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1.
South Med J ; 112(11): 591-597, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31682741

RESUMO

OBJECTIVE: The primary objective of this study was to determine whether patients prescribed nonpreferred antibiotics received appropriate alternative antibiotics. METHODS: This was a retrospective observational analysis of military veteran patients with a ß-lactam allergy treated in an outpatient clinic or emergency department for an infection during a 5-year span. Antibiotic regimens were first stratified as preferred or nonpreferred based on infection-specific guidelines. The nonpreferred regimens were then evaluated for appropriateness based on allergy history and culture and sensitivity reports. RESULTS: Of 445 fills of antibiotics evaluated, 269 met inclusion criteria, comprising 253 unique infections in 80 patients. Patients received nonpreferred antibiotics for their infection type in 57% of cases. Of the nonpreferred antibiotics, 56% were inappropriate based on guideline-recommended alternatives, allergy history, and culture and sensitivity data. Of the 88 allergies, 97% were historical/self-reported and 48% were cutaneous. In addition, 39% of patients safely received ß-lactam antibiotics after documentation of their allergy. CONCLUSIONS: Patients with documented ß-lactam allergies are at high risk of receiving nonpreferred and inappropriate antibiotics, and many reactions likely do not reflect true allergies. These data emphasize the negative impact of the "ß-lactam allergy" label and the importance of reassessing allergies.


Assuntos
Antibacterianos/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Prescrições de Medicamentos/estatística & dados numéricos , Prescrição Inadequada/estatística & dados numéricos , beta-Lactamas/efeitos adversos , Idoso , Antibacterianos/uso terapêutico , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Ambulatório Hospitalar , Estudos Retrospectivos , Tennessee , Veteranos , Serviços de Saúde para Veteranos Militares
2.
J Intensive Care ; 6: 53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30155260

RESUMO

An updated meta-analysis incorporating nine randomized trials (n = 816) investigating low-to-moderate dose prolonged glucocorticoid treatment in acute respiratory distress syndrome (ARDS) show moderate-to-high quality evidence that glucocorticoid therapy is safe and reduces (i) time to endotracheal extubation, (ii) duration of hospitalization, and (iii) mortality (number to treat to save one life = 7), and increases the number of days free from (i) mechanical ventilation, (ii) intensive care unit stay, and (iii) hospitalization. Recent guideline suggests administering methylprednisolone in patients with early moderate-to-severe (1 mg/kg/day) and late persistent (2 mg/kg/day) ARDS (conditional recommendation based on moderate quality of evidence).

3.
J Control Release ; 249: 32-41, 2017 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-28130039

RESUMO

Melanoma is the most aggressive type of skin cancer. It is highly metastatic, migrating through lymph nodes to distant sites of the body, especially to lungs, liver and brain. Systemic chemotherapy remains the mainstay of treatment; however, the development of multidrug resistance (MDR) restricts the efficacy of current chemotherapeutic drugs. We synthesized a series of microtubule destabilizers, substituted methoxybenzoyl-ary-thiazole (SMART) compounds, which inhibited tubulin polymerization and effectively circumvented MDR. Due to poor water solubility of SMART compounds, co-solvent delivery is required for their systemic administration, which is usually associated with hepatotoxicity, nephrotoxicity and hemolysis. To solve this problem and also to increase circulation time, we synthesized a new SMART analogue, SMART-OH, and its polymer-drug conjugate, methoxy-poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate-graft-SMART-graft-dodecanol) (abbreviated as P-SMART), with 14.3±2.8% drug payload of SMART-OH. Similar to its parent drug, P-SMART showed significant anticancer activity against melanoma cells in cytotoxicity, colony formation, and cell invasion studies. In addition, P-SMART treatment led to cell cycle arrest at G2/M phase and cell accumulation in sub-G1 phase. We established a model of metastatic melanoma to the lung in C57/BL6 albino mice to determine in vivo efficacy of P-SMART and SMART-OH at the dose of 20mg/kg. P-SMART treatment resulted in significant inhibition of tumor growth and prolonged mouse median survival. In conclusion, P-SMART, a novel polymer-microtubule destabilizer conjugate, has the potential to treat metastatic melanoma.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Melanoma/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Invasividade Neoplásica/prevenção & controle , Polímeros/uso terapêutico , Tiazóis/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/patologia , Modelos Moleculares , Invasividade Neoplásica/patologia , Polímeros/administração & dosagem , Polímeros/química , Tiazóis/administração & dosagem , Tiazóis/química , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/química
4.
Nat Commun ; 7: 10880, 2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-26979622

RESUMO

Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation.


