Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.285
Filtrar
1.
Expert Opin Drug Saf ; 18(11): 1009-1015, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478396

RESUMO

Introduction: Therapeutic drug monitoring in oncology is used to prevent major toxicities of selected anticancer agents due to overexposure by individualizing the dose based on a pharmacokinetic target. Areas covered: Numerous studies relating a relation between pharmacokinetic variability and toxicity have been reported since the eighties but very few have been implemented in clinical practice due to a lack of validation and harmonization, logistical constraints and reluctance from oncologists. Following recent recommendations, this paper highlights the current-validated applications of pharmacokinetic monitoring in oncology focusing on the safety of anticancer therapies. Expert opinion: Paradoxically given the oldness of the agents, guidelines of dose adjustment have been recently available for intravenous busulfan, 5-fluorouracil, and high-dose methotrexate. Interestingly, besides the enhancement of tolerability, it applies to potential curative clinical situations. In an era of personalized oncology that integrates complex molecular factors in the treatment of cancer, education is needed for oncologists to show the benefits of this valuable (even old) resource for the safety of patients. Therapeutic drug monitoring for busulfan, 5-fluorouracil and methotrexate will still hold in the future unless more active agents are available in the concerned indications.


Assuntos
Antineoplásicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Bussulfano/farmacocinética , Relação Dose-Resposta a Droga , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Guias de Prática Clínica como Assunto , Medicina de Precisão/métodos
2.
Bioelectrochemistry ; 130: 107347, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31437809

RESUMO

A multifunctional nanocomposite theranostic system is constructed of manganese oxide (Mn3O4) nanoparticles (NPs), as a tumor diagnostic agent, in conjunction with polyacrylic acid (PAA), as a pH-sensitive drug delivery agent, and methotrexate (MTX), as a model of targeting agent and anticancer drug. Physicochemical characteristics of the Mn3O4@PAA/MTX system is studied in detail by several techniques, including X-ray and Auger photoelectron spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, field-emission scanning electron microscopy, transmission electron microscopy, and electrochemical methods. The system performance is studied based on (i) in-vitro MRI measurements to support efficiency of the Mn3O4@PAA NPs as a diagnostic agent, (ii) drug release performance of the Mn3O4@PAA/MTX NPs at pHs of 5.4 and 7.4 through in-vitro method to evaluate application of the NPs as pH-sensitive nanocarriers for MTX, and (iii) impedance spectroscopy measurements to show Mn3O4@PAA/MTX NPs affinity for capturing of cancer cells. The results show that (i) Mn3O4@PAA NPs can be used as a contrast agent in MRI measurements (r1 ≅ 6.5 mM-1 s-1), (ii) the MTX, loaded on Mn3O4@PAA NPs, is released faster and more efficient at pH 5.4 than 7.4, and (iii) the GC-Mn3O4@PAA/MTX electrode system captures the 4T1 cells 3.32 times larger than L929 cells.


Assuntos
Resinas Acrílicas/química , Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Compostos de Manganês/química , Metotrexato/administração & dosagem , Nanopartículas/química , Óxidos/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Meios de Contraste/química , Liberação Controlada de Fármacos , Feminino , Concentração de Íons de Hidrogênio , Imagem por Ressonância Magnética , Metotrexato/farmacocinética , Metotrexato/farmacologia , Camundongos , Nanomedicina Teranóstica
3.
Int J Nanomedicine ; 14: 4949-4960, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308665

RESUMO

Purpose: The objective of this study was to exploit a novel methotrexate (MTX)-loaded solid self-microemulsifying drug delivery system (SMEDDS) with enhanced bioavailability and photostability. Materials and methods: The optimized liquid SMEDDS was composed of castor oil, Tween® 80, and Plurol® diisostearique at a voluminous ratio of 27:63:10. The solid SMEDDS was formulated by spray drying liquid SMEDDS with the solid carrier (calcium silicate). Particle size analyzer, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy experiments characterized the physiochemical properties of the MTX-loaded solid SMEDDS. These properties include a z-average diameter of emulsion around 127 nm and the amorphous form of the solid SMEDDS. Furthermore, their solubility, dissolution, and pharmacokinetics in Sprague-Dawley rats were analyzed in comparison with the MTX powder. Results: The final dissolution rate and required time for complete release of solid SMEDDS were 1.9-fold higher and 10 min shorter, respectively, than those of MTX powder. Pharmacokinetic analysis demonstrated 2.04- and 3.41-fold increments in AUC and Cmax, respectively in comparison to MTX powder. The AUC and Cmax were significantly increased in solid SMEDDS. Finally, the photostability studies revealed the substantially enhanced photostability of the MTX-loaded SMEDDS under the forced degradation and confirmatory conditions. Conclusion: This solid SMEDDS formulation could be an outstanding candidate for improving the oral bioavailability and photostability of MTX.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Luz , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Metotrexato/sangue , Metotrexato/farmacocinética , Petróleo , Transição de Fase , Ratos Sprague-Dawley , Solubilidade , Difração de Raios X
4.
Pharm Res ; 36(8): 123, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31218557

