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1.
Rev. chil. infectol ; 40(4): 328-333, ago. 2023. tab, graf
Article in Spanish | LILACS | ID: biblio-1521844

ABSTRACT

INTRODUCCIÓN: La infección por citomegalovirus (CMV) sigue siendo la infección con relevancia clínica más frecuente luego del trasplante alogénico de progenitores hematopoyéticos (TPHa), presentando alta morbilidad y mortalidad. Por este motivo, es importante implementar estrategias de prevención para reducir la frecuencia de la infección por CMV. OBJETIVO: Describir la frecuencia de infección, infección clínicamente significativa (ICS) y enfermedad por CMV en pacientes seropositivos que recibieron un TPHa y profilaxis primaria con letermovir. PACIENTES Y MÉTODOS: Estudio descriptivo de cohorte longitudinal, en pacientes con TPHa seropositivos para CMV que recibieron profilaxis primaria con letermovir hasta el día 100 posTPH. RESULTADOS: Se incluyeron 25 pacientes adultos con una mediana de edad de 41 años, el 44% fue de donante no relacionado y 36% de donante haploidéntico. Ochenta por ciento tenía tres o más factores de riesgo para infección por CMV y a 52% se le estratificó como de alto riesgo para enfermedad por CMV. La profilaxis con letermovir tuvo una mediana de duración de 97 días. Durante los 100 días pos-TPH, 20% de los pacientes presentaron infección por CMV, con carga viral plasmática detectable no cuantificable, que se negativizó en el siguiente control semanal sin discontinuación del letermovir. Ningún paciente presentó ICS ni enfermedad por CMV durante este período. CONCLUSIÓN: La profilaxis con letermovir fue efectiva para prevenir la ICS y la enfermedad por CMV.


BACKGROUND: Cytomegalovirus (CMV) infection remains the most common clinically significant infection after allogeneic stem cell transplantation (aSCT), with a high morbidity and mortality rate. In order to reduce its frequency, prevention strategies should be implemented. AIM: To describe the frequency of infection, clinically significant infection (CSI) and CMV disease in seropositive patients who received aSCT and primary prophylaxis with letermovir. METHODS: Longitudinal descriptive cohort study in seropositive patients who received aSCT and primary prophylaxis with letermovir until day 100 post-SCT. RESULTS: Twenty-five adult patients with a median age of 41 years were included; 44% were unrelated donors, and 36% were haploidentical donors. Eighty percent had three or more risk factors for CMV infection, and 52% were stratified as high risk for CMV disease. Letermovir prophylaxis had a median duration of 97 days. Twenty percent of the patients developed CMV infection through day 100 post-SCT, with detectable non-quantifiable CMV viral load in plasma. This became negative in the following weekly control without discontinuation of letermovir. No patient developed CSI or CMV organ disease during this period. CONCLUSION: Letermovir prophylaxis proved to be effective in preventing CSI and CMV disease.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Antiviral Agents/administration & dosage , Cytomegalovirus Infections/prevention & control , Cytomegalovirus Infections/epidemiology , Hematopoietic Stem Cell Transplantation , Quinazolines/administration & dosage , Longitudinal Studies , Chemoprevention , Acetates/administration & dosage
2.
Chinese Journal of Oncology ; (12): 779-786, 2023.
Article in Chinese | WPRIM | ID: wpr-1045813

ABSTRACT

Objective: To screen the key genes involved in gefitinib resistance of lung adenocarcinoma PC9/GR cells which harbored 19 exon mutation of epidermal growth factor receptor (EGFR) gene, and discuss the effect and mechanism of downregulation of solute carrier family 7 member 11 (SLC7A11) on the gefitinib resistance of PC9/GR cells. Methods: RNA microarray was conducted to detect the gene expressions in PC9 and PC9/GR cells. The differently expressed genes were screened by using limma package of R language and analyzed by Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Western blotting was performed to determine the expression of SLC7A11 protein in PC9 and PC9/GR cells. PC9/GR cells were infected with lentivirus plasmid containing short hairpin RNA (shRNA) targeting SLC7A11 or negative control shRNA (sh-NC), respectively. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the efficacy of shRNA on the expression of SLC7A11 mRNA. Cell counting kit-8 (CCK-8) assay was conducted to determine the suppressing effect of gefitinib on PC9/GR cells. Mito-Tracker Red CMXRos probe and malondialdehyde (MDA) assay kit were used to evaluate gefitinib-induced ferroptosis in PC9/GR cells. Immunohistochemistry (IHC) was conducted to detect the expression of SLC7A11 protein in the tumor tissues of advanced stage lung adenocarcinoma patients harboring 19 exon mutation of EGFR gene. Thirty-six advanced stage lung adenocarcinoma patients who received EGFR-tyrosihe kinase inhibitor(TKI) as first-line treatment in Fourth Hospital of Hebei Medical Unviersity were enrolled. Kaplan-Meier survival curve was drawn to analyze the correlation between SLC7A11 expression and progression-free survival (PFS) of the patients. Results: RNA array demonstrated that 2 888 genes were differently expressed between PC9 and PC9/GR cells. KEGG analysis showed that ferroptosis-related gene was one of the most enriched region of the differently expressed genes between PC9 and PC9/GR cells. These ferroptosis-related gene cohort contained 13 genes, among which SLC7A11 exhibited the most significant difference. Western blotting showed that the expression of SLC7A11 protein in PC9/GR cells was significantly higher than that in PC9 cells (0.76±0.03 vs. 0.19±0.02, P<0.001). The 50% inhibiting concentration (IC(50)) of gefitinib was 35.08 μmol/L and 64.01 μmol/L for sh-SLC7A11 and sh-NC group PC9/GR cells, respectively. PC9/GR cells in sh-SLC7A11 group exhibited significantly lower density of mitochondria fluorescence after gefitinib treatment, compared to the sh-NC group (213.77±26.50 vs. 47.88±4.55, P<0.001). In addition, PC9/GR cells in sh-SLC7A11 group exhibited significantly higher MDA after gefitinib treatment, compared to the sh-NC group [(15.43±1.60) μmol/mg vs. (82.18±7.77) μmol/mg, P<0.001]. The PFS of the patients with low expression of SLC7A11 (n=18) was significantly longer than the patients with high expression of SLC7A11 (n=18, 16.77 months vs. 9.14 months, P<0.001). Conclusion: Downregulation of SLC7A11 could increase the sensitivity of PC9/GR cells to gefitinib by promoting ferroptosis.


