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1.
Medicine (Baltimore) ; 99(4): e18732, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977864

RESUMO

BACKGROUND: The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients were adults with newly diagnosed untreated, unresectable esophageal cancer in stages I to IV with lymph node metastases or cervical esophageal cancer. Patients received nedaplatin 25 mg/m per day on day 1-3, raltitrexed 3 mg/m on days 1 repeated every 21 days for 2 cycles, and combined concurrent radiotherapy (2 Gy/fraction, total dose of 60 Gy). RESULT: Thirty patients were included with squamous cell carcinoma. The median follow-up duration was 24 months. The overall response rate was 90%. The 1-year and 2-year overall survival rates for all patients were 70.4% and 55.7% with a median survival time of 30 months, and the median progression free survival was 20 month. The major toxicities were leukopenia and thrombopenia, with grade 3 to 4 leukopenia and thrombopenia were 50% and 30% of patients. CONCLUSION: Concurrent chemoradiotherapy with raltitrexed and nedaplatin agents frequently caused myelosuppression but was highly active and suggested to be a promising treatment option for locally advanced ESCC.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Quimiorradioterapia/métodos , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/terapia , Compostos Organoplatínicos/administração & dosagem , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta à Radiação , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Estudos Retrospectivos , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Resultado do Tratamento
2.
BJOG ; 127(3): 389-395, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31794098

RESUMO

OBJECTIVE: Presence of lung metastases in low-risk gestational trophoblastic neoplasia (GTN) is generally considered not to influence prognosis. However, in a recent study in the Netherlands, GTN patients with lung metastases had a higher recurrence rate and more disease-specific deaths compared with patients without metastases. The aim of the present study was to validate these findings in a different country. DESIGN: Historical cohort study. SETTING: Charing Cross Hospital, United Kingdom. POPULATION: A total of 1040 low-risk GTN patients treated with methotrexate (MTX) between 2002 and 2016 were identified: 65 with lung metastases (group 1) and 975 without metastases (group 2). METHODS: Baseline characteristics, MTX resistance, survival and recurrence rates were recorded and compared between both groups. MAIN OUTCOME MEASURES: MTX resistance, recurrence rate and survival. RESULTS: The occurrence of MTX resistance and median number of MTX courses to achieve remission was significantly higher in patients with lung metastases than patients without metastases (60% versus 38.9%, P = 0.001; and nine versus six courses, P < 0.001). All choriocarcinoma patients (n = 4) with lung metastases developed MTX resistance. The recurrence rate was also higher in group I (9.2% versus 2.7%; P = 0.012). Disease-specific survival was 100% in both groups. CONCLUSIONS: The presence of lung metastases at the start of MTX therapy is associated with increased incidence of MTX resistance and recurrence in low-risk GTN without affecting overall survival, which remains 100%. However, individuals with low-risk choriocarcinoma with lung metastases are likely to become resistant to MTX and primary multi-agent chemotherapy should be considered. TWEETABLE ABSTRACT: The presence of lung metastases appears to increase the risk of recurrence in low-risk GTN, but does not affect overall cure rates and survival.


Assuntos
Coriocarcinoma , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Doença Trofoblástica Gestacional , Neoplasias Pulmonares , Metotrexato , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Estudos de Coortes , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Gravidez , Recidiva , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Reino Unido/epidemiologia
4.
Support Care Cancer ; 27(12): 4389-4391, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31511982

