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ID PMID Title PublicationDate abstract
27829671 Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. 2017 Jan Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface receptors. The expression and function of adenosine receptors on different cell types change during the course of rheumatic diseases, such as rheumatoid arthritis (RA). Targeting adenosine receptors directly for the treatment of rheumatic diseases is currently under study; however, indirect targeting of adenosine receptors by enhancing adenosine levels at inflamed sites accounts for most of the anti-inflammatory effects of methotrexate, the anchor drug for the treatment of RA. In this Review, we discuss the regulation of extracellular adenosine levels and the role of adenosine in regulating the inflammatory and immune responses in rheumatic diseases such as RA, psoriasis and other types of inflammatory arthritis. In addition, adenosine and its receptors are involved in promoting fibrous matrix production in the skin and other organs, and the role of adenosine in fibrosis and fibrosing diseases is also discussed.
27330933 Management of Widespread Skin Thickening in Diffuse Systemic Sclerosis. 2016 Mar Skin thickening is one of the early organ manifestations of systemic sclerosis (SSc) and has a great impact on quality of life (QOL) as well as overall daily living in patients with SSc. The dynamic changes that occur as the disease progresses and as other organs become further involved present the treating physician with therapeutic challenges. Hence, when considering drug therapy for skin disease, the treating physician should consider a number of factors including disease duration, the rate of skin thickening, the extent of disease progression, organ involvements, and patient-related outcome measures, all of which impact the type of treatments considered. For early diffuse skin disease, we prefer the use of methotrexate (MTX). And when there is evidence of lung involvement or tendon friction rubs (given its association with ILD development), we tend to shift to the use of mycophenolate or cyclophosphamide because these agents have been shown efficacious for the specific indication of lung disease in SSc. We have managed joint disease, on the other hand when present, with MTX or other DMARDs, as well as the use of biologics when there is evidence of inflammatory polyarthritis or rheumatoid arthritis overlap. While the treatment of myositis in the setting of SSc can present a therapeutic dilemma, reluctantly, we may use steroids along with MTX, mycophenolate, intravenous immunoglobulin (IV-Ig), or rituximab. Ongoing clinical trials investigating the use of tocilizumab, abatacept, and other agents offer promising potential therapies. Great strides have been made in treating skin disease in SSc. And with recent trials focusing on early SSc disease, this will allow for a greater insight into the mechanisms underlying SSc especially as it relates to skin, and the expansion of future treatment options in this field.
25672799 Methotrexate induced apoptotic and necrotic chromatin changes in rat myeloid leukemia cell 2015 Apr OBJECTIVE: It was tested as to why low-dose methotrexate (MTX) effective against rheumatoid arthritis poses considerable health risk at higher doses. METHODS: The tumorigenic potential of My1/De blast cells was followed by cytology and by the kinetics of (18)FDG uptake. The toxicity of MTX on chromatin condensation was compared to predictive normal intermediates of chromosome condensation in control cells. RESULTS: MTX below 0.1 µg/ml did not cause visible changes in interphase chromatin structure. At its lowest toxic concentration (0.1 µg/ml) chromatin margination was confined to the outer edge of the nucleus. Between 0.1 and 5 µg/ml concentrations apoptotic chromatin shrinkage correlated with the dose of MTX. Apoptosis was exerted in early S phase excluding the mitotic effect. At higher MTX concentrations (>10 µg/ml) necrotic disruption and expansion took place. The lowest necrotic concentration (10 µg/ml) was close to highest apoptotic MTX concentration (5 µg/ml). CONCLUSIONS: The switch from apoptosis to inflammatory necrosis taking place within a narrow concentration range supports the notion of a narrow therapeutic spectrum. Chromatin changes are early markers of genotoxicity at much lower concentrations than citogenetic changes in properly chosen sensitive cells.
