RESUMO
OBJECTIVE: The main adjuvant therapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer include ALK tyrosine kinase inhibitors (TKI) and chemotherapy. We aimed to compare differences in the incidence of thromboembolism (TE) among different treatment options. DESIGN: Using a systematic review and Bayesian network meta-analysis (NMA). DATA SOURCES: We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov and Web of Science databases before 10 June 2023. ELIGIBILITY CRITERIA: We included published randomised controlled trials (RCT) involving comparisons of treatments between chemotherapy and ALK-TKI drugs. DATA EXTRACTION AND SYNTHESIS: Assessed risk bias with Cochrane tool. Conducted NMA with GEMTC in R, we evaluate the model fit using the deviation information criteria. Estimated posterior distribution using Markov Chain Monte Carlo, 4 chains, 10 fine-tuned iterations, 10 000 iterations per chain, total 50 000 iterations. Monitored potential scale reduction factor for convergence. And checked convergence with Gelman-Rubin statistics and trace plot. Provided surface under the cumulative ranking, lower values indicate less TE event probability. RESULTS: Analysis of eight RCTs showed that, compared with that for crizotinib, there was a lower risk of total TE with chemotherapy (OR, 0.28; 95% credible intervals (CrI) 0.11 to 0.63), brigatinib (OR 0.31; 95% CrI 0.11 to 0.79) and ceritinib (OR 0.13; 95% CrI 0.03 to 0.45). In addition, analysis of venous TE (VTE) showed similar results, with a lower occurrence for chemotherapy (OR 0.27; 95% CrI 0.1 to 0.62), brigatinib (OR 0.18; 95% CrI 0.04 to 0.6) and ceritinib (OR 0.1; 95% CrI 0.02 to 0.43) compared with that for crizotinib. There were no significant differences in the occurrence of arterial TE among the different treatment options. CONCLUSION: Compared with chemotherapy, alectinib, lorlatinib, brigatinib and ceritinib, crizotinib significantly increased the risk of TE and VTE. PROSPERO REGISTRATION NUMBER: CRD42023373307.
Assuntos
Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Neoplasias Pulmonares , Metanálise em Rede , Inibidores de Proteínas Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Crizotinibe/uso terapêutico , Teorema de Bayes , Pirimidinas/uso terapêutico , Piperidinas/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombose , Éteres de Coroa/uso terapêutico , Compostos Organofosforados/uso terapêutico , Terapia de Alvo Molecular , Carbazóis , SulfonasRESUMO
Fostamatinib is a spleen tyrosine kinase inhibitor indicated for the treatment of chronic immune thrombocytopenia (ITP) unresponsive to a previous treatment. Real-world studies evaluating the utilization and effectiveness of fostamatinib outside the context of a clinical trial are lacking. The objective of this analysis was to evaluate the effectiveness of fostamatinib for the treatment of ITP in a real-world cohort. We conducted a single-center, retrospective, observational study to evaluate the effectiveness of fostamatinib for the treatment of ITP. The primary endpoint was durable response as defined by the American Society of Hematology ITP response criteria. Secondary endpoints included overall response rate, time to response, and safety. Subgroup analysis was performed to assess frequency of durable response in key subgroups of patients based on prior therapies. Thirty-one patients treated with fostamatinib for ITP were included in our analysis. Patients had received a median of four prior lines of therapy. Ten patients (32%) achieved a durable response. Most durable responders maintained their response at 24 months ( n â=â7; 70%). The median time to response was 9âdays. Four patients (13%) discontinued fostamatinib due to an adverse event. Subgroups who had higher rates of durable responses included those who had received two to three prior lines of therapy (40%), splenectomized patients (50%), and those who had not received prior rituximab (55%). Fostamatinib therapy in a real-world population of patients with heavily pretreated ITP led to a durable response in a third of patients, which was maintained for most responders.
