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1.
Drug Des Devel Ther ; 13: 3281-3290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571830

RESUMO

Background: Ovarian cancer is the third leading cause of death among gynecological cancers in women in China. Chemotherapy is an important method for comprehensive treatment of ovarian cancer, but the curative effect is poor. Purpose: In this study, gemcitabine (GEM) -loaded RGD modified liposomes (LPs) were developed by the emulsification-solvent evaporation method and evaluated for their antitumor activity in vitro and in vivo. Methods: The physicochemical properties of LPs such as particle size, zeta potential and in vitro drug release were investigated. We also demonstrated the effect of RGD-GEM-PEG LPs in ovarian cancer. Results: RGD-PEG3500-DSPE GEM LPs had a uniform spherical morphology. The mean particle size and polydispersity index were determined to be 106.7 nm and 0.13 respectively. The ER% and DL% of the formulation were 79.6±3.1% and 6.1±1.4% respectively. Compared with the free drug, RGD modified GEM LPs had sustained-release properties in vitro. In vivo, compared with the DiD-RGD-PEG3500-DSPE GEM LPs group, free DiD-GEM and DiD-GEM LPs had no obvious fluorescence intensity in tumor of mice at all times, indicating that ordinary liposomes and drugs had no tumor targeting function. RGD-PEG3500-DSPE GEM LPs showed a superior antiproliferative effect on SKOV3 cells and had a better antitumor effect in vivo than non-modified LPs. Conclusion: These results indicated that RGD-PEG3500-DSPE GEM LPs were a promising candidate for antitumor drug delivery.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , China , Desoxicitidina/administração & dosagem , Desoxicitidina/metabolismo , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Lipossomos/química , Lipossomos/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Oligopeptídeos , Tamanho da Partícula , Ratos
2.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1126-1127: 121770, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31454720

RESUMO

Purine analogs like aracytine (AraC) are a mainstay for treating acute myeloid leukemia (AML). There are marked differences in drug dosing and scheduling depending on the protocols when treating AML patients with AraC. Large inter-patient pharmacokinetics variability has been reported, and genetic polymorphisms affecting cytidine deaminase (CDA), the liver enzyme responsible for the conversion of Ara-C to inactive uracil arabinoside (AraU) could be a culprit for either life-threatening toxicities or poor efficacy related to substantial changes in plasma exposure levels among patients. The quantitative determination of Ara-C in plasma is challenging due the required sensitivity because of the short half-life of this drug (i.e., <10 min) and the metabolic instability in biological matrix upon sampling possibly resulting in erratic values. We developed and validated a liquid chromatography tandem mass spectrometry method (UPLC-MS/MS) for the simultaneous determination of Ara-C and Ara-U metabolite in human plasma. After simple and rapid precipitation, analytes were successfully separated and quantitated over a 1-500 ng/ml range for Ara-C and 250-7500 ng/ml range for AraU. The performance and reliability of this method was tested as part of an investigational study in AML patients treated with low dose cytarabine and confirmed marked differences in drug exposure levels and metabolic ratio, depending on the CDA status of the patients. Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in AML patients with respect to their CDA phenotypes.


Assuntos
Antimetabólitos Antineoplásicos/sangue , Arabinofuranosiluracila/sangue , Cromatografia Líquida de Alta Pressão/métodos , Citarabina/sangue , Espectrometria de Massas em Tandem/métodos , Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Arabinofuranosiluracila/metabolismo , Arabinofuranosiluracila/farmacocinética , Arabinofuranosiluracila/uso terapêutico , Citarabina/metabolismo , Citarabina/farmacocinética , Citarabina/uso terapêutico , Monitoramento de Medicamentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Modelos Lineares , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
3.
Cancer Sci ; 110(9): 2933-2940, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278877

RESUMO

Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF-10832 as liposome-encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF-10832 with those of gemcitabine. Despite the single intravenous administration, FF-10832 treatment enabled long-term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF-10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome-encapsulated gemcitabine FF-10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Ascite/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Peritoneais/tratamento farmacológico , Peritônio/patologia , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Ascite/etiologia , Linhagem Celular Tumoral/transplante , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Estimativa de Kaplan-Meier , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Distribuição Tecidual , Resultado do Tratamento
4.
Int J Clin Pharmacol Ther ; 57(8): 402-407, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31232278