25860212 Outcome of hepatitis E virus infection in patients with inflammatory arthritides treated w 2015 Apr The clinical presentation and outcome of hepatitis E virus (HEV) infection in inflammatory rheumatic diseases are unknown. We aimed to investigate the severity of acute HEV infection and the risk of chronic viral replication in patients with inflammatory arthritides treated with immunosuppressive drugs. All rheumatology and internal medicine practitioners belonging to the Club Rhumatismes et Inflammation in France were sent newsletters asking for reports of HEV infection and inflammatory arthritides. Baseline characteristics of patients and the course of HEV infection were retrospectively assessed by use of a standardized questionnaire. From January 2010 to August 2013, we obtained reports of 23 cases of HEV infection in patients with rheumatoid arthritis (n = 11), axial spondyloarthritis (n = 5), psoriatic arthritis (n = 4), other types of arthritides (n = 3). Patients received methotrexate (n = 16), antitumor necrosis factor α agents (n = 10), rituximab (n = 4), abatacept (n = 2), tocilizumab (n = 2), and corticosteroids (n = 10, median dose 6 mg/d, range 2-20). All had acute hepatitis: median aspartate and alanine aminotransferase levels were 679 and 1300 U/L, respectively. Eleven patients were asymptomatic, 4 had jaundice. The HEV infection diagnosis relied on positive PCR results for HEV RNA (n = 14 patients) or anti-HEV IgM positivity (n = 9). Median follow-up was 29 months (range 3-55). Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Liver enzyme levels normalized and immunosuppressant therapy could be reinitiated in all patients. No chronic infection was observed. Acute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme values. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.
25311252 Atypical focal forms of Whipple's disease seen by rheumatologists. 2015 Jan We report two atypical cases of focal Whipple's disease with rheumatic presenting symptoms. In one of these cases, the patient presented with chronic intermittent polyarthritis, systemic inflammation, and leukocytosis. Tests were positive for rheumatoid factor and anti-cyclic citrullinated peptide antibodies. There was no structural joint damage. Combined glucocorticoid and methotrexate therapy was only partially effective. Endocarditis requiring emergency valve replacement surgery occurred 4 years later. Evaluation of this event led to the diagnosis of Tropheryma whipplei infection responsible for both the endocarditis and the joint disease. The other patient presented with subacute inflammatory low back pain. His medical history was chiefly remarkable for intermittent inflammatory involvement of the wrists and right knee replacement surgery for osteoarthritis followed by a febrile effusion of the operated knee. Radiographs showed destructive lesions of the wrists. Magnetic resonance imaging findings suggested L2-L3 diskitis. A PCR assay on biopsy specimens from the disk lesions recovered T. whipplei, thus establishing the cause of the diskitis and previous joint manifestations. Combined doxycycline and hydroxychloroquine therapy was followed by full resolution of all clinical and laboratory abnormalities in both patients.
26502871 A case report of successful treatment of pyoderma gangrenosum in a patient with autoimmune 2015 Oct 26 BACKGROUND: Pyoderma Gangrenosum (PG) is a cutaneous condition, its diagnosis suggested by the presence of a painful cutaneous ulcer showing rapid progression. Pyoderma gangrenosum is associated with a concomitant systemic disease in 50 to 70 % of cases, including inflammatory bowel disease (IBD), rheumatoid arthritis, and lymphoproliferative disorders. Although PG has also been reported with viral hepatitis, it is rarely associated with autoimmune hepatitis. CASE PRESENTATION: A 19-year-old Caucasian female, with a prior diagnosis of autoimmune hepatitis (AIH) in remission, presented with bilateral lower limb ulcers 4 years after the diagnosis of AIH. She was diagnosed with PG and treated with high-dose prednisolone, methotrexate and cyclosporine. One year later she was well, the ulcers completely healed, and with the autoimmune hepatitis still in remission. CONCLUSION: We report a case of autoimmune hepatitis and the subsequent, rarely occurring, extra-hepatic onset of pyoderma gangrenosum, with the AIH in remission, strengthening the association between the two conditions. Since both the AIH and the PG can present serious diagnostic challenges, thus delaying vital therapy, it is important that the development of either prompts us to consider the possibility of the other developing in the future or if already present facilitate its diagnosis, such considerations making the case for a systematic follow up.
26234512 Chemometrics-assisted Spectrofluorimetric Determination of Two Co-administered Drugs of Ma 2015 Methotrexate (MTX) is widely used to treat rheumatoid arthritis (RA), mostly along with non-steroidal anti-inflammatory drugs (NSAIDs), the most common of which is aspirin or acetyl salicylic acid (ASA). Since NSAIDs impair MTX clearance and increase its toxicity, it was necessary to develop a simple and reliable method for the monitoring of MTX levels in urine samples, when coadministered with ASA. The method was based on the spectrofluorimetric measurement of the acid-induced hydrolysis product of MTX, 4-amino-4-deoxy-10-methylpteroic acid (AMP), along with the strongly fluorescent salicylic acid (SA), a product of acid-induced hydrolysis of aspirin and its metabolites in urine. The overlapping emission spectra were resolved using the derivative method (D method). In addition, the corresponding derivative emission spectra were convoluted using discrete Fourier functions, 8-points sin xi polynomials, (D/FF method) for better elimination of interferences. Validation of the developed methods was carried out according to the ICH guidelines. Moreover, the data obtained using derivative and convoluted derivative spectra were treated using the non-parametric Theil's method (NP), compared with the least-squares parametric regression method (LSP). The results treated with Theil's method were more accurate and precise compared with LSP since the former is less affected by the outliers. This work offers the potential of both derivative and convolution using discrete Fourier functions in addition to the effectiveness of using the NP regression analysis of data. The high sensitivity obtained by the proposed methods was promising for measuring low concentration levels of the two drugs in urine samples. These methods were efficiently used to measure the drugs in human urine samples following their co-administration.
