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1.
Antioxidants (Basel) ; 13(4)2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38671896

RESUMO

The glutamine-histidine-glycine-valine (QHGV), a peptide derived from oysters, exhibits antioxidant activity and is being actively researched as a potential pharmaceutical and functional cosmetic ingredient. In this study, we synthesized the QHGV peptide and explored the hitherto unknown anti-inflammatory effects of QHGV. The antioxidant property was also characterized by conjugating with various naturally derived phenolic acids, such as caffeic, gallic, ferulic, sinapinic, and vanillic acids. Conjugation with phenolic acids not only enhanced the antioxidant activity of QHGV but also diminished the lipopolysaccharide-induced generation of reactive oxygen species (ROS) in the murine macrophage cell line, RAW 264.7. The reduction in the levels of reactive oxygen species led to the reduced mRNA expression of inducible nitric oxide synthase (iNos) and cyclooxygenase 2 (Cox-2), resulting in an anti-inflammatory effect through the inhibition of the phosphorylation of mitogen-activated protein kinase, including extracellular signal-activated protein kinase, c-Jun NH2-terminal kinase, and p38. Furthermore, the phenolic acid-conjugated peptides increased the mRNA and protein levels of collagen type I, indicative of a wrinkle-improvement effect. The phenolic acid conjugates of the peptide were not cytotoxic to human keratinocytes such as HaCaT cells. These results suggest that phenolic acid conjugation can enhance the potential of peptides as drug and cosmetic resources.

2.
Chemosphere ; 345: 140441, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37844697

RESUMO

We present lead (Pb) concentrations and isotope ratios in a continuous series of 38 snow samples from a 1.9-m snow pit, covering the period from winter 2012 to summer 2017, at the East Greenland Ice-core Project (EGRIP) ice core drill site in northwestern Greenland. Pb concentrations were highly variable, ranging from 1.53 to 94.9 pg g-1 (mean value of 10.6 pg g-1), with higher concentrations during winter and spring and lower concentrations during summer and fall. Our results show a substantial reduction in the Pb concentration of ∼50% between the 2000s and 2010s, reaching a level close to that observed in the mid-18th century, that is, the time of the Industrial Revolution. Remarkably low radiogenic Pb isotope compositions were observed in our samples compared to previously reported values during the 2000s. The Pb isotope mixing model results indicated a decreasing Chinese contribution from the 2000s onwards, while Europe/Russia emerged as a relatively more important contributor to the anthropogenic Pb input to central Greenland during the corresponding period. Thus, we hypothesized that the reduction in Pb pollution in central Greenland is largely due to a decreasing contribution from Chinese sources in response to the effectiveness of stringent emission control measures in China.


Assuntos
Poluentes Atmosféricos , Poluentes Atmosféricos/análise , Groenlândia , Chumbo , Neve , Monitoramento Ambiental/métodos , Isótopos/análise
3.
Obstet Gynecol Sci ; 66(6): 477-483, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37532226

RESUMO

A vanishing twin (VT) is the early demise of a twin fetus. It is estimated to occur in 20-30% of pregnancies associated with assisted reproductive technology. VT becomes increasingly prominent when assisted fertilization is used, because one or more embryos are transferred to the uterus. Maternal serum screening tests during pregnancy can screen for trisomy chromosomes 21, 18, and 13 and are divided into first- and second-trimester tests. In singleton pregnancies, the first trimester screening test is performed at 11-13 weeks and 6 days of gestation. It consists of two serum markers, pregnancy-associated plasma protein A and ß-human chorionic gonadotropin (ß-hCG), and measures nuchal translucency thickness. The second-trimester screening test was performed at 15-20 weeks and 6 days of gestation. It consists of four serum markers: alpha-fetoprotein, ß-hCG, unconjugated estriol, and inhibin A. More effective screening for trisomy 21 in singleton pregnancies is achieved by analyzing cell-free DNA in the maternal blood. A VT includes a demise of the fetus. Although it affects maternal serum markers, it has not been corrected. Five studies examined the effect of VT on maternal serum markers, but the results were controversial. This study aimed to review the patterns of changes in maternal serum markers in VTs, interpret prenatal tests for pregnant women with VTs in clinical practice, and consider what information should be provided.

