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Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.
Zhu, T, Moy, S, Valluri, U, Cao, Y, Zhang, W, Sawamoto, T, Chindalore, V, Akinlade, B
Clinical drug investigation. 2020;(9):827-838
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Abstract
BACKGROUND Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf®), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate. OBJECTIVE The objective of this study was to investigate potential drug-drug interactions of peficitinib with methotrexate and the short-term safety of coadministration. PATIENTS AND METHODS This phase I, open-label, single-sequence study included patients with rheumatoid arthritis taking a stable dose of methotrexate. Patients received their prescribed methotrexate dose (Day 1) and then peficitinib (100 mg) twice daily from Day 3 until the morning of Day 9; a second methotrexate dose was coadministered with peficitinib on Day 8. Serial blood samples were collected for methotrexate concentration after dosing on Days 1 (methotrexate alone) and 8 (methotrexate plus peficitinib) and for peficitinib concentration after dosing on Days 7 (peficitinib alone) and 8 (methotrexate plus peficitinib). Pre-dose concentrations of peficitinib were measured (Days 3-8). RESULTS Peficitinib concentrations reached steady state on Day 5. Administration of peficitinib did not result in changes to methotrexate area under the concentration-time curve from time zero to infinity or maximum observed concentration following a methotrexate dose (15-25 mg), and there was no significant effect of methotrexate (15-25 mg) on peficitinib area under the concentration-time curve within a 12-hour dosing interval. There were no new tolerability or safety signals after coadministration of peficitinib and methotrexate. One patient experienced two serious adverse events and withdrew from the study without receiving peficitinib. CONCLUSIONS Pharmacokinetic results showed no significant interactions between peficitinib and methotrexate. CLINICALTRIALS. GOV IDENTIFIER NCT01754805.
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The role of Chinese herbal medicine in the management of adverse drug reactions of leflunomide in treating rheumatoid arthritis.
Wang, W, Zhou, H, Liu, L
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2020;:153136
Abstract
BACKGROUND The high discontinuation rate in RA patients who use LEF might be attributed to their intolerance rather than irresponsibility. The concomitant administration of Leflunomide (LEF) with Chinese herbal medicine (CHM) provides a potential solution to preventing the adverse drug reactions (ADRs) induced by LEF during the treatment of rheumatoid arthritis (RA). PURPOSE To investigate whether co-administration of LEF with CHM could bring in both increased therapeutic outcomes and reduced ADRs due to the framework of treatment at the level of entire body. STUDY DESIGN The mechanism of LEF in RA treatment and the ADRs it induced was introduced based on recent papers. Reported clinical examples of CHM concurrent use with LEF was revealed to provide more evidence. The management of the ADRs caused by LEF was suggested by current researches on the concomitant therapy of CHM with LEF. RESULTS The active ingredients, compounds and medicinal herbs all demonstrated properties in relieving toxicities and reducing ADRs when used with LEF and reported in several clinical cases. The wide application of concurrent use of CHM with LEF is however hindered by the complex pathogenesis of RA which requires further scientific grounds for diagnosis and treatment. CONCLUSION This review introduced that the adoption of CHM is emerging as a novel strategy for the management of ADRs caused by LEF.
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Herbal compounds for rheumatoid arthritis: Literatures review and cheminformatics prediction.
Li, XZ, Zhang, SN
Phytotherapy research : PTR. 2020;(1):51-66
Abstract
Rheumatoid arthritis (RA) is a systemic disease characterized by autoimmunity, joint inflammation, and cartilage destruction, which affects 0.5-1% of the population. Many compounds from herbal medicines show the potentials to treat RA. On this basis, the compounds with good pharmacokinetic behaviors and drug-likeness properties will be further studied and developed. Therefore, the herbal compounds with anti-RA activities were reviewed in this paper, and the cheminformatics tools were used to predict their drug-likeness properties and pharmacokinetic parameters. A total of 90 herbal compounds were analyzed, which were reported to be effective on RA models through anti-inflammation, chondroprotection, immunoregulation, antiangiogenesis, and antioxidation. Most of the herbal compounds have good drug-likeness properties. Most of the compounds can be an alternative and valuable source for anti-RA drug discovery.
