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1.
Ann Hematol ; 99(9): 1989-2007, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32683457

RESUMO

Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.


Assuntos
Antineoplásicos/sangue , Inibidores do Citocromo P-450 CYP3A/sangue , Aprovação de Drogas , Interações Medicamentosas/fisiologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Humanos , Síndrome do QT Longo/sangue , Síndrome do QT Longo/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Estaurosporina/sangue , Sulfonamidas/efeitos adversos , Sulfonamidas/sangue
2.
Pharm Res ; 37(5): 89, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382808

RESUMO

PURPOSE: Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). METHODS: Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. RESULTS: A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. CONCLUSION: The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1-14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Capecitabina/administração & dosagem , Capecitabina/farmacologia , Cronoterapia Farmacológica , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Capecitabina/efeitos adversos , Capecitabina/sangue , Ritmo Circadiano , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Fluoruracila/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Timidilato Sintase/metabolismo , Uridina Trifosfato/análogos & derivados , Uridina Trifosfato/sangue
3.
Pediatr Blood Cancer ; 67(7): e28244, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32323890

RESUMO

It is unclear if dosing intervals for Erwinase can be extended with intramuscular (i.m.) versus intravenous (i.v.) dosing. Children with acute lymphoblastic leukemia received Erwinase at 30 000-42 000 IU/m2 i.v. or i.m. I.m. Erwinase (n = 22) achieved activity above 0.1 IU/mL for longer than i.v. Erwinase (n = 33) (3.4 vs 2.9 days, P = 0.0007). With 30 000 IU/m2 Monday, Wednesday, Friday, more patients achieved adequate concentrations over the weekend with i.m. vs i.v. dosing (P = 5 × 10-36 ). A schedule with i.v. doses on Monday and Wednesday and i.m. doses on Friday of 30 000 IU/m2 maintained activity > 0.1 IU/mL over the weekend in 80% of patients.


Assuntos
Asparaginase/administração & dosagem , Asparaginase/sangue , Erwinia/enzimologia , Injeções Intramusculares/métodos , Injeções Intravenosas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Criança , Seguimentos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
4.
Biol Pharm Bull ; 43(6): 976-984, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32188833

RESUMO

Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure-activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.


Assuntos
Alcaloides/química , Alcaloides/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Isoflavonas/química , Isoflavonas/farmacocinética , Alcaloides/sangue , Animais , Antineoplásicos/sangue , Azocinas/sangue , Azocinas/química , Azocinas/farmacocinética , Feminino , Isoflavonas/sangue , Fígado/metabolismo , Simulação de Acoplamento Molecular , Quinolizinas/sangue , Quinolizinas/química , Quinolizinas/farmacocinética , Ratos Sprague-Dawley , Distribuição Tecidual
5.
Mar Drugs ; 18(3)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121066

RESUMO

Fucoidans are a class of fucose-rich sulfated polysaccharides derived from brown macroalgae that exert a range of biological activities in vitro and in vivo. To generate an unbiased assessment of pathways and processes affected by fucoidan, a placebo-controlled double-blind pilot study was performed in healthy volunteers. Blood samples were taken immediately before and 24 h after ingestion of a single dose of 1 g of Undaria pinnatifida fucoidan (UPF) or placebo. Levels of isolated miRNAs were analyzed using Taqman Open Array Human MicroRNA panels. Out of 754 miRNAs screened, UPF affected a total of 53 miRNAs. Pathway analysis using the TALOS data analysis tool predicted 29 different pathways and processes that were largely grouped into cell surface receptor signaling, cancer-related pathways, the majority of which were previously associated with fucoidans. However, this analysis also identified nine pathways and processes that have not been associated with fucoidans before. Overall, this study illustrates that even a single dose of fucoidans has the potential to affect the expression of genes related to fundamental cellular processes. Moreover, it confirms previous data that fucoidans influence immunity, cancer cells, inflammation, and neurological function.


