RESUMO
Methotrexate (MTX) is a first line anti-rheumatic drug. This study was designed to investigate the impact of rheumatoid arthritis (RA) conditions on its oral absorption, and clarify the relevance with changes of MTX absorption-related transporters in rheumatic models. MTX was orally administered to healthy, collagen-induced arthritis (CIA), and adjuvant-induced arthritis (AIA) rats. MTX plasma concentrations were determined by a validated liquid chromatography-mass spectrometry method. We found that intestinal MTX absorption was significantly increased in CIA/AIA rats versus healthy controls. This finding was supported by small intestine-based MTX uptake assay in vitro. Meanwhile, intestinal expression of both reduced folate carrier 1 (RCF1) and proton-coupled folate transporter (PCFT) remained unchanged. The everted intestinal sac assay confirms RFC1 is the key transporter accounting for intestinal MTX absorption, as its antagonist salicylazosulfapyridine showed potent capacity in reducing MTX uptake. No correlation between RA-related cytokines and RCF1 expression was observed in clinical samples. We further revealed that when cultured with AIA rat or RA patient serum, lactate and adenosine triphosphate (ATP) production as well as MTX uptake in MDCKII cells were significantly increased, and this increase was completely abrogated by ATP production-related metabolic inhibitors. Thanks to its inhibitory effects on MTX bioavailability, the glycolysis inhibitor shikonin diminished MTX-induced injuries of kidney and liver in AIA rats. These data demonstrate that glycolysis-driven high energy metabolism increases MTX absorption in rheumatic subjects, leading to the exacerbated toxicity. These findings will have important implications in optimizing MTX regimens for RA treatment with better efficacy and lower toxicity.
Assuntos
Antirreumáticos , Artrite Experimental , Artrite Reumatoide , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Trifosfato de Adenosina/metabolismo , Animais , Antirreumáticos/uso terapêutico , Antirreumáticos/toxicidade , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Glicólise , Humanos , Absorção Intestinal , Metotrexato/farmacologia , RatosRESUMO
Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Crotonatos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Durapatita/química , Ácido Hialurônico/química , Metotrexato/administração & dosagem , Nanopartículas/administração & dosagem , Toluidinas/administração & dosagem , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Antirreumáticos/toxicidade , Artrite Experimental/patologia , Crotonatos/farmacocinética , Crotonatos/uso terapêutico , Crotonatos/toxicidade , Citocinas/sangue , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Hidroxibutiratos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Metotrexato/toxicidade , Camundongos , Nanopartículas/toxicidade , Nitrilas , Células RAW 264.7 , Ratos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual , Toluidinas/farmacocinética , Toluidinas/uso terapêutico , Toluidinas/toxicidadeRESUMO
AIM: The present study was carried out to evaluate the anti-inflammatory and antiarthritic activity of Rosa centifolia aqueous extract (RC) in a carrageenan-induced paw edema model and complete Freund's adjuvant (CFA)-induced arthritis. METHODS: Anti-inflammatory activity of RC was evaluated using the carrageenan-induced paw edema model in rats. Arthritis was induced in rats by sub-plantar administration of CFA. Joint size was measured at regular intervals by using a micrometer screw gauge. Serum and ankle joints of rats immunized with CFA were collected and subjected to enzyme-linked immunosorbent assay for estimation of tumor necrosis factor (TNF)-α level and dot blot for secretory cytokines interleukin (IL)-1ß and IL-6. An acute and 28-day oral toxicity study was carried out to evaluate the safety of the test drug. RESULTS: Pre-treatment with RC produced a dose-dependent reduction in carrageenan-induced paw edema and CFA-induced arthritis models and was effective as indomethacin. RC also inhibited the delayed increase in joint diameter as seen in control and indomethacin-treated animals in CFA-induced arthritis. The expression of proinflammatory mediators TNF-α, IL-6 and IL-1ß was also found to be less in the RC-treated group as compared to controls. CONCLUSION: Based on these results, it was suggested that Rosa centifolia could be considered as a potential anti-inflammatory and anti-arthritic agent.
Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Edema/prevenção & controle , Articulações/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rosa , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/toxicidade , Antirreumáticos/isolamento & purificação , Antirreumáticos/toxicidade , Artrite Experimental/sangue , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Adjuvante de Freund , Indometacina/farmacologia , Mediadores da Inflamação/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Articulações/metabolismo , Articulações/patologia , Masculino , Fitoterapia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Plantas Medicinais , Ratos Wistar , Rosa/química , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression. METHODS: The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined. RESULTS: Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII. CONCLUSIONS: A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/toxicidade , Formação de Anticorpos/efeitos dos fármacos , Antirreumáticos/administração & dosagem , Antirreumáticos/toxicidade , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Etanercepte/administração & dosagem , Etanercepte/uso terapêutico , Etanercepte/toxicidade , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Terapia de Alvo Molecular/métodos , Piperazinas/administração & dosagem , Piperazinas/toxicidade , Piridinas/administração & dosagem , Piridinas/toxicidade , Receptores de Interleucina-6/antagonistas & inibidoresRESUMO
Glycyrol is a natural compound extracted from Glycyrrhiza uralensis, first reported by us to be a new immunosuppressant. Here, we demonstrate its beneficial effect in collagen-induced arthritis (CIA) in mice, a model for rheumatoid arthritis (RA) in man, and we document the underlying mechanisms. Peroral administration of glycyrol significantly reduced clinical scores, alleviated cartilage and bone erosion and reduced levels of serum inflammatory cytokines. Glycyrol also decreased delayed-type hypersensitivity, improved carbon clearance and reduced acetic acid-induced capillary permeability. Furthermore, glycyrol decreased NF-κB and NFAT transcriptional activities and inhibited IL-2 expression. The therapeutic effect of glycyrol was associated with down-regulation of both autoimmune and inflammatory reactions. In addition, we demonstrated that glycyrol has minimal acute toxicity in mice. Therefore, we propose that glycyrol may hold promise for future treatment of RA.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Flavonoides/uso terapêutico , Imunossupressores/uso terapêutico , Fitoterapia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Antirreumáticos/farmacologia , Antirreumáticos/toxicidade , Artrite Experimental/imunologia , Artrite Experimental/patologia , Permeabilidade Capilar/efeitos dos fármacos , Cartilagem Articular/patologia , Citocinas/sangue , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Flavonoides/farmacologia , Flavonoides/toxicidade , Hipersensibilidade Tardia/tratamento farmacológico , Imunossupressores/farmacologia , Imunossupressores/toxicidade , Inflamação , Interleucina-2/biossíntese , Interleucina-2/genética , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/antagonistas & inibidores , Fatores de Transcrição NFATC/metabolismo , Fagocitose/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
CONTEXT: Rheumatoid arthritis (RA) is a chronic autoimmune disorder. Habb-e-Asgand (HEA) is a polyherbal, Unani formulation widely used in the treatment of RA. Traditional systems of medicine or plant-based drugs are an attractive alternative treatment because of their professed efficacy in curing the disease. Medicinal herbs and herbal formulations are generally considered to be safer than the conventional drugs for RA. Unani drugs are known not to produce toxic effects and are presumed to be nontoxic. However, no objective, verifiable data exists to support the claims of nontoxicity and efficacy. OBJECTIVES: The present study was designed to evaluate the safety and therapeutic efficacy of HEA in Wistar rats. SETTING: The study took place at the University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi, India. DESIGN: Oral toxicity studies--one acute (14 d) and one long-term (90 d)--were carried out using three doses of HEA--57.5, 115, and 230 mg/kg body weight (BWT)--in both male and female rats. The research team also carried out a study on antirheumatic activity. The team induced arthritis in three groups of male rats using collagen type II (CII), and for 20 d, one group was treated once weekly with saline; a second group was treated once weekly with methotrexate (MTX) at 0.25 mg/kg BWT IP; and a third group was treated daily with HEA at 115 mg/kg BWT orally. A control group received saline but was not induced with RA. OUTCOME MEASURES: Rheumatoid factor (RF); anticyclic citrullinated peptide (a-CCP) antibody; antinuclear antibody (ANA); and C-reactive protein (CRP) were measured. RESULTS: The acute and long-term, oral toxicity studies showed that HEA administration did not produce any overt toxicity or mortality and that it was safe at all dose levels tested. No major alterations were observed in hematology, serum biochemistry, necropsy, and histopathology at the therapeutic equivalent dose (ie, 115 mg/kg BWT). HEA administration for 20 d in arthritis-induced rats significantly reduced the levels of autoantibodies and CRP, and the results were comparable with those of MTX, the standard, disease-modifying antirheumatic drug (DMARD). CONCLUSION: The study's results provided evidence that HEA is not toxic at the therapeutic dose. The antiarthritic activity of HEA may be due to its disease-modifying activities, thus supporting the traditional use of this formulation for treatment of RA.