5.
Appl Health Econ Health Policy ; 21(1): 141-152, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36136263

RESUMO

OBJECTIVES: The aim of this study was to assess the cost effectiveness of allogeneic umbilical cord blood-derived mesenchymal stem cells with sodium hyaluronate (hUCB-MSC) compared with microfracture in patients with knee cartilage defects caused by osteoarthritis (OA) in South Korea. METHODS: A partitioned survival model approach was taken consisting of five mutually exclusive health states: excellent, good, fair, poor, and death over a 20-year time horizon. Utility values were obtained from a randomized clinical trial. Cost data were extracted from a database provided by the Health Insurance Review & Assessment Service, and the utilization of healthcare services was estimated from an expert panel of orthopedic surgeons using a structured questionnaire. The incremental cost-effectiveness ratio (ICER) in terms of quality-adjusted life-years (QALY) was calculated. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: In the base case, the incremental costs of US$14,410 for hUCB-MSC therapy along with its associated QALY gain of 0.857 resulted in an ICER of US$16,812 (₩18,790,773) per QALY (95% confidence interval [CI] US$13,408-US$20,828) when compared with microfracture treatment from a healthcare payer perspective. From a societal perspective, the ICER was US$268 (₩299,255) per QALY (95% CI -US$2915 to US$3784). When using a willingness-to-pay threshold of US$22,367/QALY, the probability of hUCB being cost effectiveness compared with microfracture was 99% from the healthcare payer perspective and 100% from the societal perspective. CONCLUSIONS: The study demonstrated that hUCB-MSC therapy was cost effective compared with microfracture when treating patients with knee OA. These findings should inform health policy decision makers about considerations for cost-effective therapy for treating knee OA to ultimately enhance population health.


Assuntos
Fraturas de Estresse , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/terapia , Análise de Custo-Efetividade , Sangue Fetal , Análise Custo-Benefício , Anos de Vida Ajustados por Qualidade de Vida
6.
Toxics ; 10(12)2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36548604

RESUMO

Biocides are widely used in everyday life, and accordingly, human exposure to them is inevitable. Especially, the inhalational exposure of humans to biocides and resultant respiratory toxicity are gaining public interest due to the recent catastrophe associated with humidifier disinfectants. Aerosolized chemicals are subject to gravitational deposition and chemical degradation. Therefore, the characterization of the disposition of aerosols is essential to estimate the inhalational exposure to biocides. Here, we compared the disposition of aerosols of one of the commonly used biocide classes, isothiazolinone-based biocides, BIT, MIT, and OIT. An acrylic chamber (40 cm × 40 cm × 50 cm) was created to simulate the indoor environment, and a vacuum pump was used to create airflow (1 LPM). Biocides were sprayed from a vertical nebulizer placed on the ceiling of the chamber, and the distribution of particle sizes and volume was measured using the Optical Particle Sizer (OPS) 3330 device. During and after the aerosol spraying, airborne biocides and those deposited on the surface of the chamber were sampled to measure the deposition using LC-MS/MS. As a result, the broad particle size distribution was observed ranging from 0.3 to 8 µm during the nebulization. The inhalable particle faction (>2 µm) of the isothiazolinones was 32−67.9% in number but 1.2 to 6.4% in volume. Most of the aerosolized biocides were deposited on the chamber's surface while only a minimal portion was airborne (<1%) after the nebulization. More importantly, significant amounts of MIT and OIT were degraded during aerosolization, resulting in poor total recovery compared to BIT (31%, 71% vs. 97% BIT). This result suggests that some isothiazolinones may become unstable during nebulization, affecting their disposition and human exposure significantly.