Assuntos
Antineoplásicos/farmacocinética , Polissacarídeos/farmacocinética , Administração Oral , Adulto , Idoso , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Polissacarídeos/administração & dosagem , Polissacarídeos/sangue , Alga Marinha
6.
PLoS One ; 15(3): e0228557, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32142553

RESUMO

Early diagnosis along with new drugs targeted to cancer receptors and immunocheckpoints have improved breast cancer survival. However, full remission remains elusive for metastatic breast cancer due to dose-limiting toxicities of heavily used, highly potent drug combinations such as gemcitabine and paclitaxel. Therefore, novel strategies that lower the effective dose and improve safety margins could enhance the effect of these drug combinations. To this end, we developed and evaluated a novel drug combination of gemcitabine and paclitaxel (GT). Leveraging a simple and scalable drug-combination nanoparticle platform (DcNP), we successfully prepared an injectable GT combination in DcNP (GT DcNP). Compared to a Cremophor EL/ethanol assisted drug suspension in buffer (CrEL), GT DcNP exhibits about 56-fold and 8.6-fold increases in plasma drug exposure (area under the curve, AUC) and apparent half-life of gemcitabine respectively, and a 2.9-fold increase of AUC for paclitaxel. Using 4T1 as a syngeneic model for breast cancer metastasis, we found that a single GT (20/2 mg/kg) dose in DcNP nearly eliminated colonization in the lungs. This effect was not achievable by a CrEL drug combination at a 5-fold higher dose (i.e., 100/10 mg/kg GT). A dose-response study indicates that GT DcNP provided a therapeutic index of ~15.8. Collectively, these data suggest that GT DcNP could be effective against advancing metastatic breast cancer with a margin of safety. As the DcNP formulation is intentionally designed to be simple, scalable, and long-acting, it may be suitable for clinical development to find effective treatment against metastatic breast cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Nanopartículas/química , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Linhagem Celular , Desoxicitidina/análogos & derivados , Desoxicitidina/sangue , Desoxicitidina/química , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Relação Dose-Resposta a Droga , Composição de Medicamentos , Sinergismo Farmacológico , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Paclitaxel/sangue , Paclitaxel/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Resultado do Tratamento
7.
Bioanalysis ; 12(3): 159-174, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32052636

RESUMO

Aim: A high throughput ultra-performance liquid chromatography (UPLC)-ultraviolet method for quantification of nintedanib in rat and human plasma was developed and optimized using chemometrical approach. Method: Design of experiment and multivariate statistical approach was used for definition of optimized method. Final separation was performed using protein precipitation method on ACQUITY HSS T3 C18 column in isocratic mode using potassium phosphate buffer (pH 7.5): acetonitrile. Results: Method was validated as per US-FDA guidelines linearly from 15-750 ng/ml. All quality control samples showed <15% relative standard deviation for precision and 85-115% accuracy along with >98% extraction recovery. Conclusion: The developed method is easily applicable in determining pharmacokinetic parameters in preclinical subjects along with successful implementation for quantification in human plasma samples.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Indóis/sangue , Animais , Antineoplásicos/farmacologia , Humanos , Indóis/farmacologia , Ratos
8.
Anticancer Res ; 40(2): 665-676, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014907

