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1.
Sci Rep ; 11(1): 11710, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083681

RESUMO

The low mobility and large contact resistance in organic thin-film transistors (OTFTs) are the two major limiting factors in the development of high-performance organic logic circuits. Here, solution-processed high-performance OTFTs and circuits are reported with a polymeric gate dielectric and 6,6 bis (trans-4-butylcyclohexyl)-dinaphtho[2,1-b:2,1-f]thieno[3,2-b]thiophene (4H-21DNTT) for the organic semiconducting layer. By optimizing and controlling the fabrication conditions, a high saturation mobility of 8.8 cm2 V-1 s-1 was demonstrated as well as large on/off ratios (> 106) for relatively short channel lengths of 15 µm and an average carrier mobility of 10.5 cm2 V-1 s-1 for long channel length OTFTs (> 50 µm). The pseudo-CMOS inverter circuit with a channel length of 15 µm exhibited sharp switching characteristics with a high signal gain of 31.5 at a supply voltage of 20 V. In addition to the inverter circuit, NAND logic circuits were further investigated, which also exhibited remarkable logic characteristics, with a high gain, an operating frequency of 5 kHz, and a short propagation delay of 22.1 µs. The uniform and reproducible performance of 4H-21DNTT OTFTs show potential for large-area, low-cost real-world applications on industry-compatible bottom-contact substrates.

2.
Anal Sci ; 37(8): 1105-1110, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-33390413

RESUMO

A rapid analytical method developed for the analysis of ß-lapachone in in vitro samples could not be directly applied to the analysis of clinical samples because of interference from unknown substances. Here, we developed and validated a rapid interference-free analytical method to accurately determine ß-lapachone levels in human plasma using liquid chromatography-tandem mass spectrometry. First, we achieved the baseline-separation of ß-lapachone from any interfering substances within a total run time of 4 min by adjusting the eluent strength of the mobile phase. Second, precursor-ion scanning revealed the identity of the interfering substances. Sulfonate- or glucuronide-conjugated metabolites were converted to ß-lapachone in an electrospray ion source, causing interference. In a method validation study, calibration curves for ß-lapachone in human plasma were linear over a concentration range from 0.5 to 200 ng/mL (r > 0.999), and the lower limit of quantification was 0.5 ng/mL. The other validation parameters, including intra- and interday accuracy and precision, were acceptable with a coefficient of variation less than 10% (n = 5). The validated analytical method was successfully applied to a pharmacokinetic study of a single, oral dose of 100 mg MB12066 (a clinical form of ß-lapachone) in healthy volunteers.


Assuntos
Naftoquinonas , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray
3.
Drug Des Devel Ther ; 14: 2101-2111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32546973

RESUMO

OBJECTIVE: Fimasartan, an angiotensin II type 1 receptor blocker, and linagliptin, a dipeptidyl-peptidase-4 inhibitor, are frequently coadministered to treat patients with hypertension and diabetes, respectively. This study sought to evaluate the pharmacokinetic interactions between fimasartan and linagliptin after co-administration in healthy Korean subjects. METHODS: The overall study was divided into two separate parts, with each part designed as an open-label, multiple-dose, two-period, and single-sequence study. In Part A, to investigate the effect of linagliptin on fimasartan, 25 subjects received 120 mg fimasartan alone once daily for seven days during Period I, and 120 mg fimasartan with 20 mg linagliptin for seven days during Period II. In Part B, to examine the effect of fimasartan on linagliptin, 12 subjects received only linagliptin once daily for seven days during Period I, followed by concomitant administration of fimasartan for seven days during Period II, at the same doses used in Part A. Serial blood samples were collected at scheduled intervals for up to 24 h after the last dose to determine the steady-state pharmacokinetics of both drugs. RESULTS: Thirty-six subjects completed the study. The geometric mean ratio and 90% confidence intervals for maximum plasma concentration at steady state (Cmax,ss) and area under the concentration-time curve at steady state (AUCτ,ss) of fimasartan with or without linagliptin were 1.2633 (0.9175-1.7396) and 1.1740 (1.0499-1.3126), respectively. The corresponding values for Cmax,ss and AUCτ,ss of linagliptin with or without fimasartan were 0.9804 (0.8480-1.1336) and 0.9950 (0.9322-1.0619), respectively. A total of eight adverse events (AEs) were reported and the incidence of AEs did not increase significantly with co-administration of the drugs. CONCLUSION: Our results suggest that there are no clinically significant pharmacokinetic interactions between fimasartan and linagliptin when co-administered. Treatments were well tolerated during the study, with no serious adverse effects. CLINICAL TRIAL REGISTRY: http://clinicaltrials.gov, NCT03250052.


