RESUMO
BACKGROUND: Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. METHODS: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). RESULTS: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. CONCLUSIONS: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.).
Assuntos
Antineoplásicos , Carcinoma de Células Renais , Everolimo , Indenos , Neoplasias Renais , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Estimativa de Kaplan-Meier , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Intervalo Livre de Progressão , Indenos/administração & dosagem , Indenos/efeitos adversos , Administração Oral , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Adulto Jovem , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the efficacy and safety of perioperative melatonin and melatonin agonists in preventing postoperative delirium (POD). METHODS: We conducted a systematic search for randomized controlled trials (RCTs) published through December 2022. The primary outcome was efficacy based on the incidence of POD (POD-I). Secondary outcomes included efficacy and safety according to the length of hospital or intensive care unit stay, in-hospital mortality, and adverse events. Subgroup analyses of POD-I were based on the type and dose of drug (low- and high-dose melatonin, ramelteon), the postoperative period (early or late), and the type of surgery. RESULTS: In the analysis (16 RCTs, 1981 patients), POD-I was lower in the treatment group than in the control group (risk ratio [RR] = 0.57). POD-I was lower in the high-dose melatonin group than in the control group (RR = 0.41), whereas no benefit was observed in the low-dose melatonin and ramelteon groups. POD-I was lower in the melatonin group in the early postoperative period (RR = 0.35) and in patients undergoing cardiopulmonary surgery (RR = 0.54). CONCLUSION: Perioperative melatonin or melatonin agonist treatment suppressed POD without severe adverse events, particularly at higher doses, during the early postoperative period, and after cardiopulmonary surgery.
Assuntos
Delírio , Melatonina , Complicações Pós-Operatórias , Melatonina/uso terapêutico , Melatonina/administração & dosagem , Melatonina/efeitos adversos , Humanos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/tratamento farmacológico , Delírio/prevenção & controle , Delírio/tratamento farmacológico , Assistência Perioperatória/métodos , Indenos/uso terapêutico , Indenos/efeitos adversos , Indenos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Tempo de Internação , Resultado do Tratamento , Mortalidade HospitalarRESUMO
Psoriasis is a long-lasting, immune-related inflammatory skin disease that affects 2-3% of the global population. It is distinguished by erythematous, silvery, and scaly patches. Ramelteon is a type of melatonin agonist that is used to treat insomnia. It has enhanced non-classical immunomodulatory and anti-inflammatory activities. The aim of the study is to assess the ameliorative effects of topical ramelteon on imiquimod (IMQ)-aggravated psoriasiform-like dermatosis in mice. The 32 albino mouse males were placed into six groups of eight animals, all of them. With the exception of the control group, all groups gained a once-a-day regimen of topical imiquimod 5% cream at a dose of 62.5 mg for eight uninterrupted days, while mice in the control group gained vaseline-based ointment alternately. Immediately after an 8-day induction period in the imiquimod group, mice in the clobetasol and ramelteon treatment groups obtained a twice-daily regimen of topical clobetasol propionate 0.05% ointment and 0.1% ointment, respectively, for a further 8 days. This extends the total duration of the experimental study to 16 continuous days. The findings of our study found that ramelteon significantly mitigated the concentrations of inflammatory cytokines in the skin tissue, including interleukin (IL)-6, IL-17A, IL-23, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF), as well as the scores associated with psoriatic lesions, including erythema, scaling, skin thickening, ear thickness, and overall cumulative PASI scores. Additionally, the anti-inflammatory impact of ramelteon was achieved by markedly increasing IL-10 levels in the skin tissue and correcting cutaneous histopathological alterations. Ramelteon ointment (0.1%) was comparable to that of clobetasol (0.05%) ointment in alleviating a mouse model of imiquimod-induced psoriasiform inflammation; this is probably due to its potential anti-inflammatory and immunomodulatory activities. Therefore, ramelteon could be a good additive option for therapeutic management of immune-triggered inflammatory conditions such as psoriasis.
