Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.102
Filtrar
1.
Pediatr Rheumatol Online J ; 20(1): 104, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401314

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation primarily driven by the cytokine interferon gamma. It can be either a genetic or acquired disorder associated with infection, malignancy, and rheumatologic disorders. Trisomy 21 can express a wide range of phenotypes which include immune dysregulation and shares inherent pathophysiology with a group of disorders termed interferonopathies. Knowledge of this overlap in seemingly unrelated conditions could provide a basis for future research, and most importantly, alternative therapeutic interventions in acute life threatening clinical scenarios. Herein, we describe two patients with trisomy 21 presenting with HLH that was refractory to conventional treatment. Both patients were successfully managed with novel interventions targeting the interferon pathway. CASE PRESENTATION: We describe a 17-month-old male and 15-month-old female with trisomy 21 presenting with a myriad of signs and symptoms including fever, rash, cytopenias, and hyperferritinemia, both ultimately diagnosed with HLH. Each had relapsing, refractory HLH over time requiring several admissions to the hospital receiving conventional high dose corticosteroids and interleukin-1 inhibition therapy. Successful steroid-free remission was achieved after targeting interferon inhibition with emapalumab induction followed by long-term maintenance on baricitinib. CONCLUSION: To our knowledge, these are the first reported cases of relapsed, refractory HLH in patients with trisomy 21 successfully treated with emapalumab and transitioned to a steroid-sparing regimen with oral baricitinib for maintenance therapy. Trisomy 21 autoimmunity and HLH are both thought to be driven by interferon gamma. Targeting therapy toward interferon signaling in both HLH and autoimmunity in trisomy 21 may have potential therapeutic benefits. Further investigation is needed to determine if trisomy 21 may predispose to the development of HLH given this common pathway.


Assuntos
Azetidinas , Síndrome de Down , Linfo-Histiocitose Hemofagocítica , Masculino , Feminino , Humanos , Interferons , Síndrome de Down/complicações , Interferon gama , Azetidinas/uso terapêutico , Trissomia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Antivirais/uso terapêutico
2.
Front Immunol ; 13: 1008392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389811

RESUMO

Background: Livedoid vasculopathy is a rare, chronic, and recurrent disease with limited effective treatments. Its etiopathogenesis remains incompletely understood. Baricitinib, a selective Janus kinase 1 and 2 inhibitor, has been used to treat rheumatoid arthritis and could reduce the disease severity in patients with livedoid vasculopathy. Methods: We retrospectively observed eight patients who received 2 mg/day of baricitinib for the treatment of refractory livedoid vasculopathy. We evaluated their clinical scores before and after treatment to determine its effectiveness and safety. Results: Improvement in livedoid vasculopathy was observed with significant regression in the clinical scores after baricitinib treatment. The mean clinical scores were 7.0 ± 1.6 and 1.4 ± 1.2 before and after baricitinib treatment, respectively (P <0.01). Furthermore, six out of the eight patients achieved a clinical score of 0 or 2 after treatment. These scores indicated remission. Clinical findings, including erythema, ulceration, and pain, improved in all the patients. The remission times ranged from 3 to 13 weeks, with a mean remission time of 7.75 ± 3.45 weeks. There were no reports of adverse events in any patient. Conclusions: Our study showed that baricitinib treatment was safe and could significantly relieve the signs and symptoms of livedoid vasculopathy. However, randomized controlled studies should be conducted to confirm these results.


Assuntos
Azetidinas , Vasculopatia Livedoide , Humanos , Estudos Retrospectivos , Azetidinas/uso terapêutico , Purinas/uso terapêutico
3.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362063

RESUMO

Siponimod (Mayzent®), a sphingosine 1-phosphate receptor (S1PR) modulator which prevents lymphocyte egress from lymphoid tissues, is approved for the treatment of relapsing-remitting and active secondary progressive multiple sclerosis. It can cross the blood-brain barrier (BBB) and selectively binds to S1PR1 and S1PR5 expressed by several cell populations of the central nervous system (CNS) including microglia. In multiple sclerosis, microglia are a key CNS cell population moving back and forth in a continuum of beneficial and deleterious states. On the one hand, they can contribute to neurorepair by clearing myelin debris, which is a prerequisite for remyelination and neuroprotection. On the other hand, they also participate in autoimmune inflammation and axonal degeneration by producing pro-inflammatory cytokines and molecules. In this study, we demonstrate that siponimod can modulate the microglial reaction to lipopolysaccharide-induced pro-inflammatory activation.