7.
Toxics ; 10(10)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36287839

RESUMO

Cleaners such as dishwashing liquids contain various chemicals that cause skin damage. Alkaline agents used in cleaners alter the lipid composition of the skin and damage the skin barrier. However, little is known about the effects of acids used in cleaners on the skin. Here, we investigated the effects of acidic pH on the skin and evaluated the skin irritation of acids commonly used in cleaners with a 3D-reconstructed human epidermis model, KeraSkinTM, according to OECD TG439. First, to examine the effects of acidic pH, we evaluated the skin irritation of citrate buffers (0.1 M, McIlvaine buffer) prepared in a wide pH range (pH 1.5-6.0). Surprisingly, cell viability was not significantly affected even at pH 1.5, reflecting that the acidity alone may not be sufficient to induce skin irritation. Even after longer exposure (180 min), the cell viability was not reduced below 50%, a cutoff to determine an irritant. To examine the effect of the anionic part, several organic acids used in cleaners (citric acid, glycolic acid, lactic acid, malic acid, and succinic acid) were examined. These organic acids also failed to reduce viability at 0.1 M. However, at 1 M, most of the acids tested, except lactic acid, were determined to be skin irritants. Histology further supported the skin irritancy of acids at 1 M. Similarly, inorganic acids (hydrogen bromide, hydrogen chloride, nitric acid, and sulfuric acid) were determined to be irritants only at 1 M. In the case of alkaline agents, pH and concentrations were also important factors to determine the skin irritancy, although the epidermal structure and lipids were more damaged than acids. Collectively, we demonstrated that both the pH and concentration are important factors for the skin irritancy of acids, shedding an important insight into the mechanism of skin irritation.

8.
Healthcare (Basel) ; 10(9)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36141336

RESUMO

As incidences of osteoporotic hip fractures (OHFs) have increased, identifying OHFs has become important to establishing the medical guidelines for their management. This study was conducted to develop an operational definition to identify patients with OHFs using two diagnosis codes and eight procedure codes from health insurance claims data and to assess the operational definition's validity through a chart review. The study extracted data on OHFs from 522 patients who underwent hip surgeries based on diagnosis codes. Orthopedic surgeons then reviewed these patients' medical records and radiographs to identify those with true OHFs. The validities of nine different algorithms of operational definitions, developed using a combination of three levels of diagnosis codes and eight procedure codes, were assessed using various statistics. The developed operational definition showed an accuracy above 0.97 and an area under the receiver operating characteristic curve above 0.97, indicating excellent discriminative power. This study demonstrated that the operational definition that combines diagnosis and procedure codes shows a high validity in detecting OHFs and can be used as a valid tool to detect OHFs from big health claims data.

9.
J Org Chem ; 87(10): 6552-6561, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35533361

RESUMO

Imines are important building blocks in organic chemistry. Iminines, aldimines and ketimines, have been traditionally synthesized by the condensation reaction of the corresponding carbonyl compound with an amine moiety. More recently, palladium-catalyzed synthesis of ketimines using imidoyl chlorides has been reported. As an alternative, we report the reversed-polarity synthesis of N-sulfonyl ketimines using an anion equivalent imidoylsilane as a new nucleophilic coupling partner in the presence of a palladium catalyst. To the best of our knowledge, this is the first report of the use of imidoylsilanes in transition-metal-catalyzed coupling reactions. Diaryliodonium salt as an electrophile, various aryl-aryl or heteroaryl-aryl N-sulfonyl ketimines were successfully prepared in up to 99% isolated yields.


