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1.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(9): 841-847, 2019 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-31550823

RESUMO

Objective: To investigate the significance of monitoring imatinib mesylate (IM) plasma concentrations in patients with gastrointestinal stromal tumor (GIST). Methods: A retrospective descriptive study was carried out. Inclusion criteria: (1) patients with GIST confirmed by postoperative pathology or puncture pathology receiving maintenance therapy of IM; (2) administration of same dose of IM for at least 4 weeks (achieving steady - state plasma concentration). Patients who had severe organ dysfunction, received IM generics, or received IM simultaneously with other drugs significantly affecting IM pharmacokinetic were excluded. A total of 185 patients at the GIST Clinic of Renji Hospital, Shanghai Jiaotong University School of Medicine from August 2018 to May 2019 were enrolled, including 114 males (61.6%) and 71 females (38.4%) with a median age of 60 years old (range, 30-89 years), and 63 advanced cases. Patients receiving preoperative or postoperative adjuvant therapy were given IM 400 mg QD; patients with KIT exon 9 mutation or with disease progression during IM 400 mg QD treatment were given IM 600 mg QD. If the patient had adverse reactions such as myelosuppression during the medication, IM would be reduced or given BID per day. The peripheral venous blood was collected (22 to 24 hours after the last dose for patients who took IM QD and 2 hours before the first dose per day for those who took IM BID). IM plasma concentration was measured through high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Correlation analysis between IM plasma concentration results and clinical data was performed using linear regression analysis. Results: A total of 241 stable blood samples of IM plasma concentration from 185 patients were finally collected. The IM plasma concentrations were significantly different between the doses of 300 mg/d and 400 mg/d [(942.4±433.5) µg/L vs. (1340.0±500.1) µg/L, t=6.317, P<0.001], and between 400 mg/d and 600 mg/d [(1340.0±500.1) µg/L vs. (2188.0±875.5) µg/L, t=3.557, P=0.004]. Among the blood samples of 57 patients receiving IM 300 mg/d, the IM plasma concentration of the advanced patients was significantly lower than that of the non-advanced patients [(795.6±225.8) µg/L vs. (992.2±484.4) µg/L, t=2.088, P=0.042]. Among the 137 blood samples of patients receiving IM 400 mg/d, the IM plasma concentration was higher in patients aged >60 years than those aged ≤60 years [(1461.0±595.3) µg/L vs. (1240.0±380.9) µg/L, t=2.528, P=0.013] and the IM plasma concentration of cases with diarrhea was significantly lower than that of those without diarrhea [(745.8±249.6) µg/L vs. (1382.0±486.9) µg/L, t=6.794, P<0.001]. Gender, primary location, surgical procedure, mutated gene, mutation type, or time of administration was associated with IM plasma concentration no matter in patients taking IM doses of 400 mg/d or 300 mg/d (all P>0.05). Regression analysis showed that body mass (P=0.004 and P=0.019), body mass index (P=0.016 and P=0.042), and body surface area (P=0.007 and P=0.028) were all negatively correlated with IM plasma concentrations in patients taking IM doses of 300 mg/d and 400 mg/d. Within the 137 patients who received a fixed oral dose of 400 mg/d IM, 17 patients received oral 200 mg BID, whose IM plasma drug concentration was not significantly different compared with that of 120 patients who received 400 mg IM QD [(1488.0±408.3) µg/L vs. (1319.0±509.7) µg/L, t=1.307, P=0.193]. Conclusions: Monitoring IM plasma concentration is significant throughout the whole process of management of GIST patients receiving IM treatment. In particular, regular monitoring IM plasma concentration and developing appropriate treatment strategies can bring better therapeutic benefits for patients with low doses, diarrhea, advanced condition and older age.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , China , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/sangue , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espectrometria de Massas em Tandem
2.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(9): 848-855, 2019 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-31550824