Assuntos
Azetidinas , Esclerose Múltipla , Humanos , Microglia/metabolismo , Compostos de Benzil/farmacologia , Azetidinas/farmacologia , Azetidinas/metabolismo , Esclerose Múltipla/metabolismo
4.
Acta Derm Venereol ; 102: adv00820, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36420885

RESUMO

Clinical trials have shown that baricitinib, an oral selective Janus kinase 1/2 inhibitor, is effective for the treatment of moderate-to-severe atopic dermatitis. However, daily practice data are limited. Therefore, this multicentre prospective study evaluated the effectiveness and safety of 16-weeks' treatment with baricitinib in adult patients with moderate-to-severe atopic dermatitis in daily practice. A total of 51 patients from the BioDay registry treated with baricitinib were included and evaluated at baseline and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed using clinician- and patient-reported outcome measurements. Adverse events and laboratory assessments were evaluated at every visit. At week 16, the probability (95% confidence interval) of achieving Eczema Area and Severity Index ≤ 7 and numerical rating scale pruritus ≤ 4 was 29.4% (13.1-53.5) and 20.5% (8.8-40.9), respectively. No significant difference in effectiveness was found between dupilumab non-responders and responders. Twenty-two (43.2%) patients discontinued baricitinib treatment due to ineffectiveness, adverse events or both (31.4%, 9.8% and 2.0%, respectively). Most frequently reported adverse events were nausea (n = 6, 11.8%), urinary tract infection (n = 5, 9.8%) and herpes simplex infection (n = 4, 7.8%). In conclusion, baricitinib can be an effective treatment option for moderate-to-severe atopic dermatitis, including patients with non-responsiveness on dupilumab. However, effectiveness of baricitinib is heterogeneous, which is reflected by the high discontinuation rate in this difficult-to-treat cohort.


Assuntos
Azetidinas , Dermatite Atópica , Inibidores de Janus Quinases , Adulto , Humanos , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Estudos Prospectivos , Azetidinas/efeitos adversos , Inibidores de Janus Quinases/efeitos adversos , Sistema de Registros
5.
Life Sci Space Res (Amst) ; 35: 69-75, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36336372

RESUMO

From antibiotics to aspirin to antimalarials and to anticancer agents, about half of the world's best-selling drugs are derived from nature. However, accelerating climatic disruption, habitat destruction, pollution, and biodiversity loss all negatively impact the potential of natural sources to continue to serve as repositories of novel pharmaceuticals. On that basis, the final frontier for drug development is perhaps not the rainforests, coral reefs, and other natural habitats but rather the aerospace industry with its virtually unlimited and inexhaustible man-made 'library' of potentially bioactive compounds. The first aerospace-sourced therapeutic to reach the clinic is RRx-001, an inhibitor of the NOD-like receptor - Nucleotide-binding oligomerization domain with Leucine rich Repeat and Pyrin domain (NLRP3) inflammasome in a Phase 3 trial for the treatment of small cell lung cancer (SCLC) and in a soon-to-start Phase 3 trial for protection against chemoradiotherapy-induced severe oral mucositis in first line head and neck cancer. As manned missions to the Moon, Mars, and asteroids as well as space tourism beckon, it is perhaps fitting that a compound like RRx-001, which is derived from 1,3,3-Trinitroazetidine (TNAZ), an explosive propellant for rockets, is a potential "all purpose" option to mitigate the major biomedical effects of space radiation exposures including cancer development and other tissue degenerations both within mission and after mission. This article highlights the promise of RRx-001 to attenuate the acute and late effects of radiation exposure on astronauts including the development of cancer.