Assuntos
Proteínas de Transporte de Cátions Orgânicos/efeitos dos fármacos , Fosfotirosina/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-yes/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Camundongos , Modelos Moleculares , Transportadores de Ânions Orgânicos/efeitos dos fármacos , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/efeitos dos fármacos , Transportador 1 de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-yes/metabolismo
5.
Chin J Nat Med ; 13(7): 481-97, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26233839

RESUMO

Vitamin D, also known as cholecalciferol, is the precursor to the active steroid hormone 1, 25-dihydroxyvitamin D3 (calcitriol; 1, 25(OH)2D3). The main physiological role for 1, 25(OH)2D3 is to regulate calcium and inorganic phosphate homeostasis for bone health. More recently, vitamin D has been investigated for its effects in the prevention and treatment of a variety of diseases such as cancer, autoimmune disorders, and cardiovascular disease. Preclinical data strongly support a role for vitamin D in the prevention of cancer through its anti-proliferative, pro-apoptotic, and anti-angiogenic effects on cells. Epidemiologic and clinical studies have shown mixed data on the correlation between serum vitamin D levels and cancer risk. This report seeks to outline results from the most recent preclinical and clinical studies investigating the potential role of vitamin D in cancer prevention.


Assuntos
Calcitriol/sangue , Colecalciferol/sangue , Neoplasias/prevenção & controle , Deficiência de Vitamina D/complicações , Humanos , Neoplasias/sangue , Neoplasias/etiologia , Vitamina D/sangue , Deficiência de Vitamina D/sangue
7.
Drug Metab Pharmacokinet ; 28(1): 19-27, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22986709

RESUMO

Several solute carriers and ATP-binding cassette transporters have been implicated in the influx or efflux of platinum-based chemotherapeutic agents such as cisplatin, carboplatin, and oxaliplatin. Given that many of these proteins are highly polymorphic, the genetic status of these proteins could be an important contributor to the extensive interindividual pharmacokinetic variability associated with the clinical use of these agents. In this review article, we provide an updated overview of the various transporters that have shown promise in animal models or patient populations in facilitating the movement of platinum-based agents across cell membranes, and how their function is associated with drug disposition or pharmacodynamic effects.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Membrana Transportadoras/genética , Compostos de Platina/farmacologia , Compostos de Platina/farmacocinética , Animais , Proteínas de Transporte de Cátions/genética , Transportador de Cobre 1 , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único
8.
Proc Natl Acad Sci U S A ; 108(42): 17396-401, 2011 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-21969579

RESUMO

The recognition and clearance of dead cells is a process that must occur efficiently to prevent an autoimmune or inflammatory response. Recently, a process was identified wherein the autophagy machinery is recruited to pathogen-containing phagosomes, termed MAPLC3A (LC3)-associated phagocytosis (LAP), which results in optimal degradation of the phagocytosed cargo. Here, we describe the engagement of LAP upon uptake of apoptotic, necrotic, and RIPK3-dependent necrotic cells by macrophages. This process is dependent on some members of the classical autophagy pathway, including Beclin1, ATG5, and ATG7. In contrast, ULK1, despite being required for autophagy, is dispensable for LAP induced by uptake of microbes or dead cells. LAP is required for efficient degradation of the engulfed corpse, and in the absence of LAP, engulfment of dead cells results in increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines. LAP is triggered by engagement of the TIM4 receptor by either phosphatidylserine (PtdSer)-displaying dead cells or PtdSer-containing liposomes. Therefore, the consequence of phagocytosis of dead cells is strongly affected by those components of the autophagy pathway involved in LAP.


