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Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related lactobacilli, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE mediates OA resistance, while OhyA is robustly active in the vaginal microbiota and enhances bacterial fitness by biochemically sequestering OA in a derivative form only ohyA-harboring organisms can exploit. OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro BV model, suggesting a metabolite-based treatment approach.
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Osimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that was initially developed to overcome the EGFR T790M mutation and is used as a standard therapy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR-activating mutations. Despite the remarkable initial efficacy, osimertinib, like other EGFR-TKIs, is limited by the emergence of acquired resistance. As the EGFR mutation C797S has been identified as a key driver of acquired resistance to osimertinib, development of a drug that targets this clinically relevant mutation could help improve patient outcomes. Here, we report the discovery and preclinical efficacy of OBX02-011, a reversible fourth-generation EGFR TKI that overcomes the EGFR C797S mutation. Compared to approved EGFR TKIs, OBX02-011 showed potent anticancer effects and inhibited EGFR-related signaling in various models, including those harboring the EGFR C797S mutation. Additionally, in transgenic mouse models (EGFRL858R/T790M/C797S), OBX02-011 treatment effectively inhibited tumor growth and EGFR activity, leading to enhanced survival. Collectively, these results suggest that OBX02-011 may be a promising new EGFR TKI to overcome C797S-mediated resistance in NSCLC.
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Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.
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Despite its outstanding clinical success, immune checkpoint blockade remains ineffective in many patients. Accordingly, combination therapy capable of achieving greater antitumor immunity is urgently required. Here, we report that limiting glutamine metabolism in cancer cells bolsters the effectiveness of anti-programmed death ligand-1 (PD-L1) antibody. Inhibition of glutamine utilization increased PD-L1 levels in cancer cells, thereby inactivating co-cultured T cells. Under glutamine-limited conditions, reduced cellular GSH levels caused an upregulation of PD-L1 expression by impairing SERCA activity, which activates the calcium/NF-κB signaling cascade. Consequently, in tumors grown in immunocompetent mice, inhibition of glutamine metabolism decreased the antitumor activity of T cells. In combination with anti-PD-L1, however, glutamine depletion strongly promoted the antitumor efficacy of T cells in vitro and in vivo due to simultaneous increases in Fas/CD95 levels. Our results demonstrate the relevance of cancer glutamine metabolism to antitumor immunity and suggest that co-targeting of glutamine metabolism and PD-L1 represents a promising therapeutic approach.
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Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/metabolismo , Glutamina/metabolismo , Glutatión/metabolismo , Neoplasias/inmunología , Neoplasias/prevención & control , Linfocitos T/inmunología , Anciano , Animales , Apoptosis , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Proliferación Celular , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias/metabolismo , Neoplasias/patología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Oncogenic signals contribute to enhanced glycolysis and mTORC1 activity, leading to rapid cell proliferation in cancer. Regulation of glycolysis and mTORC1 by PI3K/Akt signaling is well established, but how KRAS-induced MEK signaling regulates these pathways remains poorly understood. Here, we report a role for MEK-driven lactate production in mTORC1 activation in KRAS-activated cells. KRAS/MEK-induced upregulation of the chicken ovalbumin upstream promoter transcriptional factor II (COUP-TFII) increases the expression of lactate dehydrogenase A (LDHA), resulting in lactate production and mTORC1 activation. Further, lactate inhibits the interaction of TSC2 and Rheb, leading to the cellular activation of mTORC1 irrespective of growth factor stimulation. These findings suggest that COUP-TFII is a novel oncogenic mediator, connecting KRAS signaling and glycolysis, and leading to mTORC1 activation and cellular growth.