Assuntos
Anti-Inflamatórios , Imiquimode , Indenos , Psoríase , Animais , Imiquimode/toxicidade , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Psoríase/patologia , Masculino , Camundongos , Indenos/administração & dosagem , Indenos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Citocinas/metabolismo , Administração Cutânea , Administração Tópica , Modelos Animais de Doenças , Clobetasol/administração & dosagem , Clobetasol/farmacologiaRESUMO
INTRODUCTION AND AIM: Portal vein thrombosis (PVT) is associated with a higher risk of liver-related complications. Recent guidelines recommend direct-acting anticoagulants (DOAC) in patients with cirrhosis and non-tumoral PVT. However, data on the efficacy and safety of DOAC in these patients remain limited. We aim to investigate the efficacy and safety of DOAC compared to vitamin K antagonists (VKA) to treat non-tumoral PVT in patients with cirrhosis. METHODS: We performed a systematic search of six electronic databases using MeSH term and free text. We selected all studies comparing the use of DOACs with vitamin K antagonist to treat PVT in cirrhosis. The primary outcome was PVT recanalization. Secondary outcomes were and PVT progression, major bleeding, variceal bleeding and death. RESULTS: From 944 citations, we included 552 subjects from a total of 11 studies (10 observational and 1 randomized trial) that fulfilled the inclusion criteria. We found that DOAC were associated with a higher pooled rate of PVT recanalization (RR = 1.67, 95%CI: 1.02, 2.74, I2 = 79%) and lower pooled risk of PVT progression (RR = 0.14, 95%CI: 0.03-0.57, I2 = 0%). The pooled risk of major bleeding (RR = 0.29, 95%CI: 0.08-1.01, I2 = 0%), variceal bleeding (RR = 1.29, 95%CI: 0.64-2.59, I2 = 0%) and death (RR = 0.31, 95%CI: 0.01-9.578, I2 = 80%) was similar between DOAC and VKA. CONCLUSION: For the treatment of PVT in patients with cirrhosis, the bleeding risk was comparable between DOAC and VKA. However, DOAC were associated with a higher pooled rate of PVT recanalization. Dedicated randomized studies are needed to confirm these findings.
Assuntos
4-Hidroxicumarinas/administração & dosagem , Anticoagulantes/administração & dosagem , Indenos/administração & dosagem , Cirrose Hepática/complicações , Trombose Venosa/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Administração Oral , Humanos , Estudos Observacionais como Assunto , Veia Porta , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Trombose Venosa/etiologia , Vitamina K/administração & dosagemRESUMO
The investigation aimed to evaluate the effects of Mcc950, an inhibitor of the NLRP3 inflammasome, on diabetic retinopathy (DR) mice. The general physiological condition of each group of mice was recorded. Retinal blood vessels were stained for observation of the density of blood vessels, and retinas were used for further morphological examination and fluorescent staining after the intravitreal injection of Mcc950. Mcc950 partially reversed hyperglycemia-induced vascular damage and had reduced histological changes compared to DR mice. IL-1ß production in mice retinas in the diabetic model (DM) group increased, but pretreatment with Mcc950 significantly reversed these changes. Additionally, Mcc950 engineered reduced FITC dextran extravasation and vascular leakage. Therefore, it played an apparent protective role in DR and could be a new treatment strategy for DR.
Assuntos
Anti-Inflamatórios/farmacologia , Retinopatia Diabética/prevenção & controle , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Neovascularização Retiniana/prevenção & controle , Vasos Retinianos/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Glicemia/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Retinopatia Diabética/imunologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Progressão da Doença , Furanos/administração & dosagem , Indenos/administração & dosagem , Inflamassomos/metabolismo , Injeções Intravítreas , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neovascularização Retiniana/imunologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/imunologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND: The clinical effect of enteral administration of sleep-promoting medication (SPM) in mechanically ventilated patients remains unclear. This study aimed to investigate the relationship between enteral SPM administration and the intravenous sedative dose and examine the safety and cost of enteral SPM administration. METHODS: This single-center retrospective cohort study was conducted in a Japanese tertiary hospital intensive care unit (ICU). The exposure was enteral SPM administration during mechanical ventilation. The outcome was the average daily propofol dose per body weight administered as a continuous sedative during mechanical ventilation. Patients were divided into three groups based on the timing of SPM administration at ICU admission: "administration within 48 hours (early administration [EA])," "administration after 48 hours (late administration [LA])," and "no administration (NA)." We used multiple linear regression models. RESULTS: Of 123 included patients, 37, 50, and 36 patients were assigned to the EA, LA, and NA groups, respectively. The average daily propofol dose per body weight was significantly lower in the EA group than in the LA and NA groups (ß -5.13 [95% confidence interval (CI) -8.93 to -1.33] and ß -4.51 [95% CI -8.59 to -0.43], respectively). Regarding safety, enteral SPM administration did not increase adverse events, including self-extubation. The total cost of neuroactive drugs tended to be lower in the EA group than in the LA and NA groups. CONCLUSIONS: Early enteral SPM administration reduced the average daily propofol dose per body weight without increasing adverse events.
Assuntos
Nutrição Enteral/métodos , Hipnóticos e Sedativos/administração & dosagem , Indenos/administração & dosagem , Melatonina/administração & dosagem , Propofol/administração & dosagem , Respiração Artificial/métodos , Sono/efeitos dos fármacos , Administração Intravenosa , Idoso , Depressores do Sistema Nervoso Central/administração & dosagem , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
In ischemic stroke (IS) impairment of the blood-brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and-in good agreement with the in vitro results-MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC.
Assuntos
Barreira Hematoencefálica/metabolismo , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/metabolismo , Hipóxia Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Furanos/administração & dosagem , Indenos/administração & dosagem , Inflamassomos/antagonistas & inibidores , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Substâncias Protetoras/administração & dosagem , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Glucose/metabolismo , Inflamassomos/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Resultado do TratamentoRESUMO
Cerebrovascular diseases are pathological conditions involving impaired blood flow in the brain, primarily including ischaemic stroke, intracranial haemorrhage, and subarachnoid haemorrhage. The nucleotide-binding and oligomerisation (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome is a protein complex and a vital component of the immune system. Emerging evidence has indicated that the NLRP3 inflammasome plays an important role in cerebrovascular diseases. The function of the NLRP3 inflammasome in the pathogenesis of cerebrovascular diseases remains an interesting field of research. In this review, we first summarised the pathological mechanism of cerebrovascular diseases and the pathological mechanism of the NLRP3 inflammasome in aggravating atherosclerosis and cerebrovascular diseases. Second, we outlined signalling pathways through which the NLRP3 inflammasome participates in aggravating or mitigating cerebrovascular diseases. Reactive oxygen species (ROS)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS/thioredoxin-interacting protein (TXNIP) and purinergic receptor-7 (P2X7R) signalling pathways can activate the NLRP3 inflammasome; activation of the NLRP3 inflammasome can aggravate cerebrovascular diseases by mediating apoptosis and pyroptosis. Autophagy/mitochondrial autophagy, nuclear factor E2-related factor-2 (Nrf2), interferon (IFN)-ß, sirtuin (SIRT), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) reportedly alleviate cerebrovascular diseases by inhibiting NLRP3 inflammasome activation. Finally, we explored specific inhibitors of the NLRP3 inflammasome based on the two-step activation of the NLRP3 inflammasome, which can be developed as new drugs to treat cerebrovascular diseases.
Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Proteínas de Transporte/metabolismo , Diterpenos do Tipo Caurano/administração & dosagem , Furanos/administração & dosagem , Humanos , Indenos/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Sulfonamidas/administração & dosagemRESUMO
Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1ß production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3-/-) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1ß, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-ß. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.