Assuntos
Paládio , Sais , Catálise , Iminas/química , Estrutura Molecular , Nitrilas , Paládio/química
10.
BioDrugs ; 35(1): 61-73, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33331991

RESUMO

BACKGROUND: Recent studies have shown that treatment with the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor class could significantly improve survival outcomes in several oncology indications. However, there is some clinical uncertainty. OBJECTIVE: This study aimed to obtain high-level estimates of the impact of treatment with PD-1/PD-L1 inhibitor class to oncology treatment on key health outcomes in real-world situations and to inform public health policy decisions about cancer care after reducing uncertainties around new immuno-oncology therapy options in South Korea. METHODS: A model was developed to estimate the impact of PD-1/PD-L1 inhibitors on outcomes in situations wherein both anti-PD-1/PD-L1s and standard of care (SOC) were available versus SOC only. A partitioned survival model was utilized to estimate the impact of introducing anti-PD-1/PD-L1s on outcomes, including life-years gained, quality-adjusted life-years gained, progression-free survival-years obtained, and grade 3 or higher adverse events avoided for six indications over 5 years. An exponential distribution was fitted to the survival function of the SOC based on visual inspection. Outcomes associated with anti-PD-1/PD-L1s were estimated using a piecewise modeling approach with Kaplan-Meier analysis followed by best-fitting survival analysis. The incident number of patients and market share of anti-PD-1/PD-L1s during 2020-2024 were projected using published literature and Korean market survey data. Sensitivity analyses were performed to test the uncertainty of input parameters. RESULTS: During the next 5-year period (2020-2024), introducing the anti-PD-1/PD-L1 class led to a gain of 22,001 life-years (+ 31%), 19,073 quality-adjusted life-years (+ 38%), and 22,893 progression-free survival-years (+ 82%); it also avoided 3610 adverse events (- 11%) compared with SOC alone. Most adverse events associated with anti-PD-1/PD-L1s were attributed to combination therapy with cytotoxic chemotherapy (91%). In a scenario wherein the time to reimbursement of the anti-PD-1/PD-L1s was accelerated by 1 year, the life-years gained increased by 14% compared with the base-case scenario. CONCLUSIONS: Anti-PD-1/PD-L1 therapy is expected to provide marked survival benefits for patients with cancer. This study demonstrated the potentially beneficial health impacts of utilizing the anti-PD-1/PD-L1 class at the population level. The findings could inform health policy decision makers about cancer care and ultimately enhance population health through rapid access to innovative cancer drugs.


Assuntos
Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Tomada de Decisão Clínica , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , República da Coreia , Incerteza
11.
Eur J Med Chem ; 205: 112501, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758860

RESUMO

Estrogen-related receptor gamma (ERRγ) is the NR3B subgroup of associated transcription factors. In this report, a new generation of a potent and selective ERRγ inverse agonist (25) with good biocompatibility was proposed. We also explored the potential of the newly developed compound 25 in the PDTC model to expand the original indications from ATC. In addition, an X-ray crystallographic study of the ligand and ERRγ co-complex showed that 25 completely binds to the target protein (PDB 6KNR). Its medicinal chemistry, including a distinctive structural study to in vivo results, denotes that 25 may be directed towards the development of a pivotal treatment for ERRγ-related cancers.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Agonismo Inverso de Drogas , Radioisótopos do Iodo/uso terapêutico , Receptores de Estrogênio/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Receptores de Estrogênio/química , Receptores de Estrogênio/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia
12.
Ann Clin Microbiol Antimicrob ; 19(1): 13, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234065

