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1.
J Sep Sci ; 44(7): 1299-1306, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33387366

RESUMO

Arctigenin is a natural lignin and a main active component of Fructus arctii, the dried fruit of Arctium lappa. This compound was reported to have some biological activities such as anti-inflammatory, antioxidant, antiviral, renoprotective, and antitumor effects. Arctigenin is mainly metabolized to arctigenin-4'-O-glucuronide by UDP-glucuronosyltransferase. In this study, a simultaneous quantification method was established and validated for measuring arctigenin and arctigenin-4'-O-glucuronide in mouse plasma using ultra-high performance liquid chromatography with tandem mass spectrometry. The assay fulfilled the requirements of the United States Food and Drug Administration guideline for assay validation, with a lower limit of quantification of 2.00 ng/mL for arctigenin and 50.0 ng/mL for arctigenin-4'-O-glucuronide. The recovery rate and matrix effect ranged from 78.4 to 102.8% and 92.5 to 106.3%, respectively, for arctigenin, and 74.3 to 109.2% and 94.9 to 110.2% for arctigenin-4'-O-glucuronide. The method was applied to the measurement of plasma concentrations of arctigenin and arctigenin-4'-O-glucuronide in the plasma of mice after administration of arctigenin. All measured concentrations were within the calibration ranges. Our novel method may be useful to measure plasma arctigenin and arctigenin-4'-O-glucuronide concentrations, and contribute to evaluate the pharmacokinetics of arctigenin and arctigenin-4'-O-glucuronide in mice.


Assuntos
Furanos/sangue , Glucuronídeos/sangue , Lignanas/sangue , Animais , Cromatografia Líquida de Alta Pressão , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espectrometria de Massas em Tandem
2.
Cancer Sci ; 109(7): 2256-2265, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29719934

RESUMO

Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358).


Assuntos
Técnicas Biossensoriais/métodos , Transferência Ressonante de Energia de Fluorescência/métodos , Proteínas de Fusão bcr-abl/análise , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Seleção de Pacientes , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Biol Pharm Bull ; 41(7): 1017-1023, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962398

RESUMO

Although several studies have evaluated the efficacy of thiazolidinediones (TZD) for the treatment of Alzheimer's disease (AD), investigation of the impact of apolipoprotein E (ApoE) gene polymorphisms on the efficacy of TZD remains insufficient. We investigated the impact by conducting a systematic review and meta-analysis. MEDLINE, Cochrane Library, and Japana Centra Revuo Medicina were searched to identify relevant studies based on eligibility criteria. Mean differences (MD) of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score with 95% confidence intervals (CI) were calculated for subgroups stratified by ApoE genotype. To evaluate the impact of ApoE gene polymorphisms, meta-regression analysis was also conducted to calculate the regression coefficient (Coef) of ApoE expression status with 95% CI. Three randomized controlled studies comparing rosiglitazone and placebo, with a total of 2381 subjects met the eligibility criteria. ApoE expression status was reported in 983 individuals (ApoE4-positive, 141; ApoE4-negative, 842). When compared to placebo, rosiglitazone significantly decreased ADAS-Cog score in ApoE4-negative individuals (MD, -1.37; 95% CI, -2.09 to -0.65), but significantly increased ADAS-Cog score in ApoE4-positive individuals (MD, 2.18; 95% CI, 0.52 to 3.85). The meta-regression analysis showed a significant association between efficacy and ApoE expression status (Coef, 3.55; 95% CI, 1.42 to 5.68). Although the present results should be interpreted with caution because of the limited number of studies, our findings suggest that ApoE gene polymorphisms impact the efficacy of rosiglitazone for AD patients. This finding would provide useful information for the development of new agents for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Apolipoproteínas E/genética , Fármacos Neuroprotetores/uso terapêutico , PPAR gama/antagonistas & inibidores , Tiazolidinedionas/uso terapêutico , Doença de Alzheimer/genética , Humanos , Polimorfismo Genético , Resultado do Tratamento
4.
Bioorg Med Chem Lett ; 27(3): 562-566, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28003138

RESUMO

(-)-Dehydroxymethylepoxyquinomicin ((-)-DHMEQ, 1) is a specific inhibitor of NF-κB. It binds to SH group in the specific cysteine residue of NF-κB components with its epoxide moiety to inhibit DNA binding. In the present research, we have designed and synthesized an epoxide-free analog called (S)-ß-salicyloylamino-α-exo-methylene-Æ´-butyrolactone (SEMBL, 3). SEMBL inhibited DNA binding of NF-κB component p65 in vitro. It inhibited LPS-induced NF-κB activation, iNOS expression, and inflammatory cytokine secretions. It also inhibited NF-κB and cellular invasion in ovarian carcinoma ES-2 cells. Moreover, its stability in aqueous solution was greatly enhanced compared with (-)-DHMEQ. Thus, SEMBL has a potential to be a candidate for a new anti-inflammatory and anticancer agent.


