RESUMO
Parkinson's disease affects millions of people worldwide, and without significant progress in disease prevention and treatment, its incidence and prevalence could increase by more than 30% by 2030. Researchers have focused on targeting sleep and the circadian system as a novel treatment strategy for Parkinson's disease. This study investigated the association between melatonin receptor agonists and Parkinson's disease, using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS). The target drugs were melatonin receptor agonists including ramelteon, tasimelteon, and agomelatine. Parkinson's disease cases were defined according to the Medical Dictionary for Regulatory Activities (MedDRA) 25.0; Standardized MedDRA Query (SMQ) using both the "narrow" and "broad" preferred terms (PTs) associated with Parkinson's disease. The association between melatonin receptor agonists (ramelteon, tasimelteon, and agomelatine) and Parkinson's disease was evaluated by the reporting odds ratio. Upon analyzing the data from all patients registered in the FAERS, ramelteon (ROR: 0.66, 95% confidence interval [95% CI]: 0.51-0.84) and tasimelteon (ROR: 0.49, 95% CI: 0.38-0.62) showed negative correlations with Parkinson's disease. Conversely, only agomelatine was positively correlated with Parkinson's disease (ROR: 2.63, 95% CI: 2.04-3.40). These results suggest that among the melatonin receptor agonists, ramelteon and tasimelteon are negatively correlated with Parkinson's disease. In contrast, agomelatine was shown to be positively correlated with Parkinson's disease. These results should be used in research to develop drugs for the treatment of Parkinson's disease, fully considering the limitations of the spontaneous reporting system.
Assuntos
Acetamidas , Indenos , Doença de Parkinson , Receptores de Melatonina , Doença de Parkinson/tratamento farmacológico , Humanos , Indenos/uso terapêutico , Acetamidas/uso terapêutico , Receptores de Melatonina/agonistas , Masculino , Feminino , Idoso , Tetra-Hidronaftalenos/uso terapêutico , Pessoa de Meia-Idade , Benzofuranos , Ciclopropanos , NaftalenosRESUMO
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neurological disorder, characterized by cognitive deficits as one of its vital features. The nucleotide-binding oligomerization domain-like receptor (NLRP3) inflammasome is a key contributor to neuroinflammation and cognitive deficits in neurological diseases. However, the underlying mechanism of anti-NMDAR encephalitis remains unclear, and the biological function of the NLRP3 inflammasome in this condition has not been elucidated. In this study, a mouse model of anti-NMDAR encephalitis was induced by active immunization with the GluN1356-385 peptide (NEA model). The NLRP3 inflammasome in the hippocampus and temporal cortex was investigated using real-time quantitative PCR (RT-qPCR), western blotting, and immunofluorescence staining. The impact of MCC950 on cognitive function and NLRP3 inflammation was assessed. Confocal immunofluorescence staining and Sholl analysis were employed to examine the function and morphology of microglia. In the current study, we discovered overactivation of the NLRP3 inflammasome and an enhanced inflammatory response in the NEA model, particularly in the hippocampus and temporal cortex. Furthermore, significant cognitive dysfunction was observed in the NEA model. While, MCC950, a selective inhibitor of the NLRP3 inflammasome, sharply attenuated the inflammatory response in mice, leading to mitigated cognitive deficits of mice and more regular arrangements of neurons and reduced number of hyperchromatic cells were also observed in the hippocampus area. In addition, we found that the excess elevation of NLRP3 inflammasome was mainly expressed in microglia accompanied with the overactivation of microglia, while MCC950 treatment significantly inhibited the increased number and activated morphological changes of microglia in the NEA model. Altogether, our study reveals the vital role of overactivated NLRP3 signaling pathway in aggravating the inflammatory response and cognitive deficits and the potential protective effect of MCC950 in anti-NMDAR encephalitis. Thus, MCC950 represents a promising strategy for anti-inflammation in anti-NMDAR encephalitis and our study lays a theoretical foundation for it to become a clinically targeted drug.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Disfunção Cognitiva , Modelos Animais de Doenças , Hipocampo , Indenos , Inflamassomos , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfonamidas , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/etiologia , Inflamassomos/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/imunologia , Camundongos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/metabolismo , Hipocampo/imunologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/imunologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Indenos/uso terapêutico , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Furanos/uso terapêutico , Furanos/farmacologia , Sulfonas/uso terapêutico , Sulfonas/farmacologia , Camundongos Endogâmicos C57BL , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Masculino , Lobo Temporal/patologiaRESUMO
