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1.
Paediatr Drugs ; 23(2): 171-182, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33651370

RESUMO

OBJECTIVE: The aim of this study was to examine patterns of initial prescriptions, investigate time to initiation of biologic disease-modifying anti-rheumatic drugs (bDMARDs), and evaluate the impact of clinical and other baseline factors associated with the time to first bDMARD in treating children with newly diagnosed non-systemic juvenile idiopathic arthritis (JIA). METHODS: Using longitudinal patient-level data extracted from electronic medical records (EMR) in a large Midwestern pediatric hospital from 2009 to 2018, the initial prescriptions and prescribing patterns of bDMARDs, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids within 3 months of JIA diagnosis were examined. Kaplan-Meier analyses were performed to assess time to initiation of bDMARDs. Cox proportional hazard models were used to identify factors associated with time to first bDMARD. RESULTS: Of 821 children, the proportion of patients with initial csDMARDs increased from 45.3% in 2009 to 60.3% in 2018. Around 57.5% of polyarthritis rheumatoid factor-positive (Poly RF+) patients and 43.2% of polyarthritis rheumatoid factor-negative (Poly RF-) patients received a bDMARD therapy within 3 months of diagnosis, 14.4% as monotherapy and 28.3% in combination with a csDMARD. Among patients who received combination therapy, combination of methotrexate with adalimumab increased from 16.7% in 2009 to 40% in 2018. The proportion of patients treated with adalimumab gradually increased and passed etanercept in 2016. The predictors of earlier initiation of biologic therapy were JIA category enthesitis-related arthritis (ERA) [hazard ratio (HR) vs persistent oligoarthritis 4.82; p < 0.0001], psoriatic arthritis (PsA) (HR 2.46; p = 0.0002), or Poly RF- (HR 2.43; p = 0.0002); the number of joints with limited range of motion (HR 1.02; p = 0.0222), and erythrocyte sedimentation rate (ESR, HR 1.01; p = 0.0033). CONCLUSIONS: There was a substantial increase in the proportion of patients receiving the combination of methotrexate and adalimumab among patients receiving combination therapy. Adalimumab overtook etanercept as the most frequently prescribed bDMARD. Multiple factors affect the time to biologic initiation, including the number of joints with limited range of motion, ESR, and JIA category.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Terapia Biológica/métodos , Adalimumab/uso terapêutico , Adolescente , Artrite/tratamento farmacológico , Criança , Pré-Escolar , Etanercepte/administração & dosagem , Feminino , Glucocorticoides/uso terapêutico , Humanos , Estudos Longitudinais , Masculino , Metotrexato/uso terapêutico , Estudos Retrospectivos
2.
BMJ Case Rep ; 14(3)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653867

RESUMO

A previously healthy 53-year-old man was hospitalised for 12 days due to COVID-19 with shortness of breath. A few days after discharge from hospital, the patient developed fever and severe pain in several joints in the lower extremities. The pain was so severe that the patient was unable to stand on his feet. Synovial fluid from the right-side knee contained a high number of polynuclear cells and a few mononuclear cells. Microscopy, culture and PCR tests for bacterial infection were all negative. Furthermore, the patient tested negative for rheumatoid factor, anti-cyclic citrullinated peptide and human leukocyte antigen (HLA)-B27. Thus, the condition was compatible with reactive arthritis. The condition improved markedly after a few days' treatment with non-steroid anti-inflammatory drugs and prednisolone.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Reativa , Artrite , Prednisolona/administração & dosagem , Líquido Sinovial , Anti-Inflamatórios/administração & dosagem , Artralgia/diagnóstico , Artralgia/etiologia , Artrite/tratamento farmacológico , Artrite/etiologia , Artrite/fisiopatologia , Artrite Reativa/diagnóstico , Artrite Reativa/tratamento farmacológico , Artrite Reativa/fisiopatologia , Artrite Reativa/virologia , Artrite Reumatoide/diagnóstico , Autoanticorpos/análise , /fisiopatologia , Diagnóstico Diferencial , Humanos , Articulação do Joelho/diagnóstico por imagem , Extremidade Inferior/patologia , Masculino , Pessoa de Meia-Idade , Radiografia/métodos , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Resultado do Tratamento
4.
Adv Ther ; 38(2): 1290-1300, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432540