RESUMO

OBJECTIVE: To investigate the population pharmacokinetics of delayed methotrexate (MTX) excretion in children with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: A total of 1,659 plasma concentration samples of MTX from 190 patients with 1 - 4 courses (plasma concentrations > 0.1 µmol/L) were collected in this study. The data analysis was performed using Phoenix NLME 1.3 software. The covariates included age, body surface area (BSA), body weight, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), total bilirubin (TBIL), and serum creatinine (SCr). The final model was validated by bootstrap resampling procedures (1,000 runs) and visual predictive check (VPC) method. RESULTS: The data were best described by a two-compartment linear pharmacokinetic model. The mean values of clearance (CL) and distribution volume (Vd) of MTX were 6.53 L/h and 67.88 L, respectively. Analysis of covariates showed that BSA influenced the CL of MTX. CONCLUSION: The final model was demonstrated as appropriate and effective for assessing the pharmacokinetic parameters of delayed MTX excretion in children with ALL.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Aspartato Aminotransferases/metabolismo , Bilirrubina/sangue , Criança , Creatinina/sangue , Humanos
5.
AAPS PharmSciTech ; 20(5): 171, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004239

RESUMO

The aim of this study was to incorporate methotrexate (MTX) into ultra-permeable niosomal vesicles, containing cremophor RH40 as an edge activator (EA) and polyvinyl alcohol (PVA) as a stabilizer to enhance the drug permeation. Formulae were prepared by ethanol injection method following a Box-Behnken design in order to optimize the formulation variables (EA%, stabilizer %, and sonication time). To investigate the role of both cremophor RH40 and PVA, conventional MTX niosomes and MTX niosomes containing PVA only were fabricated. Drug entrapment efficiency percent (EE%), particle size (PS) analysis, zeta potential (ZP) measurements, and transmission electron microscopy (TEM) were conducted to characterize the vesicles. Cell viability studies and ex vivo permeation experiments of the optimized formula were conducted. Lastly, in vivo skin deposition of MTX from both the optimized formula and MTX solution was performed in rats. Besides, histopathological changes in rat skin were assessed. The optimized MTX ultra-permeable niosomal formula demonstrated spherical morphology, with an EE% of 65.16% and a PS of 453.6 nm. The optimized formula showed better physical stability in comparison with that of the same composition but lacking PVA. The cell viability studies verified the superior cytotoxicity of the optimized formula, and the ex vivo permeation studies revealed its ability to improve the drug permeation. The optimized formula demonstrated a significant deposition of MTX in rat dorsal skin, and histopathological evaluation confirmed the tolerability of the optimized formula in rats upon topical application. Accordingly, ultra-permeable noisomes, as a stable nanosystem, could be promising for effective delivery of MTX.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Administração Tópica , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Lipossomos , Masculino , Metotrexato/efeitos adversos , Tamanho da Partícula , Ratos , Ratos Wistar , Absorção Cutânea
6.
Biomed Pharmacother ; 112: 108725, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970523

RESUMO

Glucarpidase, also known as carboxypeptidase G2, is a Food and Drug Administration-approved enzyme used in targeted cancer strategies such as antibody-directed enzyme prodrug therapy (ADEPT). It is also used in drug detoxification when cancer patients have excessive levels of the anti-cancer agent methotrexate. The application of glucarpidase is limited by its potential immunogenicity and limited catalytic efficiency. To overcome these pitfalls, mutagenesis was applied to the glucarpidase gene of Pseudomonas sp. strain RS-16 to isolate three novels "biobetter" variants with higher specific enzyme activity. DNA sequence analysis of the genes for the variants showed that each had a single point mutation, resulting in the amino acid substitutions: I100 T, G123S and T239 A. Km, Vmax and Kcat measurements confirmed that each variant had increased catalytic efficiency relative to wild type glucarpidase. Additionally, circular dichroism studies indicated that they had a higher alpha-helical content relative to the wild type enzyme. However, three different software packages predicted that they had reduced protein stability, which is consistent with having higher activities as a tradeoff. The novel glucarpidase variants presented in this work could pave the way for more efficient drug detoxification and might allow dose escalation during chemotherapy. They also have the potential to increase the efficiency of ADEPT and to reduce the number of treatment cycles, thereby reducing the risk that patients will develop antibodies to glucarpidase.