RESUMO

PURPOSE: This investigation was aimed to explore the targeting potential of folate conjugated double liposomes (fDLs) bearing combination of synergistic drugs (Prednisolone and Methotrexate) for effective management of the rheumatoid arthritis (RA). METHODS: To overcome the drawbacks of monotherapy, a combination of prednisolone (PRD) (an anti-inflammatory agent) and methotrexate (MTX) (a disease modifying anti-rheumatoid agent, DMARDs) was chosen for dual targeting approach. fDLs were prepared in two steps i.e. development of inner liposomes (ILs) using thin film casting method followed by encapsulation of ILs within folate conjugated outer liposomes (double liposomes; fDLs). Developed liposomes were characterized for various physicochemical parameters and in vivo performance. RESULTS: fDLs were prepared using FA-PEG-4000-NH-DSPE conjugate. These double liposomes were having 429.3 ± 3.6 nm in size with 0.109 PDI, 8.01 ± 0.3 mV zeta potential (ζ) and 66.7 ± 3.9% and 45.3 ± 1.7% entrapments of PRD and MTX, respectively. After 24 h, the concentrations of PRD in blood were observed to be 8.66 ± 3.11 (ILs) and 15.13 ± 0.81% (DLs) while concentration of MTX were found to be 10.89 ± 0.69 and 2.34 ± 3.15% when given as ILs and fDLs, respectively. The concentration of both drugs in inflamed joint was observed to be higher than that in the non-inflamed joints. CONCLUSIONS: The folate conjugated double liposomes possess superior targeting efficiency than conjugated and unconjugated single liposomes.


Assuntos
Anti-Inflamatórios/farmacocinética , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Ácido Fólico/química , Lipossomos/química , Metotrexato/farmacocinética , Prednisolona/farmacocinética , Animais , Anti-Inflamatórios/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Quimioterapia Combinada , Humanos , Masculino , Metotrexato/administração & dosagem , Tamanho da Partícula , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Prednisolona/administração & dosagem , Ratos , Propriedades de Superfície , Distribuição Tecidual
5.
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
6.
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
7.
Eur J Pharm Biopharm ; 139: 197-204, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30951819

RESUMO

The purpose of this study was to quantitatively investigate how conjugation of GSH to different liposomal formulations influence the brain delivery of methotrexate (MTX) in rats. GSH-PEG liposomal MTX based on hydrogenated soy phosphatidylcholine (HSPC) or egg yolk phosphatidylcholine (EYPC) and their corresponding PEG control liposomes were prepared. The brain delivery of MTX after intravenously administering free MTX, four liposomal formulations or free MTX + empty GSH-PEG-HSPC liposomes was evaluated by performing microdialysis in brain interstitial fluid and blood. Compared to free MTX with a steady-state unbound brain-to-plasma concentration ratio (Kp,uu) of 0.10, PEG-HSPC liposomes did not affect the brain uptake of MTX, while PEG-EYPC liposomes improved the uptake (Kp,uu 1.5, p < 0.05). Compared to PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX by 4-fold (Kp,uu 0.82, p < 0.05), while GSH-coating on PEG-EYPC liposomes did not result in a further enhancement in uptake. The co-administration of empty GSH-PEG-HSPC liposomes with free MTX did not influence the uptake of MTX into the brain. This work showed that the brain-targeting effect of GSH-PEG liposomal MTX is highly dependent on the liposomal formulation that is combined with GSH, providing insights on formulation optimization of this promising brain delivery platform.