RESUMO

INTRODUCTION: Phase IV post-marketing surveillance studies are needed to evaluate the real-world safety and effectiveness of drug products. This study aimed to evaluate the safety and effectiveness of biosimilar etanercept (Altebrel, AryoGen Co., Iran) in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). METHODS: In this open-label, multicenter, prospective, observational, post-marketing surveillance study, 583 patients received biosimilar etanercept 25 mg twice weekly or 50 mg once weekly and were followed up to 12 months. The primary objective was to evaluate the safety of biosimilar etanercept by documenting all the adverse events in the case report forms throughout the study period. The secondary objective was to evaluate the effectiveness of biosimilar etanercept in study patients, where longitudinal changes in health assessment questionnaire (HAQ), pain, and disease activity scores were assessed. RESULTS: A total of 583 patients (44.80 ± 13.09 years of age) were included and followed for an average of 8.12 ± 3.96 months. Among all patients, 172 (29.50%) experienced at least one adverse event, and injection site reaction, abdominal pain, and upper respiratory tract infection were the most common. HAQ scores decreased from 1.32 ± 0.77 at baseline to 0.81 ± 0.61 at 12 months in patients with RA/PsA (p < 0.01) and from 0.82 ± 0.58 at baseline to 0.66 ± 0.63 at 12 months in patients with AS (p = 0.18). Pain scores decreased from 6.49 ± 2.41 at baseline to 3.51 ± 2.39 at 12 months (p < 0.01). CONCLUSION: The results demonstrated the real-world safety and effectiveness of biosimilar etanercept in patients with RA, PsA, and AS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04582084.


Assuntos
Antirreumáticos , Artrite/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Medicamentos Biossimilares , Antirreumáticos/uso terapêutico , Etanercepte , Humanos , Lactente , Vigilância de Produtos Comercializados , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento
5.
Am J Med Sci ; 361(4): 526-533, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33386120

RESUMO

Antisynthetase syndrome (AS) is a rare disease that affects patients with inflammatory myopathies such as polymyositis (PM) and dermatomyositis (DM). In patients with AS, up to 95% of patients develop antisynthetase syndrome-associated interstitial lung disease (AS-ILD). Although AS-ILD commonly occurs in patients with a well-established diagnosis of AS, it can be the first or only manifestation of an occult AS. The frequency of interstitial lung disease (ILD), myopathy, and skin involvement are often dependent on the type of myositis-specific antibodies present. AS-ILD patients who are positive for both anti-Jo-1 and anti-SSA/RO-52 autoantibodies often present with a severe degree of lung restriction on pulmonary function tests and radiologic imaging with an inadequate response toward immunosuppressive therapies. We describe a 65-year-old woman who presents with chronic dyspnea. She was initially diagnosed with corticosteroid-resistant cryptogenic organizing pneumonia based on the radiological findings on her CT chest. Her symptoms did not improve, and she suffered from intolerable corticosteroid-related side effects. Reviews of systems were positive for arthritis and Raynaud's phenomenon. She was found to have elevated inflammatory markers and autoantibodies such as anti-Jo-1, anti-RO-52, and anti-SSA. A diagnosis of AS-ILD resistant to corticosteroid therapy was made. Her lung function improved with combination therapy of mycophenolate and rituximab. Our case highlights that a detailed history and physical exam, compatible radiologic imaging, and autoantibodies are essential for the diagnosis of AS-ILD.


Assuntos
Artrite/tratamento farmacológico , Dispneia/tratamento farmacológico , Doenças Pulmonares Intersticiais/diagnóstico , Miosite/diagnóstico , Doença de Raynaud/tratamento farmacológico , Idoso , Antirreumáticos/uso terapêutico , Artrite/etiologia , Quimioterapia Combinada , Dispneia/etiologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Miosite/complicações , Miosite/tratamento farmacológico , Doença de Raynaud/etiologia , Rituximab/uso terapêutico
7.
Eur J Med Chem ; 213: 113174, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33515864

RESUMO

In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on "Hit" we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC50 = 2934, 2301 µM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 µM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC50 is 0.96 µM and could interfere stability and formation of the active dimeric iNOS. It's anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo, acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment.