Assuntos
Desenho de Fármacos , Pró-Fármacos , Pseudomonas putida/genética , gama-Glutamil Hidrolase/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Clonagem Molecular , Estabilidade Enzimática , Terapia Enzimática/métodos , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Mutação Puntual , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , gama-Glutamil Hidrolase/imunologia , gama-Glutamil Hidrolase/uso terapêutico
7.
Int J Nanomedicine ; 14: 2091-2102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988610

RESUMO

Background: Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%-80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. Methods: Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. Results: Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. Conclusion: Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics.


Assuntos
Decitabina/administração & dosagem , Decitabina/química , Leucemia Eritroblástica Aguda/tratamento farmacológico , Lipídeos/química , Nanocápsulas/administração & dosagem , Plasma/metabolismo , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Ciclo Celular , Proliferação de Células , Decitabina/farmacocinética , Estabilidade de Medicamentos , Humanos , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patologia , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual , Células Tumorais Cultivadas
8.
Curr Pharm Des ; 25(6): 627-634, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931851

RESUMO

BACKGROUND: Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment. METHODS: We searched PubMed for citations published in English using the terms "methotrexate", "transporter", "acute lymphoblastic leukemia", "polymorphisms", and "therapeutic drug monitoring". The retrieval papers were critically reviewed and summarized according to the aims of this mini-review. RESULTS: Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied. CONCLUSION: Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Metotrexato/farmacologia , Transportadores de Ânions Orgânicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Humanos , Metotrexato/uso terapêutico , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
9.
Expert Opin Investig Drugs ; 28(4): 311-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30879349

RESUMO

INTRODUCTION: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Citidina/análogos & derivados , Neoplasias/tratamento farmacológico , Administração Oral , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/farmacologia , Disponibilidade Biológica , Citidina/farmacocinética , Citidina/farmacologia , Citidina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Humanos , Neoplasias/patologia , Seleção de Pacientes
10.
AAPS PharmSciTech ; 20(4): 149, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30903402

RESUMO

To prepare the cocrystals of 5-fluorouracil (5-FU) with GRAS status coformers via a cocrystallization technique with an aim to improve physicochemical properties as well as bioavailability for colon cancer, breast cancer, and prostate cancer. The mechanochemical method was used in the preparations of three crystals of 5-FU with gentisic acid (5-FUGA), 3,4-dihydroxybenzoic acid (5-FUBA), and 4-aminopyridine (5-FUPN). A thermoanalytical and spectroscopic technique was used for their characterization. Their biological evaluation was done in different cancer cell lines. The new solid pure crystal forms were characterized by DSC, FTIR, and PXRD. The crystal structure was determined from single crystal and PXRD that exposed the existence of the monoclinic and triclinic crystal system with P21/n and P-1 space groups. The dermatokinetic studies on the rat skin revealed two- to threefold improvement in relative bioavailability as compared to pure 5-FU. "MTT assay was performed by varying the concentrations of the drug from 1 to 50 µg mL-1. After 24 h, the cell viability dropped to 70.67%, 74.05%, and 76.37% in MCF-7, Hela, and Caco-2 cell lines when the concentration of 5-FU was 50 µg mL-1", while it dropped dramatically in cocrystals 5-FUGA (22.06%, 24.63%, and 25.61%), 5-FUBA (31.22%, 29.46%, and 32.81%), and 5-FUPN (21.65%, 32.64%, and 21.46%). All the results indicated that 5-FU cocrystals possess better antitumor efficacy than free drug. Thus, cocrystallization expands the extent of the existing pre-formulation options ahead of pure API form to ameliorate the bioavailability and permeability.


Assuntos
Antimetabólitos Antineoplásicos/química , Fluoruracila/química , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Disponibilidade Biológica , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Cristalografia por Raios X , Fluoruracila/farmacocinética , Humanos , Masculino , Permeabilidade , Difração de Pó , Ratos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Mol Pharm ; 16(5): 1813-1826, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30883132