RESUMO

BACKGROUND: Currently the entire treatment of a child with cancer is carried out in a specialized hospital. It would be ideal to conduct part of the treatment at home. This can only be done with adequately trained personnel. In the Netherlands, specialized pediatric oncology home care nurse practitioners have been trained to deliver this kind of care. Therefore, a pilot study was conducted to administer intravenous chemotherapy at home. PURPOSE: This study aimed to safely administer chemotherapy intravenously (iv) at home by specialized nurse practitioners and aimed to increase the quality of life (QOL) of the child and decrease the social burden in families with a child with acute lymphoblastic leukemia (ALL). METHOD: The pilot study was performed by well-trained home care nurse practitioners. Low-dose methotrexate iv and low-dose cytarabine iv were administered to 11 included children with ALL in their home environment. RESULTS: QOL increased whereas social burden decreased for patients and parents. Chemotherapy administration in the home environment was safe with the help of well-trained nurse practitioners. CONCLUSION: It is feasible to administer intravenous chemotherapy at home in a safe and efficient way. The role of the specialized pediatric oncology nurse practitioner is an essential one.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Serviços de Assistência Domiciliar/organização & administração , Profissionais de Enfermagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/enfermagem , Administração Intravenosa , Antimetabólitos Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Serviços de Assistência Domiciliar/normas , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Países Baixos , Projetos Piloto , Qualidade de Vida
5.
Hematol Oncol ; 37(4): 447-455, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385337

RESUMO

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m2 /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.


Assuntos
Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Causas de Morte , Decitabina/efeitos adversos , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Estudos Observacionais como Assunto/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do Tratamento
6.
Life Sci ; 233: 116750, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408659

RESUMO

AIM: Rheumatoid arthritis (RA) is the most widespread inflammatory arthropathy, which causes severe disability. It is highly important to ameliorate the side effects caused by different drugs used to treat RA. Therefore, this study assessed the potential role of ß-caryophyllene (BCP) in treating adjuvant-induced arthritis (AIA), increasing the efficacy of methotrexate (MTX) and/or leflunomide (LEF), and ameliorating their side effects. MATERIAL AND METHODS: AIA was induced in rats by injecting complete Freund's adjuvant. The rats were divided into different groups such as sham group; control group; monotherapy groups, including BCP (300 mg/kg), MTX (1 mg/kg), and LEF (10 mg/kg); and combined groups, including MTX + BCP, LEF + BCP, MTX + LEF, and MTX + LEF + BCP groups. KEY FINDINGS: Monotherapy with BCP or MTX or LEF as well as MTX + LEF significantly reduced paw thickness and arthritic index; the histopathological changes in hind paw joints were recovered; and oxidative stress and tumor necrosis factor-alpha (TNF-α) levels in arthritic rats were reduced. The co-administration of BCP and MTX and/or LEF significantly improved the therapeutic efficacy of MTX and/or LEF and significantly reduced the myelosuppressive and hepatotoxic effects of MTX and/or LEF. Taken together, BCP could be used with MTX and/or LEF for the treatment of RA to reduce the side effects of the drugs and increase their efficacy.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Imunossupressores/administração & dosagem , Leflunomida/administração & dosagem , Metotrexato/administração & dosagem , Sesquiterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antimetabólitos Antineoplásicos/efeitos adversos , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Quimioterapia Combinada , Imunossupressores/efeitos adversos , Leflunomida/efeitos adversos , Masculino , Metotrexato/efeitos adversos , Ratos , Ratos Wistar , Sesquiterpenos/administração & dosagem
7.
BMC Cancer ; 19(1): 640, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253124

RESUMO

BACKGROUND: In the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy. METHODS: A total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed. DISCUSSION: Liquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC. TRIAL REGISTRATION: The date of trial registration ( NCT03401957 ) in this study was January 17, 2018.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas ras/genética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Protocolos Clínicos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/secundário , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Biópsia Líquida , Mutação , Análise de Sobrevida , Resultado do Tratamento , Proteínas ras/sangue
8.
Bull Cancer ; 106(9): 759-775, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31253356

RESUMO

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Deficiência da Di-Hidropirimidina Desidrogenase/diagnóstico , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Fluoruracila/efeitos adversos , Pesquisas sobre Serviços de Saúde/estatística & dados numéricos , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biologia , Pesquisa Biomédica , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Neoplasias do Sistema Digestório/tratamento farmacológico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Feminino , Fluoruracila/uso terapêutico , França , Genótipo , Humanos , Oncologistas , Neoplasias Otorrinolaringológicas/tratamento farmacológico , Farmacovigilância , Guias de Prática Clínica como Assunto , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Mecanismo de Reembolso
9.
Chemotherapy ; 64(1): 42-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31163446