Assuntos
4-Butirolactona/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Fármacos , NF-kappa B/antagonistas & inibidores , Salicilamidas/farmacologia , 4-Butirolactona/síntese química , 4-Butirolactona/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Salicilamidas/síntese química , Salicilamidas/química , Relação Estrutura-Atividade
5.
Cancer Sci ; 107(12): 1818-1824, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27685612

RESUMO

GBS-01, an extract from the fruit of Arctium lappa L. is an orally administered drug rich in arctigenin, which has been reported to exert antitumor activity by attenuating the tolerance of cancer cells to glucose deprivation. We investigated the maximum tolerated dose of GBS-01 based on the frequency of the dose-limiting toxicities (DLTs) and pharmacokinetics in patients with advanced pancreatic cancer refractory to gemcitabine. GBS-01 was given orally at escalating doses from 3.0 g (containing 1.0 g burdock fruit extract) to 12.0 g q.d. A DLT was defined as a grade 4 hematological toxicity and grade 3 or 4 non-hematological toxicity appearing during the first 28 days of treatment. Fifteen patients (GBS-01 dose level 1 [3.0 g], three patients; dose level 2 [7.5 g], three patients; and dose level 3 [12.0 g], nine patients) were enrolled. None of the patients at any of the three dose levels showed any sign of DLTs. The main adverse events were increased serum γ-glutamyl transpeptidase, hyperglycemia, and increased serum total bilirubin; however, all the toxicities were mild. Of the 15 patients, 1 showed confirmed partial response and 4 patients had stable disease. The median progression-free and overall survival of the patients were 1.1 and 5.7 months, respectively. The pharmacokinetic study revealed a high bioavailability of arctigenin and rapid conjugation of the drug with glucuronic acid. The recommended dose of GBS-01 was 12.0 g q.d, and favorable clinical responses were obtained. This trial was registered at UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number UMIN000005787.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Biomarcadores Tumorais , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Gencitabina
6.
Eur J Clin Pharmacol ; 72(2): 185-93, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26507546

RESUMO

PURPOSE: Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients. METHODS: The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)CD34+cells) was calculated from each patient's dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration. RESULTS: Early molecular responses were not significantly associated with PK or PD (IC50 CD34+cells) parameters. However, the PK/PD parameter-time above IC50 CD34+cells-significantly correlated with BCR-ABL transcript level at 3 months (correlation coefficient (CC) = -0.292, P = 0.0375) and the reduction of BCR-ABL level at 1 or 3 months (CC = -0.404, P = 0.00328 and CC = -0.356, P = 0.0104, respectively). Patients with more than 12.6 h at time above IC50 CD34+cells achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (P = 0.013, odds ratio = 4.8 and P = 0.024, odds ratio = 4.3, respectively). CONCLUSION: These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50 CD34+cells could significantly improve prognosis.


Assuntos
Antineoplásicos , Dasatinibe , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteína Oncogênica v-crk/antagonistas & inibidores , Inibidores de Proteínas Quinases , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dasatinibe/efeitos adversos , Dasatinibe/farmacocinética , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína Oncogênica v-crk/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
7.
Br J Clin Pharmacol ; 80(6): 1421-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26773964