RESUMO

The plasticity of cancer epigenetics makes them plausible candidates for therapeutic intervention. We took advantage of elevated expression of lysophosphatidic acid receptor 1 (LPAR1) in triple negative breast cancer (TNBC) tissues to target decitabine (DAC) and panobinostat (PAN) to breast cancer cells. DAC and PAN were shown to reverse abnormal methylation of DNA and altered chromatin structure, respectively, leading to increased expression of tumor suppressor genes and decreased expression of oncogenes. Although DAC and PAN have therapeutic benefits, they are limited by chemical instability and systemic toxicity. Herein, we present LPAR1-targeted, lipid nanoemulsions (LNEs) encapsulating both DAC and PAN. Our results demonstrated that the cell uptake and in vivo biodistribution of LNEs was dependent on LPAR1 expression in TNBCs. DAC/PAN-LNEs were effective in inhibiting the growth of mesenchymal breast cancer cells by restoring CDH1/E-cadherin and suppressing forkhead box M1 (FOXM1) expression. Epithelial breast cancer cells that inherently express low FOXM1 and high CDH1 were unaffected by DAC/PAN-LNEs. Overall, we successfully designed LPAR1-targeted LNEs that selectively act on CDH1(low)/FOXM1(high) TNBC cell lines.


Assuntos
Antígenos CD/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Caderinas/metabolismo , Decitabina/farmacocinética , Proteína Forkhead Box M1/metabolismo , Lipídeos/química , Nanocápsulas/química , Panobinostat/farmacocinética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Decitabina/uso terapêutico , Desenho de Fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Panobinostat/uso terapêutico , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Neoplasias de Mama Triplo Negativas/patologia
12.
J Chemother ; 31(1): 30-34, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30773130

RESUMO

Delayed elimination of plasma methotrexate (MTX), which leads to elevated toxicity, is often observed in patients receiving high-dose methotrexate (HD-MTX) therapy, despite of the preventive measures. In this study, we investigated the factors that delay elimination of plasma MTX in patients on HD-MTX therapy. Fifteen patients who received HD-MTX therapy (21 cycles) were classified into two groups: delayed elimination of plasma MTX (38.1%, 8/21) and normal elimination of plasma MTX (61.9%, 13/21). Patient characteristics, plasma MTX concentrations, laboratory values, and adverse reactions were compared between the two groups using Fisher's exact test. Univariate analysis showed that co-administration of calcium channel blockers was significantly associated with delayed elimination of plasma MTX (p = 0.042). This is the first report demonstrating that co-administration of calcium channel blockers may be a predictive factor of delayed elimination of plasma MTX in patients receiving HD-MTX therapy.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Metotrexato/farmacocinética , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Interações Medicamentosas , Feminino , Humanos , Linfoma/tratamento farmacológico , Masculino , Metotrexato/administração & dosagem , Metotrexato/sangue , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Eur J Pharm Sci ; 130: 44-53, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30660800

RESUMO

The magadiite (MAG) was modified by cetyltrimethyl ammonium-Bromide (CTAB) and then further modified by Chitosan (CS) which is called organic modified-magadiite as magadiite-cetyltrimethyl ammonium bromide (MAG-CTAB) and magadiite-cetyltrimethyl ammonium bromide-Chitosan (MAG-CTAB-CS), respectively, in this research study. The MAG, MAG-CTAB, and MAG-CTAB-CS were used as 5-Fluorouracil (5-FU) drug carrier materials; the drug carrier's materials were marked as magadiite-5-Fluorouracil (MAG/5-FU), magadiite-cetyltrimethyl ammonium bromide-5-Fluorouracil (MAG-CTAB/5-FU), and magadiite-cetyltrimethyl ammonium bromide-Chitosan (MAG-CTAB-CS/5-FU). X-ray diffraction(XRD, Flourier transform infrared spectrometry (FTIR) and scanning electron microscopy (SEM) results were shown that 5-Fluorouracil was combined with carrier materials through physical apparent adsorption, ion exchange, chemical bond, hydrogen bond, and electrostatic interaction. The drug carriers in vitro release behavior in simulated gastric fluids (SGF,pH = 1.35) and intestinal fluids (SIF,pH = 7.40) were investigated. The drug loading capacity and accumulated release ration were as follows the order: MAG-CTAB-CS/5-FU > MAG-CTAB/5-FU > MAG/5-FU. The drug loading capacity of MAG-CTAB-CS/5-FU was 162.29 mg/g, 48 h later the drug accumulated release ratio was 61.24%, and the release amount was 97.52 mg/g for 24 h. Korsmeyer-Peppas model and First order model were found to be suitable to describe the vitro release behavior of 5-Fluorouracil. This would be an economically viable and efficient method for the preparation of advanced drug delivery system.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Fluoruracila/farmacocinética , Silicatos/farmacocinética , Antimetabólitos Antineoplásicos/química , Portadores de Fármacos/química , Fluoruracila/química , Silicatos/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
14.
Int J Pharm ; 557: 293-303, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30599225