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Factor de Transcripción COUP II/metabolismo , Ácido Láctico/biosíntesis , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal , Factor de Transcripción COUP II/genética , Línea Celular Tumoral , Expresión Génica , Técnicas de Silenciamiento del Gen , Glucólisis , Humanos , Modelos Biológicos , Proteína Homóloga de Ras Enriquecida en el Cerebro/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa/metabolismoRESUMEN
Research studies related to the polymorphs of l-Carnitine orotate (CO), a medication used for the treatment and prevention of liver diseases, are insignificant or almost nonexistent. Accordingly, in the present study, l-Carnitine orotate (CO) was prepared for investigating CO polymorphs. Here, a reactive crystallization was induced by reacting 1g of l-Carn (1 equivalent) and 0.97 g of OA (1 equivalent) in methanol (MeOH); as a result, CO form-I and CO form-II polymorphs were obtained after 1 h and 16 h of stirring, respectively. The characterization of CO polymorphs was carried out utilizing Powder X-ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA) and solid-state Nuclear Magnetic Resonance Spectroscopy (solid-state CP/MAS 13C-NMR). The solution-mediated polymorphic transformation (SMPT) of CO polymorphs was investigated in MeOH at controlled temperature and fixed rotational speed. The results revealed that CO form-I is a metastable polymorph while CO form-II is a stable polymorph. From the same results, it was confirmed that CO form-I was converted to CO form-II during the polymorphic phase transformation process. Moreover, it was assessed that the increase in temperature and supersaturation level significantly promotes the rate of nucleation, as well as the rate of mass transfer of CO form-II. In addition, nucleation and mass transfer equations were employed for the quantitative determination of SMPT experimental results. Lastly, it was suggested that CO form-II was more thermodynamically stable than CO form-I and that both polymorphs belong to the monotropic system.
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BACKGROUND: Despite remarkable activity in epidermal growth factor receptor (EGFR)-mutant lung cancer patients, the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) is limited by the emergence of acquired resistance, which is mostly caused by a secondary T790M mutation. Fortunately, newly developed, mutant-selective EGFR-TKIs against T790M have been proven as an effective therapeutic approach although only osimertinib has received the FDA approval until now. OBJECTIVE: To determine the in vitro and in vivo efficacy of a new EGFR TKI, OBX1-012 in cells with mutant EGFR. METHODS: Effects of OBX1-012 on cellular viability and EGFR-related signaling were determined in EGFR-mutant non-small cell lung cancer (NSCLC) cells, including cells harboring T790M mutations. In addition, in vivo efficacy of OBX1-012 was evaluated in xenograft models. RESULTS: We report the discovery and preclinical assessment of another novel, mutant-selective EGFR-TKI, OBX1-012. Compared with other mutant-selective EGFR-TKIs such as olumitinib and osimertinib, it showed similar potency and selectivity for mutant EGFR. OBX1-012 treatment was highly effective against human EGFR-mutant lung cancer models with or without EGFR T790M, not only in vitro but also in vivo. However, OBX1-012 like other EGFR-TKIs failed to exhibit efficacy for the exon 20 insertion mutation or C797S mutation, which was generated by site-directed mutagenesis and stable transfection of Ba/F3 cells. CONCLUSIONS: These results identify OBX1-012 as a highly effective, mutant-selective EGFR-TKI for the treatment of T790M-mediated resistance in NSCLC.
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Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the N-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound 12c as a highly potent GnRH antagonist with moderate CYP inhibition. Compound 12c showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys compared to a known antagonist, Elagolix. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.
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Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/metabolismo , Receptores LHRH/antagonistas & inhibidores , Uracilo/farmacología , Animales , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/química , Relación Dosis-Respuesta a Droga , Humanos , Hormona Luteinizante/antagonistas & inhibidores , Hormona Luteinizante/sangre , Macaca fascicularis , Estructura Molecular , Relación Estructura-Actividad , Uracilo/análogos & derivados , Uracilo/químicaRESUMEN
This research focuses on the analysis regarding disclosure of financial conflicts of interest (FCOI) after Gelsinger v. University of Pennsylvania (Penn). The main legal issue was that the participants did not have enough opportunity to make an autonomous decision about participating in the research because he was not informed about the researchers' and the institution's substantial FCOI. The disclosure system was adopted by the Code of Federal Regulations. Under the regulation, researchers and institutions need to report FCOI over $5,000 to the institution, and the internal review boards have to report to the federal authority if needed. In case of human research, the disclosure to Food and Drug Administration is mandatory. FCOI disclosure system would help participants to make an autonomous decision, and increase trust to the research process and researchers. Moreover, the system would let researchers keep fiduciary duty while (possibly) lowering legal liability in case of a lawsuit. There were discussions about the disclosure methodology in the United States. However, there have not been a lot of discussions in Korea even after the "Humidifier Disinfectant" case. Therefore, new legislations need to be considered. First, the system requires disclosure funded by not only government but also private institutions. Second, like California Supreme Court, the subject would be reviewed under the reasonable person standard by participants, including patents, equity, and stock. Third, the disclosure needs to include simple or brief explanation to the FCOI to be better understood by the participants. Fourth, the disclosure should be in the informed consent process.