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
AIM: Causes of nocturia may extend beyond primary bladder pathology and it has been commonly associated as a side effect of sleep disorders. This has led to the study of melatonin and melatonin receptor agonists as a primary treatment for nocturia hypothesized to be secondary to sleep disorders. We aim to systematically review the efficacy and reported safety of melatonin and melatonin receptor agonists in the treatment of nocturia. METHODS: A search strategy of EMBASE and Pubmed/Medline databases was utilized to identify eligible studies. Two thousand and twenty-eight unique references were identified in concordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines for systematic reviews, of which nine papers met the inclusion criteria. The Cochrane Collaboration risk of bias criteria in the open label and nonplacebo studies was used to assess bias. RESULTS: The nine studies identified included 3 randomized double-blinded placebo-controlled trials, 2 randomized non-placebo trial, and 4 prospective open-label trials. Three utilized the melatonin-receptor agonist ramelteon (8 mg) and six utilized melatonin (four 2 mg extended release, two 2 mg normal release). Nocturia improved in 8 studies varying from moderate to low efficacy related to reduction in nocturia episodes. Five studies evaluated sleep parameters finding improvement in both nocturia and sleep quality. Male subjects represented 76.8% of 371 total subjects in prospective and randomized trials. Ramelteon and melatonin were both reported as well tolerated during nocturia treatment. A meta-analysis was not able to be performed due to the heterogeneity of bladder diagnoses. CONCLUSIONS: At this time, there is insufficient evidence to routinely recommend melatonin as an effective treatment for nocturia given the limitations of current clinical studies. Randomized placebo-controlled trials and prospective open label studies in non-neurogenic populations report a trend towards nocturia improvement with good tolerability and rare side effects. Therefore, further larger scale randomized trials with focused urologic diagnoses in well-characterized patient populations are warranted.
Assuntos
Indenos , Melatonina , Noctúria , Receptores de Melatonina , Humanos , Noctúria/tratamento farmacológico , Melatonina/efeitos adversos , Melatonina/agonistas , Receptores de Melatonina/agonistas , Indenos/efeitos adversos , Indenos/uso terapêutico , Resultado do Tratamento , MasculinoRESUMO
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with a pathogenesis that remains incompletely understood, resulting in limited treatment options. MCC950, a highly specific NLRP3 inflammasome inhibitor, effectively suppresses the activation of NLRP3, thus reducing the production of caspase-1, the pro-inflammatory cytokines IL-1ß and IL-18. This review highlights the pivotal role of NLRP3 inflammasome activation pathways in the pathogenesis of SLE and discusses the potential therapeutic application of MCC950 in SLE. Notably, it comprehensively elucidates the mechanism of MCC950 targeting the NLRP3 pathway in SLE treatment, outlining its potential role in regulating autophagy and necroptosis. The insights gained contribute to a deeper understanding of the value of MCC950 in SLE therapy, serving as a robust foundation for further research and potential clinical applications.
Assuntos
Doenças Autoimunes , Indenos , Lúpus Eritematoso Sistêmico , Humanos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Furanos/uso terapêutico , Indenos/uso terapêutico , SulfonamidasRESUMO
The author recently observed a case involving a 12-year-old sighted girl who exhibited symptoms typical of non-24-hour sleep-wake rhythm disorder (N24SWD). This disorder, more commonly found in blind individuals, presents a unique challenge when diagnosed in those with vision. Several interventions can be attempted, ranging from behavioral adjustments to light therapy. Although melatonin has been noted for its effectiveness in realigning the patient's sleep-wake cycle, the use of ramelteon, a melatonin receptor agonist, has seldom been reported in managing N24SWD. However, this case illuminates the potential of ramelteon as another therapeutic option for sighted individuals with N24SWD. Further study is suggested to determine the potential of ramelteon in managing this disorder among sighted individuals of varying age groups. CITATION: Huang C-H. Managing non-24-hour sleep-wake rhythm disorder with ramelteon in a 12-year-old girl with Pierre Robin sequence and developmental delay: a case report. J Clin Sleep Med. 2024;20(6):995-997.