RESUMO

Objective: To explore the features of imatinib mesylate (IM) plasma concentration during adjuvant therapy and clinical factors associated with IM plasma concentration in patients with high risk gastrointestinal stromal tumors (GIST), and to determine whether IM plasma concentration <1100 µg/L influences the efficacy of adjuvant therapy. Methods: A retrospective case control study method was used. Case inclusion criteria: (1) complete resection of lesion and GIST confirmed by pathology; (2) high risk classified according to modified National Institutes of Health classification system (2008); (3) administration of IM 400 mg/d for at least 1 month; (4) not taking the medication likely affecting IM pharmacokinetic, such as rifampicin, dilantin, and carbamazepine, within 1 month before blood collection. Data of GIST patients who visited GIST Disease - Oriented Outpatient, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 to December 2018 were retrospectively analyzed. After taking IM for 22-26 hours, 5 ml of peripheral venous blood was collected into EDTA anticoagulant tube. IM plasma concentration was detected by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Patients were divided into <1100 µg/L group and ≥1100 µg/L group according to plasma concentration. Linear regression was used to analyze the relevance between clinical features and IM plasma concentration. Parameters with normal distribution were analyzed by Pearson correlation coefficient, and parameters with non-normal distribution were analyzed by Spearman correlation. Kaplan-Meier survival curves and COX regression model were used for survival analysis. Results: Among the 85 patients enrolled in the study, 49 patients (57.6%) were male and 36 (42.4%) were female, with mean age of (51.9±11.0) years. The body mass index was (22.5±2.9) kg/m(2) and body surface area was (1.6±0.2) m(2). Thirty patients received gene test, including 23 patients with c-Kit exon 11 mutation, 4 with c-Kit exon 9 mutation, 1 with c-Kit exon 11 and 17 mutation and 2 without c-Kit or PDGFRA gene mutation. The mean IM plasma concentration was (1391.4±631.3) µg/L, and there were 32 patients with plasma concentration <1100 µg/L and 53 patients with plasma concentration ≥1100 µg/L. There were no statistically significant differences between the two groups in gender, age, body mass index, body surface area, hematological examination (white blood cells, albumin, alanine aminotransferase, aspartate aminotransferase and serum creatinine), tumor location, tumor size, mitotic counts, duration of adjuvant therapy and methods of operation (all P>0.05). Positive correlation between IM plasma concentration and serum creatinine was observed in linear regression analysis (r=0.297, P=0.007), but there were no correlations between IM plasma concentration and age (r=0.044, P=0.686), body mass index (r=0.066, P=0.547), body surface area (r=-0.010, P=0.924), white blood cells (r=-0.080, P=0.478), albumin (r=-0.065, P=0.563), alanine aminotransferase (r=0.114, P=0.308), aspartate aminotransferase (r=0.170, P=0.127) and duration of adjuvant therapy (ρ=0.060, P=0.586). There was no statistically significant difference in IM plasma concentration between patients with different genders (t=0.336, P=0.738) and patients with different surgical methods (F=0.888, P=0.451). Up to March 1, 2019. the median follow-up time was 30 (range 4-49) months. Tumor recurrence was detected in two patients with plasma concentration <1100 µg/L and two with plasma concentration ≥1100 µg/L. One recurrent patient with plasma concentration <1100 µg/L was detected to harbor c-Kit exon 11 and exon 17 mutations, and the other did not receive gene detection. Two recurrent patients with plasma concentration ≥1100 µg/L were both detected to harbor c-Kit exon 9 mutation. The 3-year relapse-free survival rate was 96.4% in the cohort, 96.2% in patients with plasma concentration <1100 µg/L, and 96.6% in patients with plasma concentration ≥1100 µg/L. No significant difference in relapse-free survival was observed between the two groups (P=0.204). Univariate Cox analysis showed that IM plasma concentration <1100 µg/L was not a risk factor for patients with high risk GIST (HR=0.238, 95% CI: 0.022-2.637, P=0.242). Conclusions: IM plasma concentration of adjuvant therapy in patients with high risk GIST varies with individual. Patients with higher level of serum creatinine are more likely to have a higher plasma concentration. A blood drug concentration standard of less than 1100 µg/L for advanced GIST patients may not influence the prognosis of patients with high risk GIST.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Estudos Retrospectivos , Fatores de Risco , Espectrometria de Massas em Tandem
3.
Int J Nanomedicine ; 14: 6339-6356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496690

RESUMO

Objective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy. Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP). Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively. Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.


Assuntos
Ácido Desoxicólico/química , Composição de Medicamentos , Intestinos/efeitos dos fármacos , Pemetrexede/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/química , Humanos , Íons , Lisina/análogos & derivados , Lisina/química , Camundongos Endogâmicos BALB C , Pemetrexede/administração & dosagem , Pemetrexede/sangue , Pemetrexede/farmacocinética , Permeabilidade , Ratos Sprague-Dawley
4.
Can J Vet Res ; 83(3): 187-196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31308591