Assuntos
Aminopiridinas , Morfolinas , Oxazinas , Púrpura Trombocitopênica Idiopática , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Oxazinas/uso terapêutico , Morfolinas/uso terapêutico , Aminopiridinas/uso terapêutico , Idoso , Adulto , Resultado do Tratamento , Pirimidinas/uso terapêutico , Doença Crônica , Piridinas/uso terapêutico , Compostos Organofosforados/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Brigatinib is a next-generation tyrosine kinase inhibitor (TKI) targeting ALK and ROS1. The Barossa study is a multicenter, phase II basket study of brigatinib in patients with ROS1-rearranged solid tumors. ROS1 TKI-naive patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) were enrolled in cohort 1, and ROS1-rearranged NSCLC patients treated previously with crizotinib were enrolled in cohort 2. Patients with ROS1-rearranged solid tumors other than NSCLC were enrolled in cohort 3. PATIENTS AND METHODS: Eligible patients received brigatinib at the dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary endpoint was the objective response rate (RECIST 1.1) assessed by independent central review in cohorts 1 and 2. RESULTS: Between July 2019 and June 2021, 51 patients were enrolled into the study. Of the 51, 47 patients had ROS1-rearranged NSCLC; 28 and 19 of these patients were enrolled in cohort 1 and cohort 2, respectively. The remaining four patients had other ROS1-rearranged solid tumors, including rectal, brain, and pancreas tumor in one patient each, and primary unknown tumor in one patient. The confirmed objective response rate was 71.4% [95% confidence interval (CI) 51.3% to 86.8%] in cohort 1 (TKI-naive NSCLC patients) and 31.6% (95% CI 12.6% to 56.6%) in cohort 2 (NSCLC patients treated previously with crizotinib). The median progression-free survival was 12.0 months (95% CI 5.5-22.9 months) in cohort 1 and 7.3 months (95% CI 1.3-17.5 months) in cohort 2. None of the patients in cohort 3 showed any treatment response. Pneumonitis was observed in 9.8% of all the patients. CONCLUSIONS: Brigatinib was effective in TKI-naive patients with ROS1-rearranged NSCLC. The safety profile of brigatinib was consistent with that reported from previous studies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos Organofosforados , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas/genética , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/farmacologia , Compostos Organofosforados/efeitos adversos , Idoso , Adulto , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Idoso de 80 Anos ou mais , Rearranjo GênicoRESUMO
PURPOSE: There is a lack of real-world data in Asian populations for brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non-small cell lung cancer (NSCLC). This study analysed real-world outcomes and dosing patterns for brigatinib in patients with crizotinib-refractory ALK+ NSCLC in South Korea. METHODS: This retrospective, non-interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed. RESULTS: The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3-48) months. Median follow-up after brigatinib initiation was 18 (range 0-34) months. Overall, 88.5% of patients received full-dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2-not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2-year OS rate was 68.7%. CONCLUSIONS: In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real-world clinical benefit as second-line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea.
Assuntos
Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Neoplasias Pulmonares , Compostos Organofosforados , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Masculino , Feminino , República da Coreia , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Estudos Retrospectivos , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Adulto , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next-generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial-mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.
Assuntos
Adenocarcinoma de Pulmão , Aminopiridinas , Quinase do Linfoma Anaplásico , Carbazóis , Resistencia a Medicamentos Antineoplásicos , Lactamas Macrocíclicas , Lactamas , Neoplasias Pulmonares , Compostos Organofosforados , Piperidinas , Pirazóis , Pirimidinas , Humanos , Masculino , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/farmacologia , Compostos Organofosforados/administração & dosagem , Lactamas/uso terapêutico , Adulto , Aminopiridinas/uso terapêutico , Aminopiridinas/farmacologia , Quinase do Linfoma Anaplásico/genética , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Lactamas Macrocíclicas/uso terapêutico , Lactamas Macrocíclicas/farmacologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Carbazóis/uso terapêutico , Carbazóis/farmacologia , Carbazóis/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundárioAssuntos
Quinase do Linfoma Anaplásico , Antineoplásicos , Brentuximab Vedotin , Linfoma Anaplásico de Células Grandes , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Imunoconjugados/uso terapêutico , Imunoconjugados/efeitos adversos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Falha de TratamentoRESUMO
Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse. The treatment of gliomas relies on surgery, radiotherapy and chemotherapy. Only 12 anti-brain tumor chemotherapies (AntiBCs), mostly alkylating agents, have been approved so far. Glioma subtype-specific metabolic models were reconstructed to simulate metabolite exchanges, in silico knockouts and the prediction of drug and drug combinations for all three subtypes. The simulations were confronted with literature, high-throughput screenings (HTSs), xenograft and clinical trial data to validate the workflow and further prioritize the drug candidates. The three subtype models accurately displayed different degrees of dependencies toward glutamine and glutamate. Furthermore, 33 single drugs, mainly antimetabolites and TXNRD1-inhibitors, as well as 17 drug combinations were predicted as potential candidates for gliomas. Half of these drug candidates have been previously tested in HTSs. Half of the tested drug candidates reduce proliferation in cell lines and two-thirds in xenografts. Most combinations were predicted to be efficient for all three glioma types. However, eflornithine/rifamycin and cannabidiol/adapalene were predicted specifically for GBM and low-grade glioma, respectively. Most drug candidates had comparable efficiency in preclinical tests, cerebrospinal fluid bioavailability and mode-of-action to AntiBCs. However, fotemustine and valganciclovir alone and eflornithine and celecoxib in combination with AntiBCs improved the survival compared to AntiBCs in two-arms, phase I/II and higher glioma clinical trials. Our work highlights the potential of metabolic modeling in advancing glioma drug discovery, which accurately predicted metabolic vulnerabilities, repurposable drugs and combinations for the glioma subtypes.