RESUMO

OBJECTIVES: We aimed to identify an optimal regimen for low-risk gestational trophoblastic neoplasia (LR-GTN) providing reduction in dosage and toxicity/side effects, enhancement of therapeutic efficacy, and a shorter treatment duration. METHODS: A total of 149 LR-GTN patients were enrolled in the affiliated Beijing Maternity Hospital of Capital Medical University from January 2014 to January 2017 and randomly divided into 3 groups with 50 cases in the methotrexate (MTX) group, 49 in actinomycin D (ACT-D) group, and 50 in ACT-D+MTX group. Follow-up recorded symptoms, physical and bimanual gynecological examinations, routine blood test, serum ß-HCG level, liver and renal functions, electrolytes, electrocardiogram before each treatment course, and pelvic and abdominal B-mode ultrasound or pelvic/abdominal/chest computed tomography. RESULTS: Serum complete remission (SCR) was 96.0, 87.8, and 83.7% for the ACT-D+MTX, ACT-D, and MTX groups, respectively, with SCR being highest in the ACT-D+MTX group, statistically higher than in the MTX group. Vomiting was the only side effect differing significantly by chemotherapy regimen, with a distinctly higher incidence in the ACT-D+MTX group compared with the MTX group (p = 0.028). The reduction rate of serum ß-HCG in the ACT-D+MTX group was significantly greater than in the other 2 groups. CONCLUSION: Combined ACT-D+MTX chemotherapy achieved overall better efficacy and showed less toxicity than ACT-D or MTX alone, and thus can be prioritized for the treatment of LR-GTN.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Dactinomicina/uso terapêutico , Doença Trofoblástica Gestacional/tratamento farmacológico , Metotrexato/uso terapêutico , Adulto , Antimetabólitos Antineoplásicos/efeitos adversos , Gonadotropina Coriônica/sangue , Dactinomicina/efeitos adversos , Quimioterapia Combinada , Feminino , Doença Trofoblástica Gestacional/patologia , Doenças Hematológicas/etiologia , Humanos , Modelos Logísticos , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Úlceras Orais/etiologia , Gravidez , Prognóstico , Resultado do Tratamento , Adulto Jovem
10.
Hematology ; 24(1): 507-515, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31242832

RESUMO

Background: Approximately, one-third of adult patients with acute myeloid leukemia (AML) are refractory to initial induction chemotherapy and relapse occurs in most patients who achieve remission. This study evaluates the efficacy of decitabine in the management of refractory or relapsed AML. Methods: After literature search in electronic databases (Google Scholar, Embase, Ovid, and PubMed) studies were selected by following pre-determined eligibility criteria. Random-effects meta-analyses were performed to achieve effect sizes of complete remission (CR) rate, response rate (RR), and median survival after therapy. Subgroup analyses were performed with regards to use of decitabine with either epigenetics-based therapy, molecular therapy or chemotherapy. Results: Twenty studies were included (310 patients; age 55.1 years [95% confidence interval (CI): 43.8, 66.4]; 57% [52%, 63%] males). Overall RR was 46.1% [95% CI: 36.1%, 56.1%]. Overall CR rate was 23.5% [95% CI: 22.1%, 24.9%] but was 14.85% [95% CI: 3.8%, 25.9%] for decitabine with epigenetics-based therapies, 15.4% [95% CI: 6.7%, 24.0%] for decitabine with immunotherapy or molecular therapy, 34.8% [95% CI: 18.7%, 50.9%] for decitabine with chemotherapy, and 37.5% [36.4%, 38.7%] for decitabine with chemotherapy and molecular therapy. Median survival was 7.2 months [95% CI: 5.17, 9.3]. Major adverse events were neutropenia, nausea/vomiting, infections, fatigue, febrile neutropenia, diarrhea, thrombocytopenia, anemia, anorexia, leukopenia, hemorrhage, and hyperglycemia. Conclusion: Decitabine in combination with chemotherapy or molecular therapy has shown efficacious properties in refractory or relapsed AML patients.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Decitabina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Terapia de Salvação , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Decitabina/farmacologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Fadiga/induzido quimicamente , Neutropenia Febril/induzido quimicamente , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Hiperglicemia/induzido quimicamente , Imunoterapia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão
11.
Surg Oncol ; 29: 97-101, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31196501