RESUMO

AIMS: It has been reported that cytochrome P450 (CYP)3A activity increases significantly in patients with end stage renal disease (ESRD) after kidney transplantation, with wide interindividual variability in the degree of increase. The aim of this study was to evaluate the influence of CYP3A5 polymorphism on the increase in CYP3A activity after living kidney transplantation, by measuring the plasma concentration of 4ß-hydroxycholesterol. METHODS: This prospective study recruited 22 patients with ESRD who underwent a first living kidney allograft transplantation, comprising 12 patients with CYP3A5*1 allele (CYP3A5*1/*1 or *1/*3) and 10 patients without CYP3A5*1 allele (CYP3A5*3/*3). RESULTS: No significant difference in estimated glomerular filtration rate over time was observed between patients with the CYP3A5*1 allele and patients without the CYP3A5*1 allele, suggesting that the degrees of recovery in renal function after living kidney transplantation were similar in the two groups. However, plasma concentrations of 4ß-hydroxycholesterol on days 90 (57.1 ± 13.4 vs. 39.5 ± 10.8 ng ml(-1)) and 180 (55.0 ± 14.5 vs. 42.4 ± 12.6 ng ml(-1)) after living kidney transplantation were significantly higher in the presence of the CYP3A5*1 allele than in the absence of the CYP3A5*1 allele [P = 0.0034 (95% confidence interval of difference 6.55, 28.6) and P = 0.043 (95% confidence interval of difference 0.47, 24.8), respectively], suggesting that CYP3A activity may increase markedly associated with recovery of renal function in patients with the CYP3A5*1 allele. CONCLUSIONS: These findings suggest that the presence of the CYP3A5*1 allele contributes to marked elevation of CYP3A activity associated with recovery of renal function after kidney transplantation.


Assuntos
Citocromo P-450 CYP3A/genética , Falência Renal Crônica/genética , Transplante de Rim , Doadores Vivos , Polimorfismo Genético , Adulto , Idoso , Citocromo P-450 CYP3A/metabolismo , Feminino , Humanos , Falência Renal Crônica/enzimologia , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
8.
Drug Metab Dispos ; 42(1): 105-10, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24135442

RESUMO

Several studies have shown that renal failure decreases CYP3A activity and that uremic toxins may play a role via transcriptional or translational modifications of cytochrome P450 (P450) enzymes and direct inhibition of P450-mediated metabolism. In this study, we evaluated the relationship between CYP3A activity (using plasma concentration of 4ß-hydroxycholesterol as a biomarker) and clinical characteristics including plasma concentrations of indoxyl sulfate (3-INDS) and indole-3-acetic acid (3-IAA) in stable kidney transplant recipients. Forty-five Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. Morning blood samples were collected and plasma concentrations of 4ß-hydroxycholesterol, 3-INDS, and 3-IAA were measured. Plasma concentrations of 4ß-hydroxycholesterol were 57.1 ± 11.2, 42.1 ± 11.8, and 34.5 ± 7.3 ng/ml in recipients with CYP3A5*1/*1 (n = 5), *1/*3 (n = 15), and *3/*3 (n = 25) genotypes, respectively, with significant differences between three genotypes. A significant correlation was observed between plasma concentrations of 4ß-hydroxycholesterol and 3-INDS but not 3-IAA. Multiple regression analysis identified the number of CYP3A5*3 alleles in genotype, plasma concentration of 3-INDS, and body weight as independent variables associated with plasma concentration of 4ß-hydroxycholesterol. In conclusion, these results suggest that CYP3A5 polymorphism and plasma concentration of 3-INDS may account for the interindividual variability of CYP3A activity, and that plasma concentration of 3-INDS may partially explain the gap in CYP3A activity that cannot be explained by genetic contribution in patients with renal failure.


Assuntos
Citocromo P-450 CYP3A/genética , Hidroxicolesteróis/sangue , Indicã/sangue , Polimorfismo Genético/genética , Adolescente , Adulto , Idoso , Alelos , Povo Asiático/genética , Biomarcadores/sangue , Feminino , Genótipo , Humanos , Ácidos Indolacéticos/sangue , Rim/metabolismo , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Eur J Drug Metab Pharmacokinet ; 39(2): 93-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23771854

RESUMO

Micafungin (MCFG) concentrations in the plasma and in burn eschar were investigated after daily intravenous infusion (1 h) of MCFG (200 mg) in three patients with severe burns. MCFG treatment was initiated more than 72 h after the burn injuries. The MCFG concentrations in the plasma were determined at the end of the first administration of MCFG, immediately before the second dosing, at the end of the MCFG infusion after at least 4 days from the initial treatment, and immediately before the subsequent dosing using high-performance liquid chromatography. In addition, the trough levels in burn eschar after both the initial administration and repeated administration were measured. The peak and trough levels in the plasma were comparable to or slightly lower than the reported values in healthy volunteers. The mean (range) MCFG concentrations in the burn eschar after initial administration and repeated administration were 1.41 µg/mL (<0.1-3.98 µg/mL) and 6.65 µg/mL (1.10-14.81 µg/mL), respectively. In most cases, the MCFG concentrations in the burn eschar, especially after repeated administration, were higher than the reported MIC90 of MCFG against the clinically important pathogenic species of Candida and Aspergillus. These results suggest that MCFG is capable of penetrating burn eschar.