Assuntos
Glioma , Humanos , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Canabidiol/uso terapêutico , Canabidiol/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Animais , Modelos Biológicos , Linhagem Celular Tumoral , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/farmacologiaRESUMO
In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 µM) significantly enhanced the anti-tumor efficacy of osimertinib (1 µM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg-1·d-1) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg-1·d-1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.
Assuntos
Acrilamidas , Compostos de Anilina , Antineoplásicos , Receptor Tirosina Quinase Axl , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Camundongos Nus , Compostos Organofosforados , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas , Pirimidinas , Receptores Proteína Tirosina Quinases , Animais , Feminino , Camundongos , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Mutação , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
For critically ill patients with non-small cell lung cancer (NSCLC) in need of life-saving treatment, there is currently no reported evidence regarding the use of medication specifically targeting epidermal growth factor receptor ( EGFR ) p.C797S mutation, which is known to cause resistance to third-generation tyrosine kinase inhibitors (TKIs). Our report aims to investigate and explore treatment strategies to overcome resistance associated with EGFR p.C797S mutation in order to provide potential therapeutic options for these patients. Here, we reported two cases with NSCLC who initially harbored an EGFR -sensitive mutation and were both treated with osimertinib, a third-generation TKI. Next-generation sequencing tests conducted prior to the initiation of fifth-line therapy in critically ill patients revealed the presence of EGFR p.C797S mutations in both patients, suggesting acquired resistance. In the course of fifth-line therapy, the administration of a combination of brigatinib and cetuximab proved vital in saving critically ill patients, moderately extending their overall survival period. Our findings suggested that a combined regimen of brigatinib and cetuximab could serve as a potentially life-saving therapeutic strategy for critically ill patients with NSCLC, particularly those demonstrating EGFR p.C797S-mediated resistance. Further studies, however, are required to validate and expand upon these promising findings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Cetuximab , Receptores ErbB , Neoplasias Pulmonares , Mutação , Compostos Organofosforados , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Masculino , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/administração & dosagem , Pessoa de Meia-Idade , Feminino , Estado Terminal , Idoso , Resistencia a Medicamentos Antineoplásicos , Acrilamidas/uso terapêutico , Compostos de Anilina , IndóisRESUMO
Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.