RESUMO

The proposed advantages of intra-arterial chemotherapy (IAC) are based on the premises of local dose escalation to the tumor and reduced availability of systemic drugs. There is a lack of objective pharmacokinetic data to confirm the advantage of IAC in dogs with naturally occurring urogenital tumors. The objective of this study was to determine if IAC administration in urogenital tumors would result in decreased systemic drug exposure when compared to intravenous routes. Twenty-two dogs with naturally occurring urogenital tumors were enrolled in this prospective case-controlled study. Mitoxantrone, doxorubicin, or carboplatin were administered by IAC and intravenous routes [intravenous awake (intravenous chemotherapy - IVC) and under general anesthesia (IVGAC)] 3 weeks apart. Serum assays were used to determine the extent of systemic drug exposure. Dose-normalized peak systemic serum concentration (Cmax) and area under the serum drug concentration-time curve (AUC) were used to quantify systemic exposure. A total of 26 mitoxantrone treatments were administered to 10 dogs. While there was no significant difference in Cmax, the AUC was significantly lower after IAC compared with IVGAC. Ten doxorubicin treatments were administered to 5 dogs. There were no significant differences in Cmax or AUC. A total of 14 carboplatin treatments were administered to 7 dogs. The Cmax was significantly lower for IAC compared to IVC, while the AUC values were equivocal. This study demonstrates certain lower serum values may be achieved after IAC delivery of carboplatin and mitoxantrone. These chemotherapy agents may have a preferred pharmacological profile for regional chemotherapy delivery in dogs with urogenital tumors.


Assuntos
Carboplatina/uso terapêutico , Doenças do Cão/tratamento farmacológico , Injeções Intra-Arteriais/veterinária , Injeções Intravenosas/veterinária , Mitoxantrona/uso terapêutico , Neoplasias Urológicas/veterinária , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Área Sob a Curva , Carboplatina/administração & dosagem , Carboplatina/sangue , Carboplatina/farmacocinética , Cães , Feminino , Masculino , Mitoxantrona/administração & dosagem , Mitoxantrona/sangue , Mitoxantrona/farmacocinética , Projetos Piloto , Neoplasias Urológicas/tratamento farmacológico
5.
Pharm Res ; 36(8): 115, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161432

RESUMO

PURPOSE: Fibrin gels (FBGs) are potential delivery vehicles for many drugs, and can be easily prepared from purified components. We previously demonstrated their applicability for the release of different doxorubicin (Dox) nanoparticles used clinically or in an experimental stage, such as its inclusion complex with the amino ß-cyclodextrin polymer (oCD-NH2/Dox). Here we extend these studies by in vitro and in vivo evaluations. METHODS: An in vitro cytotoxicity model consisting of an overlay of a neuroblastoma (NB) cell-containing agar layer above a drug-loaded FBG layer was used. Local toxicity in vivo (histology and blood analysis) was studied in a mouse orthotopic NB model (SHSY5YLuc+ cells implanted into the left adrenal gland). RESULTS: In vitro data show that FBGs loaded with oCD-NH2/Dox have a slightly lower cytotoxicity against NB cell lines than those loaded with Dox. Fibrinogen (FG), and Ca2+ concentrations may modify this activity. In vivo data support a lower general and local toxicity for FBGs loaded with oCD-NH2/Dox than those loaded with Dox. CONCLUSION: Our results suggest a possible increase of the therapeutic index of Dox when locally administered through FBGs loaded with oCD-NH2/Dox, opening the possibility of using these releasing systems for the treatment of neuroblastoma.


Assuntos
Antineoplásicos/farmacologia , Celulose/química , Ciclodextrinas/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Fibrina/química , Nanopartículas/química , Neuroblastoma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Portadores de Fármacos/toxicidade , Feminino , Géis , Xenoenxertos , Humanos , Camundongos Nus , Nanopartículas/toxicidade
6.
Biol Pharm Bull ; 42(6): 1034-1037, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155579

RESUMO

Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis. We focused on the anticancer activity of tocotrienol (T3) and have reported that a new redox-inactive T3 derivative (6-O-carboxypropyl-α-tocotrienol; T3E) exerts stronger inhibitory effects on MM cell growth than that of T3 in vitro. Furthermore, we have revealed some mechanisms of T3E that are involved in anti-MM effects. However, the effect of T3E in vivo remains unclear. In this study, we compared the plasma concentrations of T3E to that of T3 using mice to clarify differences in pharmacokinetics. Blood was sequentially collected after oral administration of T3 or T3E, and plasma concentrations were analyzed by HPLC. The area under the plasma T3 and T3E concentration-time curve from 0 to 24 h (AUC0-24 h) of T3E was two times higher than that of T3. In addition, we evaluated the effect of T3E oral administration on tumor growth using a xenograft model of mice that were transplanted with human MM cells (H2052 cell line). Tumor volume was significantly reduced without body weight loss in mice orally administered 150 mg/kg T3E once per 2 d for 10 d, which suggests that T3E has potential anti-MM effects.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Tocotrienóis/uso terapêutico , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/metabolismo , Mesotelioma/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Oxirredução , Tocotrienóis/sangue , Tocotrienóis/farmacocinética , Carga Tumoral/efeitos dos fármacos
7.
Artigo em Inglês | MEDLINE | ID: mdl-31082683

