite of MMP-8 by the bulky tryptophan side chain. The (R)-2-(biphenyl-4-ylsulfonyl)-1,2,3, 4-tetrahydroisochinolin-3-carboxylic acid, a conformationally constrained D-Tic derivative, accommodates its biphenyl substituent into the deep primary specificity S(1)' subsite, inducing a widening of the entrance to this pocket; this modification of the protein, mainly consisting in a shift of the segment centered at Pro217, is observed for the first time in MMP-8 complexes. Cation-aromatic interactions can stabilize the formation of both complexes, and the beneficial effect of aromatic substituents in proximity of the catalytic zinc ion is discussed. The phosphonate group bound to either a primed- or unprimed-side inhibitor maintains the same relative position with respect to the catalytic zinc ion, suggesting that this binding function can be exploited for the design of combined inhibitors assembled to interact with both primed and unprimed regions of the active cleft.

Phosphonate analogues of the peptidomimetic N-(Furan-2-yl)carbonyl-Leu-Trp-OH were prepared with the goal of evaluating the effect of phosphonate for carboxylate replacement on binding with snake venom metalloproteinases and MMPs. N-(Furan-2-yl)carbonyl-Leu-L-Trp(P)-(OH)2 showed a 75-fold increase of the inhibiting activity against adamalysin II, a snake venom metalloproteinase structurally related to MMPs and TACE. Both the phosphonate and carboxylate peptidomimetics fit into the active site adopting a retrobinding mode and provide the structural base for a new class of metalloproteinases inhibitors.

Annals of the New York Academy of SciencesVolume 878, Issue 1 p. 700-702 Phosphonate Inhibitors of Adamalysin II and Matrix Metalloproteinases C. GALLINA, C. GALLINA Istitituto di Scienze del Farmaco, Università G. d'Annunzio, Chieti, ItalySearch for more papers by this authorE. GAVUZZO, E. GAVUZZO Istituto di Strutturistica Chimica, CNR, Rome, ItalySearch for more papers by this authorC. GIORDANO, C. GIORDANO Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorB. GORINI, B. GORINI Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorF. MAZZA, Corresponding Author F. MAZZA Istituto di Strutturistica Chimica, CNR, Rome, Italy Dipartimento di Chimica, Università di L'Aquila, L'Aquila, Italy Address for correspondence: Fernando Mazza, Istituto di Strutturistica Chimica, CNR, C.P. 10, 00016 Moterotondo Stazione, Rome, Italy. phone, 0039-06-90625142; fax, 0039-06-90673630; e-mail, [email protected]Search for more papers by this authorM. PAGLIALUNGA-PARADISI, M. PAGLIALUNGA-PARADISI Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorG. PANINI, G. PANINI Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorG. POCHETTI, G. POCHETTI Istituto di Strutturistica Chimica, CNR, Rome, ItalySearch for more papers by this authorV. POLITI, V. POLITI Polifarma Research Center, Rome, ItalySearch for more papers by this author C. GALLINA, C. GALLINA Istitituto di Scienze del Farmaco, Università G. d'Annunzio, Chieti, ItalySearch for more papers by this authorE. GAVUZZO, E. GAVUZZO Istituto di Strutturistica Chimica, CNR, Rome, ItalySearch for more papers by this authorC. GIORDANO, C. GIORDANO Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorB. GORINI, B. GORINI Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorF. MAZZA, Corresponding Author F. MAZZA Istituto di Strutturistica Chimica, CNR, Rome, Italy Dipartimento di Chimica, Università di L'Aquila, L'Aquila, Italy Address for correspondence: Fernando Mazza, Istituto di Strutturistica Chimica, CNR, C.P. 10, 00016 Moterotondo Stazione, Rome, Italy. phone, 0039-06-90625142; fax, 0039-06-90673630; e-mail, [email protected]Search for more papers by this authorM. PAGLIALUNGA-PARADISI, M. PAGLIALUNGA-PARADISI Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorG. PANINI, G. PANINI Centro di Chimica del Farmaco, CNR, Università La Sapienza, Rome, ItalySearch for more papers by this authorG. POCHETTI, G. POCHETTI Istituto di Strutturistica Chimica, CNR, Rome, ItalySearch for more papers by this authorV. POLITI, V. POLITI Polifarma Research Center, Rome, ItalySearch for more papers by this author First published: 06 February 2006 https://doi.org/10.1111/j.1749-6632.1999.tb07766.xCitations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume878, Issue1INHIBITION OF MATRIX METALLOPROTEINASES THERAPEUTIC APPLICATIONSJune 1999Pages 700-702 RelatedInformation

Source of material: The title compound was synthesized following the procedure described in ref. 1 starting from a solution of 3-indolacetic acid (28.5 mmol) containing oxalyl chloride (31.4 mmol). Crystals have been obtained by slow evaporation fiOm a methanol solution kept at room temperature. The title molecule belongs to a class of compounds which are common intermediates in the synthesis of many diasteroisomeric dipeptides. In the present structure two water molecules have been localized.

The search of reprolysin inhibitors offers the possibility of intervention against both matrixins and ADAMs. Here we report the crystal structure of the complex between adamalysin II, a member of the reprolysin family, and a phosphonate inhibitor modeled on an endogenous venom tripeptide. The inhibitor occupies the primed region of the cleavage site adopting a retro-binding mode. The phosphonate group ligates the zinc ion in an asymmetric bidentate mode and the adjacent Trp indole system partly fills the primary specificity subsite S1'. An adamalysin-based model of tumor necrosis factor-alpha-converting enzyme (TACE) reveals a smaller S1' pocket for this enzyme.