Assuntos
Adenocarcinoma de Pulmão , Antineoplásicos , Neoplasias Pulmonares , Proteínas de Fusão Oncogênica , Compostos Organofosforados , Inibidores de Proteínas Quinases , Pirimidinas , Humanos , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Animais , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Prognóstico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Lactamas/uso terapêutico , Carbazóis/uso terapêutico , Carbazóis/farmacologia , Sulfonas/uso terapêutico , Sulfonas/farmacologia , Crizotinibe/uso terapêutico , Crizotinibe/farmacologia , Linhagem Celular Tumoral , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Feminino , Camundongos , Inflamação/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Masculino , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Proliferação de Células/efeitos dos fármacos , Mutação , Aminopiridinas/uso terapêutico , Aminopiridinas/farmacologiaRESUMO
Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linfoma Anaplásico de Células Grandes , Criança , Humanos , Quinase do Linfoma Anaplásico , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Receptores Proteína Tirosina Quinases/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/patologia , Xenoenxertos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Recently a novel humanized mouse strain has been successfully generated, in which serum carboxylesterase (CES) knock out (KO) mice (Es1-/-) were further genetically modified by knocking in (KI), or adding, the gene that encodes the human form of acetylcholinesterase (AChE). The resulting human AChE KI and serum CES KO (or KIKO) mouse strain should not only exhibit organophosphorus nerve agent (NA) intoxication in a manner more similar to humans, but also display AChE-specific treatment responses more closely mimicking those of humans to facilitate data translation to pre-clinic trials. In this study, we utilized the KIKO mouse to develop a seizure model for NA medical countermeasure investigation, and then applied it to evaluate the anticonvulsant and neuroprotectant (A/N) efficacy of a specific A1 adenosine receptor (A1AR) agonist, N-bicyclo-(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA), which has been shown in a rat seizure model to be a potent A/N compound. Male mice surgically implanted with cortical electroencephalographic (EEG) electrodes a week earlier were pretreated with HI-6 and challenged with various doses (26 to 47 µg/kg, SC) of soman (GD) to determine a minimum effective dose (MED) that induced sustained status epilepticus (SSE) activity in 100% of animals while causing minimum lethality at 24 h. The GD dose selected was then used to investigate the MED doses of ENBA when given either immediately following SSE initiation (similar to wartime military first aid application) or at 15 min after ongoing SSE seizure activity (applicable to civilian chemical attack emergency triage). The selected GD dose of 33 µg/kg (1.4 x LD50) generated SSE in 100% of KIKO mice and produced only 30% mortality. ENBA at a dose as little as 10 mg/kg, IP, caused isoelectric EEG activity within minutes after administration in naïve un-exposed KIKO mice. The MED doses of ENBA to terminate GD-induced SSE activity were determined to be 10 and 15 mg/kg when treatment was given at the time of SSE onset and when seizure activity was ongoing for 15 min, respectively. These doses were much lower than in the non-genetically modified rat model, which required an ENBA dose of 60 mg/kg to terminate SSE in 100% GD-exposed rats. At MED doses, all mice survived for 24 h, and no neuropathology was observed when the SSE was stopped. The findings confirmed that ENBA is a potent A/N for both immediate and delayed (i.e., dual purposed) therapy to victims of NA exposure and serves as a promising neuroprotective antidotal and adjunctive medical countermeasure candidate for pre-clinical research and development for human application.
Assuntos
Agentes Neurotóxicos , Fármacos Neuroprotetores , Soman , Estado Epiléptico , Animais , Masculino , Camundongos , Ratos , Acetilcolinesterase , Anticonvulsivantes/efeitos adversos , Agentes Neurotóxicos/toxicidade , Fármacos Neuroprotetores/efeitos adversos , Compostos Organofosforados/uso terapêutico , Agonistas do Receptor Purinérgico P1/efeitos adversos , Receptores Purinérgicos P1 , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Soman/toxicidade , Soman/uso terapêutico , Estado Epiléptico/induzido quimicamenteRESUMO
Recently, synthetic polymers have attracted great interest in the field of biomedical science. Among these, polyphosphazenes (PPZs) are regarded as one of the most promising materials, due to their structural flexibility and biodegradability compared to other materials. PPZs have been developed through numerous studies. In particular, multi-functionalized PPZs have been proven to be potential biomaterials in various forms, such as nanoparticles (NPs) and hydrogels, through the introduction of various functional groups. Thus, PPZs have been applied for the delivery of therapeutic molecules (low molecular weight drugs, genes and proteins), bioimaging, phototherapy, bone regeneration, dental liners, modifiers and medical devices. The main goal of the present review is to highlight the recent and the most notable existing PPZ-based biomaterials for aforementioned applications, with future perspectives in mind.