RESUMO

BACKGROUND/AIM: Sorafenib results in several adverse events, the mechanism and predictors of which are unknown. Recently, it was reported that metabolism by microbiome changes the structure and effects of drugs. The blood levels of sorafenib may be affected by enterohepatic recycling of sorafenib due to microbial enzymes in the gut. We evaluated the relationship between adverse events caused by sorafenib treatment and microbiome in patients with advanced hepatocellular carcinoma. MATERIALS AND METHODS: Twenty-five patients were classified into two groups based on the presence of hand-foot syndrome (HFS) or diarrhea within 12 weeks post-sorafenib treatment. Before sorafenib treatment, the fecal samples were analyzed targeting the V3-V4 region of 16s ribosomal RNA. Microbiome and predicted functional gene were compared between two groups. RESULTS: The non-HFS group had a richer abundance of Veillonella, Bacillus, Enterobacter, Faecalibacterium, Lachnospira, Dialister, and Anaerostipes than the HFS group at genus level. Carotenoid biosynthesis and bacterial invasion of epithelial cells were enriched in the HFS group. The former three bacteria are classified as oral-origin bacteria, and the two predicted functions are associated with dysbiosis. The non-diarrhea group had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae than the diarrhea group. Eight categories of predicted functional genes were detected with differences between the two groups. CONCLUSION: The non-HFS group had a higher relative abundance of oral-origin bacteria, which likely led to more robust dysbiosis in the gut. This dysbiosis may affect enterohepatic recycling. Additionally, the metabolism of these short-chain fatty acids in the gut may be different between the diarrhea and non-diarrhea groups.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/microbiologia , Microbiota , Sorafenibe/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Sorafenibe/administração & dosagem , Sorafenibe/sangue , Sorafenibe/farmacocinética
9.
Artigo em Inglês | MEDLINE | ID: mdl-31931326

RESUMO

Cabozantinib is a novel multi-target tyrosine kinase inhibitor recently approved in metastatic renal cell carcinoma (mRCC) leading to frequent severe toxicities requiring empirical dose reduction. Therapeutic drug monitoring (TDM) could help to predict the risk for severe toxicities by quickly detecting overexposed patients followed by prospective adaptive dosing strategy. To achieve this goal, a simple and rapid assay to monitor cabozantinib plasma concentration was developed and validated. After a single precipitation step with 87% recovery, cabozantinib was assayed by liquid chromatography tandem mass spectrometry (electrospray ionization interface) over a 25-5000 ng/ml range covering usual plasma levels in clinical setting. For cabozantinib and cabozantinib 2H4 used as internal standard, quantification was performed using the m/z 502 â†’ m/z 323 and m/z 506 â†’ m/z 323 transitions, respectively. Analytical runtime was 5 min. Both inter-days and intra-day accuracy and precision were <15%. When tested in routine clinical practice in a subset of mRCC patients treated with standard 60 mg quaque die (QD) dosing, the method proved to be fully adapted and neither analytical interferences nor matrix effect was observed. Results showed that cabozantinib trough levels were highly variable among patients (i.e., 973 ± 501 ng/ml, CV = 52%), calling for implementing TDM in patients with mRCC to monitor exposure levels and evaluate concentration-response relationship.


Assuntos
Anilidas/sangue , Antineoplásicos/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas/métodos , Piridinas/sangue , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Modelos Lineares , Piridinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
10.
Nat Commun ; 11(1): 567, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992692

RESUMO

Since the discovery of metal nanoparticles (NPs) in the 1960s, unknown toxicity, cost and the ethical hurdles of research in humans have hindered the translation of these NPs to clinical use. In this work, we demonstrate that Pt NPs with protein coronas are generated in vivo in human blood when a patient is treated with cisplatin. These self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body for an extended period of time. Additionally, the Pt NPs are safe for use in humans and can act as anti-cancer agents to inhibit chemotherapy-resistant tumor growth by consuming intracellular glutathione and activating apoptosis. The tumor inhibitory activity is greatly amplified when the Pt NPs are loaded in vitro with the chemotherapeutic drug, daunorubicin, and the formulation is effective even in daunorubicin-resistant models. These in vivo-generated metal NPs represent a biocompatible drug delivery platform for chemotherapy resistant tumor treatment.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacologia , Nanopartículas Metálicas/química , Platina/sangue , Platina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Daunorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Tolerância a Medicamentos , Feminino , Glutationa/metabolismo , Células Hep G2 , Humanos , Células K562 , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Tamanho da Partícula , Coroa de Proteína , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
11.
Biomed Chromatogr ; 34(3): e4758, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31758580