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Investigación Biomédica/legislación & jurisprudencia , Revelación/legislación & jurisprudencia , Conflicto de Intereses , Regulación Gubernamental , Consentimiento Informado , República de Corea , Estados UnidosRESUMEN
Tenofovir disoproxil (TD), an anti-virus drug, is currently marketed under its most stable form, Form-I of Tenofovir disoproxil fumarate (TDF). However, studies regarding the properties of TD free base crystal as a promising drug as well as its crystal structure have not yet been reported. This assumption was made because TD free base is not directly produced in a solid form during the manufacturing process. TD free base is first obtained in an oil form, and is then synthesized into TDF crystal. In this regard, the present study was conducted to investigate both the potentiality of TD free base to be an active pharmaceutical ingredient (API) and its crystal structure. Here, TD free base solid was produced by means of drowning-out crystallization. Next, single crystal X-ray diffraction (SXD) was employed to determine the crystal structure. Powder X-ray diffraction (PXRD) and a differential scanning calorimetry (DSC) analysis were performed to evaluate the crystal's properties. Furthermore, experiments were carried out at 15%, 35%, 55%, 75%, and 95% relative humidity (RH) for 12 h using a hygroscopic tester to determine and to compare the hygroscopicity and stability of TD free base with TDF crystal. Additionally, experiments were conducted under accelerated (40 °C, RH 75%) and stress storage (60 °C, RH 75%) conditions for 30 days to investigate the changes in purity and the formation of dimer. In this work, we report that TD free base possesses lower hygroscopicity, and thus does not generate dimer impurity from hydrolysis. Primarily, this is attributed to the fact that TD free base is not an easily ionized salt but comprises neutral hydrophobic molecules. According to the structural properties, the improved hygroscopic property of the TD free base crystal was due to the decrease of crystal polarity owing to the intermolecular H-bonds present in TD free base rings. In addition, the solubility investigation study carried out in aqueous solution and at gastrointestinal pH revealed a similarity in TDF and TD free base solubility under the mentioned conditions. Accordingly, we could confirm the potentiality of TD free base as an active pharmaceutical ingredient.
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Antivirales/química , Cristalografía por Rayos X/métodos , Composición de Medicamentos/métodos , Tenofovir/química , Rastreo Diferencial de Calorimetría/métodos , Cristalización/métodos , Estabilidad de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Solubilidad , HumectabilidadRESUMEN
A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound 9. The combination of the replacement of a pyridine ring of 9 with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, 18a (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity. Repeated oral administration of 18a significantly reduced blood glucose and HbA1c levels and improved the lipid profiles in ob/ob mice. Moreover, the HbA1c-lowering effect of metformin was synergistically enhanced in combination with 18a.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/administración & dosificación , Adamantano/química , Adamantano/farmacología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirimidinas/administración & dosificación , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Ionic liquids (ILs) are defined as salts with a melting point below 100 °C. ILs have received increasing attention as new alternative to organic solvents because of their unique physicochemical properties. Therefore, this study was conducted in the purpose to present the efficacy of ILs as new solvents capable to control the Polymorphic transformation phenomenon. Here, the polymorphic transformation phenomenon of adefovir dipivoxil, an efficient antiviral active pharmaceutical ingredient on human immunodeficiency virus, was investigated. The phase transformation phenomenon from the metastable polymorph, new form (NF) to the stable polymorph, Form-X in 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF4) and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (BDMImBF4) ILs solutions was observed utilizing the solvent-mediated phase transformation method The thermodynamic factors, AEImBF4/BDMImBF4 solvent composition ratio of 3:7-6:4 and the temperature in range of 25-100 °C, as well as the dynamic factor, the rational speed in range of 300-1000 rpm were parameters studied in this experiment. The thermodynamic and dynamic equations involving nucleation and mass transfer were applied for the quantitative analysis. The result of the present study confirmed the use of ILs as substitute solvent for volatile organic solvents, and demonstrated the efficacy of ILs as potential solvent-media to control the polymorphic transformation.