Subject(s)
Humans , Gefitinib/therapeutic use , Antineoplastic Agents/therapeutic use , Lung Neoplasms/pathology , Down-Regulation , Quinazolines/therapeutic use , Drug Resistance, Neoplasm/genetics , ErbB Receptors/metabolism , Adenocarcinoma of Lung , Protein Kinase Inhibitors/therapeutic use , RNA, Small Interfering/genetics , Cell Line, Tumor , Amino Acid Transport System y+/metabolism
3.
Chinese Journal of Oncology ; (12): 779-786, 2023.
Article in Chinese | WPRIM | ID: wpr-1046136

ABSTRACT

Objective: To screen the key genes involved in gefitinib resistance of lung adenocarcinoma PC9/GR cells which harbored 19 exon mutation of epidermal growth factor receptor (EGFR) gene, and discuss the effect and mechanism of downregulation of solute carrier family 7 member 11 (SLC7A11) on the gefitinib resistance of PC9/GR cells. Methods: RNA microarray was conducted to detect the gene expressions in PC9 and PC9/GR cells. The differently expressed genes were screened by using limma package of R language and analyzed by Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Western blotting was performed to determine the expression of SLC7A11 protein in PC9 and PC9/GR cells. PC9/GR cells were infected with lentivirus plasmid containing short hairpin RNA (shRNA) targeting SLC7A11 or negative control shRNA (sh-NC), respectively. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the efficacy of shRNA on the expression of SLC7A11 mRNA. Cell counting kit-8 (CCK-8) assay was conducted to determine the suppressing effect of gefitinib on PC9/GR cells. Mito-Tracker Red CMXRos probe and malondialdehyde (MDA) assay kit were used to evaluate gefitinib-induced ferroptosis in PC9/GR cells. Immunohistochemistry (IHC) was conducted to detect the expression of SLC7A11 protein in the tumor tissues of advanced stage lung adenocarcinoma patients harboring 19 exon mutation of EGFR gene. Thirty-six advanced stage lung adenocarcinoma patients who received EGFR-tyrosihe kinase inhibitor(TKI) as first-line treatment in Fourth Hospital of Hebei Medical Unviersity were enrolled. Kaplan-Meier survival curve was drawn to analyze the correlation between SLC7A11 expression and progression-free survival (PFS) of the patients. Results: RNA array demonstrated that 2 888 genes were differently expressed between PC9 and PC9/GR cells. KEGG analysis showed that ferroptosis-related gene was one of the most enriched region of the differently expressed genes between PC9 and PC9/GR cells. These ferroptosis-related gene cohort contained 13 genes, among which SLC7A11 exhibited the most significant difference. Western blotting showed that the expression of SLC7A11 protein in PC9/GR cells was significantly higher than that in PC9 cells (0.76±0.03 vs. 0.19±0.02, P<0.001). The 50% inhibiting concentration (IC(50)) of gefitinib was 35.08 μmol/L and 64.01 μmol/L for sh-SLC7A11 and sh-NC group PC9/GR cells, respectively. PC9/GR cells in sh-SLC7A11 group exhibited significantly lower density of mitochondria fluorescence after gefitinib treatment, compared to the sh-NC group (213.77±26.50 vs. 47.88±4.55, P<0.001). In addition, PC9/GR cells in sh-SLC7A11 group exhibited significantly higher MDA after gefitinib treatment, compared to the sh-NC group [(15.43±1.60) μmol/mg vs. (82.18±7.77) μmol/mg, P<0.001]. The PFS of the patients with low expression of SLC7A11 (n=18) was significantly longer than the patients with high expression of SLC7A11 (n=18, 16.77 months vs. 9.14 months, P<0.001). Conclusion: Downregulation of SLC7A11 could increase the sensitivity of PC9/GR cells to gefitinib by promoting ferroptosis.