RESUMO

Thiazolidinediones and quinazolin-4-ones compounds, previously known for their activity against Type 2 diabetes and antifungal activity respectively, are currently being investigated for their anti-cancer activity. The determination of pharmacokinetic parameters for these two classes of compounds using a simultaneous chromatographic method with a low detection limit is a challenge. In this study, a highly sensitive and simultaneous LC-MS/MS-based bioanalytical method was developed and validated in rat plasma for the estimation of four novel anti-cancer compounds, BIT-15-67 and BNT-11, belonging to the Thiazolidinedione class, and BNUA-108 and BNUA-48, from the quinazolin-4-one class. The analytes were extracted from plasma samples by protein precipitation and separated on a short reverse phase Hypersil Phenyl BDS, 50 × 4.6 mm, 2.4 µm column at a column oven temperature of 40 °C. An isocratic mobile phase, a 20:80 (v/v) mixture of 5 mM ammonium acetate solution and acetonitrile containing 0.1% formic acid, was used for the elution at a flow rate of 0.4 mL/min. The analytes and internal standard, sulfaphenazole, were quantified in the multiple reaction monitoring mode using positive electrospray ionization with specific pair of mass by charge ratio. All standard validation parameters were assessed as per current bioanalytical method validation guidelines in rat plasma. The area response for the four analytes was found to be linear over the concentration range of 1.00 to 1000 ng/mL in rat plasma. The signal to noise at LLOQ of 1 ng/mL was adequate for application to different pre-clinical studies. The intra- and inter-day precision were <11% and accuracy deviated -1.8 to 9.60% from the nominal. The mean recovery was high (about 90%) and consistent for all the analytes over the linear dynamic range of the method. This simple, robust and validated method can be employed to determine the rat plasma concentrations of the four selected anticancer compounds in preclinical studies such as the pharmacodynamic and the pharmacokinetic studies including tissue distribution and excretion, and the toxicokinetic studies. In this study, pharmacokinetic parameters were determined using this method for all the four compounds individually following intravenous administration in rats.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Quinazolinonas/sangue , Espectrometria de Massas em Tandem/métodos , Tiazolidinedionas/sangue , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética
8.
Talanta ; 201: 217-225, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122414

RESUMO

This study describes, for the first time, the development of two platforms of competitive fluorescent immunoassays for bioanalysis of crizotinib (CZT), a potent drug used for the treatment of non-small cell lung cancer (NSCLC). These platforms were microwell-based heterogeneous fluoroimmunoassay (FIA) and a kinetic exclusion assay (KinExA) with KinExA™ 3200 immunosensor. Both FIA and KinExA were developed using same reagents; mouse anti-CZT antibody and a capturing reagent of CZT conjugated with bovine serum albumin (CZT-BSA). In the FIA, the CZT-BSA coated onto the microwells of the assay plate was present simultaneously in the assay mixture (CZT and its antibody). In the KinExA, the antibody was allowed to pre-equilibrate with CZT, and then the incubation mixture was rapidly passed through a microcolumn containing CZT-BSA coated onto polymethyl methacrylate (PMMA) beads. The analytical performances of both assays were comparatively evaluated in terms of assay working range, limit of detection, precision profile, and accuracy. The results revealed that KinExA yielded higher sensitivity and better precision than FIA; whereas, both assays had comparable accuracies. Both FIA and KinExA were superior to all the existing chromatographic methods for CZT in terms of the assay sensitivity, convenience, analysis throughputs. The proposed FIA and KinExA are anticipated to effectively contribute to the therapeutic drug monitoring (TDM) of CZT in clinical settings.


Assuntos
Antineoplásicos/sangue , Crizotinibe/sangue , Fluorimunoensaio/métodos , Animais , Anticorpos/imunologia , Antineoplásicos/química , Antineoplásicos/imunologia , Calibragem , Carcinoma Pulmonar de Células não Pequenas/sangue , Bovinos , Crizotinibe/química , Crizotinibe/imunologia , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Cabras , Humanos , Limite de Detecção , Neoplasias Pulmonares/sangue , Camundongos , Polimetil Metacrilato/química , Soroalbumina Bovina/química
9.
ACS Appl Mater Interfaces ; 11(17): 16065-16074, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30990996

