942 resultados para preclinical drug development


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The ISSP Position Stand on Career Development and Transitions of Athletes draws attention to viewing athletes from the perspective of their career development and their broader historical and socio‐cultural contexts. The particular focus of this paper is on career transitions as turning phases in career development. Successfully coping with transitions both within and outside of sport allows greater opportunity for an athlete to live a long and successful life in sport as well as being able to adjust effectively to the post‐career. Alternatively, failure in coping with a transition is often followed by negative consequences (e.g., premature dropout from sport, neuroses, alcohol/drug abuse, etc.). Therefore, helping athletes prepare for and/or cope with career transitions should be of primary concern for coaches, managers, athletes’ parents, and sport psychology consultants. In this paper we emphasize the role of contextual factors in career development/transition research and practice. Based on the literature review, we propose six statements and related recommendations for athletes and their significant others, as well as for researchers and consultants

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Concern about the growth in adolescent problem behaviours (e.g. delinquency, drug use) has led to increased interest in positive youth development, and a surge in funding for ‘after school programs.’ We evaluate the potential of youth sport programs to foster positive development, while decreasing the risk of problem behaviours. Literature on the positive and negative outcomes of youth sport is presented. We propose that youth sport programs actively work to assure positive outcomes through developmentally appropriate designs and supportive child–adult (parent/coach) relationships. We also highlight the importance of sport programs built on developmental assets (Benson, 1997 ) and appropriate setting features (National Research Council and Institute of Medicine, 2002 ) in bringing about the five ‘C’s of positive development (competence, confidence, character, connections, and compassion/caring: Lerner et al., 2000 ). An applied sport-programming model, which highlights the important roles of policy-makers, sport organizations, coaches and parents in fostering positive youth development is presented as a starting point for further applied and theoretical research.

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BACKGROUND Although it has been well established that methadone use can result in prolonged QTc/torsades de pointes (TdP) and has been labeled as one of the main drugs that cause TdP, it is still prescribed indiscriminately, and several cases of methadone-associated TdP have been seen in our community. METHODS Our objective was to determine the associated factors for prolonged QTc and the development of torsades de pointes (TdP) in our underserved patient population. We found 12,550 ECGs with prolonged QTc between 2002 and 2013. Medical records were reviewed in order to identify precipitating factors for prolonged QTc and to detect incidence of TdP. RESULTS We identified 2735 patients with prolonged QTc who met the inclusion criteria. Of these, 89 (3%) experienced TdP. There was a greater prevalence of HIV infection in the TdP group (11.2 vs. 3.7%, p < 0.001). Furosemide, hydrochlorothiazide, selective serotonin reuptake inhibitors (SSRIs), amiodarone, ciprofloxacin, methadone, haloperidol, and azithromycin were the drugs most often associated with prolonged QTc (31, 8.2, 7.6, 7.1, 3.9, 3.4 and 3.3%, respectively). However, the agents most commonly associated with TdP were furosemide (39.3%), methadone (27%), SSRIs (19.1%), amiodarone (18%), and dofetilide (9%). The medications with statistical significance in the multivariate analysis for TdP development in descending order were as follows: ranolazine (odds ratios [OR] = 53.61, 95% confidence interval [CI] 5.4-524, p < 0.001), dofetilide (OR = 25, CI 6.47-103.16, p < 0.001), voriconazole (OR = 21.40, CI 3.24-124.25, p < 0.001), verapamil (OR = 10.98, CI 2.62-44.96, p < 0.001), sotalol (OR = 12.72, 1.95-82.81, p = 0.008), methadone (OR = 9.89, CI 4.05-24.15, p < 0.001), and SSRI (OR = 2.26, CI 1.10-5.96, p < 0.001). This multivariate analysis revealed that amiodarone and HIV infection were not implicated in TdP. CONCLUSION Methadone was by far the leading medication implicated in the development of TdP and an independent predictor in both univariate and multivariate analyses despite the fact that it was not the most common QT-prolonging medication in our population.

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Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

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Description based on 2.

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Includes bibliographies.

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National Highway Traffic Safety Administration, Washington, D.C.

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Shipping list no.: 92-205-P.

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National Highway Traffic Safety Administration, Washington, D.C.

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National Highway Traffic Safety Administration, Washington, D.C.

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Item 467-A-1