Assuntos
Artrite/tratamento farmacológico , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Administração Oral , Animais , Artrite/metabolismo , Células Cultivadas , Dimerização , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Adjuvante de Freund , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/administração & dosagem , Pirazóis/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
Arthritis Res Ther ; 22(1): 290, 2020 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-33380344

RESUMO

BACKGROUND: Prevalence and outcomes of coronavirus disease (COVID)-19 in relation to immunomodulatory medications are still unknown. The aim of the study is to investigate the impact of glucocorticoids and immunosuppressive agents on COVID-19 in a large cohort of patients with chronic immune-mediated inflammatory arthritis. METHODS: The study was conducted in the arthritis outpatient clinic at two large academic hospitals in the COVID-19 most endemic area of Northern Italy (Lombardy). We circulated a cross-sectional survey exploring the prevalence of severe acute respiratory syndrome-coronavirus-2 nasopharyngeal swab positivity and the occurrence of acute respiratory illness (fever and/or cough and/or dyspnea), administered face-to-face or by phone to consecutive patients from 25 February to 20 April 2020. COVID-19 cases were defined as confirmed or highly suspicious according to the World Health Organization criteria. The impact of medications on COVID-19 development was evaluated. RESULTS: The study population included 2050 adults with chronic inflammatory arthritis receiving glucocorticoids, conventional-synthetic (cs), or targeted-synthetic/biological (ts/b) disease-modifying drugs (DMARDs). Laboratory-confirmed COVID-19 and highly suspicious infection were recorded in 1.1% and 1.4% of the population, respectively. Treatment with glucocorticoids was independently associated with increased risk of COVID-19 (adjusted OR [95% CI] ranging from 1.23 [1.04-1.44] to 3.20 [1.97-5.18] depending on the definition used). Conversely, patients treated with ts/bDMARDs were at reduced risk (adjusted OR ranging from 0.46 [0.18-1.21] to 0.47 [0.46-0.48]). No independent effects of csDMARDs, age, sex, and comorbidities were observed. CONCLUSIONS: During the COVID-19 outbreak, treatment with immunomodulatory medications appears safe. Conversely, glucocorticoids, even at low-dose, may confer increased risk of infection. TRIAL REGISTRATION: Retrospectively registered. Not applicable.


Assuntos
Corticosteroides/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite/tratamento farmacológico , Imunossupressores/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Idoso , Artrite/diagnóstico , Artrite/epidemiologia , /epidemiologia , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade
9.
Inflamm Res ; 69(12): 1245-1256, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32975609

RESUMO

OBJECTIVE AND DESIGN: Biochanin A (BCA), a phytoestrogen, has various pharmacological properties. This study was conducted to compare BCA's therapeutic property against 17-ß estradiol replacement therapy in zymosan-induced arthritis (ZIA) in mice. Additionally, we further investigated in vitro the anti-inflammatory action on neutrophils. TREATMENT: Ovariectomized (OVX) and non-OVX mice were pretreated with BCA (1, 3 and 9 mg/kg) or estrogen (50 µg/kg) for 14 days prior to ZIA. Neutrophils were pretreated with BCA (1, 10 and 100 µM) for 1 h prior to phorbol 12-myristate 13-acetate. METHODS: Anti-inflammatory effects of BCA were evaluated by cellular infiltrate, paw edema and cytokine measurement. In vitro, apoptosis was assessed by morphology and flow cytometry. Neutrophil extracellular traps (NET) were determined by fluorescent microscopy and DNA release. Statistical differences were determined by one- or two-way ANOVA. RESULTS: BCA inhibited neutrophil accumulation, paw edema and proinflammatory cytokine (TNF-α and IFN-γ) and increased anti-inflammatory cytokines (IL-4 and IL-10) in OVX and non-OVX mice, similar to 17-ß estradiol replacement therapy. In vitro, BCA increased apoptosis and consequently reduced NETs. CONCLUSION: BCA has a notable anti-inflammatory effect, similar to 17-ß estradiol, and is especially effective for treatment of ZIA. These results suggest that BCA may be promising for the treatment of postmenopausal arthritis.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite/tratamento farmacológico , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Genisteína/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Artrite/induzido quimicamente , Citocinas/metabolismo , DNA/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Camundongos , Neutrófilos/efeitos dos fármacos , Ovariectomia , Acetato de Tetradecanoilforbol , Zimosan
11.
Isr Med Assoc J ; 22(5): 289-293, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32378820