RESUMO

In this work, a nanohybrid-based imprinted polymer consisting of N-doped hollow carbon nanospheres and palladium is reported for the electroanalysis of ultratrace level of anticancer drug, 6-mercaptopurine, used in the treatment of leukemia. For this, N-doped carbon nanospheres decorated with palladium were first developed, and subsequently, a molecular imprinted polymer layer was grown onto their surfaces. The so-produced silica-embedded nanocomposite was made hollow by etching silica moieties with hydrofluoric acid. Finally, the whole system was doped on an ionic-liquid-modified pencil graphite electrode. The underlying synergistic effect of hollow carbon nanosphere-supported palladium nanoparticles inculcated electrocatalytic action. Notably, all rebinding sites in solid core-shells were confined within the shell, which hampers the effective diffusion of template. However, in this work, an effective diffusion of template across the hollow structure of inner and outer surfaces was observed. Consequently, this rendered approximately 2-fold heterogeneous rate constant as compared to the solid core-shell-based sensor. Differential pulse voltammetric transduction was used for ultratrace detection of 6-mercaptopurine through anodic stripping method. The hollow imprinted sensor revealed a linear dependence of current with concentration range 0.80-70.748 ng mL-1. The limits of detection 0.11-0.22 ng mL-1 were realized in water, human blood plasma, urine, and pharmaceuticals. Thus, the proposed sensor demonstrated an attractive sensitivity reproducibility, as well as endurance requisite for the treatment of leukemia patients.


Assuntos
Antineoplásicos/análise , Técnicas Eletroquímicas/métodos , Mercaptopurina/análise , Impressão Molecular , Nanocompostos/química , Nanosferas , Polímeros/química , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Antineoplásicos/urina , Carbono/química , Eletrodos , Humanos , Leucemia/tratamento farmacológico , Limite de Detecção , Mercaptopurina/sangue , Mercaptopurina/uso terapêutico , Nitrogênio/química , Paládio/química , Preparações Farmacêuticas/análise , Reprodutibilidade dos Testes
10.
Artif Cells Nanomed Biotechnol ; 47(1): 1505-1512, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30991858

RESUMO

1G, a novel derivative of curcumin, exhibits promising anticancer activities in various cancer cell lines. To support its further pharmacological studies, a liquid chromatography-tandem mass spectrometry method was developed and validated in accordance with FDA's Guidance. After extraction by protein precipitation, analytes were separated by a 4.5 min gradient elution (water/0.1% formic acid and methanol) on a reverse-phase C18 column at 40 °C. The multiple reaction monitoring mode was used for quantification on a triple quadrupole mass spectrometer with positive ionization. The assay was linear over the concentration range of 5-1000 ng/mL with a correlation coefficient (r) greater than 0.99. Values of intra- and inter-day precision and accuracy were satisfactory, i.e. <10.1% for precision and within ± 14.5% for accuracy. No obvious matrix effect was observed. Recovery of the analyte was higher than 95.3%. 1G was stable during the whole analytic process. The validated method was successfully applied to the pharmacokinetic study of 1G after intravenous and intraperitoneal administration in rats. Favorable pharmacokinetic profiles were demonstrated, including good abdominal absorption (F = 62.58%), moderate clearance and high extravascular distribution. Results indicated that as a novel antitumor agent, 1G exhibited acceptable pharmacokinetic properties for further in vivo pharmacologic evaluation.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Curcumina/farmacocinética , Isotiurônio/química , Pirimidinas/química , Animais , Antineoplásicos/química , Cromatografia Líquida , Curcumina/química , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Distribuição Tecidual
11.
Biopharm Drug Dispos ; 40(3-4): 151-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30931529

RESUMO

GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, an in situ single-pass perfusion model and a Caco-2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (Fa × Fg ) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (Fgut wall ) was 98.59 ± 9.74%, while the hepatic bioavailability (Fh ) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL-V9. The effective permeability (Peff ) in the duodenum and jejunum was 1.34 ± 0.50 × 10-4 and 0.90 ± 0.27 × 10-4  cm/s, respectively. The high permeability of GL-V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Clint, CYP450s and UGT of GL-V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL-V9 possesses higher permeability than wogonin and the metabolism of GL-V9 is related to its disposition in rat intestine and liver.


Assuntos
Antineoplásicos/farmacocinética , Flavonoides/farmacocinética , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Disponibilidade Biológica , Células CACO-2 , Flavonoides/sangue , Flavonoides/química , Suco Gástrico/química , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Secreções Intestinais/química , Fígado/metabolismo , Masculino , Microssomos/metabolismo , Ratos Sprague-Dawley
12.
Pharm Res ; 36(6): 82, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30989405

RESUMO

PURPOSE: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. METHODS: Twenty B cell non-Hodgkin's lymphoma patients who were treated with rituximab for the first time or after more than one year's abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. RESULTS: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. CONCLUSION: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.