Subject(s)
Humans , Gefitinib/therapeutic use , Antineoplastic Agents/therapeutic use , Lung Neoplasms/pathology , Down-Regulation , Quinazolines/therapeutic use , Drug Resistance, Neoplasm/genetics , ErbB Receptors/metabolism , Adenocarcinoma of Lung , Protein Kinase Inhibitors/therapeutic use , RNA, Small Interfering/genetics , Cell Line, Tumor , Amino Acid Transport System y+/metabolism
5.
Article in Chinese | WPRIM | ID: wpr-921665

ABSTRACT

Evodiamine, a bioactive indole alkaloid from Evodia rutaecarpa, E. rutaecarpa var. officinalis, or E. rutaecarpa var. bodinieri, has been extensively investigated due to its pharmacological activities in recent years. At present, evodiamine is proved to significantly suppress the proliferation of a variety of cancer cells and mediate cell processes such as cell cycle arrest and cell migration. In addition, evodiamine displays significant pharmacological activities against cardiovascular diseases(hyperlipidemia, etc.), and tinea manus and pedis. Recently, evodiamine has been found to have potential toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiotoxicity. However, the pharmacological and toxicological mechanism of evodiamine is not clear, and its toxicity in vitro and in vivo has been rarely reported. Therefore, this study reviewed the pharmacological and toxicological articles of evodiamine in recent years, aiming at providing new ideas and references for future research.


Subject(s)
Humans , Evodia , Hand Dermatoses , Plant Extracts , Quinazolines/toxicity , Tinea
6.
Article in Chinese | WPRIM | ID: wpr-942305

ABSTRACT

OBJECTIVE@#To investigate evodiamine (EVO)-induced hepatotoxicity and the underlying mechanism.@*METHODS@#HepG2 cells were treated with EVO (0.04-25 μmol/L) for different time intervals, and the cell survival rate was examined by cell counting kit-8 (CCK-8) method. After HepG2 cells were treated with EVO (0.2, 1 and 5 μmol/L) for 48 h, the alanine transaminase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) activities and total bilirubin (TBIL) content of supernatant were detected. A multifunctional microplate reader was used to detect the intracellular superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in HepG2 cells to evaluate the level of cell lipid peroxidation damage. The interactions between EVO and apoptosis, autophagy or ferroptosis-associated proteins were simulated by molecular docking. The HepG2 cells were stained by mitochondrial membrane potential (MMP) fluorescent probe (JC-10) and annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI), and MMP and apoptosis in HepG2 cells were detected by flow cytometry. The protein expression levels of caspase-9, caspase-3, bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) were detected by Western blot.@*RESULTS@#The cell survival rate was significantly reduced after the HepG2 cells were exposed to EVO (0.04-25 μmol/L) in a time- and dose-dependent manner. The half maximal inhibitory concentration (IC50) of the HepG2 cells treated with EVO for 24, 48 and 72 h were 85.3, 6.6 and 4.7 μmol/L, respectively. After exposure to EVO (0.2, 1 and 5 μmol/L) for 48 h, the ALT, AST, LDH, ALP activities and TBIL content in the HepG2 cell culture supernatant, and the MDA content in the cells were increased, and SOD enzyme activity was decreased. Molecular docking results showed that EVO interacted with apoptosis-associated proteins (caspase-9 and caspase-3) better. JC-10 and Annexin V-FITC/PI staining assays demonstrated that EVO could decrease MMP and promote apoptosis in the HepG2 cells. Western blot results indicated that the protein expressions of cleaved caspase-9 and cleaved caspase-3 were upregulated in the HepG2 cell treated with EVO for 48 h. In contrast, the protein expressions of pro-caspase-3, BSEP and MRP2 were downregulated.@*CONCLUSION@#These results suggested that 0.2, 1 and 5 μmol/L EVO had the potential hepatotoxicity, and the possible mechanism involved lipid peroxidation damage, cell apoptosis, and cholestasis.


Subject(s)
Humans , ATP Binding Cassette Transporter, Subfamily B, Member 11 , Apoptosis , Caspase 3 , Caspase 9 , Cholestasis , Hep G2 Cells/drug effects , Lipid Peroxidation , Liver/drug effects , Molecular Docking Simulation , Multidrug Resistance-Associated Protein 2 , Quinazolines/toxicity
7.
Braz. j. infect. dis ; 24(2): 150-159, Mar.-Apr. 2020. tab, graf
Article in English | LILACS, ColecionaSUS | ID: biblio-1132431