Assuntos
Azetidinas , Neoplasias , Voo Espacial , Humanos , Astronautas , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Meio Ambiente Extraterreno , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Ensaios Clínicos Fase III como Assunto
6.
J Psychopharmacol ; 36(11): 1280-1293, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36321267

RESUMO

BACKGROUND: Because of their implications in several pathological conditions, α4ß2* nicotinic acetylcholine receptors (nAChRs) are potential targets for the treatment of nicotine dependence, pain, and many psychiatric and neurodegenerative diseases. However, they exist in various subtypes, and finding selective tools to investigate them has proved challenging. The nicotinic receptor agonist, 5-iodo-A-85380 (5IA), has helped in delineating the function of ß2-containing subtypes in vitro; however, much is still unknown about its behavioral effects. Furthermore, its effectiveness on α6-containing subtypes is limited. AIMS: To investigate the effects of 5IA on nociception (formalin, hot-plate, and tail-flick tests), locomotion, hypothermia, and conditioned reward after acute and repeated administration, and to examine the potential role of ß2 and α6 nAChR subunits in these effects. Lastly, its selectivity for expressed low sensitivity (LS) and high sensitivity (HS) α4ß2 receptors is investigated. RESULTS: 5IA dose-dependently induced hypothermia, locomotion suppression, conditioned place preference, and antinociception (only in the formalin test but not in the hot-plate or tail-flick tests). Furthermore, these effects were mediated by ß2 but not α6 nicotinic subunits. Finally, we show that 5-iodo-A-85380 potently activates both stoichiometries of α4ß2 nAChRs with differential efficacies, being a full agonist on HS α4(2)ß2(3) nAChRs, and a partial agonist on LS α4(3)ß2(2) nAChRs and α6-containing subtypes as well.


Assuntos
Azetidinas , Receptores Nicotínicos , Animais , Camundongos , Azetidinas/farmacologia , Agonistas Nicotínicos/farmacologia
7.
Int J Med Sci ; 19(11): 1628-1630, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36237984

RESUMO

RRx-001 is a small molecule NLRP3 inflammasome inhibitor with anti-CD47 and antiangiogenic/vascular normalization properties in a Phase 3 clinical trial that has been designated as a drug-device combination by the FDA. In the Phase 1 first-in-man dose escalation clinical trial, where RRx-001 was given by direct intravenous (IV) infusion, the main adverse event was a sterile painful infusion phlebitis (IP). Less pain was experienced when RRx-001 was infused at a slower rate over multiple hours which was impractical on an outpatient basis. In Phase 2, for reasons of convenience and safety, RRx-001 was co-administered with an aliquot of autologous blood from an ex-vivo device called the eLOOP on the premise that RRx-001 binds to hemoglobin on red blood cells (RBCs), making it unavailable to directly interact with venous nociceptors. Phlebitis has the potential to progress to deep venous thrombosis or septic thrombophlebitis or post-thrombotic syndrome in hypercoagulable and immunosuppressed cancer patients. In this 13-week toxicology study of once weekly IV RRx-001 administration to Wistar Han rats followed by a recovery period of 28 days. The main observed toxicity was a significant inflammatory response in the vein wall, consistent with superficial venous thrombosis observed in man. Due to this development, direct IV infusion of RRx-001 is relatively contraindicated in favor of co-administration with autologous blood.


Assuntos
Inflamassomos , Flebite , Animais , Azetidinas , Hemoglobinas/metabolismo , Inflamação/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nitrocompostos , Ratos , Ratos Wistar
8.
Medicine (Baltimore) ; 101(38): e30676, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36197174