Assuntos
Inflamassomos/antagonistas & inibidores , Pulmão/imunologia , Pulmão/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Doenças Respiratórias/prevenção & controle , Animais , Animais Recém-Nascidos , Citocinas/imunologia , Feminino , Furanos/administração & dosagem , Indenos/administração & dosagem , Inflamassomos/genética , Inflamassomos/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Vírus Sincicial Respiratório Humano/imunologia , Doenças Respiratórias/imunologia , Doenças Respiratórias/virologia , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND: In this analysis, we aimed to compare the efficacy and safety of dual therapy (DT) with a non-vitamin K oral anticoagulant (NOAC) and an adenosine diphosphate receptor antagonist (P2Y12 inhibitor) vs triple therapy (TT) with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus (DM) patients with co-existing atrial fibrillation (AF) following percutaneous coronary intervention (PCI). METHODS: Medical Literature Analysis and Retrieval System Online (MEDLINE), http://www.ClinicalTrials.gov, Excerpta Medical data BASE (EMBASE), Web of Science, Cochrane Central and Google Scholar were the searched databases. Studies that were randomized trials or observational studies comparing DT vs TT for the treatment of DM patients with co-existing AF following PCI were included in this analysis. The adverse cardiovascular outcomes and bleeding events were the endpoints. This meta-analysis was carried out by the RevMan version 5.4 software. Risk ratios (RR) with 95% confidence intervals (CI) were used to represent data and interpret the analysis. RESULTS: A total number of 4970 participants were included whereby 2456 participants were assigned to the DT group and 2514 participants were assigned to the TT group. The enrollment period varied from year 2006 to year 2018. Our current results showed that major adverse cardiac events (RR: 1.00, 95% CI: 0.84-1.20; Pâ=â.98), mortality (RR: 1.08, 95% CI: 0.78-1.48; Pâ=â.66), myocardial infarction (RR: 1.02, 95% CI: 0.74-1.42; Pâ=â.90), stroke (RR: 0.94, 95% CI: 0.53-1.67; Pâ=â.84) and stent thrombosis (RR: 1.09, 95% CI: 0.56-2.10; Pâ=â.80) were similar with DT versus TT in these patients. However, the risks for total major bleeding (RR: 0.66, 95% CI: 0.54-0.82; Pâ=â.0001), total minor bleeding (RR: 0.74, 95% CI: 0.64-0.85; Pâ=â.0001), Thrombolysis in Myocardial Infarction (TIMI) defined major bleeding (RR: 0.58, 95% CI: 0.35-0.95; Pâ=â.03), TIMI defined minor bleeding (RR: 0.62, 95% CI: 0.42-0.92; Pâ=â.02), intra-cranial bleeding (RR: 0.34, 95% CI: 0.13-0.95; Pâ=â.04) and major bleeding defined by the International Society on Thrombosis and Hemostasis (RR: 0.68, 95% CI: 0.51-0.90; Pâ=â.008) were significantly higher with TT. CONCLUSIONS: DT with a NOAC and a P2Y12 inhibitor was associated with significantly less bleeding events without increasing the adverse cardiovascular outcomes when compared to TT with aspirin, a P2Y12 inhibitor and a Vitamin K antagonist for the treatment of DM patients with co-existing AF following PCI. Hence, DT is comparable in efficacy, but safer compared to TT. This interesting hypothesis will have to be confirmed in future studies.
Assuntos
4-Hidroxicumarinas/administração & dosagem , Aspirina/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Fármacos Hematológicos/administração & dosagem , Indenos/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Vitamina K/antagonistas & inibidores , Idoso , Fibrilação Atrial/etiologia , Diabetes Mellitus/terapia , Cardiomiopatias Diabéticas/etiologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Estudos Observacionais como Assunto , Intervenção Coronária Percutânea/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Vitamina K/administração & dosagemRESUMO
Chronic pain affects the life quality of the suffering patients and posts heavy problems to the health care system. Conventional medications are usually insufficient for chronic pain management and oftentimes results in many adverse effects. The NLRP3 inflammasome controls the processing of proinflammatory cytokine interleukin 1ß (IL-1ß) and is implicated in a variety of disease conditions. Recently, growing number of evidence suggests that NLRP3 inflammasome is dysregulated under chronic pain condition and contributes to pathogenesis of chronic pain. This review provides an up-to-date summary of the recent findings of the involvement of NLRP3 inflammasome in chronic pain and discussed the expression and regulation of NLRP3 inflammasome-related signaling components in chronic pain conditions. This review also summarized the successful therapeutic approaches that target against NLRP3 inflammasome for chronic pain treatment.
Assuntos
Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Furanos/administração & dosagem , Indenos/administração & dosagem , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonamidas/administração & dosagem , Animais , Sistemas de Liberação de Medicamentos/tendências , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidoresRESUMO
Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing to the development of mechanical allodynia and gait disturbances in a murine model of vincristine-induced neuropathy, as well as to identify novel treatment approaches. Here, we show that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1ß from macrophages, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the IL-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumor progression in patient-derived medulloblastoma xenograph models. These results detail the neuro-inflammatory mechanisms leading to vincristine-induced peripheral neuropathy and suggest that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.
Assuntos
Hiperalgesia/genética , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças do Sistema Nervoso Periférico/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/administração & dosagem , Antirreumáticos/administração & dosagem , Cisplatino/administração & dosagem , Furanos/administração & dosagem , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indenos/administração & dosagem , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxaliplatina/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Sulfonamidas/administração & dosagem , VincristinaRESUMO
Autoimmune diseases are chronic immune diseases characterized by dysregulation of immune system, which ultimately results in a disruption in self-antigen tolerance. Cumulative data show that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) play essential roles in various autoimmune diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, multiple sclerosis (MS), etc. NLR proteins, consisting of a C-terminal leucine-rich repeat (LRR), a central nucleotide-binding domain, and an N-terminal effector domain, form a group of pattern recognition receptors (PRRs) that mediate the immune response by specifically recognizing cellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and triggering numerous signaling pathways, including RIP2 kinase, caspase-1, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and so on. Based on their N-terminal domain, NLRs are divided into five subfamilies: NLRA, NLRB, NLRC, NLRP, and NLRX1. In this review, we briefly describe the structures and signaling pathways of NLRs, summarize the recent progress on NLR signaling in the occurrence and development of autoimmune diseases, as well as highlight numerous natural products and synthetic compounds targeting NLRs for the treatment of autoimmune diseases.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Proteínas NLR/antagonistas & inibidores , Proteínas NLR/metabolismo , Animais , Doenças Autoimunes/imunologia , Furanos/administração & dosagem , Furanos/imunologia , Furanos/metabolismo , Humanos , Indenos/administração & dosagem , Indenos/imunologia , Indenos/metabolismo , Proteínas NLR/imunologia , Piridinas/administração & dosagem , Piridinas/imunologia , Piridinas/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/imunologia , Sulfonamidas/metabolismoRESUMO
Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder, which has an increased incidence worldwide. The NLRP3 inflammasome has recently been assigned as a promising target for several inflammatory diseases including bowel inflammation. We aimed to investigate the potential complementary effects of combined therapy of metformin and MCC950 in dextran sodium sulfate (DSS)-induced colitis in rats. Metformin/MCC950 mitigated colon shortening, disease activity index (DAI), and macroscopic damage index (MDI). It also improved the colon histology picture and reduced the inflammation score. In addition, metformin/MCC950 augmented the antioxidant defense machinery and attenuated the myeloperoxidase (MPO) activity. Moreover, the levels of the pro-inflammatory mediators tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were reduced. This pharmacological activity might be attributed to interrupting the priming signal of the NLRP3 inflammasome activation through inactivating Toll-like receptor 4 (TLR4)/nuclear transcription factor kappa-B (NF-κB) signalling (effect of metformin) as well as interrupting the activation signal through potent inhibition of NLRP3 expression and caspase-1 (effect of MCC950). As a result, significant inhibition of the production of the bioactive IL-1ß and IL-18 occurred, and hence the pyroptosis process was inhibited. Moreover, the metformin/MCC950 leads to the induction of autophagy by AMP-activated protein kinase (AMPK)-dependent mechanisms leading to the accumulation of Beclin-1 and a substantial decline in the levels of p62 SQSTM1 (effect of metformin). The observed impeding effect on HSP90 along with inducing autophagy (effect of metformin) suggests that NLRP3 is prone to autophagic degradation. In conclusion, we reveal that the combination of metformin with MCC950 has a protective role in DSS-induced colitis and might become a candidate in a promising approach for the future treatment of human UC.
Assuntos
Autofagia/efeitos dos fármacos , Colite/prevenção & controle , Furanos/farmacologia , Indenos/farmacologia , Metformina/farmacologia , Sulfonamidas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Furanos/administração & dosagem , Proteínas de Choque Térmico HSP90/metabolismo , Indenos/administração & dosagem , Masculino , Metformina/administração & dosagem , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagemRESUMO
Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.