Assuntos
Antirreumáticos/farmacologia , Antirreumáticos/toxicidade , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Feminino , Masculino , Medicina Unani , Metotrexato/efeitos adversos , Metotrexato/farmacologia , Extratos Vegetais/toxicidade , Distribuição Aleatória , Ratos , Ratos Wistar , Aumento de Peso/efeitos dos fármacosRESUMO
AIM OF THE STUDY: Sinomenine, an alkaloid isolated from the root of Sinomenium acutum, has been used to alleviate the symptoms of rheumatic diseases. Liang Miao San (LMS), composed of the herbs Rhizoma Atractylodis (Cangzhu) and Cotex Phellodendri (Huangbai), is another traditional Chinese medicine formula for rheumatoid arthritis (RA) treatment. Although numerous studies have demonstrated the potential anti-inflammatory activities of sinomenine and LMS, the underlying intracellular mechanisms regulating the anti-inflammatory activities of sinomenine and LMS on human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects have not been elucidated. MATERIALS AND METHODS: We investigated the in vitro anti-inflammatory activity of sinomenine and LMS on inflammatory cytokine tumor necrosis factor (TNF)-α-mediated activation of human normal and RA-FLS. The underlying intracellular signaling molecules were analyzed quantitatively using flow cytometry. RESULTS: Sinomenine was found to significantly inhibit TNF-α induced cell surface expression of vascular cell adhesion molecule (VCAM)-1 and release of inflammatory cytokine and chemokine IL-6, CCL2 and CXCL8 from both normal and RA-FLS (all p<0.05). Moreover, the suppression of sinomenine on TNF-α induced VCAM-1 expression and IL-6 release of RA-FLS was significantly higher than that of normal FLS (p<0.05). LMS significantly inhibited TNF-α-induced inflammatory chemokines CXCL10 and CCL5 release from both normal and RA-FLS, with significantly higher suppression on CXCL10 secretion in RA-FLS than that of normal FLS (all p<0.05). Further investigations showed that sinomenine and LMS could significantly suppress TNF-α-induced phosphorylation of inhibitor κBα and extracellular signal-regulated protein kinase, the central signaling molecules mediating TNF-α-induced VCAM-1 expression and chemokine production. CONCLUSION: Our results therefore provide a new insight into the differential anti-inflammatory activities of sinomenine and LMS through the suppression of TNF-α-activated FLS by modulating distinct intracellular signaling pathways in RA.
Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Fibroblastos/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Morfinanos/farmacologia , Membrana Sinovial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Anti-Inflamatórios/toxicidade , Antirreumáticos/toxicidade , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/toxicidade , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/imunologia , Citometria de Fluxo , Humanos , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Medicina Tradicional Chinesa , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Colchicum luteum (CL) has been traditionally used in the Unani system of medicine as a chief ingredient of many polyherbal formulations for the treatment of joint pain and rheumatoid arthritis (RA). AIM OF THE STUDY: To evaluate the antiarthritic activity of CL hydroalcoholic extract (CLHE) in formaldehyde and complete Freund's adjuvant (CFA) induced arthritis. MATERIALS AND METHODS: Arthritis was induced by administration of either formaldehyde (2% v/v) or CFA into the subplantar surface of the hind paw of the animal. Joint swelling was measured on days 8, 9 and 10 in formaldehyde induced arthritis and days 3, 7, 14 and 21 in CFA induced arthritis. In order to evaluate the effect of CLHE on disease progression, serum TNF-α level and synovial expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1ß) was determined in CFA induced arthritis. RESULTS: CLHE produced a significant and dose dependent inhibition of joint swelling during the entire duration of the study in both, formaldehyde and CFA induced arthritis. Serum TNF-α level was also reduced significantly in a dose dependent manner in all the CLHE treated groups. The expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1ß) was also found to be less in the CLHE treated group as compared to control. CONCLUSION: We believe that the antiarthritic activity of CLHE was due to its modulatory effect on the expression of proinflammatory cytokine in the synovium. Our results contribute towards validation of the traditional use of CL in the treatment of RA and other inflammatory joint disorders.
Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Colchicum , Fitoterapia , Animais , Antirreumáticos/toxicidade , Artrite Experimental/imunologia , Artrite Experimental/patologia , Colchicum/química , Etnofarmacologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Plantas Medicinais/química , Ratos , Ratos Wistar , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: This study evaluates the anti-arthritic effect of Terminalia chebula hydroalcoholic extract (TCHE) in experimental models and attempts to correlate the effect of treatment on macrophage-derived pro-inflammatory cytokine expression and extent of disease activity. METHODS: Arthritis was induced in rats by subplantar administration of either formaldehyde or complete Freund's adjuvant (CFA). Joint size was measured at regular intervals by using a micrometer screw gauge. Serum and ankle joints of rats immunized with CFA were collected and subjected to ELISA for estimation of TNF-α level and immuno-histochemistry for detection of IL-1ß, IL-6 and TNF-R1, respectively. An acute and 28-day oral toxicity study was carried out to evaluate the safety of the test drug. KEY FINDINGS: TCHE produced a significant inhibition of joint swelling as compared with control in both formaldehyde-induced and CFA-induced arthritis. TCHE treatment also reduced serum TNF-α level and synovial expression of TNF-R1, IL-6 and IL-1ß. Results of acute toxicity study showed that the oral LD50 of TCHE was >2000 mg/kg. Chronic administration also did not produce any significant physiological changes as compared with normal rats. CONCLUSION: Results indicate that the anti-arthritic activity of TCHE was at least in part due to its modulatory effect on pro-inflammatory cytokine expression in the synovium. We believe that TCHE has the potential to be used as a disease-modifying agent in treatment of rheumatoid arthritis.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Terminalia , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/toxicidade , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Frutas , Interleucina-1beta/metabolismo , Interleucina-6/análise , Interleucina-6/metabolismo , Articulações/metabolismo , Dose Letal Mediana , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Membrana Sinovial/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Methotrexate is a folic acid antagonist recognised as one of the most important DMARD's in the rheumatoid arthritis treatment. Although the indisputable efficacy and the good tolerance profile, the broad toxicity spectrum is very variable with respect both to symptoms and intensity. The side effects vary from malaise and asthenia to pneumonitis or pancytopenia, which can be fatal. OBJECTIVES: To review the adverse effects of methotrexate in the treatment of rheumatoid arthritis. MATERIALS AND METHODS: Literature review, using Medline as a starting point, searching with the keywords "methotrexate", "toxic effects", "adverse effects", "rheumatoid arthritis". The relevant papers and selected references found therein were used. RESULTS: The gastrointestinal symptoms are the most frequent, but myelossupression and pneumonitis are the most feared ones. Elevation of transaminases could indicate hepatic toxicity, placing the risk of cirrhosis. Cutaneous lesions, neurologic symptoms, changes in the bone metabolism, teratogenecity and hyperhomocysteinemia are other examples of the adverse effects of methotrexate. The post-dosing reactions are still not well known. The folate supplementation is important in the prevention of folate metabolism dependent symptoms. The farmacogenomics may help to identify patients in greater risk for multiple side effects. CONCLUSIONS: Knowing and monitoring the methotrexate side effects is extremely important and should be carefully considered in order to prevent both therapeutic withdrawals due to toxicity as well as fatal outcomes.