RESUMO

BACKGROUND: To evaluate the comparative efficacy and safety of baricitinib with different dosages in patients with rheumatoid arthritis (RA). METHODS: PubMed, Embase, and the Cochrane Library were retrieved by computer to gather randomized controlled trials (RCTs) of baricitinib for RA from their beginning to September 2021. After 2 researchers independently screened the literature and extracted the data, the risk of bias of included RCTs was assessed, and Bayesian network meta-analysis was performed by GeMTC0.14.3 and Stata15.1 software. RESULTS: Ten publications reporting 9 RCTs were included, with 4129 patients randomized to receive 1 of the 7 interventions. Seven interventions were baricitinib 1 mg + conventional disease-modifying antirheumatic drugs (cDMARD), baricitinib 2 mg + cDMARD, baricitinib 4 mg + cDMARD, baricitinib 8 mg + cDMARD, baricitinib 4 mg, placebo + cDMARD, and cDMARD. In the efficacy outcomes at 12 weeks, nearly all doses of baricitinib with or without cDMARD were superior to placebo plus cDMARD and baricitinib 8 mg combined with cDMARD might have the best curative effect in most outcomes. In the efficacy outcomes at 24 weeks, all doses of baricitinib with or without cDMARD were superior to placebo plus cDMARD and baricitinib 4 mg monotherapy might have the best curative effect in most outcomes. The intervention with the highest incidence of adverse events (AEs) might be baricitinib 8 mg combined with cDMARD, and the intervention with the highest incidence of infections might be baricitinib 4 mg combined with cDMARD. CONCLUSIONS: Baricitinib 8 mg combined with cDMARDs was suitable for short-term control of RA symptoms, and baricitinib 4 mg was more effective for treating RA over a longer period of time. But attention should be paid for the risk of baricitinib at 4 to 8 mg in clinical application due to the high incidence of AEs and infections.


Assuntos
Antirreumáticos , Artrite Reumatoide , Azetidinas , Antirreumáticos/efeitos adversos , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Azetidinas/efeitos adversos , Humanos , Metanálise em Rede , Purinas , Pirazóis , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas , Resultado do Tratamento
10.
Drug Saf ; 45(12): 1491-1499, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36310331

RESUMO

INTRODUCTION AND OBJECTIVE: Serous retinopathy can be associated with MEK inhibitors, including cobimetinib. We present results of an integrated safety analysis to further characterize ocular functional and structural changes due to serous retinopathy. METHODS: Four studies evaluating cobimetinib at the approved dose and schedule in combination with other oncology drugs were included. Study CO39721 incorporated standardized ophthalmologic assessments to fully characterize serous retinopathy events over time and was the primary study for analysis. Supporting information was provided by studies GO28141, WO29479, and GO30182. RESULTS: In total, 655 patients received one or more doses of cobimetinib and comprised the safety-evaluable population. Overall, 117 patients (17.9%) had one or more serous retinopathy events, 24 (3.7%) had two or more events, and four (0.6%) had three or more events. Grade 3 events occurred in < 2.5% of patients. In CO39721, the median time to onset was 15 days (range 7-111); median time to resolution of first occurrence was 26 days (range 6-591 + days). Twelve of 25 patients (48.0%) recovered without a dose modification and 4/25 (16.0%) were recovered/recovering following a dose modification. The most frequent presentation of serous retinopathy was focal subretinal fluid on optical coherence tomography (62.8% of cases); in some instances (25.7% of cases), subretinal fluid was multifocal. There was no loss of visual function or visual acuity at serous retinopathy onset or resolution. CONCLUSIONS: Results from this integrated safety analysis indicate that cobimetinib-associated serous retinopathy can be managed with or without a dose modification of cobimetinib at the discretion of the treating physician. No visual loss or permanent retinal damage was identified on comprehensive ophthalmologic assessments. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03178851, NCT01689519, NCT02322814, and NCT02788279.


Assuntos
Azetidinas , Doenças Retinianas , Humanos , Azetidinas/efeitos adversos , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Doenças Retinianas/tratamento farmacológico
11.
Parasit Vectors ; 15(1): 370, 2022 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-36244989