Assuntos
Compostos de Bifenilo/farmacocinética , Linagliptina/farmacocinética , Pirimidinas/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Relação Dose-Resposta a Droga , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Linagliptina/administração & dosagem , Linagliptina/sangue , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Tetrazóis/administração & dosagem , Tetrazóis/sangue
4.
Drug Des Devel Ther ; 13: 3127-3136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564829

RESUMO

PURPOSE: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. METHODS: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. RESULTS: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. CONCLUSION: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antineoplásicos/farmacocinética , Fluoruracila/farmacocinética , Ácido Oxônico/farmacocinética , Piridinas/farmacocinética , Neoplasias Gástricas/metabolismo , Tegafur/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Cromatografia Líquida , Estudos Cross-Over , Composição de Medicamentos , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Humanos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/sangue , Piridinas/administração & dosagem , Piridinas/sangue , República da Coreia , Neoplasias Gástricas/química , Espectrometria de Massas em Tandem , Tegafur/administração & dosagem , Tegafur/sangue , Equivalência Terapêutica
5.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1118-1119: 157-163, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31054449

RESUMO

To improve early renal allograft function, it is important to develop a noninvasive diagnostic method for acute T cell-mediated rejection (TCMR). This study aims to explore potential noninvasive urinary biomarkers to screen for acute TCMR in kidney transplant recipients (KTRs) using untargeted metabolomic profiling. Urinary metabolites, collected from KTRs with stable graft function (STA) or acute TCMR episodes, were analyzed using liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analyses were performed to discriminate differences in urinary metabolites between the two groups. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of potential urinary biomarkers. Statistical analysis revealed the differences in urinary metabolites between the two groups and indicated several statistically significant metabolic features suitable for potential biomarkers. By comparing the retention times and mass fragmentation patterns of the chemicals in metabolite databases, samples, and standards, six of these features were clearly identified. ROC curve analysis showed the best performance of the training set (area under the curve value, 0.926; sensitivity, 90.0%; specificity, 84.6%) using a panel of five potential biomarkers: guanidoacetic acid, methylimidazoleacetic acid, dopamine, 4-guanidinobutyric acid, and L-tryptophan. The diagnostic accuracy of this model was 62.5% for an independent test dataset. LC-MS-based untargeted metabolomic profiling is a promising method to discriminate between acute TCMR and STA groups. Our model, based on a panel of five potential biomarkers, needs to be further validated in larger scale studies.


Assuntos
Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/urina , Transplante de Rim , Metaboloma/fisiologia , Metabolômica/métodos , Adulto , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Feminino , Rejeição de Enxerto/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Linfócitos T/metabolismo , Espectrometria de Massas em Tandem
6.
Adv Ther ; 36(7): 1642-1656, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31119689

RESUMO

INTRODUCTION: Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug-drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. METHODS: In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10 mg/160 mg alone for 10 consecutive days in period I, and the same FDC for 10 days with concomitant 7-day administration of 20 mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7 days in period I, and the FDC for 10 days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72 h for amlodipine and rosuvastatin, and for up to 48 h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography-tandem mass spectrometry. RESULTS: Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029-0.9763) and 0.9316 (0.8970-0.9675) for amlodipine, 0.7698 (0.6503-0.9114) and 0.7888 (0.6943-0.8962) for valsartan, and 0.9737 (0.8312-1.1407) and 0.9596 (0.8826-1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. CONCLUSION: When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. CLINICAL TRIAL REGISTRATION: https://cris.nih.go.kr CRIS KCT0001660. FUNDING: KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.