Assuntos
Antirreumáticos/toxicidade , Artrite Reumatoide/tratamento farmacológico , Metotrexato/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Doenças Ósseas/induzido quimicamente , Doenças do Sistema Nervoso Central/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ácido Fólico/uso terapêutico , Gastroenteropatias/induzido quimicamente , Humanos , Pneumopatias/induzido quimicamente , Metotrexato/farmacocinética , Metotrexato/farmacologia , Dermatopatias/induzido quimicamenteRESUMO
OBJECTIVES: Nuclear factor kappa B (NF-kappaB) is a major regulator of pivotal proinflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA). Bortezomib inhibits NF-kappaB activation by blocking the degradation of the NF-kappaB inhibitor, I-kappaB. In this study, the efficacy of bortezomib on murine collagen-induced arthritis (CIA) was investigated. METHODS: Thirty-five male DBA/1 mice were divided into five groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were injected intraperitoneally with 0.01, 0.1 and 1 mg/kg bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also injected intraperitoneally with phosphate-buffered saline in the same manner. Arthritis score and paw thickness were measured and histopathological assessment of joint sections was performed. The expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using three-dimensional micro-computerised tomography (CT). Blood cells were counted and liver and kidney functions were monitored. RESULTS: Bortezomib significantly attenuated the severity of arthritis and histopathological findings in CIA mice. The expression of tumour necrosis factor alpha, IL-1beta, IL-6, matrix metalloproteinase 3, cyclooxygenase 2 and inducible nitric oxide synthase decreased in bortezomib-treated mice compared with untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver or kidneys were observed with bortezomib treatment. CONCLUSIONS: These data suggest that bortezomib may play an anti-inflammatory role in the pathophysiology of RA and serve as a new therapeutic modality for RA.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Ácidos Borônicos/uso terapêutico , Inibidores de Proteases/uso terapêutico , Pirazinas/uso terapêutico , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/toxicidade , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/patologia , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/toxicidade , Bortezomib , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/toxicidade , Pirazinas/administração & dosagem , Pirazinas/toxicidade , Índice de Gravidade de Doença , Resultado do Tratamento , Microtomografia por Raio-XRESUMO
D-chiro-Inositol (DCI) enhances reproductive function in insulin-resistant women with polycystic ovarian disease and enhances the effects of insulin in the periphery, suggesting that this compound may act in part by sensitizing the hypothalamus to effects of insulin. Effects of gold-thioglucose (GTG) to produce hypothalamic lesions and subsequent obesity are insulin-dependent, suggesting that responses to GTG may be a marker of hypothalamic sensitivity to insulin. To assess these hypotheses, the present study assessed if DCI would enhance the ability of a subthreshhold dose of GTG to produce hypothalamic lesions and subsequent obesity. At the subthreshhold dose used (0.4 mg/kg i.p.), injection of GTG produced no subsequent effect on body weight compared to saline; similarly, at the dose of DCI used (10 mg/kg/day in drinking water), DCI produced no effect on body weight. In contrast, when given to mice exposed to DCI, this dose of GTG produced significant increase in body weight and evidence of an enhanced medial arcuate hypothalamic lesion.
