Sigma Tau Industrie Farmaceutiche Riunite

Pomezia, Italy

Sigma Tau Industrie Farmaceutiche Riunite

Pomezia, Italy
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Valecha N.,National Institute of Malaria Research | Phyo A.P.,Shoklo Malaria Research Unit | Mayxay M.,University of Oxford | Mayxay M.,Health Science University | And 18 more authors.
PLoS ONE | Year: 2010

Background: The artemisinin-based combination treatment (ACT) of dihydroartemisinin (DHA) and piperaquine (PQP) is a promising novel anti-malarial drug effective against multi-drug resistant falciparum malaria. The aim of this study was to show non-inferiority of DHA/PQP vs. artesunate-mefloquine (AS+MQ) in Asia. Methods and Findings: This was an open-label, randomised, non-inferiority, 63-day follow-up study conducted in Thailand, Laos and India. Patients aged 3 months to 65 years with Plasmodium falciparum mono-infection or mixed infection were randomised with an allocation ratio of 2:1 to a fixed-dose DHA/PQP combination tablet (adults: 40 mg/160 mg; children: 20 mg/320 mg; n = 769) or loose combination of AS+MQ (AS: 50 mg, MQ: 250 mg; n = 381). The cumulative doses of study treatment over the 3 days were of about 6.75 mg/kg of DHA and 54 mg/kg of PQP and about 12 mg/kg of AS and 25 mg/kg of MQ. Doses were rounded up to the nearest half tablet. The primary endpoint was day-63 polymerase chain reaction (PCR) genotype-corrected cure rate. Results were 87.9% for DHA/PQP and 86.6% for AS+MQ in the intention-to-treat (ITT;97.5% one sided confidence interval, CI: >-2.87%), and 98.7% and 97.0%, respectively, in the per protocol population (97.5% CI: >-0.39%). No country effect was observed. Kaplan-Meier estimates of proportions of patients with new infections on day 63 (secondary endpoint) were significantly lower for DHA/PQP than AS+MQ: 22.7% versus 30.3% (p = 0.0042; ITT). Overall gametocyte prevalence (days 7 to 63; secondary endpoint), measured as person-gametocyte-weeks, was significantly higher for DHA/PQP than AS+MQ (10.15% versus 4.88%; p = 0.003; ITT). Fifteen serious adverse events were reported, 12 (1.6%) in DHA/ PQP and three (0.8%) in AS+MQ, among which six (0.8%) were considered related to DHA/PQP and three (0.8%) to AS+MQ. Conclusions: DHA/PQP was a highly efficacious drug for P. falciparum malaria in areas where multi drug parasites are prevalent. The DHA/PQP combination can play an important role in the first-line treatment of uncomplicated falciparum malaria. Trial Registration: ISRCTN81306618. © 2010 Valecha et al.

Gargano N.,Sigma Tau Industrie Farmaceutiche Riunite | Ubben D.,Medicines for Malaria Venture MMV | Tommasini S.,Sigma Tau Industrie Farmaceutiche Riunite | Bacchieri A.,Sigma Tau Industrie Farmaceutiche Riunite | And 9 more authors.
Malaria Journal | Year: 2012

Background: Resistance in Plasmodium falciparum to commonly used anti-malarial drugs, especially chloroquine, is being increasingly documented in India. By 2007, the first-line treatment for uncomplicated malaria has been revised to recommend artemisinin-based combination therapy (ACT) for all confirmed P. falciparum cases. Objective. The objective of this study was to compare the efficacy, safety and tolerability between dihydroartemisinin- piperaquine (DP) and artesunate plus mefloquine (A+M) drug combinations in the treatment of uncomplicated P. falciparum malaria in India. Methods. Between 2006 and 2007, 150 patients with acute uncomplicated P. falciparum malaria were enrolled, randomized to DP (101) or A+M (49) and followed up for 63days as part of an open-label, non-inferiority, randomized, phase III multicenter trial in Asia. Results: The heterogeneity analysis showed no statistically significant difference between India and the other countries involved in the phase III study, for both the PCR-corrected and uncorrected cure rates. As shown at the whole study level, both forms of ACT were highly efficacious in India. In fact, in the per protocol population, the 63-day cure rates were 100% for A+M and 98.8% for DP. The DP combination exerted a significant post-treatment prophylactic effect, and compared with A+M a significant reduction in the incidence of new infections for DP was observed (respectively 17.1% versus 7.5% of patients experienced new infection within follow up). Parasite and fever clearance was rapid in both treatment arms (median time to parasite clearance of one day for both groups). Both DP and A+M were well tolerated, with the majority of adverse events of mild or moderate severity. The frequencies of individual adverse events were generally similar between treatments, although the incidence of post treatment adverse events was slightly higher in patients who received A+M with respect to those treated with DP. Conclusion: DP is a new ACT displaying high efficacy and safety in the treatment of uncomplicated P. falciparum malaria and could potentially be considered for the first-line treatment of uncomplicated falciparum malaria in India. Trial registration. Current Controlled Trials ISRCTN 81306618. © 2012 Gargano et al.; licensee BioMed Central Ltd.