ABSTRACT

ABSTRACT Background: Latent HIV-1 is a major hurdle in obtaining HIV-1 sustained virological remission (SVR). Here we explored histone deacetylation inhibition property of nicotinamide (NAM; n = 17) for the first time in comparison to a combination of methyltransferase inhibitors (MTIs; Chaetocin and BIX01294; n = 25) to reactivate latent HIV ex vivo in CD8-depleted PBMCs from antiretroviral treated aviremic individuals. Results: NAM reactivated HIV-1 from 13/17 (76.4%) samples compared to 20/25 (80.0%) using MTIs with mean viral load (VLs) of 4.32 and 3.22 log10 RNA copies/mL, respectively (p = 0.004). Mean purging time after NAM and MTIs stimulation was 5.1 and 6.75 days, respectively (p = 0.73). Viral purging in autologous cultures exhibited blunted HIV recovery with fluctuating VLs followed by a complete viral extinction when expanded in allogenic system. Electron microscopy from five supernatants revealed anomalous viral particles, with lack of complete viral genomes when characterized by ultradeep sequencing through metagenomics approach (n = 4). Conclusion: NAM alone was more potent HIV-1 activator than combination of MTIs, with potential of clinical use.


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Young Adult , Quinazolines/pharmacology , Azepines/pharmacology , Virus Activation/drug effects , HIV Infections/virology , HIV-1/drug effects , Niacinamide/pharmacology , Methyltransferases/antagonists & inhibitors , Piperazines/pharmacology , Leukocytes, Mononuclear/virology , CD4-Positive T-Lymphocytes , Gene Expression Regulation, Viral , Virus Latency , Viral Load/drug effects , Viral Tropism/drug effects
8.
Article in Chinese | WPRIM | ID: wpr-828005

ABSTRACT

This study aimed to prepare evodiamine-glycyrrhizic acid(EVO-GL) micelles to enhance the anti-hepatic fibrosis activity of evodiamine. Firstly, EVO-GL micelles were prepared with use of thin film dispersion method. With particle size, encapsulation efficiency, loading capacity of micelles and the solubility of evodiamine as the indexes, the effect of different factors on micelles was observed to screen the optimal preparation methods and process. Then the pharmaceutical properties and the therapeutic effects of EVO-GL micelles prepared by optimal process were evaluated on CCl_4-induced hepatic fibrosis. The results showed that the micelles prepared by the thin film dispersion method had an even size, with an average particle size of(130.80±12.40)nm, Zeta potential of(-41.61±3.12) mV, encapsulation efficiency of 91.23%±1.22%, drug loading of 8.42%±0.71%, high storage stability at 4 ℃ in 3 months, and slow in vitro release. Experimental results in the treatment of CCl_4-induced hepatic fibrosis in rats showed that EVO-GL micelles had a synergistic anti-hepatic fibrosis effect, which significantly reduced the liver function index of hepatic fibrosis rats. In conclusion, the EVO-GL micelles prepared with glycyrrhizic acid as a carrier would have a potential application prospect for the treatment of hepatic fibrosis.


Subject(s)
Animals , Rats , Drug Carriers , Glycyrrhizic Acid , Liver Cirrhosis , Micelles , Particle Size , Quinazolines , Solubility
9.
São Paulo med. j ; 137(6): 505-511, Nov.-Dec. 2019. tab, graf
Article in English | LILACS | ID: biblio-1094519

ABSTRACT

ABSTRACT BACKGROUND: Lung cancer is the fourth most common cancer in Brazil. In the 2000s, better understanding of molecular pathways led to development of epidermal growth factor receptor (EGFR)-targeted treatments that have improved outcomes. However, these treatments are unavailable in most Brazilian public healthcare services (Sistema Único de Saúde, SUS). OBJECTIVE: To assess the potential number of years of life not saved, the budget impact of the treatment and strategies to improve access. DESIGN AND SETTING: Pharmacoeconomic study assessing the potential societal and economic impact of adopting EGFR-targeted therapy within SUS. METHODS: We estimated the number of cases eligible for treatment, using epidemiological data from the National Cancer Institute. We used data from a single meta-analysis and from the Lung Cancer Mutation Consortium (LCMC) study as the basis for assessing differences in patients' survival between use of targeted therapy and use of chemotherapy. The costs of targeted treatment were based on the national reference and were compared with the amount reimbursed for chemotherapy through SUS. RESULTS: There was no life-year gain with EGFR-targeted therapy in the single meta-analysis (hazard ratio, HR, 1.01). The LCMC showed that 1,556 potential life-years were not saved annually. We estimated that the annual budget impact was 125 million Brazilian reais (BRL) with erlotinib, 48 million BRL with gefitinib and 52 million BRL with afatinib. Their incremental costs over chemotherapy per life-year saved were 80,329 BRL, 31,011 BRL and 33,225 BRL, respectively. A drug acquisition discount may decrease the budget impact by 30% (with a 20% discount). A fixed cost of 1,000 BRL may decrease the budget impact by 95%. CONCLUSION: Reducing drug acquisition costs may improve access to EGFR-targeted therapy for lung cancer.