Assuntos
Barreira Hematoencefálica/metabolismo , Glutationa/química , Metotrexato/administração & dosagem , Polietilenoglicóis/química , Animais , Lipossomos , Masculino , Metotrexato/farmacocinética , Microdiálise , Permeabilidade , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Distribuição Tecidual
8.
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 Drogas , 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
9.
Drug Dev Ind Pharm ; 45(7): 1181-1192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30932720

RESUMO

The aim of this investigation is the management of rheumatoid arthritis (RA) by developing methotrexate-loaded calcium phosphate nanoparticles (MTX-CAP-NP) and to evaluate pharmacokinetic and pharmacodynamic behavior in adjuvant induced arthritis model. The nanoparticles were synthesized by wet precipitation method and optimized by Box-Behnken experimental design. MTX-CAP-NPs were characterized by TEM, FTIR, DSC and XRD studies. The particle size, zeta potential and entrapment efficiency of the optimized nanoparticles were found to be 204.90 ± 64 nm, -11.58 ± 4.80 mV, and 88.33 ± 3.74%, respectively. TEM, FTIR, DSC and XRD studies revealed that the developed nanoparticles were nearly spherical in shape and the crystalline structure of CAP-NP was not changed after MTX loading. The pharmacokinetic studies revealed that MTX-CAP-NP enhanced bioavailability of MTX by 2.6-fold when compared to marketed formulation (FOLITRAX-10). Under pharmacodynamic evaluation, arthritic assessment, radiography and histopathology studies revealed that CAP has ability to regenerate cartilage and bone therefore, together with MTX, MTX-CAP-NPs have shown significant reduction in disease progression. The overall work demonstrated that the developed nanodelivery system was well tolerated and more effective than the marketed formulation.


Assuntos
Fosfatos de Cálcio/química , Metotrexato/química , Metotrexato/farmacocinética , Nanopartículas/química , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Portadores de Fármacos/química , Feminino , Metotrexato/farmacologia , Tamanho da Partícula , Ratos , Ratos Wistar
10.
Artif Cells Nanomed Biotechnol ; 47(1): 540-547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30829085

RESUMO

A green and simple process for preparing the polyethylene glycol passivated fluorescent carbon dots (CDs-PEG) have been studied by a microwave pyrolysis method, using gelatin and PEG as starting materials. This method is very effective for development of carbon-based quantum dots from gelatin with high quantum yield (QY). The synthesized CDs-PEG were found to emit blue photoluminescence (PL) with a maximum QY of 34%. At the following research, we investigated the effect of the presence of PEG on PL intensity, and the result showed that CDs-PEG becomes stronger PL properties than pure CDs from gelatin. The synthesized CDs-PEG were characterized by FTIR, TEM, UV-vis, PL, zeta potential and XRD analyses. The anticancer performance of developed CDs-PEG was evaluated by in vitro tests such as MTT assay and fluorescence microscopy analyses. The examination of CDs-PEG as an anti-cancer drug nanocarrier for methotrexate (MTX) illustrated a better antitumor efficacy than free MTX due to its enhanced nuclear delivery in vitro, which resulting in highly effective tumour growth inhibition and improving targeted cancer therapy in clinical medicine.


Assuntos
Carbono , Portadores de Fármacos , Gelatina/química , Metotrexato , Micro-Ondas , Polietilenoglicóis/química , Pontos Quânticos , Carbono/química , Carbono/farmacocinética , Carbono/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Metotrexato/química , Metotrexato/farmacocinética , Metotrexato/farmacologia , Pontos Quânticos/química , Pontos Quânticos/uso terapêutico
11.
Microvasc Res ; 124: 76-90, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30923021

RESUMO

Systemic administration of chemotherapeutic drugs is widely used in the treatment of cancer. However, a good understanding of drug transport barriers that influence the treatment efficacy is still lacking. In this study, a voxelized numerical model based on dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and computational fluid dynamics (CFD) is employed to study the transport and efficacy of three different chemotherapeutic drugs, namely methotrexate, doxorubicin and cisplatin in human brain tumors. DCE-MRI data provides realistic heterogeneous vasculature of the tumor, the permeability of tissue to contrast agent, interstitial volume fraction (porosity) of the tissue and patient-specific arterial input function (AIF). The permeability of tissue to aforementioned drugs is determined by correlating it with the permeability of tissue to the contrast agent. The model is employed to simulate drug concentration in the tissue and compare the effect of heterogeneous vasculature on the distribution of the drugs in the tumor. The drug accumulation is observed to be higher in high permeability areas initially, and in higher porosity areas at later times. Furthermore, it is observed that methotrexate remains in the interstitial space of the tumor in higher concentration for a longer duration as compared to other two drugs, facilitating more tumor cell killing.