RESUMO

Molecularly imprinted polymers (MIPs) have drawn extensive attention as carriers on drug delivery. However, most of MIPs suffer from insufficient drug loading capacity, burst release of drugs and/or low bioavailability. To solve the issues, this study designed an imprinted material with superior floating nature for oral drug delivery system of capecitabine (CAP) rationally. The MIPs was synthesized in the presence of 4-methylphenyl dicyclohexyl ethylene (liquid crystalline, LC) and polyhedral oligomeric silsesquioxanes (POSS) via polymerization reaction. The LC-POSS MIPs had extended release of the template molecules over 13.4 h with entrapment efficiency of 20.53%, diffusion coefficient of 2.83 × 10-11 cm2 s-1, and diffusion exponent of 0.84. Pharmacokinetic studies further revealed the prolong release and high relative bioavailability of CAP in vivo of rats, showing the effective floating effect of the LC-POSS MIPs. The in vivo images revealed visually that the gastroretentive time of the LC-POSS MIPs was longer than non-LC-POSS imprinted polymers. The physical characteristics of the polymers were also characterized by nitrogen adsorption experiment, scanning electron microscopy, thermogravimetric analysis and differential scanning calorimetry analysis. As a conclusion, the LC-POSS MIPs can be used as an eligible CAP carrier and might hold great potential in clinical applications for sustained release drug.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Impressão Molecular , Compostos de Organossilício/administração & dosagem , Polímeros/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/química , Capecitabina/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Humanos , Cristais Líquidos/química , Células MCF-7 , Masculino , Modelos Moleculares , Compostos de Organossilício/química , Compostos de Organossilício/farmacocinética , Polímeros/química , Polímeros/farmacocinética , Ratos Wistar
15.
Cancer Chemother Pharmacol ; 83(2): 349-360, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30488179

RESUMO

PURPOSE: High-dose methotrexate (HDMTX) is critical to the successful treatment of pediatric acute lymphoblastic leukemia (ALL) but can cause significant toxicities. This study prospectively evaluated the effectiveness of a fixed algorithm which requires no real-time pharmacokinetic modeling and no previous patient exposure to HDMTX, to individualize HDMTX dosing for at-risk patients with the aim of avoiding methotrexate-related toxicities. METHODS: We developed a simple algorithm to individualize HDMTX infusions with 0-2 rate adjustments based on methotrexate levels during the infusion. This was a prospective, open-label, study; eligible patients were identified and referred by their oncologist. RESULTS: Fifty-four evaluable cycles of HDMTX (5 g/m2 over 24 h) were administered to 22 patients. Blood samples were obtained in 21 patients to examine single nucleotide polymorphisms (SNPs) related to methotrexate disposition. Twelve (54.5%) subjects had a history of previous HDMTX toxicities including seven (31.8%) who previously required glucarpidase rescue and seven (31.8%) with an entry glomerular filtration rate < 80 ml/min/1.73 m2. 107/110 (97.2%) of methotrexate levels were drawn properly and 100% of algorithm dosing instructions were performed correctly at the bedside. Thirty-five (64.8%) of all cycles and 24 of 33 (72.7%) cycles that required a dose-adjustment had an end 24-h methotrexate level (Cpss) within our goal range of 65 ± 15 µM with only 3 (5.6%) resulting in Cpss higher than goal. Grade 3/4 toxicities were rare; no patients developed > Grade 1 acute kidney injury. CONCLUSION: This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL. CLINICALTRIALS. GOV REGISTRY: NCT02076997.