Subject(s)
Humans , Health Care Costs , Quality-Adjusted Life Years , Protein Kinase Inhibitors/economics , ErbB Receptors/economics , Lung Neoplasms/economics , Quinazolines/economics , Quinazolines/therapeutic use , Brazil , Budgets , Survival Analysis , Cost-Benefit Analysis/economics , Risk Sharing, Financial/methods , Protein Kinase Inhibitors/therapeutic use , Molecular Targeted Therapy/economics , ErbB Receptors/therapeutic use , Health Services Accessibility/economics , Lung Neoplasms/mortality , Lung Neoplasms/drug therapy
10.
Article in Chinese | WPRIM | ID: wpr-776537

ABSTRACT

OBJECTIVE@#To investigate the effects of rutaecarpine on high glucose-induced Alzheimer's disease-like pathological and cognitive dysfunction and its mechanism in rats.@*METHODS@#Adult male SD rats were randomly divided into three groups (n=20): control group, high glucose group and rutaecarpine group. Rats in the control group were fed with conventional feed and tap water. The rats in the high glucose group were fed with conventional feed and 20% sucrose water. The rutaecarpine group was fed with fodder contain 0.01% rutaecarpine and 20% sucrose water. Morris water maze test was used to detect learning and memory and cognitive function of three groups rats after 24 weeks of feeding. Western blot analysis was used to detect tau protein at Thr205 and Ser214 sites in each group. Phosphorylation levels of GSK-3β in serine 9 site (S9-GSK-3β) and PP2A at cycline 307 site (Y307-PP2AC) were also detected. Immunohistochemistry further confirmed tau protein at Thr205 site in each group both in hippocampus and cortex.@*RESULTS@#Compared with the control group, Morris water maze results showed that the latency of finding the hidden platform of the rats in high glucose group was increased significantly and the number of crossing platforms and the target quadrant residence time were significantly decreased (all P<0.05). Immunohistochemistry showed that the phosphorylation level of tau protein at Thr205 site was significantly increased in the high glucose group compared with the control group, and the phosphorylation level of tau protein at Thr205 site in the rutaecarpine group was higher than that in the high glucose group. Western blot analysis showed that the phosphorylation level of tau protein in the high glucose group was significantly increased at Thr205 and Ser214 site compared with the control group, but the phosphorylation level of pS9-GSK-3β was significantly decreased (all P <0.05). Compared with the high glucose group, the latency of finding the hidden platform of the rats in rutaecarpine group was significantly decreased, and the number of crossing platforms and the target quadrant residence time were significantly increased (both P<0.05). Compared with the high glucose group, the phosphorylation levels of tau protein at Thr205 and Ser214 sites showed a significant decrease, but the phosphorylation level of pS9-GSK-3β was significantly increased (all P<0.05).@*CONCLUSION@#Rutaecarpine can alleviate AD-like cognitive dysfunction induced by high glucose, possibly by enhancing pS9-GSK-3β phosphorylation, down-regulating GSK-3β activity, and thus reducing hyperphosphorylation of tau-associated sites.


Subject(s)
Animals , Male , Rats , Alzheimer Disease , Drug Therapy , Cognitive Dysfunction , Drug Therapy , Glucose , Glycogen Synthase Kinase 3 beta , Chemistry , Indole Alkaloids , Pharmacology , Maze Learning , Phosphorylation , Quinazolines , Pharmacology , Random Allocation , Rats, Sprague-Dawley , tau Proteins , Chemistry
11.
Article in English | WPRIM | ID: wpr-1008980

ABSTRACT

A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor (EGFR) 19 del mutation positive. Treatment with icotinib was given, but her disease progressed after 6 months remission. CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis, and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) confirmed EGFR T790M mutation. Treatment with osimertinib was initiated. After 2 months remission, the disease progressed. Re-biopsy was performed for the tumor in the inferior lobe of left lung, and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del. Icotinib was re-challenged, but disease progressed continuously. Bevacizumab was added, and partial response was achieved after 2-cycle of combination therapy. The non-small cell lung cancer (NSCLC) in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment. This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.


Subject(s)
Female , Humans , Middle Aged , Acrylamides/therapeutic use , Adenocarcinoma of Lung/pathology , Aniline Compounds/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Crown Ethers/therapeutic use , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/pathology , Quinazolines/therapeutic use , Tomography, X-Ray Computed , Treatment Outcome
12.
Arch. endocrinol. metab. (Online) ; 62(6): 636-640, Dec. 2018. tab, graf
Article in English | LILACS | ID: biblio-983805

ABSTRACT

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Young Adult , Piperidines/adverse effects , Quinazolines/adverse effects , Carcinoma/drug therapy , Carcinoma, Medullary/drug therapy , Protein Kinase Inhibitors/adverse effects , Antineoplastic Agents/adverse effects , Oophoritis/chemically induced , Phenylurea Compounds/adverse effects , Quinolines/adverse effects , Thrombocytopenia/chemically induced , Time Factors , Thyroid Neoplasms/drug therapy , Retrospective Studies , Risk Factors , Follow-Up Studies , Kaplan-Meier Estimate , Sorafenib/adverse effects , Heart Failure/chemically induced , Intestinal Perforation/chemically induced
13.
Int. braz. j. urol ; 44(3): 600-607, May-June 2018. tab, graf
Article in English | LILACS | ID: biblio-954052