Cunha C.,University of Perugia | Aversa F.,University of Parma | Lacerda J.F.,University of Lisbon | Busca A.,Trapianto di Cellule Staminali Ematologia 2 | And 24 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P = 0.003) and the confirmation study (adjusted odds ratio, 2.78; P = 0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT. Copyright © 2014 Massachusetts Medical Society.

Marazziti D.,University of Pisa | Baroni S.,University of Pisa | Pirone A.,University of Pisa | Giannaccini G.,University of Pisa | And 11 more authors.
Neurochemical Research | Year: 2012

The aim of this study was to investigate the distribution of serotonin (5-HT) receptors of type 6 (5-HT 6) in postmortem human prefrontal cortex, striatum and hippocampus. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT 6 receptor distribution was explored by the [ 125I]SB-258585 binding to brain membranes followed by the pharmacological characterization, where possible, and by autoradiographic, immunohistochemical and immunofluorescence evaluations. A specific and saturable [ 125I]SB-258585 binding was detected in striatum only, with a pharmacological characterization consistent with that of a 5-HT 6 receptor. The autoradiography showed the presence of a specific [ 125I]SB-258585 binding distributed homogeneously in caudate, putamen and accumbens. The immunohistochemistry, carried out in the striatum only, coupled with the immunofluorescence with glial fibrillary acidic protein (GFAP) and parvalbumin (PV) showed the co-localization of 5-HT 6 receptor with PV, while indicating that this receptor subtype was expressed in neurons and not in astrocytes. Taken together, the present findings showed the presence of a higher density of 5-HT 6 receptors, as labeled by [ 125I]SB-258585, in striatum than in hippocampus and prefrontal cortex, and specifically within the neuronal body. In addition, they would suggest that striatum is one of the major potential CNS targets linked to 5-HT 6 receptor modulation. © Springer Science+Business Media, LLC 2012.

PubMed | Sigma Tau Industrie Farmaceutiche Riunite, Institute Hospital del Mar dInvestigacions Mediques, University of Minho, University of Lisbon and 5 more.
Type: Journal Article | Journal: The Journal of experimental medicine | Year: 2016

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation-related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell-independent and T cell-dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.

Marazziti D.,University of Pisa | Baroni S.,University of Pisa | Pirone A.,University of Pisa | Giannaccini G.,University of Pisa | And 11 more authors.
Neurochemistry International | Year: 2013

Given the paucity of data on the distribution of serotonin (5-HT) receptors of type 6 (5-HT6) in the human brain, the aim of this study was to investigate their distribution in postmortem human prefrontal cortex, striatum and hippocampus by either immunohistochemical or immunofluorescence techniques. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT6 receptor distribution was explored by the [125I]SB-258585 binding to brain membranes followed by immunohistochemical and immunofluorescence evaluations. A specific [125I]SB-258585 binding was detected in all the regions under investigation, whilst the content in the hippocampus and cortex being about 10-30 times lower than in the striatum. Immunohistochemistry and double-label immunofluorescence microscopy experiments, carried out in the prefrontal cortex and hippocampus only, since data in the striatum were already published, showed the presence of 5-HT6 receptors in both pyramidal and glial cells of prefrontal cortex, while positive cells were mainly pyramidal neurons in the hippocampus. The heterogeneous distribution of 5-HT6 receptors provides a preliminary explanation of how they might regulate different functions in different brain areas, such as, perhaps, brain trophism in the cortex and neuronal firing in the hippocampus. This study, taking into account all the limitations due to the postmortem model used, represents the starting point to explore the 5-HT6 receptor functionality and its sub-cellular distribution. © 2012 Elsevier Ltd. All rights reserved.

Marazziti D.,University of Pisa | Baroni S.,University of Pisa | Borsini F.,Sigma Tau Industrie Farmaceutiche Riunite | Picchetti M.,University of Pisa | And 3 more authors.
Current Medicinal Chemistry | Year: 2013

The serotonin (5-HT) receptors of type 6 (5-HT6) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long C-terminal tail, and one intron located in the middle of the third cytoplasmatic loop. A lot of controversies still exist regarding their binding affinity, effects of 5-HT6 ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution. In spite of the lack of information on metabolic pattern of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic, antidepressant and anti-obese drugs. The present paper is a comprehensive review on the state of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists. © 2013 Bentham Science Publishers.

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