Assuntos
Antifúngicos/farmacocinética , Queimaduras/metabolismo , Equinocandinas/farmacocinética , Lipopeptídeos/farmacocinética , Idoso , Feminino , Humanos , Masculino , Micafungina , Pessoa de Meia-Idade
10.
J Lipid Res ; 54(9): 2568-72, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23833241

RESUMO

Several previous studies have shown that renal failure decreases not only renal elimination but also metabolic clearance of drugs, particularly those metabolized by CYP3A. However, whether recovery of renal function results in recovery of hepatic CYP3A activity remains unknown. In this study, we evaluated the effect of renal function on CYP3A activity after kidney transplantation in patients with end-stage renal disease (ESRD) by measuring the change in CYP3A activity using plasma concentration of 4ß-hydroxycholesterol as a biomarker. The study enrolled 13 patients with ESRD who underwent the first kidney allograft transplantation. Morning blood samples were collected before and 3, 7, 10, 14, 21, 30, 60, 90, 120, 150 and 180 days after kidney transplantation. Plasma concentration of 4ß-hydroxycholesterol was measured using GC-MS. Compared with before kidney transplantation, creatinine clearance increased significantly from day 3 after kidney transplantation and stabilized thereafter. Plasma concentration of 4ß-hydroxycholesterol was elevated significantly on days 90 and 180 after kidney transplantation. In conclusion, this study suggests the recovery of CYP3A activity with improvement in renal function after kidney transplantation in patients with ESRD.


Assuntos
Hidroxicolesteróis/sangue , Transplante de Rim , Citocromo P-450 CYP3A , Feminino , Humanos , Rim/fisiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/enzimologia , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Masculino , Recuperação de Função Fisiológica
11.
Antimicrob Agents Chemother ; 57(8): 4027-30, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23689706

RESUMO

Eight eyes of 7 patients with fungal disease received intravenous injections of 150 to 300 mg micafungin, and samples of blood, cornea, retina-choroid, aqueous humor, and vitreous humor were collected. The micafungin levels in all collected samples exceeded the MICs; however, the levels in the vitreous and aqueous humors were lower. Our findings suggest that intravenous micafungin should be given in combination with intravitreal antifungal agents after vitrectomy in severe cases of intraocular fungal diseases.


Assuntos
Antifúngicos/administração & dosagem , Córnea/microbiologia , Equinocandinas/administração & dosagem , Endoftalmite/tratamento farmacológico , Lipopeptídeos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/farmacocinética , Humor Aquoso/metabolismo , Aspergillus/efeitos dos fármacos , Aspergillus/isolamento & purificação , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Córnea/efeitos dos fármacos , Equinocandinas/farmacocinética , Endoftalmite/microbiologia , Feminino , Humanos , Injeções Intraoculares/métodos , Lipopeptídeos/farmacocinética , Masculino , Micafungina , Vitrectomia/métodos , Corpo Vítreo/metabolismo
12.
Antimicrob Agents Chemother ; 56(2): 1113-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22083486

RESUMO

Micafungin concentrations in plasma and burn eschar after daily intravenous infusion (1 h) of micafungin (200 to 300 mg) were investigated for six patients with severe burns. Micafungin treatment was initiated more than 72 h after the burn injuries. The peak and trough levels in the plasma after the initial administration and repeated administrations for more than 4 days were comparable with or slightly lower than the reported values for healthy volunteers. Micafungin concentrations in the plasma and burn eschar were between 3.6 and >1,000 times higher than the reported MIC(90)s of micafungin against clinically important Candida and Aspergillus species.