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Adenina/análogos & derivados , Fármacos Anti-VIH/química , Líquidos Iónicos/química , Organofosfonatos/química , Adenina/química , Cristalización , Estabilidad de Medicamentos , Modelos Teóricos , Transición de Fase , Solubilidad , Soluciones , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura de TransiciónRESUMEN
The synthesis and structure-activity relationship of a series of 6-substituted picolinamide inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 are described. The optimization of the left-hand side of lead compound 1 resulted in the discovery of the highly potent, selective, and orally available inhibitor 24, which demonstrated an excellent activity in a mouse ex vivo pharmacodynamic model. Moreover, compound 24 reduced the blood glucose and improved the lipid profiles in ob/ob mice after oral administration.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Inhibidores Enzimáticos/síntesis química , Ácidos Picolínicos/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Glucemia/análisis , Catálisis , Diabetes Mellitus Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Células HEK293 , Semivida , Humanos , Lípidos/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Paladio/química , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/uso terapéutico , Unión Proteica , Relación Estructura-ActividadRESUMEN
Synthesis of a series of 6-substituted picolinamide derivatives and their inhibitory activities against 11ß-hydroxysteroid dehydrogenase type 1 are described. Optimization of the initial hit compound, N-cyclohexyl-6-(piperidin-1-yl)picolinamide (1) from high throughput screening of in-house library resulted in the discovery of the highly potent and metabolically stable compound 25, which was efficacious in a mouse ex vivo pharmacodynamic model and reduced the fasting blood glucose and insulin levels in a HF/STZ mouse model after oral dosing.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Ácidos Picolínicos/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Amidas/química , Amidas/uso terapéutico , Amidas/toxicidad , Animales , Sitios de Unión , Glucemia/análisis , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/toxicidad , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación de Dinámica Molecular , Ácidos Picolínicos/uso terapéutico , Ácidos Picolínicos/toxicidad , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
AIM: To evaluate the impact of surgical volume on nationwide hospital mortality after pancreaticoduodenectomy (PD) for periampullary tumors in South Korea. METHODS: Periampullary cancer patients who underwent PD between 2005 and 2008 were analyzed from the database of the Health Insurance Review and Assessment Service of South Korea. A total of 126 hospitals were divided into 5 categories, each similar in terms of surgical volume for each category. We used hospital mortality as a quality indicator, which was defined as death during the hospital stay for PD, and calculated adjusted mortality through multivariate logistic models using several confounder variables. RESULTS: A total of eligible 4975 patients were enrolled in this study. Average annual surgical volume of hospitals was markedly varied, ranging from 215 PDs in the very-high-volume hospital to < 10 PDs in the very-low-volume hospitals. Admission route, type of medical security, and type of operation were significantly different by surgical volume. The overall hospital mortality was 2.1% and the observed hospital mortality by surgical volume showed statistical difference. Surgical volume, age, and type of operation were independent risk factors for hospital death, and adjusted hospital mortality showed a similar difference between hospitals with observed mortality. The result of the Hosmer-Lemeshow test was 5.76 (P = 0.674), indicating an acceptable appropriateness of our regression model. CONCLUSION: The higher-volume hospitals showed lower hospital mortality than the lower-volume hospitals after PD in South Korea, which were clarified through the nationwide database.