RESUMO

BACKGROUND: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management. OBJECTIVES: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu. METHODS: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies. RESULTS: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2-6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed. CONCLUSIONS: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Síndrome de Behçet/tratamento farmacológico , Adalimumab/efeitos adversos , Adulto , Anti-Inflamatórios/efeitos adversos , Artrite/sangue , Artrite/etiologia , Síndrome de Behçet/sangue , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Citocinas/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
12.
Ann Rheum Dis ; 79(7): 969-974, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32299797

RESUMO

BACKGROUND: Juvenile idiopathic arthritis is one of the most prevalent chronic inflammatory diseases in children. Evidence suggests that early effective treatment minimises the burden of disease during childhood and in further life. We hypothesise that a guided treat-to-target (T2T) approach is superior to routine care in polyarticular juvenile idiopathic arthritis (pJIA) in terms of reaching a clinical remission after 12 months of treatment. METHODS: Patients with early and active pJIA were enrolled. Targets for treatment were the following: Recognisable Juvenile Arthritis Disease Activity Score (JADAS) improvement after 3 months, acceptable disease at 6 months, minimal disease activity at 9 months and as primary endpoint remission after 12 months. Initially, patients received methotrexate. Failure to meet a defined target required treatment modification at the specified intervals. The choice of biologics was not influenced by the protocol. Finally, T2T patients were compared with a cohort of matched controls of patients with pJIA with unguided therapy documented by BIKER. RESULTS: Sixty-three patients were enrolled. Treatment targets after 3/6/9 and 12 months were reached by 73%/75%/77% and 48% of patients. Fifty-four patients completed the protocol. Compared with matched controls, on T2T guidance significantly more patients reached JADAS remission (48% vs 32%; OR 1.96 (1.1-3.7); p=0.033) and JADAS minimal disease activity (JADAS-MDA) (76% vs 59%; OR 2.2 (1.1-4.4); p=0.028). Patients from the T2T cohort received a biologic significantly more frequent (50% vs 9% after 12 months; OR 9.8 (4.6-20.8); p<0.0001). CONCLUSION: The T2T concept was feasible and superior to unguided treatment. High rates of patients reached JADAS-MDA and JADA remission after 12 months. Approximately half of the patients achieved their therapy goals without a biologic.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Quimioterapia de Indução/métodos , Adolescente , Artrite/diagnóstico por imagem , Artrite Juvenil/diagnóstico por imagem , Criança , Pré-Escolar , Protocolos Clínicos , Feminino , Humanos , Masculino , Índice de Gravidade de Doença
14.
Artigo em Inglês | MEDLINE | ID: mdl-32164967

RESUMO

Meloxicam, an oxicam derivative: 4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide, is a nonsteroidal anti-inflammatory drug (NSAID). It is a selective inhibitor of cyclooxygenase-2 (COX-2). It is used in the management of rheumatoid arthritis, acute exacerbations of osteoarthritis, ankylosing spondylitis and juvenile idiopathic arthritis. It is given in a single oral dose of 7.5mg, increased if necessary to a maximum of 15mg daily (7.5mg in the elderly). It may also be given by rectal suppository in doses similar to those used orally. The reported side effects of meloxicam are similar to those of nonsteroidal anti-inflammatory drugs (NSAIDs), such as abdominal pain, anemia, and edema. There is also an increased risk of serious gastrointestinal (GI) adverse events, including ulceration and bleeding. This profile is prepared to discuss and explain physical characteristics, Proprietary and nonproprietary names of meloxicam. It also includes methods of preparation, thermal and spectral behavior, methods of analysis, pharmacokinetics, metabolism, excretion and pharmacology.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Meloxicam/farmacologia , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Artrite/classificação , Artrite/tratamento farmacológico , Humanos , Meloxicam/efeitos adversos , Tiazinas , Tiazóis
15.
Clin Orthop Surg ; 12(1): 86-93, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32117543