Assuntos
Antineoplásicos/química , Linfócitos B/efeitos dos fármacos , Glicoproteínas/química , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/química , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Feminino , Glicoproteínas/administração & dosagem , Glicoproteínas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Plasma , Conformação Proteica , Rituximab/administração & dosagem , Rituximab/farmacocinética
13.
Anal Bioanal Chem ; 411(12): 2587-2596, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30828756

RESUMO

Pharmacokinetic analysis of antibody-drug conjugates (ADCs) requires characterization and quantification of both the antibody-conjugated cytotoxic drug molecule (acDrug) as well as the antibody vehicle, among other analytes, in order to assess the safety and efficacy of ADCs. Due to the complexity of biological matrices, immunoaffinity capture is widely used for enrichment of the biotherapeutic, followed by enzymatic or chemical release of the drug and LC-MS/MS analysis to provide the concentration of acDrug. This bioanalytical strategy has been used successfully with ADCs, but is limited to ADCs having cleavable linkers. Herein, we developed a sensitive and specific method that involved subjecting the ADC to tryptic digestion, and measured a peptide that included cysteine conjugated to the drug to provide quantification of acDrug. Using this method for a THIOMAB™ antibody-drug conjugate (TDC) conjugated to MMAE via a cleavable linker, valine-citrulline, we compared peptide-linker MMAE data from the new assay format with earlier MMAE data for acDrug. This showed that the new assay format provides robust acDrug as well as total antibody concentration to study in vitro stability of the TDC in multiple matrices and in vivo pharmacokinetic models of TDC in rat and mouse. The data from the two orthogonal modes of acDrug analysis showed good agreement with each other, allowing us to successfully quantify acDrug to study the stability in vitro and the pharmacokinetic parameters in vivo. This new assay strategy allows acDrug quantification for ADCs with non-cleavable linkers where the resulting acDrug analyte is a peptide-linker drug.


Assuntos
Cromatografia de Afinidade/métodos , Imunoconjugados/farmacocinética , Peptídeos/química , Espectrometria de Massas em Tandem/métodos , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Antineoplásicos/farmacocinética , Área Sob a Curva , Feminino , Meia-Vida , Humanos , Imunoconjugados/sangue , Imunoconjugados/química , Limite de Detecção , Camundongos , Camundongos SCID , Controle de Qualidade , Ratos , Ratos Sprague-Dawley
14.
Bioanalysis ; 11(6): 495-508, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30892068

RESUMO

Aim: The aim of this study was to develop and validate a LC-MS/MS assay for tacrolimus, sirolimus, everolimus, cyclosporin A and mycophenolic acid using volumetric absorptive microsampling tips as a sampling device and to investigate the effect on the recoveries of the analyte concentration in combination with the hematocrit (HT), which included temsirolimus (a structural analog). Results: The maximum observed overall bias was 9.6% for the sirolimus LLOQ, while the maximum overall coefficient of variation was 8.3% for the everolimus LLOQ. All five immunosuppressants demonstrated to be stable in the volumetic absorbtive microsampling tips for at least 14 days at 25°C. Biases caused by HT effects were within 15% for all immunosuppressants between HT levels of 0.20 and 0.60 l/l, except for cyclosporin A, which was valid between 0.27 and 0.60 l/l. Reduced recoveries were observed at high analyte concentrations in combination with low HT values for sirolimus, everolimus and temsirolimus. Conclusion: A robust extraction and analysis method in volumetric absorptive microsampling tips was developed and fully validated. HT- and concentration-related recovery effects were observed but were within requirements of the purpose of the analytical method.


Assuntos
Imunossupressores/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Hematócrito , Humanos , Limite de Detecção , Espectrometria de Massas em Tandem/métodos
15.
Mikrochim Acta ; 186(3): 141, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707311

RESUMO

An electrochemical sensor is described for the determination of nilutamide (NLM) in biological fluids. A flexible mat of nitrogen-doped carbon nanofibers (NCNFs) was prepared by electrospinning. This was followed by carbonization and the growth of one-dimensional vanadium tetrasulfide (VS4) nanorods in the circumference of the NCNFs by a solvothermal route. The material was used to modify a glassy carbon electrode (GCE). Cyclic voltammetry and amperometry revealed an excellent electrocatalytic activity of the VS4/NCNF mat towards NLM at a working potential of - 0.57 V (vs Ag/AgCl). The modified GCE has a wide linear range (0.001-760 µM), a low limit of detection (90 pM), good stability, and fast response. It was used to detect NLM in spiked serum and urine samples. Graphical abstract Schematic presentation of a glassy carbon electrode (GCE) composed of free-standing nitrogen-doped carbon nanofibers decorated with vanadium tetrasulfide (Patronite) nanorods (VS4/NCNF). It was fabricated by electrospinning followed by stabilization and carbonization. The GCE responds to nilutamide (NLM) with excellent selectivity and nanomolar sensitivity.