RESUMO

A sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of seven oral oncolytics (two PARP inhibitors, i.e. olaparib and niraparib, and five tyrosine kinase inhibitors, i.e. cobimetinib, cabozantinib, dabrafenib, vemurafenib and regorafenib, plus its active metabolite regorafenib M2) in EDTA plasma was developed and validated. Stable isotope-labelled internal standards were used for each analyte. A simple protein precipitation method was performed with acetonitrile. The LC-MS/MS system consisted of an Acquity H-Class UPLC system, coupled to a Xevo TQ-S micro tandem mass spectrometer. The compounds were separated on a Waters CORTECS UPLC C18 column (2.1 × 50 mm, 1.6 µm particle size) and eluted with a gradient elution system. The ions were detected in the multiple reaction monitoring mode. The method was validated for cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and regorafenib M2 over the ranges 6-1000, 100-5000, 10-4000, 200-2000, 200-20,000, 5000-100,000, 500-10,000 and 500-10,000 µg/L, respectively. Within-day accuracy values for all analytes ranged from 86.8 to 115.0% with a precision of <10.4%. Between-day accuracy values ranged between 89.7 and 111.9% with a between-day precision of <7.4%. The developed method was successfully used for guiding therapy with therapeutic drug monitoring in cancer patients and clinical research programs in our laboratory.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos/sangue , Espectrometria de Massas em Tandem/métodos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Monitoramento de Medicamentos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
Biomed Chromatogr ; 34(2): e4704, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629371

RESUMO

Abivertinib represents a highly selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor. Two major metabolites of abivertinib, M7 and MII-6, were detected in human plasma, which are recommended to be monitored for safety reasons in clinical trial. A high-throughput quantification method utilizing liquid chromatography-tandem mass spectrometry was designed and verified to quantify abivertinib's primary metabolites in human plasma. Solid-phase extraction was used to process the plasma, and then the analytes underwent a gradient elution separation in an Aquity UPLC BEH C18 column (1.7 µm, 2.1 × 50 mm) with mobile phase A (10 mm ammonium acetate containing 0.1% formic acid) and mobile phase B (methanol-acetonitrile, 2:8, v/v, with 0.1% formic acid). Ion transitions of M7 (m/z 490.2 → 405.1) and MII-6 (m/z 476.2 → 391.1) were monitored under multiple reaction monitoring mode and electrospray ionization in positive ion mode. This simultaneous determination method was found to have acceptable precision, accuracy and linearity in the 0.5-500 ng/mL range for M7 and the 0.5-500 ng/mL range for MII-6, accompanied by a mild matrix effect but high recovery. Further stability assessments indicated that both analytes remained stable throughout the entire experimental process from harvesting whole blood to plasma extraction and analysis.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estabilidade de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Limite de Detecção , Modelos Lineares , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Extração em Fase Sólida
13.
Clin Biochem ; 75: 40-47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669513

RESUMO

OBJECTIVES: Multiple myeloma (MM) is characterized by malignant growth of plasma cells, usually producing a monoclonal antibody (mAb). New treatments for MM include therapeutic monoclonal antibodies (tmAbs), but patients treated with tmAb demonstrate interference on serum electrophoresis (SPE) and immunoprecipitation electrophoresis (IEP). Evaluation of treatment efficacy and determination of MM remission include SPE and IEP which identifies mAb, but cannot differentiate between disease associated mAb and tmAb. We hypothesized that tmAb could be removed from patient sera before testing by SPE and IEP to provide accurate diagnoses for clinicians. DESIGN AND METHODS: We developed the Antigen Specific therapeutic monoclonal Antibody Depletion Assay (ASADA), that utilizes magnetic beads coated with the cognate antigen of the tmAbs, to deplete two different tmAb (daratumumab, elotuzumab) from saline and patient sera and assessed for complete removal of tmAb by SPE and IEP. RESULTS: We found that tmAb could be efficiently removed from saline and patient sera. ASADA demonstrated acceptable analytical specificity and sensitivity in IEP. Recovery of appropriate quantitative values by SPE was demonstrated with clinically acceptable precision. A single bead cocktail could be used to treat both daratumumab and elotuzumab. CONCLUSIONS: This demonstrates proof of principle that ASADA can be used to remove current and future tmAb from patient sera, regardless of platform. This research provides for accurate diagnosis, disease monitoring, and remission status in MM patients being treated with tmAb.