Assuntos
Antineoplásicos/metabolismo , Neoplasias Encefálicas/metabolismo , Cisplatino/metabolismo , Doxorrubicina/metabolismo , Metotrexato/metabolismo , Antineoplásicos/farmacocinética , Transporte Biológico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Cisplatino/farmacocinética , Simulação por Computador , Doxorrubicina/farmacocinética , Humanos , Imagem por Ressonância Magnética , Metotrexato/farmacocinética , Modelos Biológicos , Permeabilidade
12.
Biomed Pharmacother ; 112: 108644, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798135

RESUMO

Paeoniflorin-6'-O-benzene sulfonate (CP-25), is a novel derivative of paeoniflorin (Pae) with improved anti-arthritic effects. The aim of this study was to evaluate the therapeutic effects and pharmacokinetics of CP-25 when co-administered with MTX in adjuvant-induced arthritis (AA) rats. AA rats were randomly divided into 6 groups and treated as follows: TGP (50 mg/kg/day, ig), CP-25 (50 mg/kg/day, ig), MTX (0.5 mg/kg, 3 times/week, ig), TGP (50 mg/kg/day, ig) + MTX (0.5 mg/kg, 3 times/week, ig) and CP-25 (50 mg/kg/day, ig) + MTX (0.5 mg/kg, 3 times/week, ig) from days 14 - 35 after induction. Clinical, biochemical, and histological scores were used to assess the severity of arthritis while novel ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) was used to detect plasma concentration of CP-25. Co-administration of CP-25 and MTX significantly reduced clinical signs of inflammation, suppressed the serum production of IL-17 compared to TGP (50 mg/kg/day, ig) and MTX (0.5 mg/kg, 3 times/week, ig). Pharmacokinetics studies showed increased AUC0-t, Cmax, and t1/2 of CP-25 while V/F and CL/F decreased when co-administered with MTX. We observed an increase concentration and longer exposure with decreased clearance of CP-25 when combined with MTX, that should be further explored for clinical RA therapy.


Assuntos
Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Glucosídeos/farmacocinética , Glucosídeos/uso terapêutico , Metotrexato/uso terapêutico , Monoterpenos/farmacocinética , Monoterpenos/uso terapêutico , Administração Oral , Animais , Anti-Inflamatórios/sangue , Área Sob a Curva , Artrite Experimental/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Glucosídeos/sangue , Meia-Vida , Masculino , Taxa de Depuração Metabólica , Metotrexato/farmacocinética , Monoterpenos/sangue , Ratos Sprague-Dawley
13.
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 de Medicamentos , Feminino , Humanos , Linfoma/tratamento farmacológico , Masculino , Metotrexato/administração & dosagem , Metotrexato/sangue , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
Int J Pharm ; 557: 86-96, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30584909

RESUMO

In an attempt to prepare novel core shell nanocapsules, lipid and Stearic acid-Valine conjugate (Biosurfactant) based nanosystem was prepared to attain high drug loading of hydrophilic drug methotrexate (MTX), with sustained release. Antisolvent nanoprecipitation technique was employed for the formulation of nanoparticles (NPs). Optimized formulation depicted 209.6 ±â€¯31.3 nm particle size, 0.209 ±â€¯0.072 PDI and 14.98 ±â€¯1.33 %w/w drug loading. In vitro release depicted biphasic release for 12 h with initial burst phase followed by sustained release phase. In vitro Haemolytic study on RBCs revealed haemocompatible nature of MTX-Biosurfactant NPs compared to Biotrexate® (Zydus). In vitro cell culture studies showed 3.33 folds and 3.50 folds increase in cellular uptake of MTX at 10 µg/ml and 15 µg/ml concentration respectively for developed nanoparticles with 4.16 folds decrease in IC50 value. Higher apoptosis and increased lysosomal membrane permeability were obtained in MTX-Biosurfactants NPs. AUC and T1/2 was found to increase by 2.55 and 3.25 folds respectively in pharmacokinetic study. Significant reduction in tumor burden and serum toxicity marker level depicted efficacy and safety respectively of the formulation as compared to Biotrexate®. RBCs morphology was retained after MTX-Biosurfactants NPs exposure proving its haemocompatibility in vivo.