Assuntos
Deficiências do Desenvolvimento , Indenos , Síndrome de Pierre Robin , Transtornos do Sono do Ritmo Circadiano , Humanos , Feminino , Criança , Indenos/uso terapêutico , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Transtornos do Sono do Ritmo Circadiano/terapia , Deficiências do Desenvolvimento/complicações , Síndrome de Pierre Robin/complicações , PolissonografiaRESUMO
Epilepsy is one of the most common serious chronic brain disorders, affecting up to 70 million people worldwide. Vascular disruption, including blood-brain barrier impairment and pathological angiogenesis, exacerbates its occurrence. However, its underlying mechanisms remain elusive. MCC950 is a specific small-molecule inhibitor that selectively blocks NLRP3 inflammatory vesicle activation across the blood-brain barrier, limits downstream IL-1ß maturation and release, and exerts therapeutic effects across multiple diseases. In the present study, an epilepsy model was established by intraperitoneal administration of Kainic acid to adult male C57BL/6J wild-type mice. The results revealed that the epilepsy susceptibility of MCC950-treated mice was decreased, and neural damage following seizure episodes was reduced. In addition, immunofluorescence staining, RT-qPCR, and Western blot demonstrated that MCC950 inhibited the expression of the NLRP3 inflammasome and its related proteins in microglia, whereas microangiogenesis was found to be increased in the cerebral cortex and hippocampus of epileptic mice, and these effects could be reversed by MCC950. Furthermore, neurobehavioral impairment was observed in the epileptic mouse model, and MCC950 similarly alleviated the aforementioned pathological process. To the best of our knowledge, this is the first study to establish that pathological microangiogenesis is associated with NLRP3/IL-1ß signaling pathway activation in a Kainic acid-induced epilepsy mouse model and that MCC950 administration attenuates the above-mentioned pathological changes and exerts neuroprotective effects. Therefore, MCC950 is a promising therapeutic agent for the treatment of epilepsy.
Assuntos
Epilepsia , Indenos , Humanos , Adulto , Masculino , Animais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonas/uso terapêutico , Sulfonas/farmacologia , Piroptose , Angiogênese , Ácido Caínico , Camundongos Endogâmicos C57BL , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Inflamassomos/metabolismo , Transdução de Sinais , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Furanos/uso terapêutico , Furanos/farmacologia , Indenos/uso terapêuticoRESUMO
Kleine-Levin syndrome (KLS) is a rare disorder characterized by episodic bouts of severe hypersomnia associated with cognitive and behavioral abnormalities and normal alertness and functioning in between episodes. The pathophysiology is unclear but may involve neurotransmitter abnormalities, hypothalamic/thalamic dysfunction, viral/autoimmune etiology, or circadian abnormalities. No single treatment has been shown to be reliably efficacious; lithium has demonstrated the most consistent efficacy, although many do not respond and its use is limited by side effects. Due to the evidence of circadian involvement, we hypothesized that strengthening circadian signals may ameliorate symptoms. Ramelteon is a potent melatonin receptor agonist. In this report, two patients with KLS are described with apparent resolution of hypersomnia episodes following ramelteon initiation. CITATION: Dominguez D, Rudock R, Tomko S, Pathak S, Mignot E, Licis A. Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon. J Clin Sleep Med. 2024;20(4):657-662.
Assuntos
Distúrbios do Sono por Sonolência Excessiva , Indenos , Síndrome de Kleine-Levin , Humanos , Síndrome de Kleine-Levin/complicações , Síndrome de Kleine-Levin/tratamento farmacológico , Síndrome de Kleine-Levin/diagnóstico , Receptores de Melatonina/uso terapêutico , Indenos/uso terapêuticoRESUMO
Melatonin has gained growing interest as a treatment of insomnia, despite contradictory findings, and a low level of evidence. A systematic review and meta-analysis was conducted following PRISMA criteria, to assess the efficacy of melatonin and ramelteon compared with placebo on sleep quantity and quality in insomnia disorder, while also considering factors that may impact their efficacy. This review included 22 studies, with 4875 participants, including 925 patients treated with melatonin, 1804 treated with ramelteon and 2297 receiving a placebo. Most studies evaluated the acute efficacy of prolonged release (PR) melatonin in insomnia disorder. Compared with placebo, PR melatonin appears efficacious with a small to medium effect size on subjective sleep onset latency (sSOL) (p = 0.031; weighted difference = -6.30 min), objective sleep onset latency (oSOL) (p < 0.001; weighted difference = -5.05 min), and objective sleep efficiency (oSE) (p = 0.043; weighted difference = 1.91%). For the subgroup mean age of patients ≥55, PR melatonin was efficacious on oSE with a large effect size (p < 0.001; weighted difference = 2.95%). Ramelteon was efficacious with a large effect size at 4 weeks on objective total sleep time (oTST) (p = 0.010; weighted difference = 17.9 min), subjective total sleep time (sTST) (p = 0.006; weighted difference = 11.7 min), sSOL (p = 0.009; weighted difference = -8.74 min), and oSOL (p = 0.017; weighted difference = -14 min). Regarding long-term effects, ramelteon has a large effect size on oTST (p < 0.001; weighted difference = 2.02 min) and sTST (p < 0.001; weighted difference = 14.5 min). PR melatonin and ramelteon appear efficacious compared with placebo for insomnia symptoms with PR melatonin showing mostly small to medium effect sizes. PR melatonin for individuals with a mean age ≥ 55 and ramelteon show larger effect sizes.
