Randomized clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip arthroplasty

Abstract Background: The aim was to evaluate the analgesic efficacy and safety of the dexketoprofen/tramadol 25 mg/75 mg fixed-dose combination vs dexketoprofen (25 mg) and tramadol (100 mg) in moderate-to-severe acute pain after total hip arthroplasty. Methods: This was a randomized, double-blind, parallel-group study in patients experiencing pain of at least moderate intensity on the day after surgery, compared with placebo at first administration to validate the pain model. The study drugwas administered orally every 8 h throughout a 5 day period. Rescue medication, metamizole 500 mg, was available during the treatment period. The evaluation of efficacy was based on patient assessments of pain intensity and pain relief. The primary end point was the mean sum of the pain intensity difference values throughout the first 8 h (SPID8). Results: Overall, 641 patients, mean age 62 (range 29–80) yr, were analysed; mean () values of SPID8 were 247 (157) for dexketoprofen/tramadol, 209 (155) for dexketoprofen, 205 (146) for tramadol, and 151 (159) for placebo. The primary analysis confirmed the superiority of the combination over dexketoprofen 25 mg (P=0.019; 95% confidence interval 6.4–73) and tramadol 100 mg (P=0.012; 95% confidence interval 9.5–76). The single components were superior to placebo (P<0.05), confirming model sensitivity. Most secondary analyses supported the superiority of the combination. The incidence of adverse drug reactionswas low and similar among active treatment groups. Conclusions: The efficacy results confirmed the superiority of dexketoprofen/tramadol over its single components, even at higher doses (tramadol), with a safety profile fully in line with that previously known for these agents in monotherapy

Finding peculiar patterns of kinetoplastida enzymes to be exploited in drug design

If a parasite and host metabolic ways differ, such as an enzyme is present only in parasite, obviously this is a good target in drug design. Also, essential enzymes present in both can be good targets if we exploit selective patterns of the parasite enzyme. At this aim, comparison of the pentose phosphate pathway (PPP) 2nd dehydrogenase, 6-phosphogluconate dehydrogenase (6PGDH), between mammal host and Trypanosoma brucei, has been done in our lab. PPP provides above all necessary NADPH to all cell reduction reactions, including those contrasting both oxidative, parasite environment and host response. Although kinetoplastids 6PGDH shows only 33% amino acid identity with mammal 6PGDH, 3D-structure and general acid-base mechanism are similar, with many conserved residues in the active site. Anyway, by studying enzymes in more detail, several differences were found. Looking for the affinity of some polycyclic compounds, preferential binding of T. brucei 6PGDH to triphenylmethane with either nitrogen or oxygen as substituent in two rings and a sulfonate in the 3rd ring was found compared to the mammal enzyme. A selectivity of 40 was shown by Brilliant Green and this is probably due to the shorter distance between two active site lysines than in mammal. By studying homotropic cooperativity other significant differences were found. In fact substrate binding to one subunit increases homodimer catalytic efficiency; even if the two subunits have an identical sequence they are implied in different steps. This was shown by several ways, for instance in presence of the substrate 6PG there is a NADP half-site reactivity, also 6PG activates decarboxylation following 6PG oxidation, but differently from the liver enzyme the parasite's one is able to catalyse this step even in absence of an activator. Besides, allosteric modulation for the parasite enzyme is not apparent when reverse reaction is studied, while it is shown by yeast enzyme, which is very similar to the liver's one. Thus, diversity exists which allowed to find ligands more than 250-fold selective, as transition state analogues 4-phospho-erythronoxamate and 4-phospho-erythronate. This characterization has disclosed lead compounds for medicinal chemists to transform those into pro-drugs and derivatives with good stability and solubility. Last difference found is that parasite 6PGDH shows a ligand-modulated tetramerization, which is not present in mammal enzyme representing further drug exploitable potential

IRIDE: Interdisciplinary research infrastructure based on dual electron linacs and lasers

This paper describes the scientific aims and potentials as well as the preliminary technical design of IRIDE, an innovative tool for multi-disciplinary investigations in a wide field of scientific, technological and industrial applications. IRIDE will be a high intensity "particles factory", based on a combination of high duty cycle radio-frequency superconducting electron linacs and of high energy lasers. Conceived to provide unique research possibilities for particle physics, for condensed matter physics, chemistry and material science, for structural biology and industrial applications, IRIDE will open completely new research possibilities and advance our knowledge in many branches of science and technology. IRIDE is also supposed to be realized in subsequent stages of development depending on the assigned priorities