Assuntos
Antineoplásicos/administração & dosagem , Lipídeos/administração & dosagem , Metotrexato/administração & dosagem , Nanopartículas/administração & dosagem , Tensoativos/administração & dosagem , Valina/administração & dosagem , Administração Intravenosa , Animais , Antineoplásicos/química , Antineoplásicos/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 , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise , Humanos , Lipídeos/química , Lipídeos/farmacocinética , Células MCF-7 , Metotrexato/química , Metotrexato/farmacocinética , Camundongos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ratos Sprague-Dawley , Tensoativos/química , Tensoativos/farmacocinética , Carga Tumoral/efeitos dos fármacos , Valina/química , Valina/farmacocinética
15.
Methods Mol Biol ; 1872: 101-110, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30350283

RESUMO

Mass spectrometry (MS) is a highly specific and sensitive technique that is used for the detection of many different analytes with diverse chemical characteristics. It has been adopted by clinical laboratories for the quantification of small molecules and, by extension, has been widely used for therapeutic drug monitoring. It is an attractive alternative to immunoassay methods, because it is not subject to the same interferences. A limitation of MS (relative to immunoassays) is the turnaround time. However, this can be addressed by workflow parallelization with other assays. Herein we describe a tandem LC-MS/MS method for the detection and quantification of methotrexate in human plasma with a lower limit of quantification of 0.01 µM and within-assay and between-assay coefficients of variation of less than 15%. This method lacks interference from high-abundance metabolites and utilizes kindred chromatography to improve turnaround time in the therapeutic drug monitoring laboratory.


Assuntos
Cromatografia Líquida , Monitoramento de Medicamentos , Metotrexato/farmacocinética , Espectrometria de Massas em Tandem , Monitoramento de Medicamentos/métodos , Humanos , Metotrexato/sangue , Metotrexato/química , Estrutura Molecular
16.
Int J Nanomedicine ; 13: 5657-5671, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30288039

RESUMO

Background: One of the most important aspects of drug delivery is extended nanoparticle (NP) residence time in vivo. Herein, we report a series of methotrexate (MTX)-loaded chito-san (CS) NPs coated with differently sized methoxy polyethylene glycol (mPEG) at different mPEG surface densities. Materials and methods: MTX was incorporated into NPs (112.8-171.2 nm in diameter) prepared from the resulting mPEG-g-CS. The NPs had a zeta potential of +7.4-35.0 mV and MTX loading efficiency of 17.1%-18.4%. MTX/mPEG-g-CS NPs showed an initial burst release of MTX followed by a sustained-release profile in PBS at pH 7.4. Results: The in vitro cellular uptake study showed that MTX accumulation in J774A.1 macrophage cells decreased with increasing the mPEG surface density or the mPEG molecular weight. The pharmacokinetic study on Sprague Dawley rats revealed an increase in AUC0-72 h (area under the plasma drug concentration-time curve over a period of 72 hours) with increasing the mPEG surface density or the mPEG molecular weight and a linear correlation between the mPEG surface density and AUC0-72 h. Conclusion: The biodistribution study on Institute of Cancer Research (ICR) mice revealed that MTX/mPEG-g-CS NPs significantly enhanced blood circulation time in the body and decreased accumulation in liver, spleen, and lung. These results suggest the potential of the mPEG-g-CS NPs as a promising candidate for drug delivery.


Assuntos
Quitosana/química , Metotrexato/farmacocinética , Nanopartículas/química , Polietilenoglicóis/química , Animais , Área Sob a Curva , Linhagem Celular , Quitosana/síntese química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Endocitose , Metotrexato/administração & dosagem , Metotrexato/química , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polietilenoglicóis/síntese química , Ratos Sprague-Dawley , Propriedades de Superfície , Distribuição Tecidual/efeitos dos fármacos
17.
Eur J Med Chem ; 158: 502-516, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30243154

RESUMO

Methotrexate (MTX) is used as an anchor disease-modifying anti-rheumatic drugs (DMARDs) in treating rheumatoid arthritis (RA) because of its potent efficacy and tolerability. MTX benefits a large number of RA patients but partially suffered from side effects. A variety of side effects can be associated with MTX when treating RA patients, from mild to severe or discontinuation of the treatment. In this report, we reviewed the possible side effects that MTX might cause from the most common gastrointestinal toxicity effects to less frequent malignant diseases. In order to achieve regimen with less side effects, the administration of MTX with appropriate dose and a careful pretreatment inspection is necessary. Further investigations are required when combining MTX with other drugs so as to enhance the efficacy and reduce side effects at the same time. The management of MTX treatment is also discussed to provide strategies for occurred side effects. Thus, this review will provide scholars with a comprehensive understanding the side effects of MTX administration by RA patients.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Metotrexato/efeitos adversos , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Gastroenteropatias/induzido quimicamente , Humanos , Metotrexato/farmacocinética , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Neoplasias/induzido quimicamente
18.
Eur J Med Chem ; 156: 738-746, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30048923