28076752 Methotrexate-associated primary hepatic malignant lymphoma following hepatectomy: A case r 2017 INTRODUCTION: Recently, immunosuppressant-associated malignant lymphoma (ML) cases have been increasing along with the development of several effective immunosuppressant drugs for rheumatoid arthritis (RA). Among methotrexate (MTX)-associated lymphoproliferative disorders, primary hepatic lymphoma (PHL) in patients with RA following surgical resection has not been reported previously. PRESENTATION OF CASE: A 65-year-old woman who is a hepatitis B virus carrier with a history of RA was admitted. MTX was introduced seven years prior as an RA treatment. Her laboratory data showed no elevation of several tumor markers, and liver function test results were normal. On contrasted computed tomography (CT) scanning, a slightly enhanced tumor was detected at the early phase, and tumor staining was sustained at the delayed phase. Further, subsegmentectomy of the S6 was performed. The pathological diagnosis was diffuse large B-cell lymphoma. However, positron emission tomography-CT and bone marrow aspiration sample showed no resident sign of ML. DISCUSSION: Diagnosis of PHL before surgery is difficult. If the mass lesion was solitary and had a certain degree of size, then resection could be performed for its treatment and diagnosis. The treatment for ML requires a diagnosis of the subtypes to select a therapeutic agent and determine the prognosis. Once a precise preoperative diagnosis was made, withdrawing MTX could be the first treatment in case of MTX-related ML. CONCLUSION: Long-term usage of immunosuppressant drugs could cause proliferative ML. Considering the increasing occurrence of MTX-related ML, withdrawing MTX should be considered, especially in patients with long-term immunosuppressant usage for RA.
25963062 Immunogenicity of biologic treatments for psoriasis: therapeutic consequences and the pote 2015 Aug The five biologic agents approved for the treatment of psoriasis-etanercept, infliximab, adalimumab, ustekinumab, and secukinumab-have been transformative in the clinical management of severe forms of the disease. However, a significant number of patients fail to respond to these agents or experience a loss of efficacy over time, which may be attributable to the development of antidrug antibodies (ADAs). Increasing evidence, primarily in the context of rheumatoid arthritis or other chronic inflammatory diseases, suggests that concomitant administration of methotrexate may prevent or diminish the development of ADAs, thereby improving response rates. However, methotrexate is infrequently coadministered with biologic agents in patients with psoriasis, and the potential benefits of this strategy in the context of psoriasis are largely unexplored. In this review, we discuss clinical studies regarding the development and consequences of antibodies targeting biologic agents used in the treatment of psoriasis and present key findings describing the potential role of methotrexate as an inhibitor of immunogenicity. We also discuss clinical considerations pertaining to the use of methotrexate as a tool to reduce immunogenicity, and encourage further investigation into potential techniques to optimize this treatment approach in patients with psoriasis.