Assuntos
Materiais Biocompatíveis , Sistemas de Liberação de Medicamentos , Materiais Biocompatíveis/uso terapêutico , Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos/métodos , Polímeros/uso terapêutico , Polímeros/química , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/químicaRESUMO
Cyclic and polyphosphazenes are extremely interesting and versatile substrates characterized by the presence of -P=N- repeating units. The chlorine atoms on the P atoms in the starting materials can be easily substituted with a variety of organic substituents, thus giving rise to a huge number of new materials for industrial applications. Their properties can be designed considering the number of repetitive units and the nature of the substituent groups, opening up to a number of peculiar properties, including the ability to give rise to supramolecular arrangements. We focused our attention on the extensive scientific literature concerning their biomedical applications: as antimicrobial agents in drug delivery, as immunoadjuvants in tissue engineering, in innovative anticancer therapies, and treatments for cardiovascular diseases. The promising perspectives for their biomedical use rise from the opportunity to combine the benefits of the inorganic backbone and the wide variety of organic side groups that can lead to the formation of nanoparticles, polymersomes, or scaffolds for cell proliferation. In this review, some aspects of the preparation of phosphazene-based systems and their characterization, together with some of the most relevant chemical strategies to obtain biomaterials, have been described.
Assuntos
Materiais Biocompatíveis , Polímeros , Polímeros/uso terapêutico , Polímeros/química , Materiais Biocompatíveis/química , Engenharia Tecidual , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/químicaRESUMO
Chronic ethanol abuse is a systemic disorder and a risk factor for acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). However, the mechanisms involved are unknown. One explanation is that ethanol produces damaging reactive oxygen species (ROS) and disturbs the balance of mitochondria within the lungs to promote a pro-injury environment. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate EtOH-LPS-induced lung injury. To test this, we investigated the effects of mitochondria-targeted ubiquinone, Mitoquinone (MitoQ) on ethanol-sensitized lung injury induced by LPS. Lung inflammation, ROS, mitochondria function, and mitophagy were assessed. We demonstrated that chronic ethanol feeding sensitized the lung to LPS-induced lung injury with significantly increased reactive oxygen species ROS level and mitochondrial injury as well as lung cellular NLRP3 inflammasome activation. These deleterious effects were attenuated by MitoQ administration in mice. The protective effects of MitoQ are associated with decreased cellular mitophagy and NLRP3 inflammasome activation in vivo and in vitro. Taken together, our results demonstrated that ethanol aggravated LPS-induced lung injury, and antioxidant MitoQ protects from EtOH-LPS-induced lung injury, probably through reducing mitophagy and protecting mitochondria, followed by NLRP3 inflammasome activation. These results will provide the prevention and treatment of ethanol intake effects with new ideas.
Assuntos
Antioxidantes , Lesão Pulmonar , Mitofagia , Compostos Organofosforados , Ubiquinona , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Etanol/toxicidade , Inflamassomos , Lipopolissacarídeos/toxicidade , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Espécies Reativas de Oxigênio , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
Organophosphate compounds (OPC) cause most selfpoisoning deaths in India due to their easy availability and lack of stringent laws. AIM: To evaluate the clinical profile and outcome of the patients presenting with OPC poisoning and to study the prognostic value of Peradeniya Organophosphorus Poisoning Scale (POPS) in predicting the clinical outcomes. MATERIAL: This was a prospective study involving 100 patients of OPC poisoning admitted to Tata Main Hospital from June 2018 to May 2020 based on the inclusion criteria. Demographic profile, clinical features, treatment details, and need for ventilatory support were noted. POPS was applied on admission, and the patients were followed up for the outcome in terms of morbidity and mortality. OBSERVATION: Of the 100 patients, most patients were between 20 and 29 years with male to female ratio being 1.2:1. Vomiting (94%), followed by excessive secretions (84%) were the most common symptoms. Overall mortality was 22%. On grading of severity as per the POP scale, 27% of the patients had mild poisoning, 37% patients had moderate, whereas 36% had severe poisoning. Only 11.11% of the patients with POPS 0-3 required ventilator support, whereas 16.2% of the patients with POPS 4-7, and 100% of patients with POPS 8-11 required ventilator assistance (P < 0.0001). Similarly, the total dose of atropine required (P < 0.0001), length of intensive care unit (ICU) stay, complications, and mortality (P < 0.0001) were significantly associated with higher POPS. CONCLUSION: POPS at admission, correlated well with the need for ventilator support, the total dose of atropine required, length of stay in the ICU, complications, and mortality. It can thus be used for prognostication and risk stratification of patients with OPC poisoning.