Assuntos
Algoritmos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Distribuição Tecidual , Adulto Jovem
16.
Invest New Drugs ; 37(3): 507-518, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30511200

RESUMO

Background This first-in-human phase 1 study assessed the safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 to determine its maximum tolerated dose (MTD) and recommended dose (RD). Methods In this dose-escalation study with a 3 + 3 design, TAS-114 and S-1 were concurrently administered orally under fasting conditions at 5-240 mg/m2 and 30-36 mg/m2, respectively, in patients with advanced solid tumors. Safety, efficacy, and pharmacokinetics (PK) were evaluated. Results Seventy-six patients were enrolled. The MTD and RD were TAS-114 200 mg/m2 plus S-1 36 mg/m2 and TAS-114 240 mg/m2 plus S-1 30 mg/m2, respectively. Common treatment-related adverse events were anemia, lymphocytopenia, leukopenia, neutropenia, decreased appetite, rash, nausea, and pigmentation disorder. Partial response (PR) was observed in 10 patients (non-small cell lung cancer [NSCLC], n = 5; pancreatic neuroendocrine tumor, n = 2; gastric cancer, n = 2; gallbladder cancer, n = 1). Of these, four patients achieved PR despite prior treatment history with S-1. Patients administered TAS-114 exhibited linear PK and CYP3A4 induction, with no effect on the PK of S-1. Conclusion TAS-114 plus S-1 showed tolerable, safe, and potentially effective results. To confirm safety and efficacy, two phase 2 studies are ongoing in NSCLC and gastric cancer patients. Clinical trial registration ClinicalTrials.gov ( NCT01610479 ) .


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Pirofosfatases/antagonistas & inibidores , Tegafur/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacocinética , Combinação de Medicamentos , Quimioterapia Combinada , Inibidores Enzimáticos/farmacocinética , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Ácido Oxônico/farmacocinética , Prognóstico , Tegafur/farmacocinética , Distribuição Tecidual
17.
Ther Drug Monit ; 41(1): 75-85, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30507626

RESUMO

BACKGROUND: Concentrations of 6-thioguanine (6TG) nucleotides and 6-methylmercaptopurine (6MMP) nucleotides in RBCs were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay was validated for clinical use and was applied to blood samples from patients taking mercaptopurine (6MP). METHODS: RBCs were hemolyzed and deproteinized using perchloric acid, followed by heating for the hydrolysis of nucleotides, and the resultant base was measured using LC-MS/MS. Precision, recovery, linearity, matrix effect, and limit of quantification was validated for clinical application. Our results were compared with another institution's established LC-MS/MS assay. We measured the concentrations of 6TG and 6MMP in RBCs of pediatric patients with acute lymphoblastic leukemia (ALL), and the clinical impact of those metabolites was investigated. RESULTS: The imprecision coefficient of variations of 6TG and 6MMP were 5.7%-8.1%, and the bias was within 5%. Lower limits of quantification were set at 54 ng/mL for 6TG and 1036 ng/mL for 6MMP. Correlation coefficients for 6TG and 6MMP were 0.997 and 1.0 in a comparison study. For clinical proof-of-concept, 74 blood samples were collected from 37 pediatric ALL patients receiving maintenance therapy. Concentration of 6TG ranged from 16.1 to 880 pmol/8 × 10 RBCs and that of 6MMP from 55 to 20,937 pmol/8 × 10 RBCs. The 6MP metabolites were not correlated with WBC or absolute neutrophil count. On the other hand, the higher 6MMP level was associated with elevated alanine aminotransferase and aspartate aminotransferase. CONCLUSIONS: In this study, an assay for the quantification of 6TG and 6MMP in RBCs was established and applied to pediatric ALL patients. Interindividual variability in 6MP metabolite concentrations was considerable and associated with elevation of liver enzymes, which may be useful in the clinical monitoring of 6MP maintenance therapy in pediatric ALL patients.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Eritrócitos/efeitos dos fármacos , Nucleotídeos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Tioguanina/farmacocinética , Tioguanina/uso terapêutico , Adolescente , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Cromatografia Líquida/métodos , Eritrócitos/metabolismo , Feminino , Humanos , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/sangue , Mercaptopurina/metabolismo , Nucleotídeos/sangue , Nucleotídeos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Espectrometria de Massas em Tandem/métodos , Tioguanina/sangue
18.
Clin Pharmacol Ther ; 105(5): 1095-1105, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30447069

RESUMO

Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).