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Ampolla Hepatopancreática/cirugía , Neoplasias del Conducto Colédoco/cirugía , Mortalidad Hospitalaria/tendencias , Hospitales de Alto Volumen , Hospitales de Bajo Volumen , Pancreaticoduodenectomía/mortalidad , Anciano , Neoplasias del Conducto Colédoco/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , República de Corea , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: To confirm the efficacy and toxicity of gemcitabine and S-1 combination chemotherapy when used as a first-line therapy in patients with unresectable pancreatic cancer. METHODS: Patients with locally advanced or metastatic or recurrent pancreatic adenocarcinoma, which was histologically or cytologically proven, with at least one measurable lesion were eligible for the study. Gemcitabine at a dose of 1,000 mg/m2 was intravenously given over 30 min on days 1 and 8, while S-1 at a dose of 40 mg/m2 was orally given twice daily from day 1 to 14, and the cycle was repeated every 3 weeks. The objective response rate, which was assessed according to RECIST criteria, was the primary end point. RESULTS: A total of 38 patients were enrolled between June 2006 and June 2007. The median number of treatment courses was 5.5 (range 1-22). Thirty-four patients were evaluable for response. Although no complete response was seen, partial responses were achieved in 11 patients, resulting in an overall response rate of 32% [95% confidence interval (CI) 17-48%]. The median response duration was 6.0 months (95% CI 4.6-8.3 months), the median time-to-progression was 5.4 months (95% CI 2.9-8.0 months), and the median overall survival was 8.4 months (95% CI 5.7-11.1 months). The major grade 3/4 hematologic toxicities were neutropenia (39.5%), leukopenia (15.8%), thrombocytopenia (2.6%), and anemia (7.9%). The major grade 3/4 non-hematologic toxicities included anorexia (10.5%), stomatitis (2.6%), rash (7.9%), fatigue (7.9%) and hyperbilirubinemia (5.3%). CONCLUSIONS: Gemcitabine and S-1 combination chemotherapy was effective and tolerable in patients with unresectable pancreatic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Combinación de Medicamentos , Fatiga/inducido químicamente , Femenino , Humanos , Estimación de Kaplan-Meier , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamente , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Neoplasias Pancreáticas/patología , Tegafur/administración & dosificación , Tegafur/efectos adversos , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND/AIMS: Severe acute pancreatitis occurs in about 20% of the patients with acute pancreatitis and can be associated with multiorgan failure and local complications. In patients with predicted severe acute pancreatitis, overall mortality rates are about 15-30%. The aim of this study was to determine the factors correlated with mortality in patients with severe acute pancreatitis. METHODS: We reviewed five hundread and seventy two consecutive cases of acute pancreatitis from January, 2000 to December, 2005. Of them, 109 patients who fulfilled the criteria of Atlanta classification for severe acute pancreatitis were enrolled. Data were collected by chart reviews including age, gender, etiology, body mass index (BMI), modified Glasgow score, APACHE II score, APACHE III score, Balthazar CT index, and other laboratory parameters performed within 48 hours after the initial admission. RESULTS: Severe acute pancreatitis was most commonly caused by alcohol. Overall mortality rate was 20.2% in severe acute pancreatitis and 10 (45%) deaths occurred within the first week. Multiple logistic regression analysis identified serum creatinine, corrected calcium concentrations, and CT index as predictors of mortality in patients with severe acute pancreatitis. The risk score (R) was calculated by combining 3 prognostic values with regression coefficients; R=2.512 loge (creatinine mg/dL)+1.729 loge (CT index)??4.780 loge (corrected calcium mg/dL). The AUC for this score was 0.877 and a cutoff level of 0 was determined to predict the mortality with 83.3% sensitivity and 89.5% specificity. CONCLUSIONS: The newly designed risk score comprising 3 parameters can be used as the significant early predictor for hospital mortality in severe acute pancreatitis.
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Pancreatitis/mortalidad , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Análisis Multivariante , Pancreatitis/complicaciones , Pancreatitis/diagnóstico , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
PURPOSE: This study was done to analyze variations in unit staffing and recommend policies to improve nursing staffing levels in intensive care units (ICUs). METHOD: A cross-sectional study design was used, employing survey data from the Health Insurance Review Agency conducted from June-July, 2003. Unitstaffing was measured using two indicators; bed-to-nurse (B/N) ratio (number of beds per nurse), and patient-to-nurse (P/N)ratio (number of average daily patients per nurse). Staffing levels were compared according to hospital and ICU characteristics. RESULT: A total of 414 institutions were operating 569 adult and 86 neonatal ICUs. Tertiary hospitals (n=42) had the lowest mean B/N (0.82) and P/N (0.76) ratios in adult ICUs, followed by general hospitals (B/N: 1.34, P/N: 0.97). Those ratios indicated that a nurse took care of 3 to 5 patients per shift. Neonatal ICUs had worse staffing and had greater variations in staffing ratios than adult ICUs. About 17% of adult and 26% of neonatal ICUs were staffed only by adjunct nurses who had responsibility for a general ward as well as the ICU. CONCLUSION: Stratification of nurse staffing levels and differentiation of ICU utilization fees based on staffing grades are recommended as a policy tool to improve nurse staffing in ICUs.