Assuntos
Indenos , Melatonina , Distúrbios do Início e da Manutenção do Sono , Humanos , Adulto , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Sono , Melatonina/uso terapêutico , Melatonina/farmacologia , Indenos/uso terapêutico , Indenos/efeitos adversosRESUMO
OBJECTIVE: To assess the efficacy of melatonin and melatonergic agonist for the treatment of delirium in hospitalized patients. METHODS: Embase, MEDLINE, PsycINFO, PubMed, CENTRAL, Cochrane Database of Systematic Reviews, TRIP Medical Database, ClinicalTrials.gov and Google were searched from inception to October 2022. Randomized controlled trials (RCT) and observational studies with any type of comparator evaluating melatonin or melatonergic agonist (ramelteon) enrolling any populations (ICU, surgery, geriatric) were included. Two reviewers independently selected and extracted data using the Cochrane risk of bias tools (RoB2 and ROBINSI). RESULTS: Out of the 650 screened publications, three RCTs and six observational studies were included (n = 1211). All three RCTs compared melatonin to placebo, as the majority of observational studies compared melatonin or ramelteon to antipsychotics. Two RCTs reported the duration of delirium and a meta-analysis provided a statistical difference between melatonin and placebo (-1.72 days, 95% CI -2.66 to -0.77, p = 0.0004). Five observational studies reported the duration of delirium but only one reported a statistical reduction in the duration of delirium. CONCLUSION: Although melatonin and ramelteon may be effective treatments for delirium, particularly to shorten the duration of delirium and to limit the use of rescue medication, current data is limited in number and in its quality. Clinicians should wait until higher quality data from ongoing RCTs are available before prescribing melatonin to delirious patients.
Assuntos
Antipsicóticos , Delírio , Indenos , Melatonina , Humanos , Idoso , Melatonina/uso terapêutico , Delírio/tratamento farmacológico , Indenos/uso terapêutico , Antipsicóticos/uso terapêuticoRESUMO
BACKGROUND: Small prospective studies, case reports, as well as some randomized placebo-controlled trials and previous meta-analyses have shown that ramelteon, a melatonin agonist, may reduce the risk of developing delirium. OBJECTIVE: The goal of this systemic review and meta-analyses was to assess the current evidence supporting the use of ramelteon in delirium prevention by including data from larger (>100 subjects) and more recent trials since the most recent meta-analyses were published in 2019. There were no exclusions for trial size, age, ramelteon dose, length of treatment, or hospital setting. METHODS: Medline, Embase, PsycINFO, EBM Reviews, Scopus, and Web of Science databases were queried using the search terms delirium (with subterms including prevention and control), ramelteon, Rozerem, or melatonin receptor agonists, for English-language publications until March 16, 2021. Randomized placebo-controlled trials of hospitalized subjects receiving ramelteon for delirium prevention were included. The primary outcome of interest was delirium incidence. Odds ratios of the risk of developing incident delirium and 95% confidence intervals were calculated using a random effects model. RESULTS: A total of 177 articles were identified by the literature search. Five studies (n = 443, 53.7% male) met criteria for inclusion in the final meta-analyses. The meta-analyses of the randomized placebo-controlled trials revealed that ramelteon did not result in a reduction in the risk of incident delirium (n = 443; odds ratio = 0.49; 95% confidence interval = 0.13-1.85). A moderate degree of heterogeneity was noted among the studies (I2 = 53%). CONCLUSIONS: Current evidence suggests that ramelteon is ineffective as a prophylactic drug in reducing the incidence of delirium in hospitalized patients.