RESUMO

BACKGROUND: The influence of liver disease on the pharmacokinetic profile, the risk of acute kidney injury, and excessive drug exposure in patients treated with vancomycin was examined. METHODS: A retrospective cohort study was performed with patients discharged from a medical center between January 2011 and June 2018 who received vancomycin therapy. Patients were stratified according to liver dysfunction (no to mild liver dysfunction (NMLD) and moderate to severe liver dysfunction (MSLD) based on the Child-Pugh score. The risk of acute kidney injury was compared between patients who were stratified by the attainment of a target serum trough concentration (10 mg/dL to 20 mg/dL) and the vancomycin ratio formed between the area under the curve and minimum inhibitory concentration. The impact of liver dysfunction and a daily dose of vancomycin on the risk of acute kidney injury and vancomycin AUC:MIC > 600 were tested using logistic regression with and without adjusting for the study variables. RESULTS: A total of 408 patients empirically treated with vancomycin were included in this study (237 with NMLD and 171 with MSLD). Mean vancomycin trough concentrations (17.5 ± 8.4 mg/dL versus 15.3 ± 5.2 mg/dL, p = 0.0049) and AUC:MIC ratios (549.4 ± 217.2 versus 497.5 ± 117.3, 0.0065) were significantly higher in the MSLD group when compared to the NMLD group, respectively. Vancomycin clearance was also lower in the MSLD group and corresponded to a longer half-life. The proportion of patients who developed acute kidney injury was greater in patients with MSLD when compared to NMLD (7.6% versus 3.8%, respectively; p = 0.0932); however, the difference was statistically insignificant. Furthermore, supratherapeutic serum trough concentrations and AUC:MIC ratios were more common in the MSLD group versus the NMLD group (27.5% versus 13.9%, p = 0.0007 and 28.7% versus 17.3%, respectively; p = 0.0063). CONCLUSIONS: MSLD correlates with an increased risk of supratherapeutic vancomycin exposure. Although patients with MSLD had a higher risk of acute kidney injury, the difference was not significant.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Hepatopatias/complicações , Vancomicina/efeitos adversos , Vancomicina/farmacocinética , Injúria Renal Aguda/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Humanos , Modelos Logísticos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos , Soro/química , Infecções Estafilocócicas/tratamento farmacológico , Adulto Jovem
13.
Front Psychol ; 10: 2067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551893

RESUMO

This study aimed to validate career decision ambiguity tolerance scale-Korean form applicable to a Korean sample. In study 1, 17-items from the original 18-item career decision ambiguity tolerance scale were valid based on IRT. In study 2, using the confirmatory factor analysis, we showed that excluding item 4 from the original scale is better than including it in the three factors model. Given the results of study 1 and 2, the constructs in the 17-item career decision ambiguity tolerance scale-Korean form were valid. In study 3, career decision ambiguity tolerance positively predicted career decision-making self-efficacy, career indecision, and career adaptability, respectively, after controlling for calling and career search self-efficacy. Thus, the incremental validity of the career decision ambiguity tolerance scale-Korean form was ensured. In study 4, the reliability of the scale was retained as the test-retest (conducted over a 4-week period) demonstrated adequate results.

14.
BioDrugs ; 33(4): 423-436, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201616

RESUMO

BACKGROUND: As the economic burden of treating cancer patients has been soaring in European countries, performing a budget impact analysis is becoming one of the requirements for payers' application dossiers. OBJECTIVE: The objective of this study was to estimate the budgetary impact of introducing the biosimilar trastuzumab (CT-P6) from the payer's perspective and to determine the number of additional patients who could be treated with resulting savings in 28 European countries. METHODS: A budget impact model was developed to analyze the financial impact of switching from originator trastuzumab to biosimilar CT-P6 in the treatment of early and metastatic breast cancer and metastatic gastric cancer with a time horizon of 1-5 years. Budgetary savings and the number of patients potentially affected were measured based on epidemiological and sales volume data. The base-case analysis assumed that the price of CT-P6 is 70% of the originator price, the switching rate of originator to CT-P6 in the first year is 20%, and the annual growth in the switching rate for each subsequent year is 5%. RESULTS: For analyses using the base-case scenario following CT-P6 introduction, the total estimated budgetary savings over a 5-year period (depending on the scenario) ranged from €1.13 billion to €2.27 billion based on epidemiological data, or from €0.91 billion to €1.82 billion based on sales volume data. In the first year only, the projected budgetary savings ranged from €58 million to €136 million, and the number of additional patients who could be treated using the savings ranged from 3503 to 7078 by sensitivity analysis. CONCLUSIONS: The conducted budget impact analysis assessing a switch from originator trastuzumab to biosimilar CT-P6 in 28 European countries indicates that budget savings could be between €0.91 billion and €2.27 billion over the next 5 years. These savings could be used to help improve patient access to local biologics in their respective countries while simultaneously strengthening the overall public health landscape across the European Union.