ABSTRACT

ABSTRACT Objectives: Apoptosis effect of oral alpha-blockers is known in the prostate. Apoptosis index of silodosin has not been proved, yet. Aims are to present apoptosis index of silodosin in prostate and to compare this with other currently used alpha-blocker's apoptosis indexes together with their clinical effects. Materials and Methods: Benign prostatic hyperplasia (BPH) patients were enrolled among those admitted to urology outpatient clinic between June 2014 and June 2015. Study groups were created according to randomly prescribed oral alpha-blocker drugs as silodosin 8mg (Group 1; n=24), tamsulosin 0.4mg (Group 2; n=30), alfuzosin 10mg (Group 3; n=25), doxazosin 8mg (Group 4; n=22), terazosin 5mg (Group 5; n=15). Pa- tients who refused to use any alpha-blocker drug were included into Group 6 as control group (n=16). We investigated apoptosis indexes of the drugs in prostatic tissues that were taken from patient's surgery (transurethral resection of prostate) and/or prostate biopsies. Immunochemical dyeing, light microscope, and Image Processing and Analy- sis in Java were used for evaluations. Statistical significant p was p<0.05. Results: There were 132 patients with mean follow-up of 4.2±2.1 months. Pathologist researched randomly selected 10 areas in each microscope set. Group 1 showed statisti- cal significant difference apoptosis index in immunochemical TUNEL dyeing and im- age software (p<0.001). Moreover, we determined superior significant development in parameters as uroflowmetry, quality of life scores, and international prostate symptom score in Group 1. Conclusions: Silodosin has higher apoptosis effect than other alpha-blockers in prostate. Thus, clinic improvement with silodosin was proved by histologic studies. Besides, static factor of BPH may be overcome with creating apoptosis.


Subject(s)
Humans , Male , Aged , Aged, 80 and over , Prostate/drug effects , Prostate/pathology , Prostatic Hyperplasia/pathology , Prostatic Hyperplasia/drug therapy , Apoptosis/drug effects , Adrenergic alpha-1 Receptor Antagonists/pharmacology , Quinazolines/pharmacology , Reference Values , Sulfonamides/pharmacology , Time Factors , Biopsy , Prazosin/analogs & derivatives , Prazosin/pharmacology , Immunohistochemistry , Pilot Projects , Retrospective Studies , Treatment Outcome , Prostate-Specific Antigen/blood , Doxazosin/pharmacology , Tamsulosin , Indoles/pharmacology , Middle Aged
14.
Article in English | WPRIM | ID: wpr-687930

ABSTRACT

<p><b>OBJECTIVE</b>To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib (Iressa®) and the oriental medications Guipi Decoction (, GPD, Guibi-tang in Korean) and Bawu Decoction (, BWD, Palmul-tang in Korean).</p><p><b>METHODS</b>Methylcellulose (MC, control), GPD (1,200 mg/kg), or BWD (6,000 mg/kg) was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib (10 mg/kg) was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefitinib (10 mg/kg) was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis.</p><p><b>RESULTS</b>Gefitinib was rapidly absorbed and showed a monoexponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration (C, P<0.05) and area under the curve (P<0.05), and a delayed time to reach C (T, P<0.01) were observed in both single- and multipledose BWD-pretreated rats compared with the control rats.</p><p><b>CONCLUSIONS</b>BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.</p>


Subject(s)
Animals , Male , Chromatography, Liquid , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Pharmacology , Quinazolines , Blood , Pharmacokinetics , Rats, Sprague-Dawley , Tandem Mass Spectrometry , Time Factors
15.
Article in English | WPRIM | ID: wpr-691363

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effects of evodiamine (Evo), a component of Evodiaminedia rutaecarpa (Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) and further explore the potential mechanisms.</p><p><b>METHODS</b>Cardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model (Ang II 0.1 μmol/L), and Evo (0.03, 0.3, 3 μmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium ([Ca]) concentration, activity of nitric oxide synthase (NOS) and content of nitric oxide (NO) were measured, respectively. The mRNA expressions of atrial natriuretic factor (ANF), calcineurin (CaN), extracellular signal-regulated kinase-2 (ERK-2), and endothelial nitric oxide synthase (eNOS) of cardiomyocytes were analyzed by real-time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit (CnA) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by Western blot analysis.</p><p><b>RESULTS</b>Compared with the control group, Ang II induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF mRNA expression; increased intracellular free calcium ([Ca]) concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but decreased MKP-1 protein expression (P<0.05 or P<0.01). Compared with Ang II, Evo (0.3, 3 μmol/L) significantly attenuated Ang II-induced cardiomyocyte hypertrophy, decreased the [Ca] concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but increased MKP-1 protein expression (P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the eNOS mRNA expression (P<0.05).</p><p><b>CONCLUSION</b>Evo signifificantly attenuated Ang II-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca]i concentration, and inhibition of CaN and ERK-2 signal transduction pathways.</p>