Assuntos
Antimetabólitos Antineoplásicos , Azatioprina , Mercaptopurina , Metiltransferases/genética , Pirofosfatases/genética , Tioguanina , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Azatioprina/administração & dosagem , Azatioprina/farmacocinética , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Humanos , Inativação Metabólica/genética , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacocinética , Farmacogenética , Testes Farmacogenômicos , Tioguanina/administração & dosagem , Tioguanina/farmacocinética
19.
J Pharm Biomed Anal ; 164: 16-26, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30366147

RESUMO

DNA hypermethylation is an epigenetic event that is commonly found in malignant cells and is used as a therapeutic target for ß-decitabine (ß-DEC) containing hypomethylating agents (eg Dacogen® and guadecitabine). ß-DEC requires cellular uptake and intracellular metabolic activation to ß-DEC triphosphate before it can get incorporated into the DNA. Once incorporated in the DNA, ß-DEC can exert its hypomethylating effect by trapping DNA methyltransferases (DNMTs), resulting in reduced 5-methyl-2'-deoxycytidine (5mdC) DNA content. ß-DEC DNA incorporation and its effect on DNA methylation, however, have not yet been investigated in patients treated with ß-DEC containing therapies. For this reason, we developed and validated a sensitive and selective LC-MS/MS method to determine total intracellular ß-DEC nucleotide (ß-DEC-XP) concentrations, as well as to quantify ß-DEC and 5mdC DNA incorporation relative to 2'-deoxycytidine (2dC) DNA content. The assay was successfully validated according to FDA and EMA guidelines in a linear range from 0.5 to 100 ng/mL (ß-DEC), 50 to 10,000 ng/mL (2dC), and 5 to 1,000 ng/mL (5mdC) in peripheral blood mononuclear cell (PBMC) lysate. An additional calibrator at a concentration of 0.1 ng/mL was added for ß-DEC to serve as a limit of detection (LOD). Clinical applicability of the method was demonstrated in patients treated with guadecitabine. Our data support the use of the validated LC-MS/MS method to further explore the intracellular pharmacokinetics in patients treated with ß-DEC containing hypomethylating agents.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Azacitidina/análogos & derivados , DNA/química , Decitabina/análise , Desoxicitidina/análogos & derivados , Adulto , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/química , Azacitidina/farmacocinética , Azacitidina/uso terapêutico , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Clínicos Fase II como Assunto , DNA/metabolismo , Metilação de DNA/efeitos dos fármacos , Decitabina/química , Desoxicitidina/análise , Desoxicitidina/química , Humanos , Leucócitos Mononucleares , Limite de Detecção , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
20.
Curr Drug Deliv ; 16(2): 111-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30360740

RESUMO

BACKGROUND: Gemcitabine (GEM) is found effective in the treatment of many solid tumors. However, its use is restricted due to its small circulation half-life, fast metabolism and low capacity for selective tumor uptake. Folate receptors (FRs) have been recognized as cellular surface markers, which can be used for cancer targeting. PEGylated liposomes decorated with folic acid have been investigated for several anticancer agents not only to extend plasma half-life but also for tumor targeting via folic acid receptors which overexpressed on tumor cell surface. OBJECTIVE: Therefore, the objective of the present study was to prepare GEM-loaded folic acid tagged liposomes to improve the pharmacokinetics and tumor distribution of GEM. METHODS: The blank folate-targeted liposomes composed of HSPC/DSPE-mPEG2000/DSPE-mPEG-Folic acid were prepared first by thin film hydration technique. GEM was then loaded into liposomes by remote loading technique. The optimized liposomal formulations were evaluated in vitro for GEM release using dialysis technique, HeLa cell uptake using FACS technique, and cytotoxicity using MTT dye reduction assay. The comparative in vivo pharmacokinetic and biodistribution characteristics of radiolabeled (99mTc-labeled) plain GEM solution, and all liposomal formulations (conventional:CLs; stealth: SLs; folate targeted: FTLs) were evaluated in mice model. RESULTS: GEM-loaded FTLs showed sustained release profile, efficient uptake by HeLa cells and greater cytotoxicity. Further, FTLs displayed significantly improved pharmacokinetics, and biodistribution profile of loaded GEM. CONCLUSION: In conclusion, the developed GEM-loaded folic acid receptor-targeted liposomal formulation could be a promising and potential alternative formulation for further development.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Ácido Fólico/administração & dosagem , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/farmacocinética , Liberação Controlada de Fármacos , Feminino , Ácido Fólico/química , Ácido Fólico/farmacocinética , Células HeLa , Humanos , Lipossomos , Camundongos , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Distribuição Tecidual
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