RESUMO

PURPOSES: Oral mucositis is one of the most common reasons for discontinuation of S-1 adjuvant chemotherapy after radical gastrectomy. Some studies suggest that nutritional support with amino acids may improve oral mucositis. We conducted a prospective, randomized clinical trial of patients who underwent adjuvant chemotherapy for gastric cancer to examine whether an oral elemental diet prevents chemotherapy associated oral mucositis and body weight loss. METHODS: Patients were randomly assigned to a group consuming Elental® (the treatment group, n = 11) or a control diet group (n = 11). Patients in the treatment group consumed one pack of Elental® per day during adjuvant chemotherapy. The primary endpoint was the presence and grade of oral mucositis. Secondary endpoints included adherence to Elental® based on the doses recorded in a diary, changes in nutrition parameters, and frequency and severity of adverse events. RESULTS: The incidence of oral mucositis was significantly lower in the treatment group (9.1%) than in the control group (27.3%). The median body weight loss in the treatment group was significantly smaller than that in the control group (P = .015). According to Kaplan-Meier estimates the treatment group was significantly associated with high cumulative S-1 continuation rates (log-rank P = .047). CONCLUSION: We conclude that the amino-acid-rich elemental diet Elental® may be useful as a countermeasure for S-1 adjuvant chemotherapy-induced mucositis.


Assuntos
Adenocarcinoma/tratamento farmacológico , Diarreia/prevenção & controle , Alimentos Formulados , Apoio Nutricional , Ácido Oxônico/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Estomatite/prevenção & controle , Tegafur/efeitos adversos , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Estudos de Casos e Controles , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/patologia , Estomatite/induzido quimicamente , Estomatite/epidemiologia , Adulto Jovem
12.
BMC Complement Altern Med ; 19(1): 126, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185967

RESUMO

BACKGROUND: Gut microbiota plays a crucial role in the treatment of gastrointestinal (GI) diseases such as chemotherapy-induced diarrhea (CID). Shenzhu Capsule (SZC) is a Chinese herbal formula, which is composed of Renshen (rhizomes of Panax ginseng C. A. Mey.) and Baizhu (rhizomes of Atractylodes macrocephala Koidz.). Many Chinese traditional anti-diarrheal formulae that contain Renshen and Baizhu are capable of effectively alleviating CID. However, the efficacy in vivo and potential mechanism of SZC (the form of compatibility of Renshen and Baizhu) in the treatment of CID had not been elucidated. Here, this study aimed to investigate whether SZC exhibited the anti-diarrheal activity, and whether gut microbiota was involved in the therapeutic effect of SZC on CID. METHODS: High performance liquid chromatography (HPLC), gas chromatography-mass spectrometer (GC-MS) and infrared spectroscopy (IR) analyses were used to characterize the extracted components in SZC. The mice were orally administrated with SZC in a preventive mode on the first 2 days of this experiment, and then intraperitoneally injected with 5-FU (40 mg/kg/d) for 6 days. SZC treatment lasted until the 3rd day after the end of 5-FU chemotherapy. We investigated the effects of SZC on body weights, diarrhea, thymus/spleen indexes, colonic tissues, and gut microbiota. Colonic histology was examined by hematoxylin-eosin (HE) staining. 16S rDNA Amplicon Sequencing was used to analyze the gut microbial structure from fecal samples. RESULTS: SZC significantly increased the body weights and thymus/spleen indexes, alleviated diarrhea, and reversed histopathological changes of colons. In addition, gut microbiota analysis revealed that the overall structure of gut microbiota in CID mice was disturbed, but reversed to the normal state after SZC treatment. At genus level, SZC significantly inhibited the growth of some potential pathogens associated with diarrhea, such as Clostridiumm, Bacteroides, Parabacteroides, Alloprevotella, Acinetobacter and Pseudomonas. CONCLUSIONS: In our study, these data illustrated that SZC inhibited the growth of many potential pathogens during the alleviation of CID. Gut microbial modulation was associated with the anti-diarrheal activity of SZC.