Assuntos
Anlodipino , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Rosuvastatina Cálcica , Valsartana , Adulto , Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacocinética , Valsartana/administração & dosagem , Valsartana/farmacocinética
7.
J Cell Physiol ; 234(2): 1659-1670, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30076703

RESUMO

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor that plays an important role in various metabolic processes under physiological and pathophysiological conditions. Here, we report that ERRγ functions as a negative regulator in receptor activator of nuclear factor κΒ ligand (RANKL)-induced osteoclast differentiation. We observed that ERRγ was strongly expressed in osteoclast precursors, bone marrow-derived macrophages (BMMs) while its expression was significantly reduced by RANKL during osteoclastogenesis. Overexpression of ERRγ in BMMs suppressed the formation of multinucleated osteoclasts and attenuated the induction of c-Fos and nuclear factor of activated T cells c1, which are critical modulators in osteoclastogenesis. Similarly, the treatment of ERRγ agonists, N-(4-(diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) or GSK4716, also inhibited osteoclast generation and the expression of these key modulators. On the other hand, shRNA-mediated knockdown of ERRγ accelerated the formation of bone-resorbing cells and the expression of osteoclastogenic markers. Forced expression of ERRγ blocked RANKL-stimulated phosphorylation of the nuclear factor κB (NF-κB) inhibitor IκBα and suppressed NF-κB transcriptional activity induced by RANKL or the NF-κB subunit p65. Furthermore, by employing a pharmacological approach, we showed that the ERRγ agonist DY131 protected against inflammatory bone loss induced by lipopolysaccharide in vivo. Together, our findings reveal that ERRγ is a pivotal regulator in RANKL-mediated osteoclastogenesis and suggest that ERRγ may have potential as a therapeutic target for pathological bone loss.


Assuntos
Macrófagos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteoporose/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Estrogênios/farmacologia , Regulação da Expressão Gênica , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteoporose/genética , Osteoporose/patologia , Osteoporose/prevenção & controle , Ligante RANK/farmacologia , Células RAW 264.7 , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/genética , Transdução de Sinais
8.
Transl Clin Pharmacol ; 27(2): 52-58, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32055581

RESUMO

This tutorial introduces the mathematical skills required to obtain exact and approximate solutions for reversible reactions and provides graphical insights to help understand the pharmacokinetics of reversible metabolism. The matrix method provides an easy way to derive the exact solution for the amount of each species as a function of time. The plots of the exact solutions reveal some characteristic features of the pharmacokinetic profiles of the reversible metabolism. We also describe two approximation approaches, steady-state approximation, and equilibrium approximation, to simplify the solutions. The skills and knowledge acquired through this tutorial will provide a basis for understanding more complex reversible reaction systems.

9.
Drug Des Devel Ther ; 12: 3607-3615, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464392

RESUMO

PURPOSE: A new fixed-dose combination (FDC) formulation of 120 mg fimasartan and 20 mg rosuvastatin was developed to increase therapeutic convenience and improve treatment compliance. METHODS: A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day washout period was conducted to compare the pharmacokinetic (PK) characteristics and bioequivalence between an FDC of fimasartan/rosuvastatin and the separate co-administration of fimasartan and rosuvastatin in healthy Korean volunteers. The plasma concentrations of fimasartan and rosuvastatin were analyzed by a validated liquid chromatography-tandem mass spectrometry method, for which serial blood samples were collected for up to 48 hours post-administration of fimasartan and 72 hours post-administration of rosuvastatin, in each period. The PK parameters were calculated using a non-compartmental method. RESULTS: A total of 78 subjects completed the study. All the 90% CIs of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. The GMR and 90% CI for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the maximum plasma concentration (Cmax) for fimasartan were 0.9999 (0.9391-1.0646) and 1.0399 (0.8665-1.2479), respectively. The GMR and 90% CI for the AUC0-t and Cmax for rosuvastatin were 1.0075 (0.9468-1.0722) and 1.0856 (0.9944-1.1852), respectively. Treatment with fimasartan and rosuvastatin was generally well tolerated without serious adverse events. CONCLUSION: The new FDC formulation of 120 mg fimasartan and 20 mg rosuvastatin can be substituted for the separate co-administration of fimasartan and rosuvastatin, for the advantage of better compliance with convenient therapeutic administration.