Assuntos
Proteínas Associadas aos Microtúbulos/imunologia , Fagocitose/imunologia , Animais , Autofagia/imunologia , Proteína 5 Relacionada à Autofagia , Proteína 7 Relacionada à Autofagia , Caenorhabditis elegans/genética , Caenorhabditis elegans/imunologia , Citocinas/biossíntese , Feminino , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Necrose/imunologia , Fagossomos/imunologia , RNA Interferente Pequeno/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Receptores de Superfície Celular/imunologia , Transdução de Sinais/imunologia
9.
Arch Dermatol ; 147(2): 196-202, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20956631

RESUMO

OBJECTIVES: To identify factors associated with and not associated with successful matching and matriculation (hereinafter "matching") to dermatology residency programs for applicants who previously graduated from medical school and to distinguish which factors are within applicants' control. DESIGN: Observational cohort study. SETTING: Six accredited academic dermatology residency training programs in the United States. PARTICIPANTS: A total of 221 residency applicants who previously graduated from medical school and who applied through standardized electronic application to 1 or more of the participating residency training programs. MAIN OUTCOME MEASURE: Matriculation to a dermatology residency program by August 2008 following the 2006 residency application period. RESULTS: Forty-six of 221 former medical school graduates included in this study matched to a dermatology residency program. Factors strongly associated with matching included United States Medical Licensing Examination Step 3 score; submission of letters written by dermatologists from institutions that train dermatology residents; completion of preliminary medicine internships rather than transitional or other internship types; listing of research experience; publishing of medical manuscripts; and completion of non-Accreditation Council for Graduate Medical Examination dermatology fellowships. Factors not associated with increased matching included volunteer work; PhD status; sex; number of posters or presentations at dermatology conferences; quality of journal publications; and first authorship. Most successful applicants limited personal statements to 1 page and did not mention previously failing to match. The study sample represented at least 86% of such nontraditional applicants who matched in 2006. CONCLUSIONS: For candidates seeking to match into dermatology residency programs after graduating from medical school, there are factors within their control that are associated with higher rates of match success. This study provides evidence to assist mentors who counsel such candidates.


Assuntos
Dermatologia/educação , Internato e Residência/organização & administração , Seleção de Pessoal , Escolha da Profissão , Estudos de Coortes , Educação de Pós-Graduação em Medicina , Humanos , Estados Unidos
10.
Arch Dermatol ; 145(10): 1131-6, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19841400

RESUMO

OBJECTIVE: To determine factors related to residents' self-reported skill level for the skin cancer examination (SCE). DESIGN: Survey of residents in November 2003. SETTING: Four US residency programs. PARTICIPANTS: Medical residents in family medicine, pediatrics, obstetrics and gynecology, and internal medicine and specialists. MAIN OUTCOME MEASURE: Proportion of residents reporting their current skill level for the performance of the SCE. RESULTS: Of 454 surveys distributed, 342 residents completed the survey (75.3% response rate). Clinical training for the SCE during residency was infrequent. During residency, 75.8% were never trained in the SCE, 55.3% never observed an SCE, and 57.4% never practiced the examination. Only 15.9% of residents reported being skilled in the SCE. However, the conduct of 4 SCEs (or slightly more than 1 per each year of residency) was associated with manifold increases in self-reported skill levels. CONCLUSIONS: Information now collected from 7 medical schools and 4 residency programs underscores the need for more supervised opportunities to enable physicians in training to perform an SCE during routine patient examinations.


Assuntos
Competência Clínica , Dermatologia/educação , Programas de Rastreamento/normas , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/prevenção & controle , Adulto , Currículo/normas , Educação de Pós-Graduação em Medicina , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Internato e Residência , Masculino , Programas de Rastreamento/tendências , Determinação de Necessidades de Cuidados de Saúde , Exame Físico/métodos , Exame Físico/normas , Prevenção Primária/métodos , Prevenção Primária/normas , Inquéritos e Questionários , Estados Unidos
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