Assuntos
Atractylodes/química , Diarreia/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Panax/química , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Diarreia/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Fluoruracila/efeitos adversos , Masculino , Camundongos , Fitoterapia , Distribuição Aleatória , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 220: 117105, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31141767

RESUMO

Among the side effects of 5-fluorouracil (5-FU), the performance of the gastrointestinal reactions is faster and more obvious than others. In this work, the effects of 5-FU on the activities and conformational structures of the important digestive enzymes including α-amylase, pepsin and trypsin were studied to analyze the mechanism of the gastrointestinal adverse effects causing by 5-FU binding. The results showed that the enzymatic activity of pepsin was obviously reduced by the presence of 5-FU that bound directly to the enzyme activity cavity site. The molecular modeling and fluorescence quenching data indicated that the hydrophobic, polar and hydrogen bonding forces were involved in the ground state complex formation between proteases and 5-FU. In addition, 5-FU changed the tertiary structures of α-amylase, pepsin, and trypsin.


Assuntos
Fluoruracila/metabolismo , Fluoruracila/toxicidade , Pepsina A/metabolismo , Tripsina/metabolismo , alfa-Amilases/metabolismo , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/toxicidade , Domínio Catalítico , Fluoruracila/efeitos adversos , Modelos Moleculares , Pepsina A/química , Conformação Proteica , Espectrometria de Fluorescência , Suínos , Tripsina/química , alfa-Amilases/química
14.
PLoS One ; 14(5): e0212157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125338

RESUMO

BACKGROUND: The recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity. OBJECTIVES: To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established. DATA SOURCES: Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998-2018. METHODS: We included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included. RESULTS AND CONCLUSIONS: We included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9-25% of the ALL patients in two of the four included RCTs using 6TG doses of 40-60 mg/m2/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m2/day, NRH occurred in 14% of patients. At a 6TG dose of approximately 12 mg/m2/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m2/day are rarely associated with notable hepatotoxicity and can probably be considered safe.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doenças Inflamatórias Intestinais/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Tioguanina/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/terapia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Viés de Publicação , Tioguanina/uso terapêutico
15.
Blood Cells Mol Dis ; 77: 88-94, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31005752

RESUMO

Decitabine and low-dose chemotherapy are common treatments for intermediate and high risk myelodysplastic syndromes (MDS). In this study, we retrospectively assessed the efficacy and toxicity of the two regimens for MDS-refractory anemia with excess blasts (MDS-RAEB) patients. A total of 112 patients with a diagnosis of MDS-RAEB are included. The overall response (OR) and complete remission (CR) rate was comparable between the two groups (OR: 64.1% vs. 66.7%, p = 0.60; CR: 23.4% vs. 31.3%, p = 0.64). The OR rates of 20 mg/m2/day and 15 mg/m2/day decitabine regimen were comparable (69.0% vs. 60.0%, p = 0.46). Overall survival (OS) did not differ significantly between the groups (20.7 vs. 13.5 months, p = 0.17). In a subgroup analysis that included only patients at ≥60 years of age, survival benefit of decitabine was apparent (20.6 vs. 10.0 months, p = 0.03). In hematological toxicities, the lowest count of platelet in the decitabine group was higher significantly. And, the incidence of Grade 3-4 infection in the decitabine group was lower significantly. Our results demonstrate that both decitabine and low-dose chemotherapy are effective for MDS-RAEB, but decitabine was safer. Decitabine might be a better choice for patients at ≥60 years of age.