RESUMO

Methotrexate (MTX) is the standard of care in the treatment of rheumatoid arthritis (RA), a common autoimmune disease that is characterized by chronic inflammation in the synovial membrane of joints. Unfortunately, MTX suffers from high discontinuation rates due to a large variability in efficacy and, in particular, adverse effects. As inflammation is associated with elevated levels of reactive oxygen species (ROS) like H2O2, we propose to improve treatment through site-selective delivery of MTX to inflammatory tissue by use of a H2O2 sensitive MTX prodrug. To establish proof proof-of-concept, two novel H2O2 sensitive, thiazolidinone-based MTX prodrugs were synthesized and evaluated for this purpose. MTX-γ-thiazolidinone (MTX-γ-TZ) exhibited the most promising properties - good to high chemical and metabolic stability, excellent aqueous solubility, while being activated when subjected to patho-physiological concentrations of H2O2. In vivo, MTX-γ-TZ exhibited comparable efficacy to MTX in a murine collagen type II-induced arthritis (CIA) model while treated mice showed indications of reduced toxicity as their body weight decreased less towards the end of the study, compared to the MTX-treated group.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Metotrexato/análogos & derivados , Metotrexato/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Metotrexato/farmacocinética , Camundongos , Pró-Fármacos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/uso terapêutico
19.
Colloids Surf B Biointerfaces ; 167: 568-576, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29738983

RESUMO

pH-responsive polymersomes were obtained by self-assembling of a carboxyl-terminated PEG amphiphile achieved via esterification of PEG diacid with PEG40stearate. The obtained vesicular systems had spherical shape and a mean diameter of 70 nm. The pH sensitivity was assessed by measuring the variations of particles mean diameter after incubation in media mimicking the physiological (pH 7.4) or tumor (pH 5.0) conditions, recording a significant increase of the vesicles dimensions at acidic pH. The ability of the polymersomes to carry both hydrophobic and hydrophilic drugs was evaluated by loading the vesicles with curcumin and methotrexate, respectively, obtaining high encapsulation efficiencies and pH-dependent release profiles. The drug-loaded polymeric vesicles exhibited improved cytotoxic potential against MCF-7 cancer cell line and were found to be highly hemocompatible. Finally, cellular uptake experiments on MCF-7 cancer cells were conducted to demonstrate the ability of the designed polymersomes to enhance drug penetration inside the cells.


Assuntos
Curcumina/química , Lipídeos/química , Metotrexato/química , Polietilenoglicóis/química , Polímeros/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Transporte Biológico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Curcumina/administração & dosagem , Curcumina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Metotrexato/administração & dosagem , Metotrexato/farmacocinética
20.
Biomed Pharmacother ; 103: 915-922, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29710508

RESUMO

The regulation of renal transporters such as organic anion transporter (OATs) is a new target for treatment of acute renal failure. The purpose of this study was to investigate whether the effect of puerarin (Pur) on renal damage induced by methotrexate (MTX) is related to the expression of renal Oat1/3 in vivo and in vitro, and to explore the related mechanisms. Effect of Pur on the renal damage caused by MTX was evaluated by assessment of the changes of endogenous metabolites, toxins and H&E staining. Furthermore, Real-time PCR and western blot methods were taken to evaluate the modulation of Oat1/3 in rats. Then, the regulation of Oat1/3 by B-cell CLL/lymphoma (BCL)6 was explored by siRNA assay using NRK-52E cells in vitro. Pur reduced levels of endogenous metabolites and toxins, like creatinine, urea nitrogen and indoxyl sulfate in plasma in MTX-treated rats. Moreover, plasma concentration of MTX was significantly decreased, while the cumulative urinary excretion of MTX and the uptake of MTX by kidney slices were strongly increased after administration of multiple-dose of Pur via up-regulation of renal Oat1/3 expression. Knockdown of BCL6 by siRNA abrogated the Pur-induced Oat1/3 expression in NRK-52E cells. Pur improved MTX-induced renal toxicity through promotion of renal excretion of toxins by up-regulating renal Oat1/3 via BCL6. Pur was beneficial for the improvement of MTX-induced renal toxicity.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Isoflavonas/uso terapêutico , Rim/efeitos dos fármacos , Proteína 1 Transportadora de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Linhagem Celular , Interações de Medicamentos , Isoflavonas/farmacocinética , Rim/metabolismo , Rim/patologia , Masculino , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Ratos Wistar , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA