Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.874
Filtrar
1.
Theranostics ; 11(1): 316-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391477

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , /imunologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Imunossupressores/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
2.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33440983

RESUMO

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Assuntos
Antivirais/uso terapêutico , /terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Combinação de Medicamentos , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Indóis/farmacologia , Indóis/uso terapêutico , Interferons/farmacologia , Interferons/uso terapêutico , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico
4.
Front Immunol ; 11: 2094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973818

RESUMO

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1ß, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.


Assuntos
Betacoronavirus , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Terapia de Alvo Molecular/métodos , Pneumonia Viral/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Butirofenonas/farmacologia , Butirofenonas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Infecções por Coronavirus/virologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Pandemias , Peptidil Dipeptidase A/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pneumonia Viral/virologia , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
5.
Paediatr Drugs ; 22(5): 449-461, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32797366

RESUMO

Thiopurines have been widely used to maintain steroid-free remission in children with inflammatory bowel disease (IBD). However, within the expanding treatment armamentarium, the role of these non-selective immunomodulators has been questioned, especially in pediatric patients, who often present with a more aggressive disease course, which can impact growth and development. The less favorable safety but also inferior efficacy profile associated with thiopurines, in contrast to the newer biological therapies, has interfered with their use. The future place of thiopurines in the management of childhood IBD, therefore, needs revisiting. This review provides a practical overview on the historical and current use of thiopurines in pediatric IBD with specific attention for thiopurine S-methyltransferase testing and monitoring of thiopurine metabolite levels as an approach to improve outcomes. We also give a personal expert opinion on the future role of these drugs in childhood IBD.


Assuntos
Produtos Biológicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Purinas/uso terapêutico , Tionucleosídeos/uso terapêutico , Criança , Quimioterapia Combinada , Humanos , Fatores Imunológicos/efeitos adversos , Purinas/efeitos adversos , Tionucleosídeos/efeitos adversos
6.
Cochrane Database Syst Rev ; 8: CD012328, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746500

RESUMO

BACKGROUND: About half of patients with Crohn's disease (CD) require surgery within 10 years of diagnosis. Resection of the affected segment is highly effective, however the majority of patients experience clinical recurrence after surgery. Most of these patients have asymptomatic endoscopic recurrence weeks or months before starting with symptoms. This inflammation can be detected by colonoscopy and is a good predictor of poor prognosis.Therapy guided by colonoscopy could tailor the management and improve the prognosis of postoperative CD. OBJECTIVES: To assess the effects of prophylactic therapy guided by colonoscopy in reducing the postoperative recurrence of CD in adults. SEARCH METHODS: The following electronic databases were searched up to 17 December 2019: MEDLINE, Embase, CENTRAL, Clinical Trials.gov, WHO Trial Registry and Cochrane IBD specialized register. Reference lists of included articles, as well as conference proceedings were handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and cohort studies comparing colonoscopy-guided management versus management non-guided by colonoscopy. DATA COLLECTION AND ANALYSIS: Two review authors independently considered studies for eligibility, extracted the data and assessed study quality. Methodological quality was assessed using both the Cochrane 'Risk of bias' tool for RCTs and Newcastle-Ottawa scale (NOS) for cohort studies. The primary outcome was clinical recurrence. Secondary outcomes included: endoscopic, surgical recurrence and adverse events. We calculated the risk ratio (RR) for each dichotomous outcome and extracted the hazard ratio (HR) for time-to-event outcomes. All estimates were reported with their corresponding 95% confidence interval (CI). Data were analysed on an intention-to-treat (ITT) basis. The overall quality of the evidence was evaluated using GRADE criteria. MAIN RESULTS: Two RCTs (237 participants) and five cohort studies (794 participants) met the inclusion criteria. Meta-analysis was not conducted as the studies were highly heterogeneous. We included two comparisons. Intensification of prophylactic-therapy guided by colonoscopy versus intensification guided by clinical recurrence One unblinded RCT and four retrospective cohort studies addressed this comparison. All participants received the same prophylactic therapy immediately after surgery. In the colonoscopy-based management group the therapy was intensified in case of endoscopic recurrence; in the control group the therapy was intensified only in case of symptoms. In the RCT, clinical recurrence (defined as Crohn's Disease Activity Index (CDAI) > 150 points) in the colonoscopy-based management group was 37.7% (46/122) compared to 46.1% (21/52) in the control group at 18 months' follow up (RR 0.82, 95% CI: 0.56 to 1.18, 174 participants, low-certainty evidence). There may be a reduction in endoscopic recurrence at 18 months with colonoscopy-based management (RR 0.73, 95% CI 0.56 to 0.95, 1 RCT, 174 participants, low-certainty evidence). The certainty of the evidence for surgical recurrence was very low, due to only four cohort studies with inconsistent results reporting this outcome. Adverse events at 18 months were similar in both groups, with 82% in the intervention group (100/122) and 86.5% in the control group (45/52) (RR 0.95, 95% CI:0.83 to 1.08, 1 RCT, 174 participants, low-certainty of evidence).The most common adverse events reported were alopecia, wound infection, sensory symptoms, systemic lupus, vasculitis and severe injection site reaction. Perforations or haemorrhages secondary to colonoscopy were not reported. Initiation of prophylactic-therapy guided by colonoscopy versus initiation immediately after surgery An unblinded RCT and two retrospective cohort studies addressed this comparison. The control group received prophylactic therapy immediately after surgery, and in the colonoscopy-based management group the therapy was delayed up to detection of endoscopic recurrence. The effects on clinical and endoscopic recurrence are uncertain (clinical recurrence until week 102: RR 1.16, 95% CI 0.73 to 1.84; endoscopic recurrence at week 102: RR 1.16, 95% CI 0.73 to 1.84; 1 RCT, 63 participants, very low-certainty evidence). Results from one cohort study were similarly uncertain (median follow-up 32 months, 199 participants). The effects on surgical recurrence at a median follow-up of 50 to 55 months were also uncertain in one cohort study (RR 0.79, 95% CI 0.38 to 1.62, 133 participants, very low-certainty evidence). There were fewer adverse events with colonoscopy-based management (54.8% (17/31)) compared with the control group (93.8% (30/32)) but the evidence is very uncertain (RR 0.58, 95% CI 0.42 to 0.82; 1 RCT, 63 participants). Common adverse events were infections, gastrointestinal intolerance, leukopenia, pancreatitis and skin lesions. Perforations or haemorrhages secondary to colonoscopy were not reported. AUTHORS' CONCLUSIONS: Intensification of prophylactic-therapy guided by colonoscopy may reduce clinical and endoscopic postoperative recurrence of CD compared to intensification guided by symptoms, and there may be little or no difference in adverse effects. We are uncertain whether initiation of therapy guided by colonoscopy impacts postoperative recurrence and adverse events when compared to initiation immediately after surgery, as the certainty of the evidence is very low. Further studies are necessary to improve the certainty of the evidence of this review.


Assuntos
Colonoscopia , Doença de Crohn/prevenção & controle , Doença de Crohn/cirurgia , Prevenção Secundária/métodos , Adalimumab/efeitos adversos , Adalimumab/uso terapêutico , Adulto , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Assintomáticas , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Viés , Estudos de Coortes , Doença de Crohn/diagnóstico por imagem , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Mesalamina/efeitos adversos , Mesalamina/uso terapêutico , Metronidazol/efeitos adversos , Metronidazol/uso terapêutico , Purinas/efeitos adversos , Purinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
7.
Life Sci ; 259: 118148, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721465

RESUMO

Pancreatic cancer is a malignant cancer with poor prognosis. This study aimed to explore how O6-methylguanine-DNA methyltransferase (MGMT) affects the gemcitabine resistance of pancreatic cancer cells by the regulatory role of SHH/GLI signaling pathway. MGMT inhibition induced by lomeguatrib (LM) suppressed the proliferation, invasion, migration and autophagy, promoted the apoptosis of PanC-1/GEM cells and up-regulated the GEM inhibition rates for PanC-1/GEM cells. Moreover, MGMT inhibition increased the expression of Caspase-3 and Bax and decreased the expression of Bcl-2, Beclin1 and Atg5 in PanC-1/GEM cells. PVT1 silencing could also produce the similar effects of MGMT inhibition induced by LM on PanC-1/GEM cells. And, PVT1 silencing could inhibit the SHH/GLI signaling pathway in PanC-1/GEM cells by regulating the MGMT expression. miR-409 was demonstrated to be a potential target of PVT1 and SHH was demonstrated to be a potential target of miR-409. Furthermore, GLI overexpression could reverse the effects of PVT1 silencing. In the xenograft model of pancreatic cancer, nude mice were treated with GEM. MGMT inhibition suppressed the tumor growth and autophagy and promoted the apoptosis in tumor tissues. And, PVT1 silencing could inhibit the SHH/GLI signaling pathway in tumor tissues. In conclusion, MGMT inhibition could suppress the proliferation, invasion, migration and autophagy and promote the apoptosis of PanC-1/GEM cells in vitro and in vivo. PVT1 silencing may affect the PanC-1/GEM cells through changing the MGMT expression by inhibiting the SHH/GLI signaling pathway.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Metilases de Modificação do DNA/biossíntese , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/biossíntese , Enzimas Reparadoras do DNA/genética , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Animais , Autofagia/efeitos dos fármacos , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Metilases de Modificação do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/antagonistas & inibidores , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Neoplasias Pancreáticas/patologia , Purinas/farmacologia , Purinas/uso terapêutico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Expert Opin Pharmacother ; 21(15): 1915-1926, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32686971

RESUMO

INTRODUCTION: The outcome of patients with lymphoid malignancies has markedly improved in recent years due to the implementation of new therapeutic options. Chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphomas (NHL) are characterized by the activation of the phosphatidylinositol 3-kinase (PI3 K) pathway via B-cell receptor signaling. The PI3 K delta (PI3 Kδ) p110δ isoform inhibitor, idelalisib, showed high anti-tumor activity in this group of tumors. It was the first agent from a new class of isoform-specific inhibitors to receive regulatory approvals for the treatment of refractory/relapsed CLL, as well as small lymphocytic lymphoma and follicular lymphoma. AREAS COVERED: In this paper, the authors provide a comprehensive overview of the activity and safety profile of idelalisib and other, newly developed PI3 K inhibitors in patients with indolent B-cell malignancies. EXPERT OPINION: Idelalisib is a very potent anti-lymphoma agent in CLL and other NHL. However, there are some limitations of its broad clinical use according to some important side effects observed during treatment. Consequently, the development of new PI3 K inhibitors, which will be highly active and possess better safety profiles are warranted.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Animais , Linhagem Celular Tumoral , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
9.
Tunis Med ; 98(5): 404-412, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32548844

RESUMO

BACKGROUND: Thiopurines have proven efficacy in inflammatory bowel disease. However, their use is limited by adverse effects in a subset of patients. AIMS: The present study aimed to evaluate toxicity profile and identify clinical predictive factors of thiopurine adverse effects in inflammatory bowel disease patients. METHODS: A retrospective longitudinal study was conducted among inflammatory bowel disease patients treated with thiopurines. Multiple logistic regression was used to identify risk factors for thiopurine adverse effects. RESULTS: A total of  210 patients were enrolled in the study. Mean age at disease onset was 29.8±11.4 years.  One hundred sixty-nine (169) patients had Crohn's disease, 29 had ulcerative colitis and 12 had indeterminate colitis. During a median follow-up of 28.5 ± 20 months, 56 patients (26.6%) had thiopurine-related adverse effects including digestive intolerance (n=14; 6.6%), immunoallergic reactions (n=8; 3.8%), myelotoxicity (n=25; 11.9%) and hepatotoxicity (n=8; 3.8%). Treatment withdrawal was reported in 19 patients (9%).  The only independent predictive factor for thiopurine adverse effects found in this study was steroid-dependence (OR= 3.96; 95% CI: 1.07- 14.53; p= 0.038). CONCLUSIONS: Almost a quarter of inflammatory bowel disease patients treated with thiopurines developed adverse effects. These adverse effects lead to drug withdrawal in almost 9% of patients either as monotherapy or as in combination with biologic therapies.  Steroid-dependent patients were significantly at higher risk for thiopurine-related toxicity.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Adolescente , Adulto , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Imunossupressores/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Purinas/efeitos adversos , Purinas/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
10.
Aliment Pharmacol Ther ; 51(12): 1286-1304, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32363674

RESUMO

BACKGROUND: Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS: To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS: English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS: Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS: The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.


Assuntos
Hepatite Autoimune/tratamento farmacológico , Purinas/uso terapêutico , Alopurinol/uso terapêutico , Azatioprina/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Nucleotídeos de Guanina/uso terapêutico , Hepatite Autoimune/epidemiologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/uso terapêutico , Melhoria de Qualidade , Tioguanina/uso terapêutico , Tionucleotídeos/uso terapêutico , Resultado do Tratamento
11.
AJNR Am J Neuroradiol ; 41(5): 866-873, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354716

RESUMO

BACKGROUND AND PURPOSE: 2D measurements of diffuse intrinsic pontine gliomas are limited by variability, and volumetric response criteria are poorly defined. Semiautomated 2D measurements may improve consistency; however, the impact on tumor response assessments is unknown. The purpose of this study was to compare manual 2D, semiautomated 2D, and volumetric measurement strategies for diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: This study evaluated patients with diffuse intrinsic pontine gliomas through a Phase I/II trial (NCT02607124). Clinical 2D cross-product values were derived from manual linear measurements (cross-product = long axis × short axis). By means of dedicated software (mint Lesion), tumor margins were traced and maximum cross-product and tumor volume were automatically derived. Correlation and bias between methods were assessed, and response assessment per measurement strategy was reported. RESULTS: Ten patients (median age, 7.6 years) underwent 58 MR imaging examinations. Correlation and mean bias (95% limits) of percentage change in tumor size from prior examinations were the following: clinical and semiautomated cross-product, r = 0.36, -1.5% (-59.9%, 56.8%); clinical cross-product and volume, r = 0.61, -2.1% (-52.0%, 47.8%); and semiautomated cross-product and volume, r = 0.79, 0.6% (-39.3%, 38.1%). Stable disease, progressive disease, and partial response rates per measurement strategy were the following: clinical cross-product, 82%, 18%, 0%; semiautomated cross-product, 54%, 42%, 4%; and volume, 50%, 46%, 4%, respectively. CONCLUSIONS: Manual 2D cross-product measurements may underestimate tumor size and disease progression compared with semiautomated 2D and volumetric measurements.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Neuroimagem/métodos , Adolescente , Aminopiridinas/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Criança , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Purinas/uso terapêutico , Software , Carga Tumoral/efeitos dos fármacos , Adulto Jovem
12.
Aliment Pharmacol Ther ; 51(12): 1353-1364, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32342997

RESUMO

BACKGROUND: To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low. AIM: To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment. METHODS: Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed. RESULTS: In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring. CONCLUSION: Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval.


Assuntos
Técnicas de Laboratório Clínico , Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Quimioterapia de Manutenção , Purinas/uso terapêutico , Adulto , Alopurinol/uso terapêutico , Azatioprina/uso terapêutico , Técnicas de Laboratório Clínico/métodos , Monitoramento de Medicamentos/métodos , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/diagnóstico , Quimioterapia de Manutenção/métodos , Masculino , Mercaptopurina/uso terapêutico , Pessoa de Meia-Idade , Países Baixos , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Adulto Jovem
13.
J Med Chem ; 63(9): 4776-4789, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302115