Assuntos
Métodos Analíticos de Preparação de Amostras , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Monitoramento de Medicamentos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Eletroforese das Proteínas Sanguíneas , Humanos , Imunoprecipitação , Mieloma Múltiplo/sangue , Recidiva , Resultado do Tratamento
14.
J Chromatogr Sci ; 57(10): 892-900, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31609432

RESUMO

Capecitabine is a prodrug of 5-fluorouracil, employed as a monotherapy or combination chemotherapy agent for treatment of colorectal cancer. Combination therapy of capecitabine consists of oxaliplatin, and hence, it becomes essential to determine that co-administration does not affect its metabolism. High-performance liquid chromatography and high-performance thin-layer chromatography methods were developed and validated to determine the plasma concentration of capecitabine. In this study, blood samples from 12 patients with colorectal cancer were collected and analyzed by both methods with a reference internal standard. Two groups consisting of six patients each were formed: the first group was treated with capecitabine monotherapy, the second group with capecitabine + oxaliplatin combination therapy. The results of analysis from both the methods indicated that there is no significant drug-drug interaction. The co-administration of oxaliplatin did not affect the metabolism of capecitabine. Both assay methods were compared for their sensitivity, robustness and specificity. It was found that both the assay methods were suitable for therapeutic drug monitoring of capecitabine.


Assuntos
Antineoplásicos , Capecitabina , Cromatografia Líquida de Alta Pressão/métodos , Neoplasias Colorretais/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Capecitabina/sangue , Capecitabina/farmacocinética , Capecitabina/uso terapêutico , Cromatografia em Camada Delgada , Interações Medicamentosas , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Oxaliplatina/sangue , Oxaliplatina/farmacocinética , Oxaliplatina/uso terapêutico , Reprodutibilidade dos Testes
15.
Eur J Pharm Sci ; 143: 105201, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31866565

RESUMO

The YSNSG peptide is a synthetic cyclopeptide targeting αvß3 integrin with antitumor activity. Previous study has determined main pharmacokinetic parameters in plasma and in tissue in healthy animals using microdialysis. First we aim to assess the impact of a 20 mg/kg dosage instead of 10 mg/kg in tumor growth inhibition. Secondly we aim to investigate the YSNSG peptide distribution in two different tumor regions in animals with melanoma. C57BL/6 mice were exposed at Days 8, 10 and 12 after melanoma cells implantation (B16F1) to different dosage of YSNSG peptide or control, respectively (n = 10 per group). Data analysis was performed at D16, 20 and 24 with a Nonlinear Mixed-Effects (NLME) approach. For pharmacokinetic study n = 8 mice (same disease condition) received YSNSG peptide by intravenous after insertion of two microdialysis probes in central peripheral region of tumor, respectively. Plasma and tissue samples were collected during 2 h. A non-compartmental analysis was performed to determine main pharmacokinetic parameters. There was a significant tumor growth inhibition in mice receiving 20 mg/kg vs Control (p < 0.02). Main plasma parameters were half-life elimination 25.8 ± 8.2 min, volume of distribution 11.9 ± 0.4 mL, clearance 19.8 ± 9.4 mL/h and area under the curve 1,173.6 µg.min/mL. Penetration rate of the YSNSG peptide from plasma to tumor tissue were 3.3 ± 2.1% and 3.4 ± 2.7% in central and peripheral, respectively. Contrary to subcutaneous distribution in healthy animals the distribution of the YSNSG peptide into tumoral tissue is low but seems non-heterogeneous between central and peripheral tumor region.


