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Staessen J.A.,Catholic University of Leuven | Staessen J.A.,Maastricht University | Thijs L.,Catholic University of Leuven | Stolarz-Skrzypek K.,Jagiellonian University | And 18 more authors.
Trials | Year: 2011

Background: The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase-2 dose-finding study of rostafuroxin, a digitoxygenin derivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans.Methods: OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24-h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed).Results: Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P = 0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P = 0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P = 0.03) for systolic office BP; 0.70 mm Hg (P = 0.08) for diastolic office BP; 0.36 mm Hg (P = 0.49) for 24-h systolic BP; and 0.05 mm Hg (P = 0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤0.028), but carry-over effects were not significant (P ≥ 0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo.Conclusions: In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose.Trial Registration: ClinicalTrials (NCT): NCT00415038. © 2011 Staessen et al; licensee BioMed Central Ltd.


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: Controlled-Trials.com ISRCTN81306618. © 2010 Valecha et al.


Trademark
Sigma Tau Industrie Farmaceutiche Riunite | Date: 2013-08-27

Biologically active molecules, namely, enzyme preparations, polypeptides, hormones, all being chemically modified to enhance their therapeutic properties for use in the manufacture of pharmaceuticals; chemical preparations for use in the pharmaceutical industry. Pharmaceutical preparations for the prevention and treatment of disorders of the nervous system, the immune system, the cardio-vascular system including diabetes and metabolic diseases, the respiratory system, the musculoskeletal system, the genitourinary system, for the treatment of inflammatory disorders, for use in dermatology, in hematology, in oncology, in transplantation, in ophthalmology, for use in gastroenterological areas and the prevention and treatment of ocular disorders or diseases, anti-infectives, pharmaceutical preparations treating bacterial-bases disease, antivirals, antibiotics, antifungals, vaccines, diagnostic preparations for medical use; dietary and food supplements for use in the nutritional and alimentary industries. Medical research; scientific research; industrial research in the field of pharmaceutical preparations for the treatment of human diseases.


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.

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