RESUMO

Toll-like receptor 7 (TLR7) is an established therapeutic target in myriad autoimmune disorders, but no TLR7 antagonist is available for clinical use to date. Herein, we report a purine scaffold TLR7 antagonist, first-of-its-kind to our knowledge, which was developed by rationally dissecting the structural requirements for TLR7-targeted activity for a purine scaffold. Specifically, we identified a singular chemical switch at C-2 that could make a potent purine scaffold TLR7 agonist to lose agonism and acquire antagonist activity, which could further be potentiated by the introduction of an additional basic center at C-6. We ended up developing a clinically relevant TLR7 antagonist with favorable pharmacokinetics and 70.8% oral bioavailability in mice. Moreover, the TLR7 antagonists depicted excellent selectivity against TLR8. To further validate the in vivo applicability of this novel TLR7 antagonist, we demonstrated its excellent efficacy in preventing TLR7-induced pathology in a preclinical murine model of psoriasis.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Purinas/uso terapêutico , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/antagonistas & inibidores , Animais , Sítios de Ligação , Células CACO-2 , Fármacos Dermatológicos/síntese química , Fármacos Dermatológicos/metabolismo , Fármacos Dermatológicos/farmacocinética , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Psoríase/tratamento farmacológico , Psoríase/patologia , Purinas/síntese química , Purinas/metabolismo , Purinas/farmacocinética , Pele/patologia , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismo
14.
Expert Opin Pharmacother ; 21(11): 1299-1309, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32292084

RESUMO

INTRODUCTION: Duvelisib, a first in class, oral, dual PI3 k-delta/gamma inhibitor recently received FDA approval for previously treated CLL (chronic lymphocytic leukemia)/SLL (small lymphocytic lymphoma) and follicular lymphoma. Data coming from the phase III 'DUO' trial, in fact, showed a superior progression-free survival (PFS) in CLL patients treated with duvelisib compared to ofatumumab. AREAS COVERED: This review provides analysis of the mechanism of action of duvelisib and includes the rationale for the use of double inhibition. The authors also give their clinical experience with duvelisib. Overall, despite the high efficacy of the drug, some concern remains on duvelisib-related adverse events leading to treatment interruption in a significant proportion of patients. EXPERT OPINION: Considering the unmet need of salvage therapies in patients failing BTK and/or Bcl2 inhibitors, treatment with duvelisib represents a new valid option in the CLL therapeutic armamentarium. Therefore, the correct management of adverse events with early treatment suspension, dose reductions and prompt supportive treatment could help to manage treatment, thus improving patient outcome. Finally, the association of duvelisib with other targeted therapies, such as ibrutinib or venetoclax, could allow clinicians to capitalize on the synergistic activity of these agents.


Assuntos
Antineoplásicos/uso terapêutico , Isoquinolinas/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Purinas/uso terapêutico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Leucemia Linfocítica Crônica de Células B/epidemiologia , Intervalo Livre de Progressão , Purinas/administração & dosagem , Purinas/efeitos adversos , Purinas/farmacocinética , Terapia de Salvação
15.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(2): 204-209, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32275007