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Comparative Efficacy and Safety of Peficitinib 25, 50, 100, and 150 mg in Patients with Active Rheumatoid Arthritis: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.
Lee, YH, Song, GG
Clinical drug investigation. 2020;(1):65-72
Abstract
BACKGROUND AND OBJECTIVE Peficitinib, a JAK3-selective inhibitor that blocks the signal transduction and then suppresses immune responses, has been developed for the treatment of patients with moderate to severe active rheumatoid arthritis (RA). We assessed the relative efficacy and safety of once-daily administration of peficitinib (a JAK3-selective inhibitor) 25 mg, 50 mg, 100 mg, and 150 mg in patients with active RA. METHODS A Bayesian network meta-analysis was conducted to combine direct and indirect evidence from eligible randomized controlled trials (RCTs). The literature search was performed up to May 2019 using MEDLINE, Embase, and the Cochrane Controlled Trials Register. RESULTS Three RCTs involving 948 patients met the inclusion criteria. There were ten pairwise comparisons, including five direct comparisons and five interventions. The American College of Rheumatology 20% (ACR20) response rate was significantly higher in the peficitinib 150-mg group than in the placebo group (odds ratio (OR): 3.61; 95% credible interval (CrI): 2.35-5.57). Similarly, the ACR20 response rate was significantly higher in the peficitinib 100-mg group than in the placebo group (OR: 2.33, 95% CrI: 1.51-3.56). The peficitinib 50-mg group had a significantly higher ACR20 response rate than the placebo group. However, the ACR20 response rate was not significantly higher in the peficitinib 25-mg group than in the placebo group. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that peficitinib 150 mg was likely to achieve the best ACR20 response rate (SUCRA = 0.995), followed by peficitinib 100 mg (SUCRA = 0.696), peficitinib 50 mg (SUCRA = 0.558), peficitinib 25 mg (SUCRA = 0.153), and placebo (SUCRA = 0.098). The ACR50 and ACR70 response rates showed a similar distribution pattern to the ACR20 response rate. The difference in the number of patients with adverse events (AEs) among the intervention groups was not statistically significant. CONCLUSIONS Peficitinib 50, 100, and 150 mg once daily was effective in treating active RA, without causing a significant risk for AEs.
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Phytochemicals targeting matrix metalloproteinases regulating tissue degradation in inflammation and rheumatoid arthritis.
Alamgeer, , Hasan, UH, Uttra, AM, Qasim, S, Ikram, J, Saleem, M, Niazi, ZR
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2020;:153134
Abstract
PURPOSE Matrix metalloproteinases, zinc dependent proteolytic enzymes, have significant implications in extracellular matrix degradation associated with tissue damage in inflammation and Rheumatoid arthritis. Numerous orchestrated pathways affects instigation and blockade of metalloproteinases as well as various factors that increase the expression of MMPs including inflammatory cytokines, hormones and growth factors. Direct inhibition of these proteolytic enzymes or modulation of these pathways can provide protection against tissue destruction in inflammation and rheumatoid arthritis. Inclination towards use of plant derived phytochemicals to prevent tissue damage has been increasing day by day. Diversity of phytochemicals have been known to directly inhibit metalloproteinases. Hence, thorough knowledge of phytochemicals is very important in novel drug discovery. METHODS Present communication evaluates various classes of phytochemicals, in effort to unveil the lead molecules as potential therapeutic agents, for prevention of MMPs mediated tissue damage in inflammation and rheumatoid arthritis. Data have been analyzed through different search engines. RESULTS Numerous phytochemicals have been studied for their role as MMPs inhibitors which can be processed further to develop into useful drugs for the treatment of inflammation and rheumatoid arthritis. CONCLUSION In search of new drugs, phytochemicals like flavonoids, glycosides, alkaloids, lignans & terpenes offer a wide canvas to develop into valuable forthcoming medicaments.
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The effects of garlic (Allium sativum) supplementation on inflammatory biomarkers, fatigue, and clinical symptoms in patients with active rheumatoid arthritis: A randomized, double-blind, placebo-controlled trial.
Moosavian, SP, Paknahad, Z, Habibagahi, Z, Maracy, M
Phytotherapy research : PTR. 2020;(11):2953-2962
Abstract
Based on the antiinflammatory properties of garlic, current study was conducted to evaluate the garlic supplement effects on serum levels of some inflammatory biomarkers, clinical symptoms, and fatigue in women with active rheumatoid arthritis. In this randomized, double-blind, placebo-controlled trial study, 70 women with RA were randomly divided into two groups: The intervention group was supplemented with 1,000 mg of garlic, and the control group received placebo for 8 weeks. At baseline and at the end of the study, clinical symptoms, fatigue, serum level of C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), and erythrocyte sedimentation rate (ESR) were determined. After intervention, serum levels of CRP (p = .018) and TNF-a (p < .001) decreased significantly in the garlic group as compared with the placebo group. Also, pain intensity, tender joint count, disease activity score (DAS-28), and fatigue were significantly decreased in the intervention group compared with the control group (p < .001; for all). Swollen joint count was significantly decreased in the garlic group (p < .001), but not in the placebo group (p = .123). No significant changes were observed for ESR. Garlic supplementation by improving inflammatory mediators and clinical symptoms can be considered as a potential adjunct treatment in patients with RA. However, further studies with larger duration are needed.
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Effects of hydroalcoholic extract of Berberis Integerrima on the anthropometric indices and metabolic profile in active rheumatoid arthritis patients.
Aryaeian, N, Sedehi, SK, Khorshidi, M, Zarezadeh, M, Hosseini, A, Shahram, F
Complementary therapies in medicine. 2020;:102331
Abstract
OBJECTIVES Since, the main cause of death in Rheumatoid arthritis (RA) patients is the presence of type 2 diabetes, abnormal increase in blood lipids, blood pressure and obesity, the aim of this study was to assess the effects of Barberry on the anthropometric indices and metabolic profile in patients with RA. DESIGN present study was a double-blinded, placebo-controlled randomized clinical trial. SETTING 70 active RA patients were randomly allocated into intervention or placebo group INTERVENTION Participants received 6 capsules of 500 mg barberry extract or placebo for 3 months. MAIN OUTCOME MEASURES Serum levels of fasting blood sugar (FBS), triglyceride (TG), LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C), systolic and diastolic blood pressure and anthropometric factors were assessed at baseline and at the end of the trial. RESULTS The results of intervention on 62 patients showed that weight, BMI, and conicity index increased in both groups, but this was significant only in the placebo group (p < 0.001). Waist and hip circumference were decreased in the intervention group and increased significantly in the placebo group (p < 0.001). Body fat percent (p = 0.04), LDL-C (p = 0.05) and SBP (p = 0.02) significantly were decreased in the intervention group. The results showed a significant decrease in body fat percent (p = 0.05), hip circumference (p < 0.001), FBS (p = 0.03) and HDL-C (p = 0.03) in the intervention group compared to the placebo. CONCLUSIONS Overall, the results of this study demonstrated that the extract of Berberis Integerrima had beneficial effects on metabolic profile and anthropometric indices in RA patients.
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All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes.
Mosquera, N, Rodriguez-Trillo, A, Blanco, FJ, Mera-Varela, A, Gonzalez, A, Conde, C
The Journal of pharmacology and experimental therapeutics. 2020;(2):185-192
Abstract
Fibroblast-like synoviocytes (FLSs) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness and contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells; however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biologic retinoid, which is a candidate drug for many diseases but has reached clinical use only for a few. Here, we explored the effect of all-trans retinoic acid (ATRA) on the aggressive phenotype of FLS from patients with RA. RA FLSs were treated with ATRA, tumor necrosis factor (TNF), or TNF+ATRA, and cell migration and invasion were analyzed. In addition, a microarray analysis of expression, followed by gene-set analysis and quantitative polymerase chain reaction validation, was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that was accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors. SIGNIFICANCE STATEMENT All-trans retinoic acid (ATRA) reduced the rheumatoid arthritis (RA) fibroblast-like synoviocyte migration and invasiveness and down-regulated gene expression of cell motility and migration genes. At supraphysiological doses, some of these effects were reverted by tumor necrosis factor. Therefore, ATRA could be an RA drug candidate that would require high doses or combined treatment with anti-inflammatory drugs.