Assuntos
Delírio , Indenos , Humanos , Masculino , Feminino , Estudos Prospectivos , Delírio/tratamento farmacológico , Delírio/epidemiologia , Delírio/prevenção & controle , Indenos/uso terapêutico , Hipnóticos e Sedativos/uso terapêuticoRESUMO
Delayed sleep-wake phase disorder (DSWPD) is a common circadian sleep-wake phase disorders brings serious social impairment of the patients. Melatonin is the main medication option; however, it has not been approved in some countries, and over-the-counter melatonin is under poor quality control. The melatonin receptor agonist ramelteon might be a potential treatment option, but there are few reports regarding its use in DSWPD patients. Existing pharmacological and chronobiological studies suggest that an ultra-low dose of ramelteon in the early night is beneficial for DSWPD. Here, we present our clinical experience together with a pharmacological review and discussion. Twenty-three DSWPD patients, of whom 18 patients had a treatment history of a normal dose of ramelteon, were prescribed low-dose ramelteon (median: 0.571 mg, 1/14 of a tablet) to be taken in the early night (mean: 18:10). After the treatment, the mean sleep schedule was significantly advanced, and clinical symptoms were improved. CITATION: Shimura A, Kanno T, Inoue T. Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. J Clin Sleep Med. 2022;18(12):2861-2865.
Assuntos
Indenos , Melatonina , Transtornos do Sono do Ritmo Circadiano , Transtornos do Sono-Vigília , Humanos , Melatonina/uso terapêutico , Sono , Transtornos do Sono-Vigília/etiologia , Indenos/uso terapêutico , Ritmo Circadiano , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Transtornos do Sono do Ritmo Circadiano/complicaçõesRESUMO
Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether suvorexant with or without ramelteon prevents delirium in elderly hospitalized patients, we conducted a systematic review and meta-analysis to evaluate, searching the PubMed, Cochrane Library, Web of Science, EMBASE, and EBSCOhost databases for all randomized controlled trials (RCTs), case-control studies, and cohort studies that investigated the effects of suvorexant with or without ramelteon on delirium in adult hospitalized patients. The primary outcome was the incidence of delirium. Two randomized controlled trials, 7 cohort studies and 2 case-control studies involving 2594 patients were included in this meta-analysis. The results showed that both suvorexant alone (odds ratio (OR) = 0.30, 95% confidence interval (CI): 0.14-0.65, P = 0.002) and suvorexant with ramelteon (OR = 0.39, 95% CI 0.23-0.65, P = 0.0003) reduced the incidence of delirium in adult hospitalized patients. Six studies involved the use of benzodiazepines; subgroup analysis performed separately in the suvorexant alone and suvorexant with ramelteon groups indicated that when benzodiazepine was administered, suvorexant with ramelteon was effective at reducing the incidence of delirium (OR = 0.53, 95% CI 0.37-0.74, P = 0.0002), but no significant difference was observed for suvorexant alone (OR = 0.40, 95% CI 0.11-1.53, P = 0.18). The current literature thus supports the effectiveness of suvorexant with or without ramelteon for delirium prevention, although suvorexant alone failed to significantly reduce the incidence of delirium when benzodiazepine was administered. The present study was limited by the significant heterogeneity among the included studies, and caution should be exercised when interpreting the results. This study was registered in the PROSPERO database (CRD4202017964).
