Navegando por Palavras-chave "pharmacology"
Agora exibindo 1 - 6 de 6
Resultados por página
Opções de Ordenação
- ItemSomente MetadadadosAssessing the pharmacodynamic profile of intravenous antibiotics against prevalent Gram-negative organisms collected in Colombia(Contexto, 2011-09-01) Villegas, Maria Virginia; Briceno, David Felipe; Ruiz, Sory Jamil; Furtado, Guilherme Henrique Campos [UNIFESP]; Nicolau, David P.; Int Ctr Med Res & Training CIDEIM; CIDEIM; Hartford Hosp; Universidade Federal de São Paulo (UNIFESP)Objectives: This study was designed to simulate standard and optimized dosing regimens for intravenous antibiotics against contemporary populations of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa using MIC distribution data to determine which of the tested carbapenem regimens provided the greatest opportunity for obtaining maximal pharmacodynamic (PD) activity. Methods: The isolates studied were obtained from the COMPACT-COLOMBIA surveillance program conducted between February and November 2009. Antimicrobial susceptibility testing was conducted by broth microdilution method according to the CLSI guidelines. Doripenem, imipenem-cilastatin, and meropenem, were the modeled antibiotics. A 5,000 patient Monte Carlo simulation was performed for each regimen and PD targets were defined as free drug concentrations above the MIC for at least 40% of the dosing interval. Results: All carbapenem regimens obtained optimal exposures against E. coli, unlike the other Enterobacteriaceae tested. Against P. aeruginosa, only a prolonged infusion of doripenem exceeded the 90% cumulative fraction of response (CFR) threshold. Worrisomely, no regimens for any of the drugs tested obtained optimal CFR against A. baumannii. For P. aeruginosa intensive care unit (ICU) isolates, CFR was approximately 20% lower for isolates collected in the respiratory tract compared with bloodstream or intra-abdominal for imipenem and meropenem. Noteworthy, all doripenem and meropenem regimens achieved greater than 90% CFR against bloodstream and respiratory isolates of K. pneumoniae. Conclusions: Our data suggests that higher dosing and prolonged infusion of doripenem or meropenem may be suitable for empirically treating ICU P. aeruginosa, while none of the carbapenems achieved optimal cumulative fraction of response against A. baumannii. Standard dosing regimens of all the carbapenems tested achieved optimal CFR against E. coli isolates, but higher carbapenem dosages might be required for empiric treatment of K. pneumoniae, particularly from an intra-abdominal source. Non-standard dosage regimens studied in this modeling should be proven effective in prospective clinical trials.
- ItemSomente MetadadadosAvaliação morfofuncional e estresse oxidativo no intestino de camundongos distróficos (mdx)(Universidade Federal de São Paulo (UNIFESP), 2014-12-17) Alves, Gabriel Andrade [UNIFESP]; Nouailhetas, Viviane Louise Andree Nouailhetas [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Dystrophin is a component of the complex of dystrophin-associated proteins, which connects the cytoskeleton to the plasma membrane and the extracellular matrix. Their lack causes Duchenne Muscular Dystrophy (DMD), characterized by a progressive degeneration of skeletal and cardiac muscle, leading to death in patients third decade of life. Although DMD patients had gastrointestinal symptoms such as diarrhea and pseudo obstruction, little is known of the role of dystrophin in the intestinal smooth muscle (MLI). We aim to understand what is the role of dystrophin protein in MLI: structurally and functionally, muscle contraction. Specifically studied animal model (mdx mice), and assess the structure and ultrastructure of the ILM, the resistance loss of contractile response of the MLI exposed stretch, a loss of contractile response in medium without Ca2 + (essential for contraction) and recovery contractile respota with the replacement of the ion in the presence or absence of nifedipine (blocker Cav1.2b). Observe surprising resistance to loss of response during stretch despite the animal gut dystrophic have structural mucosal deficit and have demonstrated loss of muscle layer (30%) compared to the control, present degenerate mitochondria and sarcoplasmic reticulum change. The response in medium without calcium, dystrophic animals was more resistant both to the loss of contraction in medium without Ca2 +, as the recovery of contractility with replacement ion. Dystrophin has a peculiar role in MLI, different from that of skeletal muscle, because despite the visible structural deficit, there was an increase in resistance to loss of contractility stretch. The dystrophic mdx mice also presents kinetics in response to varying external impaired calcium concentration (thus probably with changes in Cav1.2b), which may help to understand symptoms present in DMD patients.
- ItemSomente MetadadadosThe DrugAge database of aging-related drugs(Wiley, 2017) Barardo, Diogo; Thornton, Daniel; Thoppil, Harikrishnan; Walsh, Michael; Sharifi, Samim; Ferreira, Susana; Anzic, Andreja; Fernandes, Maria; Monteiro, Patrick; Grum, Tjasa; Cordeiro, Rui; De-Souza, Evandro Araujo [UNIFESP]; Budovsky, Arie; Araujo, Natali; Gruber, Jan; Petrascheck, Michael; Fraifeld, Vadim E.; Zhavoronkov, Alexander; Moskalev, Alexey; de Magalhaes, Joao PedroAging is a major worldwide medical challenge. Not surprisingly, identifying drugs and compounds that extend lifespan in model organisms is a growing research area. Here, we present DrugAge (http://genomics. senescence. info/drugs/), a curated database of lifespan-extending drugs and compounds. At the time of writing, DrugAge contains 1316 entries featuring 418 different compounds from studies across 27 model organisms, including worms, flies, yeast and mice. Data were manually curated from 324 publications. Using drug-gene interaction data, we also performed a functional enrichment analysis of targets of lifespan-extending drugs. Enriched terms include various functional categories related to glutathione and antioxidant activity, ion transport and metabolic processes. In addition, we found a modest but significant overlap between targets of lifespan-extending drugs and known aging-related genes, suggesting that some but not most aging-related pathways have been targeted pharmacologically in longevity studies. DrugAge is freely available online for the scientific community and will be an important resource for biogerontologists.