Assuntos
Carbono/química , Imidazolidinas/sangue , Nanofibras/química , Nitrogênio/química , Neoplasias da Próstata/diagnóstico , Compostos de Vanádio/química , Antineoplásicos/sangue , Técnicas Biossensoriais , Técnicas Eletroquímicas , Eletrodos , Humanos , Limite de Detecção , Masculino , Nanocompostos/química , Nanotubos/química , Tamanho da Partícula , Sulfetos/química , Propriedades de Superfície
16.
Eur J Clin Pharmacol ; 75(6): 825-829, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30729257

RESUMO

PURPOSE: To obtain insight into the feasibility of, and the patients' perspective on, dried blood spot (DBS) self-sampling by patients with chronic myeloid leukemia (CML) using nilotinib. METHODS: Sixty-eight patients with CML using nilotinib participated in this multicenter observational study. Patients were asked to perform blood sampling by means of the DBS method at home just before drug intake (trough level) and to complete a questionnaire including demographics and five questions on their experience with DBS self-sampling. RESULTS: Sixty-one patients (57.5 ± 15.0 years, 49% female) provided 178 DBS samples of which 137 (77%) proved useful in clinical practice. Twenty percent of the samples were rejected because the spot size was too small for analysis. A further 3% were taken at the wrong time. Unsuitable DBS samples were provided by 23 patients. Their educational level was significantly lower than that of patients whose samples were all suitable (p = 0.041). Patients considered DBS self-sampling easy and not painful, and three quarters of the patients performed DBS sampling without additional assistance. Patients' belief in the reliability of DBS self-sampling was moderate to high. It was preferred over venous sampling by 37% of the patients, whereas 39% had no preference. CONCLUSION: DBS self-sampling by CML patients is feasible in clinical practice provided that patients, particularly those with a lower educational level, are adequately instructed about sample collection with emphasis on timing and volume of sample collection.


Assuntos
Antineoplásicos/sangue , Atitude Frente a Saúde , Teste em Amostras de Sangue Seco , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Participação do Paciente , Pirimidinas/sangue , Adulto , Idoso , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Autoadministração
17.
Microvasc Res ; 123: 111-124, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30711547

RESUMO

The solute transport distribution in a tumor is an important criterion in the evaluation of the cancer treatment efficacy. The fraction of killed cells after each treatment can quantify the therapeutic effect and plays as a helpful tool to evaluate the chemotherapy treatment schedules. In the present study, an image-based spatio-temporal computational model of a solid tumor is provided for calculation of interstitial fluid flow and solute transport. Current model incorporates heterogeneous microvasculature for angiogenesis instead of synthetic mathematical modeling. In this modeling process, a comprehensive model according to Convection-Diffusion-Reaction (CDR) equations is employed due to its high accuracy for simulating the binding and the uptake of the drug by tumor cells. Based on the velocity and the pressure distribution, transient distribution of the different drug concentrations (free, bound, and internalized) is calculated. Then, the fraction of killed cells is obtained according to the internalized concentration. Results indicate the dependence of the drug distribution on both time and space, as well as the microvasculature density. Free and bound drug concentration have the same trend over time, whereas, internalized and total drug concentration increases over time and reaches a constant value. The highest amount of concentration occurred in the tumor region due to the higher permeability of the blood vessels. Moreover, the fraction of killed cells is approximately 78.87% and 24.94% after treatment with doxorubicin for cancerous and normal tissues, respectively. In general, the presented methodology may be applied in the field of personalized medicine to optimize patient-specific treatments. Also, such image-based modeling of solid tumors can be used in laboratories that working on drug delivery and evaluating new drugs before using them for any in vivo or clinical studies.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Interpretação de Imagem Assistida por Computador/métodos , Modelos Biológicos , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Modelagem Computacional Específica para o Paciente , Análise Espaço-Temporal , Antineoplásicos/sangue , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Difusão , Doxorrubicina/sangue , Humanos , Microcirculação , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Análise Numérica Assistida por Computador , Distribuição Tecidual , Microambiente Tumoral
18.
Pharmazie ; 74(2): 79-82, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782255