Assuntos
Compostos de Bifenilo/farmacocinética , Pirimidinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/sangue , República da Coreia , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/sangue , Tetrazóis/administração & dosagem , Tetrazóis/sangue , Equivalência Terapêutica , Adulto Jovem
10.
Drug Des Devel Ther ; 12: 545-553, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29559771

RESUMO

PURPOSE: A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance. METHODS: The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography-tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period. RESULTS: Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan Cmax and AUC0-t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353-0.9846) and 0.9431 (0.8698-1.0226), respectively. The GMR and 90% CI for the S-amlodipine Cmax and AUC0-t (FDC/concomitant administration) were 0.9829 (0.9143-1.0567) and 0.9632 (0.8798-1.0546), respectively. As the intrasubject variability of the Cmax for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study. CONCLUSION: CKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.


Assuntos
Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Adulto , Anlodipino/efeitos adversos , Anlodipino/sangue , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Benzoatos/efeitos adversos , Benzoatos/sangue , Cromatografia Líquida , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Tolerância a Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Relação Estrutura-Atividade , Comprimidos , Espectrometria de Massas em Tandem , Telmisartan , Equivalência Terapêutica , Adulto Jovem
11.
J Cell Physiol ; 233(2): 1481-1489, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28574596

RESUMO

GPR84, a member of the G protein-coupled receptor family, is found predominantly in immune cells, such as macrophages, and functions as a pivotal modulator of inflammatory responses. In this study, we investigated the role of GPR84 in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. Our microarray data showed that GPR84 was significantly downregulated in osteoclasts compared to in their precursors, macrophages. The overexpression of GPR84 in bone marrow-derived macrophages suppressed the formation of multinucleated osteoclasts without affecting precursor proliferation. In addition, GPR84 overexpression attenuated the induction of c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which are transcription factors that are critical for osteoclastogenesis. Furthermore, knockdown of GPR84 using a small hairpin RNA promoted RANKL-mediated osteoclast differentiation and gene expression of osteoclastogenic markers. Mechanistically, GPR84 overexpression blocked RANKL-stimulated phosphorylation of IκBα and three MAPKs, JNK, ERK, and p38. GPR84 also suppressed NF-κB transcriptional activity mediated by RANKL. Conversely, GPR84 knockdown enhanced RANKL-induced activation of IκBα and the three MAPKs. Collectively, our results revealed that GPR84 functions as a negative regulator of osteoclastogenesis, suggesting that it may be a potential therapeutic target for osteoclast-mediated bone-destructive diseases.


Assuntos
Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoclastos/enzimologia , Osteogênese , Receptores Acoplados a Proteínas G/metabolismo , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Células RAW 264.7 , Interferência de RNA , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Fatores de Tempo , Transfecção
12.
Transl Clin Pharmacol ; 26(1): 1-5, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32055540

RESUMO

This tutorial explains the pharmacokinetics of a prodrug and its active metabolite (or parent drug) using a two-step, consecutive, first-order irreversible reaction as a basic model for prodrug metabolism. In this model, the prodrug is metabolized and produces the parent drug, which is subsequently eliminated. The mathematical expressions for pharmacokinetic parameters were derived step by step. In addition, we visualized these expressions to help understand the relationship between pharmacokinetic parameters easily. For the elimination rate-limited and formation rate-limited metabolism, we analyzed the plasma drug concentration versus time curve of a prodrug administered intravenously.