Assuntos
Antineoplásicos/farmacocinética , Melanoma/metabolismo , Peptídeos Cíclicos/farmacocinética , Administração Intravenosa , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Feminino , Melanoma/sangue , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos Endogâmicos C57BL , Microdiálise , Peptídeos Cíclicos/sangue , Peptídeos Cíclicos/uso terapêutico , Carga Tumoral/efeitos dos fármacos
16.
Biol Res Nurs ; 22(1): 126-138, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707784

RESUMO

OBJECTIVE: Accelerated brain aging has been proposed to explain cancer-related cognitive impairment, but empirical evidence for this relationship is lacking. The purpose of this study was to evaluate amyloid beta (Aß) and tau, biomarkers of neurodegeneration, in relation to cognition in breast cancer survivors (BCSs). We explored relationships among peripheral concentrations of Aß42, Aß-40, tau, and cytokines; cognitive function; and psychosomatic symptoms in a cohort of BCSs post-chemotherapy. METHODS: This secondary analysis of a cross-sectional study was conducted with 65 BCSs. Serum total Aß-42, Aß-40, and tau levels were measured with single molecule array technology. Cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon [IFN]-g, IL-10, IL-12, IL-13, IL1-b, IL-2, IL-4, IL-5, IL-7, and IL-8) were simultaneously measured in serum using multiplex assays. Cognitive function was measured with five standardized neuropsychological tests and psychosomatic symptoms (stress, loneliness, anxiety, depressive symptoms, fatigue, sleep quality, and daytime sleepiness) with self-report questionnaires. Data analyses included correlations and random forest regression (RFR). RESULTS: Significant correlations were identified among hip-to-waste ratio, number of treatment modalities, Aß-42, Aß-40, and tau levels (rs = .27-.35, ps < .05). RFR modeling including Aß-42, Aß-40, tau, and cytokines as features explained significant variance in cognitive function (R 2 = .71, F = 9.01, p < .0001) and psychosomatic symptoms (R 2 = .74, F = 10.22, p < .0001). CONCLUSIONS: This study suggests that neurodegenerative biomarkers interact with cytokines to influence cognitive functioning and psychosomatic symptoms in BCSs following chemotherapy, but additional research is needed.


Assuntos
Peptídeos beta-Amiloides/sangue , Antineoplásicos/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Cognição/efeitos dos fármacos , Citocinas/sangue , Proteínas tau/sangue , Adulto , Idoso , Antineoplásicos/sangue , Biomarcadores/sangue , Neoplasias da Mama/fisiopatologia , Sobreviventes de Câncer , Disfunção Cognitiva/induzido quimicamente , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
17.
Artigo em Inglês | MEDLINE | ID: mdl-31877431

RESUMO

Therapeutic drug monitoring is important in patients taking BCR-ABL and Bruton's tyrosine kinase inhibitors (TKIs). Some TKI active metabolites with long elimination half-lives, such as dihydrodiol ibrutinib (DHI), N-desmethyl imatinib (N-DI), and N-desmethyl ponatinib (N-DP), have been characterized, indicating that these active metabolites should be monitored along with the parent compounds. However, there are currently no methods for the simultaneous quantification of BCR-ABL and Bruton's TKIs and their three active metabolites. The present study aimed to develop and validate a method for the simultaneous quantification of nine pharmacologically active compounds (bosutinib, dasatinib, DHI, ibrutinib, imatinib, N-DI, N-DP, nilotinib, and ponatinib) using high-performance liquid chromatography-tandem mass spectrometry. A 150-µL sample of plasma was analyzed after purification with supported liquid extraction. The method has a run time of 7 min and was successfully validated over the following calibration ranges: 0.25-75 ng/mL for N-DP, 0.5-150 ng/mL for dasatinib and ponatinib, 10-3000 ng/mL for imatinib and nilotinib, and 1-300 ng/mL for the other analytes. Stability of the analytes after short- and long-term storage in the presence of plasma matrix was examined, and all analytes were found to be stable under all tested conditions. The recovery was ≥83%, and the relative standard deviation of internal-standard normalized matrix effects ranged from 3.9 to 13.9%. Dilution integrity up to 4-fold was ensured. The applicability of the method for all analytes was demonstrated using patient samples.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Monitoramento de Medicamentos/métodos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Inibidores de Proteínas Quinases/sangue , Adolescente , Compostos de Anilina/sangue , Compostos de Anilina/química , Compostos de Anilina/farmacocinética , Antineoplásicos/sangue , Antineoplásicos/química , Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Dasatinibe/sangue , Dasatinibe/química , Dasatinibe/farmacocinética , Humanos , Limite de Detecção , Modelos Lineares , Nitrilos/sangue , Nitrilos/química , Nitrilos/farmacocinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/sangue , Quinolinas/química , Quinolinas/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
18.
Int J Nanomedicine ; 14: 8445-8467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754301