RESUMO

IG-105, N-(2, 6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide, a novel carbazole sulfonamide, shows a potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In the present study, a rapid and convenient liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and applied to the pharmacokinetic study of IG-105 in rats. Chromatographic separation was accomplished on a C18 column using an isocratic mobile phase of acetonitrile-water-acetic acid (56:44:0.2, v/v/v). The ion transitions of IG-105 and combretastatin A4 (internal standard) in selected reaction monitoring mode were m/z 398→154 and m/z 317→286, respectively. The assay exhibited good linearity over the range of 2-512 ng/mL. Intra- and inter-day precisions were within 8.2 %, and the accuracies ranged from -6.0 to 3.7 %. The extraction recoveries were higher than 90 %, and the matrix effects were negligible. All quality control samples were stable at different storage conditions. The validated LC-MS/MS method was successfully applied to a preclinical pharmacokinetic study of IG-105 in rats after a single oral dose of 100, 250, or 1000 mg/kg which showed tumor growth inhibition activity. The absorption of IG-105 was proved to be rapid but saturated to a certain extent into the blood circulation, from where it was distributed and eliminated gradually.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Carbazóis/sangue , Carbazóis/farmacocinética , Cromatografia Líquida/métodos , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Moduladores de Tubulina , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Moduladores de Tubulina/sangue , Moduladores de Tubulina/farmacocinética
19.
Artigo em Inglês | MEDLINE | ID: mdl-30754019

RESUMO

Guadecitabine (SGI-110), a dinucleotide of ߭decitabine and deoxyguanosine, is currently being evaluated in phase II/III clinical trials for the treatment of hematological malignancies and solid tumors. This article describes the development and validation of bioanalytical assays to quantify guadecitabine and its active metabolite ߭decitabine in human plasma, whole blood and urine using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Since ߭decitabine is rapidly metabolized further by cytidine deaminase, plasma and whole blood samples were kept on ice-water after collection and stabilized with tetrahydrouridine (THU) directly upon sample collection. Sample preparation consisted of protein precipitation for plasma and whole blood and dilution for urine samples and was further optimized for each matrix and analyte separately. Final extracts were injected onto a C6-phenyl column for guadecitabine analysis, or a Nova-Pak Silica column for ߭decitabine analysis. Gradient elution was applied for both analytes using the same eluents for each assay and detection was performed on triple quadrupole mass spectrometers operating in the positive ion mode (Sciex QTRAP 5500 and QTRAP 6500). The assay for guadecitabine was linear over a range of 1.0-200 ng/mL (plasma, whole blood) and 10-2000 ng/mL (urine). For ߭decitabine the assay was linear over a range of 0.5-100 ng/mL (plasma, whole blood) and 5-1000 ng/mL (urine). The presented methods were successfully validated according to the latest FDA and EMA guidelines for bioanalytical method validation and applied in a guadecitabine clinical mass balance trial in patients with advanced cancer.


Assuntos
Antineoplásicos/sangue , Azacitidina/análogos & derivados , Cromatografia Líquida/métodos , Decitabina/sangue , Espectrometria de Massas em Tandem/métodos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/urina , Azacitidina/sangue , Azacitidina/química , Azacitidina/farmacocinética , Azacitidina/urina , Decitabina/química , Decitabina/farmacocinética , Decitabina/urina , Humanos , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
J Pharm Biomed Anal ; 166: 197-204, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30660034

RESUMO

Ribociclib is a selective, orally bioavailable inhibitor of cyclin-dependent kinase (CDK) 4/6, which has therapeutic potential for a variety of cancer types. This study was to develop and validate a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for determining total and unbound concentrations of ribociclib in human plasma and brain tumor tissue samples. Plasma and tumor homogenate samples were extracted using protein precipitation with acetonitrile. Unbound fraction in plasma or tumor homogenate was determined by equilibrium dialysis method. Chromatographic separation was achieved based on aqueous normal-phase chromatography mechanism on a Waters XBridge™ Amide column under isocratic elution with acetonitrile-ammonium formate (10 mM, pH 3) (75:25, v/v) at a flow rate of 0.8 mL/min. Ribociclib and the internal standard ([13C6]ribociclib) were monitored at the mass transitions m/z, 435.3 > 367.2 and 441.3 > 373.2, respectively, using positive electrospray ionization mode. The lower limit of quantitation (LLOQ) was 0.5 nM of ribociclib in plasma. Linear calibration curve was established at the concentration range of 0.5-1000 nM in plasma. Intra- and inter-day precision and accuracy were within the generally accepted criteria for bioanalytical method. The developed method was successfully applied to determine the plasma pharmacokinetics and central nervous system penetration of ribociclib in patients with malignant primary brain cancer.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Purinas/sangue , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Encéfalo/enzimologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Calibragem , Cromatografia Líquida , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Ligação Proteica , Purinas/farmacocinética , Purinas/uso terapêutico , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
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