13.
Exp Cell Res ; 359(1): 112-119, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28780306

RESUMO

Neuromedin B (NMB), a mammalian bombesin-like peptide, regulates diverse physiological processes, such as energy metabolism, memory and fear behavior, and cellular growth, through its cognate receptor, NMBR. In this study, we report that NMB expression was upregulated during osteoclast development and that silencing NMB or NMBR attenuated osteoclast generation mediated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). We found that knockdown of NMB or NMBR using a small hairpin RNA suppressed M-CSF-induced proliferation of osteoclast precursor cells without altering osteoclast differentiation. Interestingly, NMB or NMBR knockdown reduced the expression of the M-CSF receptor, c-Fms, which is an important modulator of osteoclast development. Consequently, NMB or NMBR silencing inhibited M-CSF/c-Fms-mediated downstream signaling pathways like activation of ERK and Akt and induction of D-type cyclins, cyclin D1 and D2. Moreover, knockdown of NMB or NMBR accelerated apoptosis in osteoclast lineage cells by inducing caspase-3, caspase-9, and Bim expression. In summary, our study demonstrates that the NMB/NMBR axis plays a pivotal role in osteoclast generation by modulating the proliferation and survival of osteoclast lineage cells.


Assuntos
Ciclina D/metabolismo , Inativação Gênica , Fator Estimulador de Colônias de Macrófagos/metabolismo , Neurocinina B/análogos & derivados , Osteoclastos/citologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptores da Bombesina/metabolismo , Células-Tronco/citologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Inativação Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Neurocinina B/genética , Neurocinina B/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ligante RANK/farmacologia , Receptores da Bombesina/antagonistas & inibidores , Receptores da Bombesina/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
14.
Transl Clin Pharmacol ; 25(4): 183-189, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32095473

RESUMO

This study describes the development of an analytical method to determine radotinib levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) for pharmacokinetic application. Plasma samples were sequentially processed by liquid-liquid extraction using methyl tert-butyl ether, evaporation, and reconstitution. Analytes were separated and analyzed using HPLC-MS/MS in selected reaction monitoring mode, monitoring the specific transitions of m/z 531 to 290 for radotinib and m/z 409 to 238 for amlodipine (internal standard). The HPLC-MS/MS analytical method was validated with respect to selectivity, linearity, sensitivity, accuracy, precision, recovery, and stability. Calibration curves were linear over a concentration range 5-3,000 ng/mL with correlation coefficients (r) > 0.998. The lower limit of quantification for radotinib in plasma was 5 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. This method was suitable to determine radotinib levels in human plasma because of its simplicity, selectivity, precision, and accuracy.

15.
Transl Clin Pharmacol ; 25(2): 106-111, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32133327

RESUMO

This study describes the development of an analytical method to determine sumatriptan levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) and its application to a pharmacokinetic study in healthy Korean volunteers. A single 50 mg dose of sumatriptan was orally administered to twelve healthy volunteers (nine women and three men). The HPLC-MS/MS analytical method was validated with respect to its specificity, linearity, sensitivity, accuracy, precision, recovery, and stability. The calibration curve was linear over a concentration range of 0.3-100 ng/mL (r > 0.999). The lower limit of quantitation for sumatriptan in plasma was 0.3 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. We compared plasma concentration-time curves as well as pharmacokinetic parameters such as the area under the curve (AUC) and maximum plasma concentration (Cmax). Both the mean AUC and Cmax of sumatriptan were 1.56 times higher in women than in men. These differences could be largely explained by the difference in body weight (44%) between women and men. The outcomes may provide insights into developing appropriate individualized treatment strategies.

16.
Chem Commun (Camb) ; 50(5): 527-9, 2014 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-24266026

RESUMO

Nickel nanotubes have been synthesized by the popular and versatile method of template-assisted electrodeposition, and a surface-directed growth mechanism based on the adsorption of the nickel-borate complex has been proposed.