Assuntos
Antineoplásicos Imunológicos/economia , Medicamentos Biossimilares/economia , Neoplasias da Mama/tratamento farmacológico , Substituição de Medicamentos/economia , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/economia , Antineoplásicos Imunológicos/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Neoplasias da Mama/economia , Orçamentos/estatística & dados numéricos , Redução de Custos/estatística & dados numéricos , Análise Custo-Benefício/estatística & dados numéricos , Custos de Medicamentos/estatística & dados numéricos , Substituição de Medicamentos/estatística & dados numéricos , Europa (Continente) , Feminino , Humanos , Modelos Econômicos , Neoplasias Gástricas/economia , Trastuzumab/uso terapêutico
16.
Artigo em Inglês | MEDLINE | ID: mdl-30669602

RESUMO

This study reviews and evaluates the national drug formulary system used to improve patient access to new drugs by making reimbursement decisions for new drugs as part of the South Korean national health insurance system. The national health insurance utilizes three methods for improving patient access to costly drugs: risk-sharing agreements, designation of essential drugs, and a waiver of cost-effectiveness analysis. Patients want reimbursement for new drugs to be processed quickly to improve their access to these drugs, whereas payers are careful about listing them given the associated financial burden and the uncertainty in cost-effectiveness. However, pharmaceutical companies are advocating for drug prices above certain thresholds to maintain global pricing strategies, cover the costs of drug development, and fund future investments into research and development. The South Korean government is expected to develop policies that will improve patient access to drugs with unmet needs for broadening health insurance coverage. Simultaneously, the designing of post-listing management methods is warranted for effectively managing the financial resources of the national health insurance system.


Assuntos
Custos de Medicamentos , Formulários Farmacêuticos como Assunto , Acessibilidade aos Serviços de Saúde , Programas Nacionais de Saúde/economia , Análise Custo-Benefício , Humanos , República da Coreia
17.
J Med Chem ; 62(2): 575-588, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30623649

RESUMO

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.


Assuntos
Hipoglicemiantes/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Administração Oral , Animais , Antraquinonas/química , Antraquinonas/metabolismo , Antraquinonas/uso terapêutico , Sítios de Ligação , Linhagem Celular , Meia-Vida , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Masculino , Doenças Metabólicas/patologia , Doenças Metabólicas/veterinária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/patologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Ratos , Relação Estrutura-Atividade
18.
J Med Chem ; 62(4): 1837-1858, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30657313

RESUMO

An inverse agonist of estrogen-related receptor-γ (ERRγ), an orphan nuclear receptor encoded by E srrg, enhances sodium iodide symporter-mediated radioiodine uptake in anaplastic thyroid cancer (ATC) cells, thereby facilitating responsiveness to radioiodine therapy in vitro. We synthesized potent, selective, and orally bioavailable ERRγ-inverse agonists and evaluated their activity by analyzing in vitro pharmacology and absorption, distribution, metabolism, excretion, and toxicity profiles. X-ray crystallographic analysis of the ligand and ERRγ complex showed that 35 completely binds to the target protein (PDB 6A6K ). Our results showed improved radioiodine avidity in ATC cells through compound 35-mediated upregulation of iodide-handling genes, leading to enhanced responsiveness to radioiodine therapy in vitro. Importantly, in vivo 124I-positron emission tomography/computed tomography imaging revealed that 35 increases radioiodine avidity in CAL62 tumors. Collectively, these results demonstrated that 35 can be developed as a promising treatment for ERRγ-related cancer in the future.