Assuntos
Transtornos da Coagulação Sanguínea/terapia , Hemorragia/prevenção & controle , Heparina/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia , 4-Hidroxicumarinas/administração & dosagem , Idoso , Anticoagulantes/efeitos adversos , Arginina/administração & dosagem , Arginina/análogos & derivados , Transtornos da Coagulação Sanguínea/complicações , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Hemorragia/etiologia , Humanos , Indenos/administração & dosagem , Trombose Intracraniana/tratamento farmacológico , Trombose Intracraniana/etiologia , Trombose Intracraniana/cirurgia , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodos , Ácidos Pipecólicos/administração & dosagem , Sulfonamidas/administração & dosagem , Vitamina K/administração & dosagem , Vitamina K/antagonistas & inibidoresRESUMO
BACKGROUND: Postoperative delirium was reported to be associated with increased postoperative mortality after liver resection. Therefore, it is crucial to prevent postoperative delirium in such cases. Ramelteon, an agonist of melatonin receptor has been suggested to be useful for preventing delirium. The aim of this study was to examine whether ramelteon is effective at preventing delirium after elective liver resection. METHODS: The cases of patients who underwent liver resection at Nara Medical University (Nara, Japan) between January 2014 and August 2018 were analyzed. During the period from January 2017 to August 2018, ramelteon was prospectively administered to patients who underwent liver resection [8 mg/day on the day before surgery and on postoperative days 1 to 3] (ramelteon group), whereas ramelteon was not administered during the period from January 2014 to December 2016 (control group). The perioperative outcomes of the two groups were compared. RESULTS: There were 120 patients in the ramelteon group and 186 patients in the control group. No significant intergroup differences in background factors, including age, gender, and preoperative serological laboratory data, were detected. The incidence of postoperative delirium was significantly lower in the ramelteon group (5.8% vs. 15.1%, P = 0.035). Multivariate analysis revealed that being aged ≥75 (P = 0.002), being male (P = 0.020), cardiovascular disease (P = 0.023), blood loss ≥1000ml (P = 0.001) and the absence of ramelteon treatment (P = 0.046) were independent risk factors for postoperative delirium. CONCLUSION: The administration of ramelteon might reduce the risk of postoperative delirium after elective liver resection.
Assuntos
Delírio do Despertar/tratamento farmacológico , Hepatectomia/efeitos adversos , Indenos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Procedimentos Cirúrgicos Eletivos/métodos , Delírio do Despertar/etiologia , Delírio do Despertar/prevenção & controle , Feminino , Hepatectomia/métodos , Humanos , Indenos/administração & dosagem , Indenos/efeitos adversos , Masculino , Pessoa de Meia-IdadeRESUMO
The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.
Assuntos
Acidentes por Quedas , Azepinas/efeitos adversos , Indenos/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Azepinas/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Indenos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sono/efeitos dos fármacos , Sono/fisiologia , Triazóis/administração & dosagemRESUMO
INTRODUCTION: Non-24-hour sleep-wake disorder (N24SWD) is often observed in the visually impaired and those who isolate indoors. Melatonin receptor agonists may be used for treatment, but there is currently no evidence that they are effective in patients without visual impairment. CASE: We report a case of a 23-year-old woman who withdrew from her social life owing to autism spectrum disorder and experienced an unusual sleep rhythm. She presented with N24SWD. The N24SWD cycle averaged 25.6 days but was extended to 42 days using ramelteon. However, this was not enough. We prescribed the addition of suvorexant and the sleep cycle returned to normal. CONCLUSION: N24SWD is a disease that seriously impairs social life and productivity. We propose a possible treatment strategy for N24SWD using ramelteon and suvorexant.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Azepinas/administração & dosagem , Indenos/administração & dosagem , Medicamentos Indutores do Sono/administração & dosagem , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Triazóis/administração & dosagem , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Quimioterapia Combinada , Feminino , Humanos , Transtornos do Sono do Ritmo Circadiano/complicações , Transtornos do Sono do Ritmo Circadiano/diagnóstico , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The growing number of cases of gastric cancer being diagnosed in elderly patients highlights the importance of preventing postoperative delirium. This phase II study aimed to evaluate the efficacy of perioperative treatment with ramelteon for preventing postoperative delirium in elderly patients undergoing gastrectomy. METHODS: This study was designed as a single-institute prospective phase II study. Patients ≥ 75 years old were eligible. Ramelteon 8 mg/day was administered from 8 days before the operation until discharge. Postoperative delirium was evaluated using the Confusion Assessment Method-Intensive Care Unit flow sheet. RESULTS: Between September 2015 and July 2017, a total of 83 patients were enrolled, 76 of whom were eligible and included in the analysis. Postoperative delirium was observed in four patients (5%) (60% confidence interval: 3.0-8.7). The upper margin of the confidence interval was lower than the prespecified threshold of 13%; therefore, the null hypothesis was rejected. CONCLUSION: This phase II study suggested that the perioperative administration of ramelteon is safe and feasible for preventing postoperative delirium in elderly patients undergoing gastrectomy. Trial registration This study was registered at UMIN (UMIN 000018697).