25760632 Specific management of post-chikungunya rheumatic disorders: a retrospective study of 159 2015 Mar BACKGROUND: Since 2003, the tropical arthritogenic chikungunya (CHIK) virus has become an increasingly medical and economic burden in affected areas as it can often result in long-term disabilities. The clinical spectrum of post-CHIK (pCHIK) rheumatic disorders is wide. Evidence-based recommendations are needed to help physicians manage the treatment of afflicted patients. PATIENTS AND METHODS: We conducted a 6-year case series retrospective study in Reunion Island of patients referred to a rheumatologist due to continuous rheumatic or musculoskeletal pains that persisted following CHIK infection. These various disorders were documented in terms of their clinical and therapeutic courses. Post-CHIK de novo chronic inflammatory rheumatisms (CIRs) were identified according to validated criteria. RESULTS: We reviewed 159 patient medical files. Ninety-four patients (59%) who were free of any articular disorder prior to CHIK met the CIR criteria: rheumatoid arthritis (n=40), spondyloarthritis (n=33), undifferentiated polyarthritis (n=21). Bone lesions detectable by radiography occurred in half of the patients (median time: 3.5 years pCHIK). A positive therapeutic response was achieved in 54 out of the 72 patients (75%) who were treated with methotrexate (MTX). Twelve out of the 92 patients (13%) received immunomodulatory biologic agents due to failure of contra-indication of MTX treatment. Other patients mainly presented with mechanical shoulder or knee disorders, bilateral distal polyarthralgia that was frequently associated with oedema at the extremities and tunnel syndromes. These pCHIK musculoskeletal disorders (MSDs) were managed with pain-killers, local and/or general anti-inflammatory drugs, and physiotherapy. CONCLUSION: Rheumatologists in Reunion Island managed CHIK rheumatic disorders in a pragmatic manner following the outbreak in 2006. This retrospective study describes the common mechanical and inflammatory pCHIK disorders. We provide a diagnostic and therapeutic algorithm to help physicians deal with chronic patients, and to limit both functional and economic impacts. The therapeutic indication of MTX in pCHIK CIR could be approved in future efficacy trials.
26190800 Methotrexate influx via folate transporters into alveolar epithelial cell line A549. 2015 Aug Methotrexate (MTX), a drug used for the treatment of certain cancers as well as rheumatoid arthritis, sometimes induces serious interstitial lung injury. Although lung toxicity of MTX is related to its accumulation, the information concerning MTX transport in the lungs is lacking. In this study, we investigated the mechanisms underlying MTX influx into human alveolar epithelial cell line A549. MTX influx into A549 cells was time-, pH-, and temperature-dependent and showed saturation kinetics. The influx was inhibited by folic acid with IC50 values of 256.1 μM at pH 7.4 and 1.6 μM at pH 5.5, indicating that the mechanisms underlying MTX influx would be different at these pHs. We then examined the role of two folate transporters in MTX influx, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT). The expression of RFC and PCFT mRNAs in A549 cells was confirmed by reverse transcription polymerase chain reaction. In addition, MTX influx was inhibited by thiamine monophosphate, an RFC inhibitor, at pH 7.4, and by sulfasalazine, a PCFT inhibitor, at pH 5.5. These results indicated that RFC and PCFT are predominantly involved in MTX influx into A549 cells at pH 7.4 and pH 5.5, respectively.
26204326 Microemulsions mediated effective delivery of methotrexate hydrogel: more than a tour de f 2016 Methotrexate (MTX), a well known drug for the treatment of cancer and rheumatoid arthritis, has gained prominence in the treatment of psoriasis over the period of years. However, the present mode of systemic administration through oral or parenteral route has always proposition, full of compromises. The toxicity of drug to the vital organs and physiological environment is the major concern. Also, its poor skin penetration is one major problem. Hence novel system based on lipid carriers has been considered here to overcome the barriers. Microemulsions (MEs) were prepared using pseudo-ternary phase diagram (PTPD) and they were characterized for various parameters such as size, shape (cryo-SEM), PDI, zeta potential, etc. The chosen MEs system (optimized) was then incorporated into secondary vehicles and characterized for rheological behavior, texture profile analysis, in vitro release, ex vivo permeation and drug distribution into different layers of skin. The developed formulations were further evaluated in ex vivo and in vivo such as cell line study, imiquimod-induced psoriatic model, allergic contact dermatitis, rat tail model (% orthokeratosis) and safety test (Draize test). The MEs based MTX gel has shown its potential in locating the drug at the desired domain of stratum corneum, epidermal and dermal layers of skin and reducing systemic absorption. Our results are suggestive of MEs potential as a novel carrier for topical delivery of MTX in topical therapeutic and safety approaches. In conclusion, developed MEs-based hydrogel has shown promising results in achieving effective delivery of MTX.
24834925 Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopath 2015 Jun OBJECTIVE: To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). METHODS: This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. RESULTS: In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). CONCLUSIONS: Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. TRIAL REGISTRATION NUMBER: NCT00988221.
26202855 Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into o 2016 Sep The increasing number of osteoporosis patients is a pressing issue worldwide. Osteoporosis frequently causes fragility fractures, limiting activities of daily life and increasing mortality. Many osteoporosis patients take numerous medicines due to other health issues; thus, it would be preferable if a single medicine could ameliorate osteoporosis and other conditions. Here, we screened 96 randomly selected drugs targeting various diseases for their ability to inhibit differentiation of osteoclasts, which play a pivotal role in development of osteoporosis, and identified methotrexate (MTX), as a potential inhibitor. MTX is currently used to treat sarcomas or leukemic malignancies or auto-inflammatory diseases such as rheumatoid arthritis (RA) through its anti-proliferative and immunosuppressive activities; however, a direct effect on osteoclast differentiation has not been shown. Here, we report that osteoclast formation and expression of osteoclastic genes such as NFATc1 and DC-STAMP, which are induced by the cytokine RANKL, are significantly inhibited by MTX. We found that RANKL-dependent calcium (Ca) influx into osteoclast progenitors was significantly inhibited by MTX. RA patients often develop osteoporosis, and osteoclasts are reportedly required for joint destruction; thus, MTX treatment could have a beneficial effect on RA patients exhibiting high osteoclast activity by preventing both osteoporosis and joint destruction.
27917700 Posterior reversible encephalopathy syndrome following elevated mean arterial pressures fo 2018 Jan BACKGROUND: Increasing the mean arterial pressure (MAP) is an accepted treatment modality to minimize the risk for irreversible neurologic damage secondary to spinal cord ischemia. Posterior reversible encephalopathy syndrome (PRES) is a rare complication occurring after transplantation surgery, in persons having an autoimmune disorder or after abrupt increases in blood pressure of various etiologies. STUDY DESIGN: Case report. METHODS: Retrospective evaluation of medical records. RESULTS: A 68-year-old female with long-standing diabetes, and rheumatoid arthritis (treated with methotrexate) presented with bilateral upper extremity weakness and numbness developing several days after a motor vehicle accident. Physical examination confirmed decreased upper extremity motor strength and decreased sensation to light touch and pinprick in the C5-C6 dermatomal distribution. Magnetic resonance imaging (MRI) demonstrated C5-C6 subluxation with spinal cord compression. The patient had traction applied and mean arterial pressures were elevated greater than 85 mmg. The following day the patient underwent anterior and posterior cervical spine fusion and decompression. Immediately post-operatively, the patient developed status epilepticus. Head MRI revealed areas of high T2 signal intensity in the bilateral occipital lobes, consistent with a diagnosis of PRES. Two weeks later, the patient had resolution of her symptoms and resolution of PRES on imaging. CONCLUSION: This is the first report of posterior reversible encephalopathy syndrome secondary to therapeutic blood pressure increase in the setting of cervical spine fracture with neurological deficits. The patients had resolution of symptoms following discontinuation of the MAP goals. Posterior reversible encephalopathy syndrome (PRES) is a life-threatening condition characterized by seizures, confusion, visual disturbance, and headaches alongside neuroradiological findings indicative of posterior cerebral hemispheric white matter edema.(1,2) PRES has been described in association with abrupt blood pressure elevation, autoimmune disorders, or transplantation.(1-4) In this case report PRES presented with typical status epilepticus(5) but in an unexpected clinical setting, immediately after anterior cervical decompression and fusion (ACDF) and posterior cervical fusion (PCF) with laminectomy of C5-C6.
26909742 Methotrexate and its therapeutic antagonists caffeine and theophylline, target a motogenic 2016 May Methotrexate (MTX) is a widely used treatment for inflammatory diseases such as rheumatoid arthritis and psoriasis, based on the concept that it is immunosuppressive. Its mechanism of action, however, remains unclear, although it is thought to depend on adenosine. Caffeine and theophylline, which have several targets including adenosine receptors, have been shown to suppress the beneficial clinical effects of MTX. Here we show that MTX and caffeine and theophylline differentially affect a motogenic T-cell mechanism driven by endogenous thrombospondin-1 (TSP-1) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1). MTX stimulated TSP-1 expression and the motogenic TSP-1/TSP-1 receptor mechanism in primary human T cells, hence mimicking IL-2 and CXCL12, which similar to MTX, dampen inflammatory disease. SiRNA-mediated gene silencing of TSP-1 and LRP1 inhibited this stimulatory effect. Caffeine and theophylline inhibited the TSP-1/TSP-1 receptor mechanism by inhibiting LRP1 expression. These results indicate that the effect of MTX on T cells is immunoregulatory rather than immunosuppressive, and suggest a pathway dependent on TSP-1/TSP-1 receptor interactions for the regulation of immune responses.
26571019 Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction. 2016 Jan Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.