Assuntos
Antirreumáticos/toxicidade , Aurotioglucose/toxicidade , Sinergismo Farmacológico , Hipotálamo/efeitos dos fármacos , Inositol/farmacologia , Proteína Relacionada com Agouti , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Hipotálamo/lesões , Hipotálamo/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Camundongos , Camundongos Endogâmicos , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Proteínas/metabolismo , RNA Mensageiro/metabolismoRESUMO
OBJECTIVE: PG201 has been formulated using 12 herbs known to have anti-inflammatory and protective effects on damaged tissue and bone among other functions. The present study was done in order to assess the therapeutic effects of PG201 in collagen-induced arthritis (CIA) in mice. METHODS: DBA/1 mice were immunized with bovine type II collagen. After a second collagen immunization, mice were treated with PG201 orally at 10 mg/kg once a day for 18 days. Paws were evaluated macroscopically for redness, swelling and deformities. The levels of TNF-alpha and IL-1beta in the ankle were examined. The severity of arthritis within the knee joints was evaluated by histological assessment of cartilage destruction and pannus formation. Molecular indicators related to CIA pathology were analysed by measuring the serum levels of matrix metalloproteinase 2 (MMP-2), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) and the anti-inflammatory cytokines interleukin (IL)-4 and IL-10. RESULTS: Administration of PG201 significantly suppressed the progression of CIA and inhibited the production of TNF-alpha and IL-1beta in the paws. The erosion of cartilage was dramatically reduced in mouse knees after treatment with PG201. In the serum of PG201-treated mice, the level of TIMP-2 and the ratio of TIMP-2 to MMP-2 were significantly elevated, and the level of IL-4, but not of IL-10, was increased. CONCLUSION: Administration of PG201 has therapeutic effects on CIA. Protection of cartilage was particularly prominent. PG201 is a potential therapy for rheumatoid arthritis.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Antirreumáticos/toxicidade , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Colágeno , Progressão da Doença , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/toxicidade , Etanol , Feminino , Interleucina-1/análise , Interleucinas/sangue , Masculino , Metaloproteinase 2 da Matriz/sangue , Camundongos , Camundongos Endogâmicos DBA , Fitoterapia/efeitos adversos , Ratos , Ratos Sprague-Dawley , Inibidores Teciduais de Metaloproteinases/sangue , Fator de Necrose Tumoral alfa/análiseRESUMO
BACKGROUND: Many patients receiving long-term total parenteral nutrition (TPN) develop liver disease; cholestasis is common and may be severe. Antitumour necrosis factor alpha (TNFalpha) antibodies have recently been used in order to treat Crohn's disease, but their effect on cholestasis in humans has not been previously described. CASE REPORT: A 45-year-old woman had complicated Crohn's disease with multiple fistulae and only 1 m of residual small bowel. She had been receiving TPN for 2.5 years when she developed cholestasis which worsened despite adjustments to her TPN regimen. Infliximab, an anti-TNFalpha antibody, was given with the aim of treating an enterocutaneous fistula, but it also produced a marked biochemical and histological improvement in the TPN-related cholestasis. CONCLUSIONS: Anti-TNFalpha antibodies appeared in this case to improve TPN-related cholestasis. This implies that TNFalpha may play an important role in the development of this condition.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/toxicidade , Colestase/tratamento farmacológico , Colestase/etiologia , Nutrição Parenteral Total/efeitos adversos , Fator de Necrose Tumoral alfa/uso terapêutico , Doença de Crohn/complicações , Doença de Crohn/terapia , Feminino , Humanos , Infliximab , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
When the immune system is stimulated there is a concomitant decrease in drug biotransformation and elimination that may results in unwanted drug response and toxic side effects. We investigated the subacute toxicity of a hydroalcoholic extract of Pterodon pubescens seeds (HEPp) to DBA1/J mice with collagen II-induced arthritis. The oral treatment with HEPp reduced the arthritic index without any concomitant alteration in their hematological examination, histopathological analysis and relative or absolute weight of several organs and in several clinical biochemical parameters when compared with the control group. We concluded that daily administration of anti-arthritic doses of HEPp did not induce any detectable subacute toxic side-effect in mice whose host defense mechanisms is active as we can observe in mice with CIA.