RESUMO

Background: In drug therapy for patients with arthritis, a naproxen/esomeprazole combination drug may be a tolerable choice because it can minimize gastrointestinal and cardiovascular adverse effects. The aim of this study was to investigate the changes in quality of life (QOL), medication adherence, and satisfaction after switch from the existing drug to the combination drug. In addition, we analyzed the correlation between the above-mentioned variables and the stratified demographic and medical data of the patients. Methods: A prospective, noninterventional, observational study was conducted in 30 hospitals between May 2014 and July 2016. In total, 2,308 patients with osteoarthritis, 99 patients with rheumatoid arthritis, and 76 patients with ankylosing spondylitis were enrolled. Demographic information (age, sex, body mass index [BMI], alcohol consumption, and smoking) and medical information (type of arthritis, duration of disease, and comorbidities) were collected via a self-administered questionnaire. Patients were observed for more than three months after switching to the combination drug. Data on the QOL (EuroQoL 5-Dimension questionnaire [EQ-5D questionnaire]), medication adherence (Morisky Medication Adherence Scale [MMAS]), and satisfaction were collected at the first and last visits. Results: A total of 2,483 patients enrolled at 30 hospitals completed the questionnaire. After the switch to the combination drug, the mean EQ-5D score improved from 0.72 ± 0.17 to 0.79 ± 0.14 (p < 0.001), and significant improvement was associated with female sex (p = 0.016), shorter disease duration (p < 0.001), and absence of comorbidities (p < 0.001). The mean MMAS score was 6.38 ± 1.77, indicating medium adherence. Satisfaction was significantly higher in female patients (p < 0.001), in patients with a shorter disease duration (p < 0.001), osteoarthritis (p = 0.003), and no comorbidities (p < 0.001). Serious drug-related adverse effects did not occur. Conclusions: The overall QOL was improved with medium adherence after the switch to the combination drug. On the basis of the analysis of stratified data, sex, age, drinking, smoking, disease duration, comorbidities, and BMI might be associated with QOL, satisfaction, and adherence.


Assuntos
Artrite/tratamento farmacológico , Esomeprazol/administração & dosagem , Naproxeno/administração & dosagem , Satisfação Pessoal , Qualidade de Vida , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Adulto Jovem
16.
Eur J Med Chem ; 193: 112216, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208222

RESUMO

Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 µM (IC50 = 6.4 µM) with the lowest cytotoxicity (IC50 > 80 µM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Chalconas/farmacologia , Desenvolvimento de Medicamentos , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/induzido quimicamente , Artrite/metabolismo , Células Cultivadas , Chalconas/síntese química , Chalconas/química , Doença Crônica , Colágeno , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
18.
Nat Rev Rheumatol ; 16(3): 145-154, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066940

RESUMO

Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA. Although methotrexate is one of the first examples of intelligent drug design, multiple mechanisms potentially contribute to the anti-inflammatory actions of methotrexate, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, translocation of nuclear factor-κB (NF-κB) to the nucleus, signalling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and nitric oxide production, as well as the promotion of adenosine release and expression of certain long non-coding RNAs.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Artrite/tratamento farmacológico , Imunidade Celular/efeitos dos fármacos , Metotrexato/uso terapêutico , Ribonucleotídeos/antagonistas & inibidores , Linfócitos T/imunologia , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacos , Aminoimidazol Carboxamida/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Artrite/imunologia , Artrite/metabolismo , Humanos , Linfócitos T/efeitos dos fármacos , Tetra-Hidrofolato Desidrogenase/metabolismo
19.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053981

RESUMO

The social and economic impact of chronic inflammatory diseases, such as arthritis, explains the growing interest of the research in this field. The antioxidant and anti-inflammatory properties of the endogenous gasotransmitter hydrogen sulfide (H2S) were recently demonstrated in the context of different inflammatory diseases. In particular, H2S is able to suppress the production of pro-inflammatory mediations by lymphocytes and innate immunity cells. Considering these biological effects of H2S, a potential role in the treatment of inflammatory arthritis, such as rheumatoid arthritis (RA), can be postulated. However, despite the growing interest in H2S, more evidence is needed to understand the pathophysiology and the potential of H2S as a therapeutic agent. Within this review, we provide an overview on H2S biological effects, on its role in immune-mediated inflammatory diseases, on H2S releasing drugs, and on systems of tissue repair and regeneration that are currently under investigation for potential therapeutic applications in arthritic diseases.


Assuntos
Artrite/tratamento farmacológico , Gasotransmissores/imunologia , Gasotransmissores/uso terapêutico , Sulfeto de Hidrogênio/imunologia , Sulfeto de Hidrogênio/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/imunologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Gasotransmissores/administração & dosagem , Humanos , Sulfeto de Hidrogênio/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/imunologia , Estresse Oxidativo/efeitos dos fármacos
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