RESUMO

Purpose: Over the past 30 years, no consistent survival benefits have been recorded for anticancer agents of advanced hepatocellular carcinoma (HCC), except for the multikinase inhibitor sorafenib (Nexavar®), which clinically achieves only ~3 months overall survival benefit. This modest benefit is attributed to limited aqueous solubility, slow dissolution rate and, consequently, limited absorption from the gastrointestinal tract. Thus, novel formulation modalities are in demand to improve the bioavailability of the drug to attack HCC in a more efficient manner. In the current study, we aimed to design a novel sorafenib-loaded carbon nanotubes (CNTs) formula that is able to improve the therapeutic efficacy of carried cargo against HCC and subsequently investigate the antitumour activity of this formula. Materials and methods: Sorafenib was loaded on functionalized CNTs through physical adsorption, and an alginate-based method was subsequently applied to microcapsulate the drug-loaded CNTs (CNTs-SFN). The therapeutic efficacy of the new formula was estimated and compared to that of conventional sorafenib, both in vitro (against HepG2 cells) and in vivo (in a DENA-induced HCC rat model). Results: The in vitro MTT anti-proliferative assay revealed that the drug-loaded CNTs formula was at least two-fold more cytotoxic towards HepG2 cells than was sorafenib itself. Moreover, the in vivo animal experiments proved that our innovative formula was superior to conventional sorafenib at all assessed end points. Circulating AFP-L3% was significantly decreased in the CNTs-SFN-MCs-treated group (14.0%) in comparison to that of the DENA (40.3%) and sorafenib (38.8%) groups. This superiority was further confirmed by Western blot analysis and immunofluorescence assessment of some HCC-relevant biomarkers. Conclusion: Our results firmly suggest the distinctive cancer-suppressive nature of CNTs-SFN-MCs, both against HepG2 cells in vitro and in a DENA-induced HCC rat model in vivo, with a preferential superiority over conventional sorafenib.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Fármacos , Neoplasias Hepáticas/tratamento farmacológico , Nanotubos de Carbono/química , Sorafenibe/uso terapêutico , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Peso Corporal/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Nanotubos de Carbono/ultraestrutura , Niacinamida/farmacologia , Ratos Wistar , Sorafenibe/sangue , Sorafenibe/farmacocinética , Sorafenibe/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
19.
Artigo em Inglês | MEDLINE | ID: mdl-31678788