Assuntos
Ácidos Bóricos/química , Nanotubos/química , Níquel/química , Adsorção , Eletrólitos/química , Galvanoplastia , Propriedades de Superfície
17.
Talanta ; 101: 537-40, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23158360

RESUMO

The paper presents the development of a multiple consecutive extraction method enabling the determination of the total amount of bisphenol A (BPA) released from porous polysulfone (PS) membranes in a hemodialyzer or hemoconcentrator under simulated-use conditions. The levels of BPA were determined using solid phase extraction (SPE) coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS). We demonstrated that it was difficult to determine the total amount of BPA released from the PS membranes using a single extraction method with finite solvent volume because of the chemical equilibrium between the extraction solution and the polymer phase. Repeated extractions gave more accurate results than a single extraction for the determination of the total amount of leachables in porous membranes. A general equation was derived to fit the elution profile of BPA released during multiple consecutive extractions.


Assuntos
Compostos Benzidrílicos/análise , Membranas Artificiais , Fenóis/análise , Polímeros/química , Sulfonas/química , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas
18.
Talanta ; 94: 353-5, 2012 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-22608460

RESUMO

Ultrapure water produced by a water purification system is one of the most essential and widely used reagents in laboratories. However, its quality is usually the least well-characterized and often overlooked. Here we investigate the contamination of ultrapure water by bisphenol A (BPA) leached from a polysulfone (PS) ultrafilter in a water purification system. To evaluate the level of BPA in ultrapure water, we used an offline solid-phase extraction (SPE) coupled with liquid chromatography mass spectrometry (LC-MS). Initial BPA level leached from a new PS ultrafilter was 0.70±0.06 ng/mL. The concentration of BPA decreased gradually with continuous dispensation of purified water and was 0.20±0.02 ng/mL at 33.5-L dispensation. The total amount of extractable BPA was 64.4±1.4 µg per PS ultrafilter. The cumulative amount of BPA leached during dispensation of 33.5-L water was 1.2±0.1 µg, which only accounts for 2% of the total amount of extractable BPA.


Assuntos
Fenóis/análise , Polímeros/química , Sulfonas/química , Água/química , Compostos Benzidrílicos , Cromatografia Líquida , Filtração , Espectrometria de Massas , Extração em Fase Sólida , Purificação da Água
19.
J Sep Sci ; 35(5-6): 661-5, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22331828

RESUMO

This paper presents sample stacking with in-column silylation (SIS) for quantitative analysis of less volatile polar compounds using gas chromatography-mass spectrometry (GC-MS). This was achieved by the combination of sandwiched in-column silylation and multiple injections (up to 100 times or 100 µL in total). N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) was used as a silylating reagent. For the SIS technique, samples were introduced multiple N times (N = 2~100) into a capillary column in between BSTFA injections. The quantitative characteristic of SIS technique was studied using bisphenol A (BPA) as a model compound. The sandwiched in-column silylation for the less volatile polar compounds effectively replaced polar hydrogen with trimethylsilyl group to reduce sample adsorption and band broadening. Meanwhile, multiple injections at the SIS technique contributed to increase the sensitivity quantitatively. The capability and limitation of this analytical approach were further investigated with various types of compounds such as hydroxyls, carboxylic acids, and amine.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/instrumentação , Fenóis/química , Compostos Orgânicos Voláteis/química , Acetamidas/química , Compostos Benzidrílicos , Ácidos Carboxílicos/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Compostos de Trimetilsilil/química , Volatilização
20.
Chem Commun (Camb) ; 48(21): 2725-7, 2012 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-22306978

RESUMO

Poly (3,4-(2-methylene)propylenedioxythiophene) (PMProDot) nanotubes were synthesized within the pores of polycarbonate and were further modified with styrene and vinylcarbazole by a one step electrochemical method through the methylene functional group. The enhanced electrochemical and electrochromic properties of composite nanotubes were investigated using FTIR, UV/Vis absorbance spectroscopy, and AFM.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Técnicas Eletroquímicas , Nanotubos/química , Tiofenos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Carbazóis/química , Nanotubos/ultraestrutura , Técnicas de Microbalança de Cristal de Quartzo , Estireno/química , Tiofenos/química
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