RESUMO

BACKGROUND: For a long time known as the oriental eyeworm, Thelazia callipaeda is a zoonotic nematode that infects the eyes of a wide range of vertebrate hosts including dogs, cats, wildlife carnivores, lagomorphs, and humans. The high occurrence of this infection in Europe and the first cases in the United States have increased scientific interest in the parasite, as it also represents a risk for people living in endemic areas. Therefore, treatment and prevention of thelaziosis in canine population are advocated to reduce the risk of human infection as well. Here, we assessed the efficacy of a formulation containing sarolaner/moxidectin/pyrantel (Simparica Trio®) administered orally at monthly intervals, for the prevention of establishment of infection with T. callipaeda in naturally infected dogs. In this formulation, moxidectin is expected to have efficacy against eyeworms, whereas sarolaner and pyrantel are not. METHODS: The study was conducted in eyeworm endemic areas of Italy and France, where dogs (n = 125) were assigned into two groups consisting of a negative control group (G1; n = 62), in which animals were treated monthly with a control product (sarolaner; Simparica®), and a treatment group (G2; n = 63) in which animals were treated monthly with Simparica Trio (sarolaner/moxidectin/pyrantel) from day 0 to day 150. In total, nine animals were withdrawn from the study (two animals became positive at day 30, and seven for reasons unrelated to eyeworm infection), resulting in 116 animals (n = 58 for G1; n = 58 for G2). RESULTS: In G1, 16 out of 58 animals (27.6%) were observed with eyeworms during the study, and none of the animals from G2 were ever observed with eyeworms, resulting in 100% efficacy (P < 0.0001) in the prevention of establishment of T. callipaeda infection. Adult nematodes and fourth-instar (L4)-stage larvae were recovered from the eyes of positive animals, counted, and morphologically identified as T. callipaeda. In addition, specimens from Italy were molecularly confirmed as belonging to the haplotype 1 (i.e., the only one circulating in Europe so far). CONCLUSIONS: Data presented herein demonstrated 100% efficacy of Simparica Trio for the prevention of T. callipaeda eyeworm infection in dogs from highly endemic areas of France and Italy. The use of this formulation is advantageous, as it is a licensed product in Europe with a wide efficacy spectrum against other nematodes, multiple tick species, and fleas. In addition, preventing the development of infection in dogs could also be a prophylaxis measure for zoonotic T. callipaeda infection in humans inhabiting endemic areas.


Assuntos
Doenças do Cão , Nematoides , Infecções por Spirurida , Thelazioidea , Animais , Azetidinas , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Doenças do Cão/prevenção & controle , Cães , Humanos , Macrolídeos , Pirantel/uso terapêutico , Compostos de Espiro , Infecções por Spirurida/tratamento farmacológico , Infecções por Spirurida/prevenção & controle , Infecções por Spirurida/veterinária
12.
Org Lett ; 24(43): 8041-8046, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36264267

RESUMO

Photocatalytic dehydrogenative [2 + 2] cycloadditions between amines and alkenes were developed that allow for the stereoselective and high-yielding synthesis of functionalized azetidines. The oxidative formal Aza Paternò-Büchi reactions are induced by photoredox-catalyzed aerobic oxidation of dihydroquinoxalinones 1 as the amines, and in the presence of structurally diverse alkenes 3 intermolecular [2 + 2] cyclization to dihydro-1H-azeto[1,2-a]quinoxalin-3(4H)-ones 4 occurs. The utility of the method is illustrated by the selective conversion of amino acid derived dihydroquinoxalinones 1, including oxidation-prone lysine and tryptophan derivatives.


Assuntos
Alcenos , Azetidinas , Alcenos/química , Aminas/química , Reação de Cicloadição , Catálise , Estrutura Molecular , Ciclização
13.
Ann Intern Med ; 175(10): JC115, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36191322

RESUMO

SOURCE CITATION: Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022;10:888-99. 35617986.


Assuntos
COVID-19 , Monofosfato de Adenosina/análogos & derivados , Adulto , Alanina/análogos & derivados , Azetidinas , COVID-19/tratamento farmacológico , Dexametasona/uso terapêutico , Método Duplo-Cego , Humanos , Purinas , Pirazóis , Sulfonamidas
15.
Eur J Clin Pharmacol ; 78(12): 1981-1990, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36284012

RESUMO

PURPOSE: JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE. METHODS: A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized. RESULTS: Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1-75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5-9.2] for VTE and 6.1 months [IQR: 3.0-8.5] for ATE. An IRR of 8.27 (95% CI 3.41-20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02-21.11]). An IRR of 9.27 (3.68-23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27-31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE. CONCLUSIONS: This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib.