RESUMO

Targeted therapies such as cabozantinib (CABO), pazopanib (PAZO), sorafenib (SORA), sunitinib (SUNI) and its main active metabolite N-desethyl-sunitinib (DST-SUNI), olaparib (OLA) and palbociclib (PALBO) display large pharmacokinetics variability impacting their responses in terms of efficacy or toxicity. For the monitoring of these drugs, an analytical method allowing to routinely measure their concentrations in human plasma is needed. Such a method has been developed and validated and is presented here. The chromatographic separation is achieved on a Zorbax Bonus-RP analytical column using an isocratic elution of 92% V/V of acetonitrile and 8% of water in 0.1% formic acid at a flow rate of 500 µl/min for 0.5 min and then 300 µl/min for 2 min. After a liquid-liquid extraction of plasma samples, a step of filtration is performed. This method was validated based on the EMA and French committee of accreditation guidelines. The analysis time is 2.5 min per run, and all analytes eluted within 0.53-1.61 min. The standard curves are linear over the range from 1 to 380 ng/ml for SUNI; from 4.3 to 450 ng/ml for DST-SUNI; from 6 to 1000 ng/ml for PALBO; from 75 to 5000 ng/ml for CABO, from 0.17 to 20 µg/ml for OLA; from 0.35 to 40 µg/ml for SORA and from 1.7 to 200 µg/ml for PAZO. The method also showed satisfactory results in terms precision (below 9.5% for within-run and below 13% for between-run) and accuracy (below 13.5% for within-run and below 14% for between-run). After sampling, all the compounds are stable in whole blood at ambient temperature at least for 6 h and plasma are stable for 48 h at ambient temperature or 4 °C. The method presented here allows to measure the concentrations of 7 targeted therapies in a routine setting. We moreover present here a method that is, to our knowledge, one of the first detailed method aimed at the measurement of palbociclib in human plasma in a routine setting, together with data useful for the management of samples in routine hospital practice.


Assuntos
Antineoplásicos , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos com 1 Anel , Antineoplásicos/sangue , Antineoplásicos/química , Antineoplásicos/metabolismo , Estabilidade de Medicamentos , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
20.
Int J Nanomedicine ; 14: 8073-8094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632019

RESUMO

Background and objective: Targeted drug delivery of nanoparticles decorated with site-specific recognition ligands is of considerable interest to minimize cytotoxicity of chemotherapeutics in the normal cells. The study was designed to develop CD-340 antibody-conjugated polylactic-co-glycolic acid (PLGA) nanoparticles loaded with a highly water-soluble potent anticancer drug, doxorubicin (DOX), to specifically deliver entrapped DOX to breast cancer cells. Methods: The study showed how to incorporate water-soluble drug in a hydrophobic PLGA (85:15) based matrix which otherwise shows poor drug loading due to leaching effect. The optimized formulation was covalently conjugated to anti-human epidermal growth factor receptor-2 (HER2) antibody (CD-340). Surface conjugation of the ligand was assessed by flow cytometry, confocal microscopy, and gel electrophoresis. Selectivity and cytotoxicity of the experimental nanoparticles were tested on human breast cancer cells SKBR-3, MCF-7, and MDA-MB-231. Both CD-340-conjugated and unconjugated nanoparticles were undergone in vitro and in vivo characterization. Result: Higher level of incorporation of DOX (8.5% W/W), which otherwise shows poor drug loading due to leaching effect of the highly water-soluble drug, was seen in this method. In HER2-overexpressing tumor xenograft model, radiolabeled antibody-conjugated nanoparticles showed preferentially more of the formulation accumulation in the tumor area when compared to the treatments with the unconjugated one or with the other control groups of mice. The ligand conjugated nanoparticles showed considerable potential in reduction of tumor growth and cardiac toxicity of DOX in mice, a prominent side-effect of the drug. Conclusion: In conclusion, CD-340-conjugated PLGA nanoparticles containing DOX preferentially delivered encapsulated drug to the breast cancer cells and in breast tumor and reduced the breast tumor cells by apoptosis. Site-specific delivery of the formulation to neoplastic cells did not affect normal cells and showed a drastic reduction of DOX-related cardiotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/uso terapêutico , Nanopartículas/química , Receptor ErbB-2/metabolismo , Carga Tumoral/efeitos dos fármacos , Animais , Anticorpos/metabolismo , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Cinética , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Distribuição Tecidual/efeitos dos fármacos
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