Assuntos
Delírio , Indenos , Idoso , Azepinas/uso terapêutico , Delírio/induzido quimicamente , Humanos , Indenos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , TriazóisRESUMO
BACKGROUND: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). METHODS: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan. RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
Assuntos
Antineoplásicos/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Indenos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Doença de von Hippel-Lindau/complicações , Adulto , Idade de Início , Idoso , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/etiologia , Progressão da Doença , Fadiga/induzido quimicamente , Feminino , Seguimentos , Hemangioblastoma/tratamento farmacológico , Humanos , Indenos/efeitos adversos , Neoplasias Renais/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Doença de von Hippel-Lindau/genéticaRESUMO
The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Indenos/uso terapêutico , Paraganglioma/tratamento farmacológico , Policitemia/tratamento farmacológico , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores/sangue , Cromograninas/sangue , Feminino , Mutação com Ganho de Função , Humanos , Indenos/efeitos adversos , Imageamento por Ressonância Magnética , Normetanefrina/sangue , Paraganglioma/genética , Policitemia/genética , Transdução de Sinais , Síndrome , Sequenciamento Completo do GenomaRESUMO
Belzutifan (Welireg™) is an oral small molecule inhibitor of hypoxia-inducible factor (HIF)-2α being developed by Peloton Therapeutics for the treatment of solid tumours, including renal cell carcinoma (RCC) with clear cell histology (ccRCC) and von Hippel-Lindau (VHL) disease-associated RCC. In August 2021, belzutifan received its first approval in the USA for the treatment of patients with VHL disease who require therapy for associated RCC, central nervous system (CNS) haemangioblastomas or pancreatic neuroendocrine tumours (pNET), not requiring immediate surgery. Clinical studies of belzutifan (as monotherapy or combination therapy) in other indications, including ccRCC, pNET and phaeochromocytoma/paraganglioma, are also underway in various countries. This article summarizes the milestones in the development of belzutifan leading to this first approval for certain VHL disease-associated tumours.
Assuntos
Antineoplásicos/uso terapêutico , Indenos/uso terapêutico , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Aprovação de Drogas , Humanos , Indenos/farmacologia , Neoplasias Renais/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Doença de von Hippel-Lindau/complicaçõesRESUMO
Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.
Assuntos
Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/sangue , Proteínas da Matriz Extracelular/sangue , Precursores de Proteínas/sangue , Calcificação Vascular/sangue , Deficiência de Vitamina K/sangue , Vitamina K/sangue , 4-Hidroxicumarinas/uso terapêutico , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/complicações , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Suplementos Nutricionais , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Indenos/uso terapêutico , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Protrombina , Diálise Renal/efeitos adversos , Uremia/sangue , Uremia/complicações , Calcificação Vascular/complicações , Vitamina K/antagonistas & inibidores , Vitamina K/uso terapêutico , Deficiência de Vitamina K/complicações , Proteína de Matriz GlaRESUMO
BACKGROUND: Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain. METHODS: To evaluate whether ketamine caused NLRP3/caspase1-dependent pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and lactate dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 inhibitor MCC950 or the caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction. RESULTS: Our findings demonstrated that ketamine exposure caused cell damage and increased the levels of pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction. CONCLUSION: NLRP3/Caspase-1 axis-dependent pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.
Assuntos
Caspase 1/metabolismo , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Ketamina/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/fisiologia , Animais , Animais Recém-Nascidos , Inibidores de Caspase/farmacologia , Inibidores de Caspase/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Furanos/farmacologia , Furanos/uso terapêutico , Hipocampo/efeitos dos fármacos , Indenos/farmacologia , Indenos/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Células PC12 , Piroptose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , para-Aminobenzoatos/farmacologia , para-Aminobenzoatos/uso terapêuticoRESUMO
NLRP3 inflammasome is a vital player in macrophages pyroptosis, which is a type of proinflammatory cell-death and takes part in the pathogenesis of atherosclerosis. In this study, we used apoE-/- mice and ox-LDL induced THP-1 derived macrophages to explore the mechanisms of MCC950, a selective NLRP3 inhibitor in treating atherosclerosis. For the in vivo study, MCC950 was intraperitoneal injected to 8-week-old apoE-/- mice fed with high-fat diet for 12 weeks. For the in vitro study, THP-1 derived macrophages were treated with ox-LDL and MCC950 for 48 h. MCC950 administration reduced plaque areas and macrophages contents, but did not improve the serum lipid profiles in aortic root of apoE-/- mice. MCC950 inhibited the activation of NLRP3/ASC/Caspase-1/GSDMD-N axis, and alleviated macrophages pyroptosis and the production of IL-1ß and IL-18 both in aorta and in cell lysates. However, MCC950 did not affect the expression of TLR4 or the mRNA levels of NLRP3 inflammasome and its downstream proteins, suggesting that MCC950 had no effects on the priming of NLRP3 inflammasome activation in macrophages. The anti-atherosclerotic mechanisms of MCC950 on attenuating macrophages inflammation and pyroptosis involved in inhibiting the assembly and activation of NLRP3 inflammasome, rather than interrupting its priming.