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A systematic review of the effects of probiotic administration in inflammatory arthritis.
Lowe, JR, Briggs, AM, Whittle, S, Stephenson, MD
Complementary therapies in clinical practice. 2020;:101207
Abstract
OBJECTIVE To systematically identify and appraise evidence of the formulation specific effects and population specific responses of probiotics in inflammatory arthritis. METHODS MEDLINE (PubMed), CINAHL, EMBASE, and SCOPUS databases were searched for studies utilising probiotics in populations with inflammatory arthritis. The Joanna Briggs Institute (JBI) method was used to conduct the systematic review. A single reviewer undertook screening and data extraction. Two independent reviewers assessed the quality of evidence using JBI tools. RESULTS The search identified 5876 unique articles, with 154 potentially relevant full text articles retrieved. Twelve studies met the inclusion criteria and were included in the review, of which ten (83%) were randomised control trials (RCT) and two (17%) were quasi-experimental studies. Four studies included a variety of spondyloarthopathies (SpAs) and eight studies focused on rheumatoid arthritis (RA). Probiotics were supplied for a median of 60 days and mode of 56 days across all included studies (range 7-365 days). Overall, 17 different probiotics were supplied in colony forming units (CFU) per 24 hrs ranging from 1 × 108 to 2.25 × 1011. The order of probiotics supplied to the most participants and across the most studies was Lactobacillales. There was no statistical difference in the relative risk (RR) of minor adverse events between probiotic and control groups (RR 1.02, 95% CI 0.69 to 1.51) when including nil event studies. Meta-analysis identified a statistically significant benefit of probiotics on quality of life with a standard mean difference (SMD) of -0.37 (95% CI -0.59,-0.15) with subgroup analysis favouring Lactobacillales-only formulations. Small but statistically significant reductions in pain were identified, with a mean difference (MD) of -8.97 (95% CI-15.38, -2.56) on a 100mm visual analogue scale, independent of formulation. Meta-analysis confirmed the known statistically significant benefit of probiotics on the inflammatory marker C-reactive protein (CRP) concentration MD (mg/L) -2.33 (95% CI -4.26, -0.41), with subgroup analysis demonstrating a greater effect in RA and from combined Bifidobacteriales and Lactobacillales formulations. CONCLUSION This review indicates there may be differential benefits to combined formulations of Bifidobacteriales and Lactobacillales compared to purely Lactobacillales formulations, with respect to reducing pain, lowering CRP and improving quality of life. It also suggests variable benefits associated with the type of inflammatory arthritis. Relatively less benefit for lowering CRP was attributed to individuals with SpA compared to individuals with RA. Generalisability of results to clinical practice is limited by the dominant demographic of older individuals with established disease beyond the 'therapeutic window of intervention'. Small but statistically significant benefits require confirmation in clinical studies with greater consideration to potentially confounding factors of age, gender, diet and individual microbial signature.
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Could Omega 3 Fatty Acids Preserve Muscle Health in Rheumatoid Arthritis?
Lanchais, K, Capel, F, Tournadre, A
Nutrients. 2020;(1)
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a high prevalence of death due to cardiometabolic diseases. As observed during the aging process, several comorbidities, such as cardiovascular disorders (CVD), insulin resistance, metabolic syndrome and sarcopenia, are frequently associated to RA. These abnormalities could be closely linked to alterations in lipid metabolism. Indeed, RA patients exhibit a lipid paradox, defined by reduced levels of total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol whereas the CVD risk is increased. Moreover, the accumulation of toxic lipid mediators (i.e., lipotoxicity) in skeletal muscles can induce mitochondrial dysfunctions and insulin resistance, which are both crucial determinants of CVD and sarcopenia. The prevention or reversion of these biological perturbations in RA patients could contribute to the maintenance of muscle health and thus be protective against the increased risk for cardiometabolic diseases, dysmobility and mortality. Yet, several studies have shown that omega 3 fatty acids (FA) could prevent the development of RA, improve muscle metabolism and limit muscle atrophy in obese and insulin-resistant subjects. Thereby, dietary supplementation with omega 3 FA should be a promising strategy to counteract muscle lipotoxicity and for the prevention of comorbidities in RA patients.