Assuntos
Antifúngicos/sangue , Antifúngicos/farmacocinética , Queimaduras/tratamento farmacológico , Equinocandinas/sangue , Equinocandinas/farmacocinética , Lipopeptídeos/sangue , Lipopeptídeos/farmacocinética , Micoses/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Antifúngicos/administração & dosagem , Queimaduras/complicações , Queimaduras/metabolismo , Equinocandinas/administração & dosagem , Feminino , Humanos , Lipopeptídeos/administração & dosagem , Masculino , Micafungina , Pessoa de Meia-Idade , Micoses/microbiologia , Adulto Jovem
13.
J Infect Chemother ; 17(5): 731-4, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21537970

RESUMO

The distribution of micafungin (MCFG) in tissue fluids, such as cerebrospinal fluid (CSF), pleural effusions, ascites, and wound tissue fluids, was examined in seven patients with invasive fungal infections. MCFG (100-300 mg) was administered once daily over a 1-h intravenous infusion. Blood and tissue fluid samples were collected from 1 to 24 h after infusion. Although two patients had similar MCFG concentrations in their plasma, the concentrations in the CSF differed between these two patients. The concentration in the CSF of one patient was much higher than the MIC(90) for Candida albicans, Candida glabrata, and Aspergillus fumigatus, whereas the MCFG concentration in the CSF of the other patient was comparable to the MIC(90). By contrast, MCFG concentrations in pleural effusions, ascites, and wound tissue fluids were above the MIC(90). These results suggest that intravenous MCFG may be effective to treat invasive fungal infections that invade the organs and tissues.


Assuntos
Antifúngicos/farmacocinética , Equinocandinas/farmacocinética , Lipopeptídeos/farmacocinética , Micoses/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/sangue , Antifúngicos/líquido cefalorraquidiano , Antifúngicos/uso terapêutico , Ascite/metabolismo , Líquidos Corporais/metabolismo , Equinocandinas/sangue , Equinocandinas/líquido cefalorraquidiano , Equinocandinas/uso terapêutico , Feminino , Humanos , Lipopeptídeos/sangue , Lipopeptídeos/líquido cefalorraquidiano , Lipopeptídeos/uso terapêutico , Masculino , Micafungina , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Derrame Pleural/metabolismo , Distribuição Tecidual
14.
Anticancer Res ; 41(12): 6003-6012, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34848454

RESUMO

BACKGROUND/AIM: Pancreatic cancer, which exhibits resistance to cytotoxic and molecular targeted drugs, has an extremely poor prognosis. Nuclear factor-κB (NF-κB) is constitutively activated in many pancreatic cancer cases. Although the NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has exhibited anti-cancer effects in pancreatic cancer models, its poor solubility limits its use to intraperitoneal administration. MATERIALS AND METHODS: Poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB) forms stable polymer aggregates with DHMEQ. The stability of DHMEQ aggregated with PMB in the human blood was measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS) ex vivo. Anti-pancreatic cancer effects in AsPC-1 and MIA PaCa-2 pancreatic cancer cells were evaluated by cell growth inhibition assay in vitro and tumor growth inhibition assay in vivo. RESULTS: DHMEQ aggregated with PMB (PMB-DHMEQ) remained detectable after 60 min of incubation in the human blood, whereas DHMEQ aggregated with carboxymethyl cellulose (CMC-DHMEQ) was barely detectable. PMB-DHMEQ significantly inhibited AsPC-1 and MIA PaCa-2 cell growth in vitro compared to CMC-DHMEQ. Intravenous administration of PMB-DHMEQ reduced the tumor volume and liver metastasis compared to untreated or CMC-DHMEQ-treated mice. CONCLUSION: Aggregation with PMB improved the solubility of DHMEQ, and effectively inhibited pancreatic cancer cell growth both in vitro and in vivo.


Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Cicloexanonas/administração & dosagem , Polímeros , Inibidores de Proteínas Quinases/administração & dosagem , Administração Intravenosa , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzamidas/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexanonas/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Estrutura Molecular , Polímeros/química , Inibidores de Proteínas Quinases/química , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Antimicrob Agents Chemother ; 53(10): 4559-62, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19687246

RESUMO

We have evaluated the antifungal activity of micafungin in serum by using the disk diffusion method with serum-free and serum-added micafungin standard curves. Serum samples from micafungin-treated patients have been shown to exhibit adequate antifungal activity, which was in proportion to both the applied dose and the actual concentration of micafungin measured by high-performance liquid chromatography. The antifungal activity of micafungin in serum was also confirmed with the broth microdilution method.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Equinocandinas/farmacologia , Lipopeptídeos/farmacologia , Soro/microbiologia , Adulto , Antifúngicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Equinocandinas/farmacocinética , Feminino , Humanos , Lipopeptídeos/farmacocinética , Masculino , Micafungina , Pessoa de Meia-Idade , Adulto Jovem
16.
Biomed Chromatogr ; 23(3): 267-72, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18814192