26693854 Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Li 2016 OBJECTIVE: The selective Janus kinase 1 inhibitor filgotinib (GLPG0634), which is currently in clinical development for the treatment of rheumatoid arthritis (RA) and Crohn's disease, demonstrated encouraging safety and efficacy profiles in RA patients after 4 weeks of daily dosing. As RA patients might be treated with multiple medications simultaneously, possible drug-drug interactions of filgotinib with cytochrome P450 enzymes and with key drug transporters were evaluated in vitro and in clinical studies. METHODS: The enzymes involved in filgotinib's metabolism and the potential interactions of the parent and its active major metabolite with drug-metabolizing enzymes and drug transporters, were identified using recombinant enzymes, human microsomes, and cell systems. Furthermore, filgotinib's interaction potential with CYP3A4 was examined in an open-label study in healthy volunteers, which evaluated the impact of filgotinib co-administration on the CYP3A4-sensitive substrate midazolam. The potential interaction with the common RA drug methotrexate was investigated in a clinical study in RA patients. RESULTS: In vitro, filgotinib and its active metabolite at clinically relevant concentrations did not interact with cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, and did not inhibit key drug transporters. In the clinic, a lack of relevant pharmacokinetic drug interactions by filgotinib and its active metabolite with substrates of CYP3A4, as well as with organic anion transporters involved in methotrexate elimination were found. CONCLUSION: the collective in vivo and in vitro data on drug-metabolizing enzymes and on key drug transporters, support co-administration of filgotinib with commonly used RA drugs to patients without the need for dose adjustments.
26276309 Reduction of oxidative stress by an ethanolic extract of leaves of Piper betle (Paan) Linn 2015 Nov Methotrexate (MTX), a folate antagonist, is currently used as first line therapy for autoimmune diseases like rheumatoid arthritis and psoriasis, but its use is limited by the associated hepatotoxicity. As leaves of Piper betle, belonging to family Piperaceae, have antioxidant and anti-inflammatory properties, the present study was undertaken to investigate the potential of Piper betle leaf extract (PB) in attenuating MTX-induced hepatotoxicity. Rats pre-treated with PB (50 or 100 mg kg(-1) b.w., p.o.) were administered with a single dose of MTX (20 mg kg(-1), b.w., i.p.) and its hepatoprotective efficacy was compared with folic acid (1 mg kg(-1) b.w., i.p.), conventionally used to minimize MTX-induced toxicity. MTX-induced hepatotoxicity was confirmed by increased activities of marker enzymes, alanine transaminase, aspartate transaminase, and alkaline phosphatase which were remitted by pre-treatment with PB and corroborated with histopathology. Additionally, MTX-induced hepatic oxidative stress which included increased generation of reactive oxygen species, enhanced lipid peroxidation, depleted levels of glutathione and decreased activities of antioxidant enzymes was effectively mitigated by PB, indicative that its promising antioxidant-mediated hepatoprotective activity was worthy of future pharmacological consideration.
27146084 Sex Differences in mRNA Expression of Reduced Folate Carrier-1, Folypolyformyl Glutamate S 2016 Dec Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well known, but little is known about those differences in relation to therapeutic response. Reduced folate carrier-1 (RFC-1), folypolyformyl glutamate synthase (FPGS), and γ-glutamyl hydrolase (GGH) are important transporters and enzymes that convert methotrexate (MTX) in the body. This study investigated the sex differences in mRNA expression of RFC-1, FPGS, and GGH in 190 unrelated healthy Japanese people. The genotypes and mRNA expression were determined using the real-time PCR method. Significant differences between men and women were observed in RFC-1, FPGS, and GGH mRNA expression. The mRNA expression of FPGS and GGH was greater in women than that in men, but the expression of RFC-1 was less in the former than the latter. In stratified analysis by genotype, significant differences in sex-specific mRNA expression were observed in G/G of FPGS, C/C of GGH 452, and C/C of GGH -401. All showed greater mRNA expression in women than in men. In the 5 single-nucleotide polymorphisms RFC-1 80G>A, RFC-1 -43T>C, FPGS 1994G>A, GGH 452C>T, and GGH -401C>T examined, the FPGS 1994 G/G (1.46-fold), GGH 452 C/C (2.16-fold), and GGH -401 C/C (2.68-fold) genotypes showed significantly higher mRNA expression in women than in men. Healthy Japanese adults in this study showed sex-specific differences in mRNA expression that differed among RFC-1, FPGS, and GGH. Therefore, the relationship between genetic polymorphisms and mRNA expression including sex differences might contribute to the variation in the efficacy/toxicity of MTX in patients with RA.