Assuntos
Azetidinas , Inibidores de Janus Quinases , Tromboembolia Venosa , Humanos , Feminino , Masculino , Inibidores de Janus Quinases/efeitos adversos , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/epidemiologia , Azetidinas/efeitos adversos , Pirazóis/efeitos adversos
16.
Org Lett ; 24(42): 7801-7805, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36263993

RESUMO

A variety of azetidine nitrones are prepared in moderate to good yields through copper(I) combined with 2-aminopyridine to catalyze skeletal rearrangement of O-propargylic oximes. Mechanistic studies reveal that the reaction undergoes a copper(I)-catalyzed tandem [2,3]-rearrangement, 4π-electrocyclization, ring opening, and recyclization over four steps in one pot. Substituents at the terminus of alkyne and oxime moieties have a significant impact on the formation of azetidine nitrones and exomethylene oxazolines, respectively. Furthermore, the obtained azetidine nitrone could easily participate in [3 + 2] cycloaddition with alkynoates, and a [2.2]-paracyclophane-derived azetidine nitrone is synthesized in 45% yield over five steps from bromo[2.2]-paracyclophane.


Assuntos
Azetidinas , Cobre , Óxidos de Nitrogênio , Oximas , Catálise
17.
Eur J Dermatol ; 32(4): 522-529, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36301752

RESUMO

Background: In adults with atopic dermatitis (AD), head and/or neck involvement is frequent, bothersome, and impacts quality of life, however, long-term topical corticosteroids (TCS) are contraindicated for this difficult-to-treat region. Baricitinib, an oral, selective, reversible inhibitor of Janus kinase 1/2 has demonstrated efficacy in adult patients with moderate-to-severe AD. Objectives: For this post hoc analysis, data from five Phase III trials were used to investigate the efficacy of baricitinib in patients with head and neck involvement. Materials & Methods: Data were obtained from BREEZE-AD1, -AD2, -AD4, -AD5, and -AD7; Phase III, multicenter, randomized, double-blind, placebo-controlled studies conducted in patients ≥18 years with moderate-to-severe AD. BREEZE-AD1, -AD2, and -AD5 evaluated baricitinib as monotherapy, and BREEZE-AD4 and -AD7 evaluated baricitinib in combination with TCS, topical calcineurin inhibitors, or topical PDE-4 inhibitors, where available. The proportion of patients with improvement of Eczema Area and Severity Index (EASI) total score from baseline of ≥50% (EASI50) and ≥75% (EASI75), as well as head/neck EASI50 and EASI75 and erythema head/neck EASI50 and EASI75 response rates were assessed up to Week 16. Results: Across the studies, 93-98% of patients had head/neck involvement at baseline (EASI head/neck score ≥1). Baricitinib was similarly effective based on EASI total score for the entire body in all studies. In the monotherapy studies, the proportion of patients achieving head/neck EASI50 and EASI75 scores was significantly higher for baricitinib 2-mg and 4-mg versus placebo at Weeks 1 and 16. Conclusion: Baricitinib 2-mg and 4-mg treatment showed rapid and substantial reduction in AD head and neck severity, including erythema.


Assuntos
Azetidinas , Dermatite Atópica , Fármacos Dermatológicos , Adulto , Humanos , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/diagnóstico , Qualidade de Vida , Azetidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Método Duplo-Cego , Resultado do Tratamento , Índice de Gravidade de Doença
18.
Molecules ; 27(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36144508

RESUMO

1,3,3-Trinitroazetidine (TNAZ) has good thermal stability and low shock sensitivity, among other properties, and it has broad prospects in insensitive ammunition applications. In this study, a molecular dynamics calculation based on the ReaxFF-lg force field and multiscale shock technique (MSST) was used to simulate the shock-induced chemical reaction of TNAZ with different shock wave directions. The results showed that the shock sensitivity of TNAZ was in the order of [100] > [010] > [001]. There were significant differences in molecular arrangements in different shock directions, which affected the reaction rate and reaction path in different directions. The molecular arrangement in the [010] and [001] directions formed a "buffer" effect. The formation and cleavage of bonds, formation of small molecules and growth of clusters were analyzed to show the effect of the "buffer". The polymerization reactions in the [010] and [001] directions appeared later than that in the [100] direction, and the cluster growth in the [010] and [001] directions was slower than that in the [100] direction. In different shock loading directions, the formation and cleavage mechanisms of the N-O bonds of the TNAZ molecules were different, which resulted in differences in the initial reaction path and reaction rate in the three directions.


Assuntos
Azetidinas , Simulação de Dinâmica Molecular , Anisotropia , Azetidinas/química , Nitrocompostos/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...