RESUMO

Therapeutic drug monitoring of sirolimus (rapamycin) is important for immunosuppressive therapy in solid organ transplantation. We have developed a simple and reliable method for determining blood concentrations of sirolimus using reversed-phase HPLC with electrochemical detection (ECD). The E(2) potential was set at +900 mV. The potential of guard cell was set at +950 mV and that of the E(1) cell at +400 mV. The method was linear for a concentration range of 1-50 ng/mL when 0.5 mL blood was used. The correlation coefficients of all standard curves were greater than or equal to 0.999. The limit of detection was 0.5 ng/mL. The inter-assay precision ranged from 3.22 to 7.48%, and the coefficient of variation (CV) for a quality control sample at 10 ng/mL was 7.48% with a bias of 8.4% from the target value. The intra-assay precision ranged from 0.72 to 3.71%, and the CV for a quality control sample at 10 ng/mL was 0.72% with a bias of 6.8% from the target value. In a solid organ transplant recipient, trough concentrations of sirolimus were well within the analytic range of the HPLC/ECD procedure. The method described here is suitable for management of sirolimus therapy in solid organ transplantation.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Técnicas Eletroquímicas/métodos , Imunossupressores/sangue , Sirolimo/sangue , Monitoramento de Medicamentos/métodos , Análise dos Mínimos Quadrados , Modelos Lineares , Modelos Químicos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tacrolimo/análogos & derivados , Tacrolimo/análise
17.
Pharmacol Rep ; 71(2): 276-281, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826567

RESUMO

BACKGROUND: Phenoconversion is a phenomenon whereby some genotypic extensive metabolizers transiently exhibit drug metabolizing enzyme activity at similar level as that of poor metabolizers. Renal failure is known to decrease CYP3A activity in humans. Indoxyl sulfate, parathyroid hormone (PTH), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have been reported to cause CYP3A downregulation in renal failure. We measured plasma concentrations of the above compounds in stable kidney transplant recipients, and evaluated their relations with phenoconversion of CYP3A evaluated by plasma concentration of 4ß-hydroxycholesterol, a biomarker of CYP3A activity. Phenoconversion was defined as a genotypic extensive/intermediate metabolizer exhibiting CYP3A activity below the cutoff value that discriminates extensive/intermediate from poor metabolizers. METHODS: Sixty-three Japanese kidney transplant recipients who underwent transplantation more than 180 days prior to the study were included. Morning blood samples were collected, and CYP3A5 polymorphism as well as plasma concentrations of 4ß-hydroxycholesterol, indoxyl sulfate, intact-PTH, IL-6 and TNF-α were determined. RESULTS: Significantly higher plasma 4ß-hydroxycholesterol concentration was observed in recipients with CYP3A5*1 allele (n = 23) compared to those without the allele (n = 40), and the cut-off value was 40.0 ng/mL. Ten recipients with CYP3A5*1 allele exhibited CYP3A activity below 40.0 ng/mL (phenoconversion). Only plasma indoxyl sulfate concentration was significantly higher in recipients with CYP3A phenoconversion compared to those without phenoconversion. CONCLUSIONS: These findings suggest that higher plasma indoxyl sulfate concentration may be involved in CYP3A phenoconversion. Dose adjustment of drugs metabolized by CYP3A may be needed in patients with CYP3A5*1 allele and high blood indoxyl sulfate.


Assuntos
Citocromo P-450 CYP3A/genética , Hidroxicolesteróis/metabolismo , Indicã/sangue , Transplante de Rim , Adulto , Idoso , Alelos , Citocromo P-450 CYP3A/metabolismo , Feminino , Genótipo , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Polimorfismo Genético , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-18620910