Assuntos
Intoxicação por Organofosfatos , Atropina/uso terapêutico , Feminino , Humanos , Masculino , Intoxicação por Organofosfatos/diagnóstico , Intoxicação por Organofosfatos/terapia , Organofosfatos/uso terapêutico , Compostos Organofosforados/uso terapêutico , Prognóstico , Estudos Prospectivos , Centros de Atenção TerciáriaRESUMO
Organophosphorus (OP) insecticide poisoning causes respiratory failure due to acetylcholinesterase (AChE) inhibition. The AChE reactivating antidote pralidoxime was developed in the 1950s and was soon noted to benefit patients occupationally poisoned with the highly potent OP insecticide parathion. Routine use of pralidoxime and other oximes such as obidoxime then became widely recommended. However, nearly all severe cases of OP poisoning now result from self-poisoning with large volumes of less potent (WHO hazard class Ib and II) insecticides and co-formulated solvents. Unfortunately, oxime clinical trials have never shown benefit from their use for these patients, and some have shown that pralidoxime may be associated with harm, including increased mortality. Oximes should not be used routinely for the care of OP insecticide-poisoned patients until translational and clinical studies have identified a safe and effective oxime regimen and identified the patients who benefit.
Assuntos
Inseticidas , Intoxicação por Organofosfatos , Intoxicação , Humanos , Inseticidas/uso terapêutico , Oximas/uso terapêutico , Acetilcolinesterase/uso terapêutico , Compostos Organofosforados/uso terapêutico , Intoxicação por Organofosfatos/tratamento farmacológico , Inibidores da Colinesterase/uso terapêuticoRESUMO
Autophagy drives drug resistance and drug-induced cancer cell cytotoxicity. Targeting the autophagy process could greatly improve chemotherapy outcomes. The discovery of specific inhibitors or activators has been hindered by challenges with reliably measuring autophagy levels in a clinical setting. We investigated drug-induced autophagy in breast cancer cell lines with differing ER/PR/Her2 receptor status by exposing them to known but divergent autophagy inducers each with a unique molecular target, tamoxifen, trastuzumab, bortezomib or rapamycin. Differential gene expression analysis from total RNA extracted during the earliest sign of autophagy flux showed both cell- and drug-specific changes. We analyzed the list of differentially expressed genes to find a common, cell- and drug-agnostic autophagy signature. Twelve mRNAs were significantly modulated by all the drugs and 11 were orthogonally verified with Q-RT-PCR (Klhl24, Hbp1, Crebrf, Ypel2, Fbxo32, Gdf15, Cdc25a, Ddit4, Psat1, Cd22, Ypel3). The drug agnostic mRNA signature was similarly induced by a mitochondrially targeted agent, MitoQ. In-silico analysis on the KM-plotter cancer database showed that the levels of these mRNAs are detectable in human samples and associated with breast cancer prognosis outcomes of Relapse-Free Survival in all patients (RSF), Overall Survival in all patients (OS), and Relapse-Free Survival in ER+ Patients (RSF ER+). High levels of Klhl24, Hbp1, Crebrf, Ypel2, CD22 and Ypel3 were correlated with better outcomes, whereas lower levels of Gdf15, Cdc25a, Ddit4 and Psat1 were associated with better prognosis in breast cancer patients. This gene signature uncovers candidate autophagy biomarkers that could be tested during preclinical and clinical studies to monitor the autophagy process.
Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Células MCF-7 , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Análise de Sequência de RNA , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
Introduction: The aim of this paper was to assess the cost-effectiveness of alectinib and brigatinib in first-line for anaplastic lymphoma kinase mutation-positive (ALK+) advanced non-small cell lung cancer (NSCLC). Pivotal phase III RCTs were considered. Four hundred and eighty-two patients were included. Both trials, which compared alectinib and brigatinib versus (vs.) crizotinib (control group), respectively, showed a gain in pharmacological costs, compared to the control group, of 194.80 for alectinib and 648.48 for brigatinib for an entire treatment of a single patient. Brigatinib was the less expensive, with a cost of 269.78 for each month of PFS for both intention-to-treat (ITT) population that patients with baseline brain metastases (BBM). In conclusion, combining pharmacological costs of drugs with the measure of efficacy represented by PFS, both alectinib and brigatinib are cost-effective treatments in first-line for ALK+ NSCLC. In the BBM population brigatinib seems to be the most cost-effectiveness.