Assuntos
Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Anemia Refratária com Excesso de Blastos/mortalidade , Antimetabólitos Antineoplásicos/uso terapêutico , Decitabina/uso terapêutico , Adulto , Idoso , Anemia Refratária com Excesso de Blastos/diagnóstico , Anemia Refratária com Excesso de Blastos/etiologia , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Biomarcadores , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Feminino , Testes Genéticos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Razão de Chances , Prognóstico , Resultado do Tratamento
16.
BMJ Case Rep ; 12(4)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962211

RESUMO

A woman in her mid-70s with metastatic pancreatic adenocarcinoma presented with fatigue, nausea and bilateral leg swelling, 4 days after an intravenous gemcitabine infusion. Additional examination and laboratory tests showed mild hypertension, low haemoglobin, high lactate dehydrogenase, low platelet count and high serum creatinine. The patient was subsequently diagnosed with haemolytic uraemic syndrome (HUS), and gemcitabine administration was immediately ceased. The patient received a 5-day course of methylprednisolone, with a full recovery being made 10 days after diagnosis. Clinicians should be aware of the rare but serious complication of gemcitabine-induced HUS (GiHUS), as early diagnosis and management, which includes prompt discontinuation of gemcitabine, are crucial in promptly resolving this condition. This case report describes one treatment that can be used for the treatment of GiHUS, while briefly covering some other novel treatments that have been described in other studies.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Desoxicitidina/análogos & derivados , Síndrome Hemolítico-Urêmica/etiologia , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Glucocorticoides/administração & dosagem , Síndrome Hemolítico-Urêmica/terapia , Humanos , Metilprednisolona/administração & dosagem , Paclitaxel/administração & dosagem
17.
Biomed Pharmacother ; 112: 108725, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970523

RESUMO

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


Assuntos
Desenho de Drogas , Pró-Fármacos , Pseudomonas putida/genética , gama-Glutamil Hidrolase/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Clonagem Molecular , Estabilidade Enzimática , Terapia Enzimática/métodos , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Mutação Puntual , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , gama-Glutamil Hidrolase/imunologia , gama-Glutamil Hidrolase/uso terapêutico
18.
Biol Pharm Bull ; 42(4): 594-600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930418

RESUMO

Sex-related incidence and outcomes were reported in various cancers, including colorectal cancer. 5-Fluorouracil (5-FU) is widely used as an essential chemotherapeutic agent for colorectal cancer. However, sex-based differences in 5-FU toxicity have yet to be reported in human cancer cell lines and xenograft mouse models to date. Here, we investigated, for the first time, sex-based differences in 5-FU toxicity using human colon cancer cell lines, xenograft mouse models, and Korean patients' data. Female-derived colon cancer cell lines exhibited greater 5-FU-induced cytotoxicity than male-derived colon cancer cell lines. We established two xenograft mouse models: one with a male-derived human colon cancer cell line injected into male mice (a male-xenograft model) and another involving a female-derived human colon cancer cell line injected into female mice (a female xenograft model). Treatment with 5-FU inhibited tumor growth and led to hematological toxicity in a female xenograft model more potently than in a male xenograft model. We analyzed the data obtained from Korean patients with colorectal cancer to examine sex differences in adverse drug reactions caused by 5-FU. Korean female patients with colorectal cancer who received 5-FU chemotherapy experienced more frequent adverse drug reactions including alopecia and leukopenia than male patients. Taken together, we demonstrated that female may be associated with increased risk of toxicity to 5-FU treatment in colorectal cancer based on in vitro and in vivo investigations and clinical data analysis. Our study suggests sex as an important clinical factor, which predicts induction of toxicity related to 5-FU treatment.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Idoso , Animais , Grupo com Ancestrais do Continente Asiático , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Caracteres Sexuais , Carga Tumoral
19.
AAPS PharmSciTech ; 20(5): 171, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004239

RESUMO

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


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Administração Tópica , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Lipossomos , Masculino , Metotrexato/efeitos adversos , Tamanho da Partícula , Ratos , Ratos Wistar , Absorção Cutânea
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