- ItemAcesso aberto (Open Access)Ictogênese, epileptogênese e mecanismo de ação das drogas na profilaxia e tratamento da epilepsia(Liga Brasileira de Epilepsia (LBE), 2008-11-01) Silva, Alexandre Valotta da [UNIFESP]; Cabral, Francisco Romero [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Hospital Albert Einstein Instituto Israelita de Ensino e Pesquisa Instituto do CérebroINTRODUCTION: The neurologist who wants to properly manage his patients with epilepsy should be familiar with the mechanisms of generation, propagation and interruption of seizures. In this article, we briefly review the mechanisms of seizure generation in patients with epilepsy (ictogenesis) and the process involved in the development of epilepsy after a brain lesion (epileptogenesis). In addition, we present the mechanisms of action of the main drugs used in each of these situations, that is, antiictogenic and antiepileptogenic drugs. PURPOSE: To present and discuss the main concepts about ictogenesis, epileptogenesis and mechanism of action of the drugs used for prevent and treat epilepsy. CONCLUSION: Different pharmacological approaches have been developed and tested in an effort to block seizures more efficiently and prevent the development of epilepsy after a brain injury. One might expect that with the advancement of knowledge, new drugs will be developed and allow a better result in the prevention and treatment of epilepsy.
- ItemAcesso aberto (Open Access)The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery(Wiley, 2017) Bohnen, Michael S.; Roman-Campos, Danilo; Terrenoire, Cecile [UNIFESP]; Jnani, Jack; Sampson, Kevin J.; Chung, Wendy K.; Kass, Robert S.Background-Heterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH). KCNK3 encodes an acid-sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK3 is widely expressed in the body, and dimerizes with other KCNK3 subunits, or the closely related, acid-sensitive KCNK9 channel. Methods and Results-We engineered homomeric and heterodimeric mutant and nonmutant KCNK3 channels associated with PAH. Using whole-cell patch-clamp electrophysiology in human pulmonary artery smooth muscle and COS7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous KCNK3 conditions lead to mutation-specific severity of channel dysfunction. Both wildtype and mutant KCNK3 channels were activated by ONO-RS-082 (10 mu mol/L), causing cell hyperpolarization. We observed robust gene expression of KCNK3 in healthy and familial PAH patient lungs, but no quantifiable expression of KCNK9, and demonstrated in functional studies that KCNK9 minimizes the impact of select KCNK3 mutations when the 2 channel subunits co-assemble. Conclusions-Heterozygous KCNK3 mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK3 channels represent novel therapeutic substrates in PAH. Pharmacological and pH-dependent activation of wildtype and mutant KCNK3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co-assembly of KCNK3 with KCNK9 subunits may provide protection against KCNK3 loss of function in tissues where both KCNK9 and KCNK3 are expressed, contributing to the lung-specific phenotype observed clinically in patients with PAH because of KCNK3 mutations.
- ItemSomente MetadadadosSize and specificity of radiopharmaceuticals for sentinel lymph node detection(Royal Soc Medicine Press Ltd, 2011-09-01) Fernandez Nunez, Eutimio Gustavo; Teodoro, Rodrigo; Wiecek, Danielle Pereira; Silva, Natanael Gomes da; Martinelli, Jose Roberto; Oliveira Filho, Renato Santos de [UNIFESP]; Inst Energet & Nucl Res; Universidade Federal de São Paulo (UNIFESP)Background: Biological performance of radiotracers for sentinel node detection analyzed in the light of molecular design and dimension is not widely available.Purpose: To evaluate the effect of dextran molecular size and the presence of tissue-binding units (mannose) within the model of (99m)Tc-carbonyl conjugate for sentinel lymph node detection.Material and Methods: Four dextran conjugates with and without mannose in the chemical backbone were included. All polymers were radiolabeled using the precursor [(99m)Tc(OH(2))(3)(CO)(3)](+). Radio labeling conditions targeted the best radiochemical purity and specific activity for each radiopharmaceutical, and partition coefficients were also defined. Lymphoscintigraphy and ex-vivo biodistribution in popliteal lymph node, liver and kidneys were performed in Wistar rats. the effects of molecular weight and mannose presence were assessed by a two-level factorial design.Results: Radiochemical purity was indirectly related to molecular weight and presence of mannose in the polymer structure. All products were able to detect popliteal lymph node, however, uptake was strongly influenced by use of mannose (4-fold higher). Excretion was similarly modulated by differences in molecular weight. Mannose-enhanced lymph node uptake and higher molecule size in the range under study benefitted lymphoscintigraphic performance.Conclusion: Screening of radiopharmaceuticals for lymphoscintigraphy might improve with attention to the mentioned physico-chemical features of the molecule.