Assuntos
Receptores de Estrogênio/metabolismo , Simportadores/metabolismo , Tamoxifeno/análogos & derivados , Tamoxifeno/uso terapêutico , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Descoberta de Drogas , Agonismo Inverso de Drogas , Estrogênios/agonistas , Estrogênios/síntese química , Estrogênios/farmacocinética , Estrogênios/uso terapêutico , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Radioisótopos do Iodo/metabolismo , Camundongos Endogâmicos BALB C , Estrutura Molecular , Relação Estrutura-Atividade , Tamoxifeno/agonistas , Tamoxifeno/farmacocinética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
19.
Int J Infect Dis ; 78: 50-56, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30385404

RESUMO

OBJECTIVES: Levofloxacin and amiodarone are both known to prolong the QT interval. This study was conducted to estimate the risk of cardiac events in patients receiving concomitant levofloxacin and amiodarone. METHODS: The study included patients who were admitted to a large academic community medical center from 1/2012 to 12/2015 and received both levofloxacin and amiodarone at some point during their hospitalization. Patients received concomitant or non-concomitant levofloxacin and amiodarone during hospitalization. The primary outcome was the occurrence of cardiac events during therapy. The secondary outcome was the proportion of patients with an electrocardiogram performed before and after initiation of therapy. Odds ratios for cardiac events were calculated using a multivariable logistic regression model with and without adjusting for the study variables. The concomitant group was further evaluated for predictors of the primary outcome using multivariable logistic regression. RESULTS: This study included 240 patients, 164 (68.3%) of whom received concomitant levofloxacin and amiodarone. Concomitant medication therapy was associated with a greater than six-fold increased risk of cardiac events after adjusting for the study variables (Odds Ratio=6.20; 95% Confidence Interval=1.34-28.62). CONCLUSIONS: Patients receiving concomitant amiodarone and levofloxacin experienced a five-fold increase in cardiac events compared to patients given either medication alone.


Assuntos
Amiodarona/efeitos adversos , Arritmias Cardíacas/epidemiologia , Morte , Levofloxacino/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiodarona/uso terapêutico , Índice de Massa Corporal , Quimioterapia Combinada , Eletrocardiografia , Feminino , Hospitalização , Humanos , Levofloxacino/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
20.
Health Qual Life Outcomes ; 16(1): 180, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208968

RESUMO

BACKGROUND: This study aimed to determine the socioeconomic and clinical characteristics affecting health-related quality of life (HRQoL) in patients with psoriasis. METHODS: A cross-sectional study was conducted between March and June 2015 using data obtained via an Internet-based survey completed by a psoriasis patient group in Korea. The survey included items regarding demographic, socioeconomic, and clinical characteristics and HRQoL. Patients' HRQoL impairment was classified as severe if their Dermatology Life Quality Index Scores were ≥ 11. Factors influencing HRQoL impairment were identified using multivariate logistic regression analysis. RESULTS: Of the 299 respondents, 161 (53.8%) exhibited severe HRQoL impairment. The Dermatology Life Quality Index scores were significantly associated with gender, annual income, neck psoriasis, psoriasis-related resignation from work, and use of oral and herbal medications. The severity of HRQoL impairment in women was twice that observed in men (odds ratio [OR] = 2.00, 95% confidence interval (CI): 1.05-3.80). Patients with psoriasis on the neck exhibited significantly greater HRQoL impairment than those with psoriasis on other areas of their bodies (OR = 2.30, 95% CI: 1.20-4.43). With respect to the socioeconomic status, patients who earned > 40 million KRW (approximately 34,000 USD; high-income group) showed less HRQoL impairment compared with those who had lower incomes (OR = 0.47, 95% CI: 0.28-0.80). Patients with severe HRQoL impairment used oral (OR = 2.04, 95% CI: 1.20-3.44) and herbal (OR = 1.86, 95% CI: 1.04-3.34) medications more often relative to patients with less severe HRQoL impairment. CONCLUSIONS: HRQoL in patients with psoriasis was significantly associated with their demographic and socioeconomic characteristics and employment status. The presence of psoriasis on exposed areas of the body was significantly associated with patients' HRQoL and employment status. Further research is required to evaluate the impact of psoriasis on patients' productivity.


Assuntos
Disparidades nos Níveis de Saúde , Psoríase/psicologia , Qualidade de Vida/psicologia , Índice de Gravidade de Doença , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Avaliação de Resultados em Cuidados de Saúde , Pobreza/estatística & dados numéricos , Psoríase/terapia , República da Coreia , Classe Social
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