Subject(s)
Animals , Angiotensin II , Atrial Natriuretic Factor , Metabolism , Calcineurin , Genetics , Metabolism , Calcium , Metabolism , Dual Specificity Phosphatase 1 , Genetics , Metabolism , Extracellular Signal-Regulated MAP Kinases , Genetics , Metabolism , Hypertrophy , Myocytes, Cardiac , Metabolism , Pathology , Nitric Oxide , Metabolism , Nitric Oxide Synthase Type III , Metabolism , Quinazolines , Pharmacology , RNA, Messenger , Genetics , Metabolism , Rats, Sprague-Dawley
16.
Article in English | WPRIM | ID: wpr-691364

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effect and potential mechanisms of rutaecarpine (Rut) in a rat artery balloon-injury model.</p><p><b>METHODS</b>The intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery (CCA) of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut (25, 50 and 75 mg/kg) with 10 rats of each group. The rats were treated with or without Rut (25, 50, 75 mg/kg) by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen (PCNA) and smooth muscle (SM) α-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 (ERK2), MAPK phosphatase-1 (MKP-1) and endothelial nitric oxide synthase (eNOS) were determined by real-time reverse transcription-polymerase chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 (p-ERK2) were examined by Western blotting. The plasma contents of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) were also determined.</p><p><b>RESULTS</b>Compared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury (P<0.05 or P<0.01). The positive expression rate of PCNA was decreased, while the expression rate of SM α-actin obviously increased in the vascular wall after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01). Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated (P<0.05 or P<0.01). The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downregulated after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01), respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma (P<0.05 or P<0.01).</p><p><b>CONCLUSION</b>Rut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways.</p>


Subject(s)
Animals , Male , Actins , Metabolism , Carotid Arteries , Metabolism , Pathology , Carotid Artery Injuries , Drug Therapy , Genetics , Pathology , Cyclic GMP , Blood , Disease Models, Animal , Gene Expression Regulation , Hyperplasia , Indole Alkaloids , Pharmacology , Therapeutic Uses , Nitric Oxide , Blood , Phosphorylation , Proliferating Cell Nuclear Antigen , Metabolism , Quinazolines , Pharmacology , Therapeutic Uses , RNA, Messenger , Genetics , Metabolism , Rats, Sprague-Dawley , Tunica Intima , Pathology
17.
Article in Chinese | WPRIM | ID: wpr-776380

ABSTRACT

BACKGROUND@#Epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) is an important subtype of lung cancer. The incidence of malignant pericardial effusion (MPCE) in EGFR-mutant NSCLC patients is high. However, there are few researches on the treatmentof this type of patients.@*METHODS@#We collected data on clinical characteristics and treatment of advanced NSCLC patients who harboring EGFR mutants and MPCE between January 2010 and December 2016. The treatments were divided into three groups: oral gefitinib combined with pericardial perfusion of hydroxycamptotheci (HCPT) group (gefitinib/HCPT); intravenous chemotherapy combined with pericardial perfusion of HCPT group (chemotherapy/HCPT) and gefitinib monotherapy group. And we retrospectively analyzed patients' outcomes in three groups.@*RESULTS@#In 273 advanced NSCLC patients with EGFR mutations, 29 cases had pericardial effusion, among which 6 patients with small amount of pericardial effusion were excluded, and 23 patients were analyzed. Median pericardium progression free survival (PFS) was 247 days. PFS for gefitinib/HCPT group (460 days) was superior to PFS for chemotherapy/HCPT group (94 days, P=0.008) and gefitinib monotherapy group (131 days, P=0.032). As for the efficacy of primary pulmonary lesions, the efficacy in gefitinib/ HCPT group was superior to chemotherapy/HCPT group [objective response rate (ORR): 33.3% vs 12.5%; disease control rate (DCR): 86.7% vs 62.5%]. There is no difference of ORR and DCR between gefitinib/HCPT group and gefitinib monotherapy group. No obvious adverse reaction was observed in all three groups.@*CONCLUSIONS@#First-line gefitinib therapy combined with pericardial perfusion of HCPT can improve pericardium PFS for advanced NSCLC patients who harboring EGFR mutants andmalignantpericardial effusion. This finding should be confirmed further through multicenter, prospective clinical trials with large sample size.


Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Metabolism , Pathology , Disease-Free Survival , ErbB Receptors , Metabolism , Gefitinib , Lung Neoplasms , Drug Therapy , Metabolism , Pathology , Perfusion , Pericardial Effusion , Pericardium , Quinazolines , Therapeutic Uses , Retrospective Studies , Treatment Outcome
18.
Article in Chinese | WPRIM | ID: wpr-776412

ABSTRACT

A quantitative nuclear magnetic resonance method(qNMR) was established for determination of the absolute content of febrifugine. Proton nuclear magnetic resonance spectroscopy of febrifugine was obtained in DMSO-d₆ with hydroquinone as the internal standard substance on a Bruker Ascend 600 MHz superconducting nuclear resonance spectrometer at 298 K. The specific parameters were as follows: the observing frequency was 600 MHz,spectra width was 7 211 Hz, pulse width was 9.70 μs, pulse sequence was zg30,scan times was 32 and relaxation time was 2 s. The proton signal peaked at δ 7.71 for febrifugine and δ 6.55 for hydroquinone were selected as the quantification peaks. Linear regression of quantitative peak area ratio of febrifugine-hydroquinone versus their mass ratio yielded a correlation coefficient of 0.999 6 and a regression equation of +0.008 6.The linear range of febrifugine was 2.17-17.07 g·L⁻¹,the precision RSD was 0.78%(=6),the repeatability RSD was 1.2%(=6),and the contents of three batches of febrifugine sample were 94.91%,95.09% and 95.52%,respectively. The content of febrifugine was 96.44% determined by high performance liquid chromatography(HPLC). The relative error of the content of febrigugine determinted by qNMR and HPLC methods was 1.27%. The results showed that the internal standard method of proton nuclear magnetic resonance spectroscopy could be used to determine the absolute content of febrifugine.


Subject(s)
Magnetic Resonance Spectroscopy , Piperidines , Protons , Quinazolines
19.
Chinese Journal of Lung Cancer ; (12): 663-669, 2018.
Article in Chinese | WPRIM | ID: wpr-772383

ABSTRACT

BACKGROUND@#Afatinib, a second-generation irreversible epidermal growth factor inhibitor receptor for the development of non-small cell lung cancer and secondary drug resistance, has low bioavailability and adverse reactions due to current oral administration. The aim of this study was to prepare a novel drug delivery system, afatinib liposome, and to establish a method for the determination of encapsulation efficiency.@*METHODS@#Four different preparation methods were used to prepare afatinib liposomes, and the optimal preparation process was determined by comparing the encapsulation efficiency and particle size.@*RESULTS@#It has been verified that sephadex microcolumn centrifugation can be used to purify afatinib liposomes, and UV spectrophotometry can be employed to determine the entrapment efficiency of liposomes. Among different preparation methods, the encapsulation efficiency of afatinib liposomes prepared by ammonium sulfate gradient method was 90.73% and the average particle size was 108.6 nm.@*CONCLUSIONS@#Ammonium sulfate gradient method can be successfully applied to prepare afatinib liposomes that performed higher encapsulation efficiency and smaller particle size. The UV spectrophotometry employed to determine the liposome encapsulation efficiency was easy operation and with high accuracy.


Subject(s)
Afatinib , Capsules , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Drug Compounding , Methods , Liposomes , Lung Neoplasms , Drug Therapy , Quinazolines , Chemistry , Therapeutic Uses
20.
Chinese Journal of Lung Cancer ; (12): 431-436, 2018.
Article in Chinese | WPRIM | ID: wpr-772421

ABSTRACT

BACKGROUND@#Tumor recurrence and drug resistance are the main causes of death in tumor patients. The family of acetaldehyde dehydrogenase (ALDH) is closely related to the proliferation, migration, invasion and resistance of tumor cells, and different ALDH subtypes are expressed in different tumor cells. The aim of this study is to elucidate the ALDH subtype in human lung adenocarcinoma HCC-827/GR cells, which resistant to the gefitinib.@*METHODS@#The human lung adenocarcinoma HCC-827 cells were used to generate the gefitinib-resistant HCC-827/GR cells; the expression of ALDH subtype in either HCC-827 or HCC-827/GR was detected by flow cytometry; The proliferative capacity and sensitivity to gefitinib of hcc-827/GR cells were analyzed by MTT assay before and after treatment with 100 μmol/L diethyllaminaldehyde (DEAB); Real-time quantitative PCR was used to detect the expression of ALDH subtypes at mRNA levels in hcc-827 cells and hcc-827/GR cells.@*RESULTS@#Compared with HCC-827 cells, the positive rate of ALDH in HCC-827/GR cells increased. The proliferation ability of HCC-827/GR cells decreased after treatment with 100 μmol/L DEAB. Compared with HCC-827 cells, the expression of ALDH1A1 and ALDH1L1 mRNA was increased in hcc-827/GR cells, but the ALDH3B2 expression was decreased.@*CONCLUSIONS@#ALDH might be used as a molecular biomarker to test the gefitinib-resistant to lung adenocarcinoma cancer cells, and the ALDH1A1 may play a role in gefitinib resistance in lung cancer.


Subject(s)
Humans , Adenocarcinoma , Pathology , Adenocarcinoma of Lung , Aldehyde Oxidoreductases , Genetics , Cell Line, Tumor , Drug Resistance, Neoplasm , Genetics , Enzyme Inhibitors , Pharmacology , Gefitinib , Gene Expression Regulation, Neoplastic , Lung Neoplasms , Pathology , Quinazolines , Pharmacology
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