RESUMO

OBJECTIVE: To investigate the role of Ribociclib in sepsis induced-acute kidney injury (AKI) and its possible mechanisms. METHODS: (1) Twenty adult male C57BL/6 mice were divided into sham operation group (Sham group; only open the abdomen without ligating or perforating the cecum, administered with sodium lactate buffer 12 hours before the sham operation), Ribociclib control group (administered with 150 mg/kg Ribociclib), cecal ligation and puncture (CLP) group (sepsis model induced by CLP; lactate buffer was given by intragastric administration 12 hours before CLP), and Ribociclib pretreatment group (administered with 150 mg/kg Ribociclib 12 hours before CLP) according to random number table, with 5 mice in each group. Kidneys were harvested 12 hours after the operation. Pathological changes in kidney were observed by hematoxylin-eosin (HE) staining. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in mice kidney homogenate were measured by enzyme linked immunosorbent assay (ELISA). Western Blot was used to detect the expression of cell cycle-related protein phosphorylate retinoblastoma protein (p-Rb), apoptosis-related protein Bcl-2 and Bax. (2) Mouse renal tubular epithelial (TCMK-1) cell line was used for in vitro experiment. The cells were divided into control group, Ribociclib group (treated with 5 µmol/L Ribociclib for 24 hours), lipopolysaccharide (LPS) group (treated with 200 mg/L LPS for 6 hours), Ribociclib+LPS group (replaced with the medium containing 5 µmol/L Ribociclib and 200 mg/L LPS for 6 hours after exposing with 5 µmol/L Ribociclib for 18 hours). Inflammatory cytokines in cell culture medium were detected by ELISA. The expression of p-Rb, Bcl-2 and Bax, autophagy-related proteins microtubule associated protein 1 light chain LC3b (LC3b II, LC3b I) and p62, phosphate protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR) were measured by Western Blot. RESULTS: (1) Animal experiments showed that, compared with the Sham group, the kidney tissue of mice were significantly damaged, the levels of TNF-α and IL-6 were increased, the expressions of p-Rb and Bcl-2/Bax ratio were decreased in kidney tissue in CLP group; but there was no significant difference in indexes between Ribociclib control group and Sham group. Compared with the CLP group, kidney injury in mice pretreated with Ribociclib was significantly ameliorated, the pathological score was significantly decreased (1.48±0.16 vs. 2.68±0.16, P < 0.01), the levels of TNF-α and IL-6 in kidney homogenate were significantly decreased [TNF-α (ng/g): 340.55±34.96 vs. 745.08±58.86, IL-6 (mg/g): 17.33±1.01 vs. 114.20±20.49, both P < 0.01], the expression of p-Rb was furtherly decreased (p-Rb/ß-tubulin: 0.14±0.01 vs. 0.73±0.06, P < 0.01), Bcl-2/Bax ratio was increased (0.89±0.06 vs. 0.62±0.10, P < 0.01). (2) In vitro experiments showed that, compared with the control group, the releases of TNF-α and IL-6 were increased, the expression of p-Rb was decreased, the ratios of Bcl-2/Bax and LC3b II/I were decreased, the expressions of p62, p-AKT and p-mTOR were increased in LPS group; the expression of p-Rb was decreased after Ribociclib treatment in TCMK-1 cells. Compared with the LPS group, TNF-α and IL-6 were decreased [TNF-α (ng/L): 2.73±0.23 vs. 4.96±0.10, IL-6 (ng/L): 36.05±5.83 vs. 53.78±24.08, both P < 0.01], the expression of p-Rb was furtherly decreased (p-Rb/ß-tubulin: 0.25±0.05 vs. 0.65±0.05, P < 0.01), the ratios of Bcl-2/Bax and LC3b II/I were increased (Bcl-2/Bax: 1.01±0.07 vs. 0.73±0.05, LC3b II/I: 2.08±0.31 vs. 1.04±0.01, both P < 0.05), the expressions of p62, p-AKT and p-mTOR were decreased (p62/ß-tubulin: 0.59±0.01 vs. 1.09±0.08, p-AKT/ß-tubulin: 0.61±0.03 vs. 1.20±0.06, p-mTOR/ß-tubulin: 0.50±0.05 vs. 1.15±0.08, all P < 0.01) in the Ribociclib+LPS group. CONCLUSIONS: Ribociclib pretreatment ameliorated sepsis-induced AKI and AKT/mTOR pathway may be involved in the protective role of Ribociclib on kidney.


Assuntos
Lesão Renal Aguda , Aminopiridinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Purinas/uso terapêutico , Sepse , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa
16.
Drugs Today (Barc) ; 56(2): 125-134, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32163528

RESUMO

Parkinson's disease (PD) is an extremely common degenerative disease with a progressive course. Unfortunately, the longer patients are treated with levodopa, the more likely they are to suffer from increasingly long periods of immobility or "OFF" time. For over 30 years Kyowa Kirin Co., Ltd. (formerly Kyowa Hakko Kirin Co., Ltd.) has been researching the possibility of finding drugs that affect adenosine receptors and that can be used successfully as additional drugs in the treatment of PD. Istradefylline is an adenosine A2A receptor antagonist that significantly reduces the "OFF" time and improves the motor function of patients with PD, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) Part III, while increasing the time without troublesome dyskinesia. It was approved for use in PD in Japan in 2013 and in the United States in 2019.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Purinas/uso terapêutico , Humanos , Levodopa/uso terapêutico , Receptor A2A de Adenosina
18.
J Med Case Rep ; 14(1): 35, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093776