RESUMO

We have developed a simple and reliable method for determining plasma concentration of dehydroxymethylepoxyquinomicin (DHMEQ), a new low molecular weight NF-kappaB inhibitor, using high performance liquid chromatography with mass spectrometry (LC-MS). An experiment of mass spectrometry with electrospray ionization in the negative ionization mode was performed to detect ion transitions at m/z 260.05 [M-H](-) for DHMEQ and 240.29 for mefenamic acid as an internal standard. The samples were purified using liquid-liquid extraction with ethyl acetate. The method yielded a standard curve which was linear for the concentration range of 0.1-125 ng/mL when 0.05 mL plasma was used. The correlation coefficients of all standard curves were greater than or equal to 0.999. The limit of detection was 50 pg/mL (signal/noise >3). Daily fluctuation of plasma standard curve was small. The intra- and inter-assay precision ranged from 2.84 to 4.76% (n=6) and 2.91 to 7.03% (n=6), respectively. The LC-MS technique described provides a simple and reliable liquid chromatographic method for the determination of DHMEQ level and for use in studies involving pharmacokinetics.


Assuntos
Benzamidas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Cicloexanonas/sangue , Espectrometria de Massas/métodos , Animais , Calibragem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Eur J Drug Metab Pharmacokinet ; 33(3): 191-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19007046

RESUMO

The plasma concentration of micafungin (MCFG) after intravenous infusion of MCFG at 150 or 300 mg/day over 1 hour to 49 patients with hematologic malignancies were determined, and the relationship between the plasma concentrations and the patients' laboratory parameters of liver and kidney function was analyzed. Plasma samples were obtained at the end of the initial administration of MCFG, 5 to 6 hours after the start of the initial administration, immediately before the second dosing, immediately before the fourth dosing, and the end of the fourth dosing. The plasma concentration of MCFG was measured by high performance liquid chromatography. The plasma concentration of MCFG was correlated with the doses of MCFG per kilogram body weight. The peak concentration after the initial administration was 3.8 times higher than the trough level after the initial administration. The steady-state peak and trough levels were 1.4-1.5 times higher than those after the initial administration. There was no correlation between the laboratory parameters of liver/kidney function and the dose-normalized plasma concentration of MCFG. These results suggest that MCFG can be administered safely to patients with liver or kidney dysfunction without adjusting the dose.


Assuntos
Antifúngicos/farmacocinética , Equinocandinas/farmacocinética , Neoplasias Hematológicas , Rim , Lipopeptídeos/farmacocinética , Fígado , Adulto , Idoso , Antifúngicos/sangue , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Equinocandinas/sangue , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Testes de Função Renal , Lipopeptídeos/sangue , Fígado/efeitos dos fármacos , Testes de Função Hepática , Masculino , Micafungina , Pessoa de Meia-Idade , Micoses/complicações , Micoses/prevenção & controle , Albumina Sérica/análise
20.
Yakugaku Zasshi ; 128(8): 1209-14, 2008 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-18670187

RESUMO

BACKGROUND: The carboplatin (CBDCA) dosage is usually calculated using the formula of Calvert. Instead of the glomerular filtration rate (GFR), 24-h creatinine clearance (24 CLcr) is often used in this formula, which is calculated based on 24-h urine collection in clinical practice. OBJECTIVE: We studied the adequacy of 24 CLcr in calculating the appropriate dosage of CBDCA using the formula of Calvert and compared CLcr and GFR using various substitutable predictive formulas (the formulae of Cockcroft and Gault, Yasuda, Orita, Jellife, Mawer, MDRD, and modified MDRD) when we were not able to use 24 CLcr. METHODOLOGY: We retrospectively studied 193 patients who received CBDCA as chemotherapy during the period April 2004 through November 2006. We evaluated the adequacy of 24-h urine collection for measurement of creatinine production and excretion. We also evaluated the appropriate urine collection within a 15% range of the difference. The correlation between the appropriate 24 CLcr resulting in the urine collection and the CLcr or GFR was examined using past predictive formulae in the patients with appropriate urine collection. RESULTS: The accuracy of 24 CLcr was evaluated in 83 patients (43%). There was a significant correlation between CLcr or GFR using various predictive formulas and the appropriate 24 CLcr. There was an especially close and significant correlation with the formulae of Cockcroft and Gault and Yasuda (r>0.950, p<0.001). CONCLUSION: When using the Calvert formula, the accuracy of 24 CLcr should be evaluated. Patients evaluated as having inaccurate urinary collection should use the formulae of Cockcroft and Gault and Yasuda.


Assuntos
Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Creatinina/urina , Monitoramento de Medicamentos/métodos , Taxa de Depuração Metabólica , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Estudos Retrospectivos
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