Assuntos
Antirreumáticos/toxicidade , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Fitoterapia , Extratos Vegetais/toxicidade , Extratos Vegetais/uso terapêutico , Animais , Antirreumáticos/isolamento & purificação , Glicemia/efeitos dos fármacos , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos DBA , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , SementesRESUMO
OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.
Assuntos
Antirreumáticos/toxicidade , Artrite Reumatoide/tratamento farmacológico , Ácido Fólico/administração & dosagem , Hematínicos/administração & dosagem , Leucovorina/administração & dosagem , Metotrexato/toxicidade , Adulto , Idoso , Antirreumáticos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos , Resultado do TratamentoRESUMO
We have reported that kalopanaxsaponin A (KPS-A) isolated from Kalopanax pictus have anti-rheumatoidal activity in the rat treated with Freunds complete adjuvant (FCA) reagent. In addition, it has been also reported that KPS-A is a potent antioxidant in the rheumatoidal rat. This research was undertaken to examine whether the saponins of KPS-A and -I could adjust the abnormal lipid metabolisms and hematological changes in immunological diseases. KPS-A significantly inhibited the increases in both triglycerides and total proteins in addition to the decrease in total cholesterol induced by FCA reagent treatment. KPS-A treatment decreased the number of leucocytes elevated by FCA reagent treatment. Excess dose of the methanol extract produced no severe toxicity on the body weight, wet organ weights and hepatic functions. Since LD50 value of K. pictus methanol extract was shown to be 4,033 mg/kg, it could be estimated to be a safe agent for anti-rheumatoidal herbal medicines.
Assuntos
Antirreumáticos/farmacologia , Antirreumáticos/toxicidade , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Ácido Oleanólico/análogos & derivados , Plantas Medicinais/química , Saponinas/farmacologia , Saponinas/toxicidade , Animais , Contagem de Células Sanguíneas , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Adjuvante de Freund , Indicadores e Reagentes , L-Lactato Desidrogenase/sangue , Dose Letal Mediana , Testes de Função Hepática , Camundongos , Camundongos Endogâmicos ICR , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/toxicidade , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangueRESUMO
OBJECTIVE: To investigate the efficacy of folinic acid in reducing the side effects associated with methotrexate (MTX) therapy in children with juvenile idiopathic arthritis (JIA) and to determine whether folate supplementation may reduce the benefit of MTX administration. METHODS: This was a retrospective, non-controlled study. Inclusion criteria were: 1) diagnosis of JIA according to the Durban 1997 criteria; 2) treatment with low to intermediate doses of MTX (10-20 mg/m2/week) as the sole second-line agent for at least 6 mos.; and 3) supplementation with folinic acid (2.5-7.5 mg) in a single weekly dose 24 hrs after MTX administration. All patients were started on folinic acid only after the development of a side effect. Exclusion criteria were: treatment with higher doses of MTX (> 20 mg/m2/week). The outcomes investigated were: hepatotoxicity (liver transaminase increase), gastrointestinal toxicity, disease flare, and clinical remission. The number of episodes per patient-year of MTX treatment of each outcome before and after folinic acid supplementation was compared by the Wilcoxon matched pairs test. RESULTS: A total of 43 children with JIA were included in the study. The mean duration of treatment before and after folinic acid supplementation was 1.1 years and 1.8 years, respectively. After the start of folinic acid supplementation, the mean number of episodes per patient-year of hepatotoxicity and gastrointestinal toxicity decreased from 2.30 to 0.32 (p < 0.001) and from 1.09 to 0.29 (p = 0.002), respectively. The mean number of disease flares and clinical remissions per patient-year did not change significantly. CONCLUSION: In our JIA patients, folinic acid supplementation resulted in a significant reduction in the most common side effects of MTX, without affecting the clinical efficacy of the drug.