RESUMO

BACKGROUND: Follicular lymphoma is an indolent non-Hodgkin lymphoma that is most commonly diagnosed in elderly individuals. The majority of patients with follicular lymphoma present with advanced disease. Despite the recent advances in treatment, there remains a substantial unmet need for effective treatments for patients with relapsed/refractory follicular lymphoma. The PI3Kδ inhibitor idelalisib was approved by the European Medicines Agency in 2014 as a monotherapy for the treatment of adult patients with follicular lymphoma that is refractory to two prior lines of treatment. Real-world evidence from patients with follicular lymphoma treated with idelalisib indicates its utility in these patients. CASE PRESENTATION: This case report describes an 82-year-old, retired, white, female patient with refractory follicular lymphoma who achieved a partial response with idelalisib treatment. Despite experiencing two incidences of a psoriasis-like rash during idelalisib treatment that required effective management with topical steroids, the patient was able to restart treatment successfully and maintain a continued partial response. CONCLUSIONS: The clinical relevance of the effective management of adverse events in this case demonstrates the opportunity to enable patients to remain on therapy, thereby maintaining long-term response and improving overall outcomes.


Assuntos
Antineoplásicos/uso terapêutico , Exantema/induzido quimicamente , Linfoma Folicular/tratamento farmacológico , Psoríase/induzido quimicamente , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Purinas/efeitos adversos , Quinazolinonas/efeitos adversos
19.
Bull Cancer ; 107(2): 148-156, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32057466

RESUMO

Over the past years, planet oncology has kept changing and moving forward. Recent results of important clinical trials are challenging our daily practices. With modesty, the Editorial Board of BulletinduCancer has selected some clinical trials they consider as "must-know about" even if they go beyond our medical fields.


Assuntos
Ensaios Clínicos como Assunto , Neoplasias/terapia , Aminopiridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Sistema Digestório/terapia , Feminino , Neoplasias dos Genitais Femininos/terapia , Humanos , Neoplasias Pulmonares/terapia , Masculino , Terapia de Alvo Molecular , Neoplasias Primárias Desconhecidas/terapia , Neoplasias da Próstata/terapia , Purinas/uso terapêutico
20.
BMJ Open ; 10(1): e033667, 2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31988233

RESUMO

INTRODUCTION: Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of androgen receptor (AR) signalling or prostate biology other than inhibition of androgen synthesis or AR binding. Neoadjuvant pharmacodynamic studies allow for a rational approach to the decisions regarding which targeted therapies should progress to phase II/III trials. CDK4/6 inhibitors have evidence of efficacy in breast cancer, and have been shown to have activity in preclinical models of hormone sensitive and castrate resistant prostate cancer. The LEEP trial aims to assess the pharmacodynamic effects of LEE011 (ribociclib), an orally bioavailable and highly selective CDK4/6 inhibitor, in men undergoing radical prostatectomy for high-risk, localised prostate cancer. METHODS AND ANALYSIS: The multicentre randomised, controlled 4:1 two-arm, phase II, open label pharmacodynamic study will recruit 47 men with high risk, localised prostate cancer who are planned to undergo radical prostatectomy. Participants who are randomised to receive the study treatment will be treated with LEE011 400 mg daily for 21 days for one cycle. The primary endpoint is the frequency of a 50% reduction in Ki-67 proliferation index from the pretreatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy. Secondary and tertiary endpoints include pharmacodynamic assessment of CDK4/6 cell cycle progression via E2F levels, apoptotic cell death by cleaved caspase-3, changes in serum and tumour levels of Prostate Specific Antigen (PSA), pathological regression, safety via incidence of adverse events and exploratory biomarker analysis. ETHICS AND DISSEMINATION: The protocol was approved by a central ethics review committee (St Vincent's Hospital HREC) for all participating sites (HREC/17/SVH/294). Results will be disseminated in peer-reviewed journals and at scientific conferences. DRUG SUPPLY: Novartis. PROTOCOL VERSION: 2.0, 30 May 2019 TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618000354280).


Assuntos
Aminopiridinas/farmacologia , Terapia Neoadjuvante , Próstata/efeitos dos fármacos , Prostatectomia , Neoplasias da Próstata , Purinas/farmacologia , Adolescente , Adulto , Aminopiridinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Caspase 3/metabolismo , Ciclo Celular , Proliferação de Células , Ensaios Clínicos Fase II como Assunto , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Intervalo Livre de Doença , Fatores de Transcrição E2F/metabolismo , Humanos , Calicreínas , Masculino , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Purinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA