甲氨蝶呤与金制剂治疗类风湿性关节炎耐受性比较的Meta分析

目的:比较甲氨蝶呤与金制剂治疗类风湿性关节炎的耐受性。方法:采用Meta分析对7项甲氨蝶呤与金制剂治疗类风湿性关节炎疗效的研究进行同质性检验和合并效应量估计。结果:同质性检验:χ2=25·14,自由度为6,P=0·0003;合并效应量估计:OR合并=2·37,OR合并95%可信限为1·18～4·78。OR合并的检验Z=2·41,P=0·02。结论:与金制剂治疗类风湿性关节炎比较,甲氨蝶呤的耐受性较好。     

甲氨蝶呤代谢酶基因多态性在类风湿关节炎治疗中的研究进展

甲氨蝶呤（MTX）是治疗类风湿关节炎的一线药物。然而,MTX的有效性和不良反应在患者间具有显著的差异,研究提示MTX的代谢及叶酸通路中关键酶的基因多态性可能影响细胞中MTX多聚谷氨酸的浓度和对叶酸通路的拮抗作用,从而影响了MTX的疗效发挥或患者对药物不良反应的差异。本文综述了近年来关于MTX治疗RA涉及基因多态性的研究进展。     

Pott's disease and hypercalcemia in a patient with rheumatoid arthritis receiving methotrexate monotherapy

Methotrexate (MTX) may have adverse effects on multiple organs and system. A few cases of pulmonary tuberculosis in-patients with rheumatoid arthritis (RA) while receiving MTX monotherapy has been reported in the literature. We submit a case of vertebral tuberculosis with hypercalcemia in a patient receiving MTX monotherapy. Patient with RA taking MTX for 15 years developed pancytopenia, skin necrosis, tuberculous spondylodiscitis and hypercalcemia. The present case showed adverse effects of MTX therapy may occur even after years of continuous treatment. Due to pancytopenia in older patients, life-threatening tuberculosis at unusual sites may develop.KEY WORDS: Hypercalcemia, methotrexate, pancytopenia, Pott''s disease, rheumatoid arthritis     

Can we predict unresponsiveness to methotrexate in rheumatoid arthritis? A pharmacogenetic study

Inflammopharmacology - Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) and the therapeutic response to MTX has been observed to vary widely among these patients....     

Methotrexate-loaded biodegradable nanoparticles exert anti-arthritic effect by downregulating pro-inflammatory cytokines in Freund’s complete adjuvant-induced arthritic rats

Inflammopharmacology - Methotrexate (MTX), the first-line drug for the treatment of rheumatoid arthritis (RA), can cause considerable toxicity, which limits effective dosage regimens. Moreover, it...     

Pharmacological re-evaluation of a GABA(B) receptor antagonist CGP 47332A in rat brain

In rat neocortical slices maintained in Mg(2+)-free Krebs medium, the gamma-aminobutyric acid (GABA(B)) receptor agonist baclofen concentration-dependently depressed the frequency of spontaneous discharges (EC(50)=12 microM). This was reversibly antagonised by (R, S)-3-amino-2-hydroxy-propyl-P-n-butyl-phosphinic acid (CGP 47332A) (25, 100, 300 microM) which produced rightwards shifts of the baclofen concentration-response curves (pA(2) value=4.8+/-0.1). In electrically stimulated slices preloaded with [3H]GABA, CGP 47332A increased its release (EC(150)=100 microM) through antagonism of GABA(B) autoreceptors. Although CGP 47332A was some six times weaker on GABA(B) auto- than on heteroreceptors, yet its congener lacking the beta-hydroxy substituent displays equal potency in both binding (IC(50)=38 microM) and GABA(B) autoreceptor functional studies (EC(150)=38 microM) as previously reported [Froestl, W., Mickel, S.J. , Von Sprecher, G., Diel, P.J., Hall, R.G., Maier, L., Strub, D., Melillo, V., Baumann, P.A., Bernasconi, R., Gentsch, C., Hauser, K., Jaekel, J., Karlsson, G., Klebs, K., Maitre, L., Marescaux, C., Pozza, M.F., Schmutz, M., Steinmann, M.W., Van Riezen, H., Vassout, A., Mondadori, C., Olpe, H.R., Waldmeier, P.C., Bittiger, H., Phosphinic acid analogues of GABA: 2. Selective, orally active GABA(B) antagonists. J. Med. Chem. 38 (1995) 3313-3331.].     

Methylenetetrahydrofolate reductase and reduced folate carrier-1 genotypes and methotrexate serum concentrations in patients with rheumatoid arthritis

We investigated the genotypes of methylenetetrahydrofolate reductase (MTHFR) and reduced folate carrier-1 (RFC-1), and the serum concentrations of methotrexate (MTX) in 100 outpatients with rheumatoid arthritis (RA). Frequencies of MTHFR C677T and A1298C were similar to those reported in Japanese RA patients, while frequencies of RFC-1 G80A genotypes differed from those reported in RA patients in the United States. No correlations were found between these genotypes and serum MTX levels.     

阿克他利与甲氨蝶呤治疗类风湿关节炎的比较

目的 :比较阿克他利和甲氨蝶呤对类风湿关节炎 (RA)的疗效和安全性。方法 :12 0例RA病人随机分为 2组 ,阿克他利组 80例 ,口服阿克他利10 0mg ,tid× 12wk。甲氨蝶呤组 4 0例 ,口服甲氨蝶呤 10mg ,qw× 12wk。结果 :阿克他利组总有效率为 73% ,甲氨蝶呤组为 78% (P >0 .0 5)。不良反应发生率分别为 9%和 18% ,差异有显著意义 (P <0 .0 5)。结论 :阿克他利治疗类风湿关节炎的疗效与甲氨蝶呤相似 ,但在安全性方面明显优于甲氨蝶呤。     

类风湿关节炎患者转运蛋白基因多态性与甲氨蝶呤疗效及不良反应的相关性研究

目的探讨类风湿关节炎（RA）患者还原型叶酸载体（RFC-1）基因G80A及三磷酸腺苷结合盒转运体B1（ABCB1）基因C3435T单核苷酸多态性（SNP）与甲氨蝶呤（MTX）疗效与不良反应的相关性。方法采用实时荧光定量聚合酶链反应（FQ-PCR）法检测136例单用MTX的RA患者RFC-1基因G80A及ABCB1基因C3435T多态性,并与MTX治疗疗效和不良反应相关分析。结果 RFC-1基因G80A及ABCB1基因C3435T多态性与MTX治疗RA的不良反应无明显相关性（P〉0.05）;RFC-1基因G80A多态性与MTX治疗RA的疗效无明显相关（P〉0.05）,而ABCB1基因C3435T的多态性与疗效相关,携带有CC基因型的患者MTX疗效明显优于携带有TT或CT基因型的患者。CT和CC比较,（P=0.015,OR=4.189,95%CI为1.314~13.353）;TT和CC比较,（P=0.02,OR=5.941,95%CI为1.320~26.739）。结论 ABCB1基因C3435T多态性可能对RA患者应用MTX的疗效有预测作用。     

通痹汤与氨甲喋呤联合治疗类风湿性关节炎疗效观察

目的 观察通痹汤与氨甲喋呤联合治疗类风湿关节炎疗效。方法 治疗组采用中药通痹汤与氨甲喋呤联合治疗类风湿性关节炎（ＲＡ）７９例，以风湿液与氨甲喋呤联合治疗的４０例ＲＡ作对照。其中治疗组１８例，对照组９例。结果与结论 两组疗效均比文献所报告的单用氨甲喋呤疗效为佳。而通痹汤更具较强的抗炎镇痛及免疫调节作用，可使关节肿痛症状迅速消失，关节功能明显改善，晨僵时间消失或缩短，并随着关节炎症的减轻，使血液中ＩｇＧ，ＩｇＭ，ＩｇＡ恢复正常，血沉下降曲线平稳，类风湿因子（ＲＦ）阴转率达６７．５７％。用药后撤停激素快，无反跳现象，副作用少。骨质修复作用明显，具有改善病情作用。其疗效明显优于对照组。     

Fostamatinib, a Syk-kinase inhibitor, does not affect methotrexate pharmacokinetics in patients with rheumatoid arthritis

Fostamatinib (R788) is being investigated as an add-on therapy for the treatment of rheumatoid arthritis (RA) in patients with inadequate response to methotrexate (MTX). This study evaluated the potential pharmacokinetic interaction between R788 and MTX. Sixteen RA subjects on a stable weekly MTX regimen were enrolled and received MTX on days 1 and 8. Twelve subjects received 100 mg of R788 orally, and 4 subjects received a matching placebo twice daily from days 4 to 8 and once daily on days 3 and 9. Blood samples were collected on days 1 and 8 for MTX and 7-hydroxymethotrexate (7-OH-MTX), and days 3 and 9 for R788 and its active metabolite, R406. MTX and 7-OH-MTX pharmacokinetic parameters were similar on days 1 and 8. In the R788 group, the mean day 8 to day 1 ratios (90% confidence intervals) of maximum concentration and area under the plasma concentration-time curve estimates were 1.01 (0.85-1.20) and 1.12 (0.90-1.40) for MTX and 1.06 (0.82-1.35) and 1.06 (0.83-1.36) for 7-OH-MTX, respectively. Urinary excretion of MTX and 7-OH-MTX was also similar with or without R788, averaging 58% to 69% and 4% to 5% of the MTX dose, respectively. The data suggest that there is no clinically significant pharmacokinetic interaction of R788 and MTX in RA patients.     

两种慢作用抗风湿药联合治疗类风湿关节炎临床观察

目的　观察两种慢作用抗风湿药联合治疗类风湿关节炎 (RA)的疗效及安全性。方法　 50例活动期RA患者随机分为两组 ,每组 2 5例 ,第 1组服用甲氨蝶呤 (MTX) 1 0mg/周 +雷公藤多甙 2 0mg ,每日 3次 ;第 2组服用MTX 1 0mg/周 +柳氮磺吡啶 (SASP) 1 0g ,每日 2次 ,观察 3个月。 结果　MTX +雷公藤多甙组在 6、1 2周的有效率分别为 84% ,92 % ,不良反应发生率为 36 % ,MTX +SASP组为 56 % ,88% ,不良反应发生率为 2 8%。结论　MTX +雷公藤多甙组及MTX +SASP组治疗RA的疗效相似 ,均优于单独应用MTX ,副作用无明显增加     

Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy

Methotrexate (MTX) is one of the most commonly used medicines in the treatment of psoriatic arthritis. The drug can produce steatosis and cirrhosis. Autoimmune hepatitis is a rare and serious adverse effect. We describe the case of a 53-year-old woman who developed autoimmune hepatitis after a long-term use of MTX for psoriatic arthritis. Hepatitis was completely resolved 4 months after stopping this drug. The pathophysiologic mechanisms of a drug-induced autoimmunity are unclear and complex. This report confirms the need to monitor liver enzymes carefully in patients using long-term treatment with MTX for psoriasis or rheumatoid arthritis.KEY WORDS: Autoimmune hepatitis, drug-induced autoimmunity, methotrexate, psoriatic arthritis     

Design and development of an injectable in situ forming drug delivery system of methotrexate for the treatment of rheumatoid arthritis

Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA). At present there exists a lacuna in delivering methotrexate in suitable dosage form to maintain optimum plasma concentration to achieve therapeutic efficacy during the treatment period. Exposure of MTX at higher concentrations resulted in severe side effects. Moreover, the treatment modality (initial and maintenance dose) of RA is not clinically uniform. Biodegradable injectable in situ gels offer versatility in delivering drug at predetermined rates, and maintaining plasma concentration with a possibility of dose adjustment. They can be developed to optimize the therapeutic properties of a drug product, render them safe, effective and reliable during therapy. The aim of the present study was to formulate a biodegradable injectable in situ gel system for methotrexate sodium in the treatment of rheumatoid arthritis. The formulations were prepared by "cold technique" using thermosensitive polymer, Pluronic F-127 (20 %) and varying concentration of co-polymers, Pluronic F-68 (2–6 %) and Carbopol 934 (1.0-1.5 %). The prepared in situ gels were evaluated in vitro for drug interactions by FT-IR, sterility, gelation characteristics, content uniformity, viscosity, syringeability and in vitro drug release. MTX was evenly distributed in all formulations, which were sterile and syringeable through an 18 gauze needle. The gels were thermosensitive and thermoresponsive, and were dependent on the concentration of co-polymers. Drug release from in situ gels was sustained for 96 h to 120 h, and influenced by the type and concentration of co-polymers employed. Drug release was significantly higher in dynamic diffusion state in comparison with static state as ascertained by student t-test. The drug release was by non-fickian diffusion mechanism and followed first-order kinetics. These findings suggested that in situ gels can be effectively used to achieve controlled drug release; are easy to administer, are effective with reduced frequency of dosage, and result in increased patient compliance and comfort. It may be concluded that methotrexate in situ gels are ideally suitable in the treatment of RA.     

羟氯喹和甲氨蝶呤对类风湿性关节炎的治疗分析

目的:探讨羟氯喹和甲氨蝶呤(MTX)联合治疗类风湿性关节炎(RA)的疗效及安全性.方法:将120例RA患者随机分为治疗组和对照组各60例,治疗组给予羟氯喹联合MTX治疗,对照组MTX联合硫氮磺胺吡啶治疗,观察患者关节症状改善程度、血沉变化情况以及药物不良作用.结果:第四周时治疗组患者关节症状改善52.8%,明显高于对照组的37.0%(P＜0.05),并且第四周时治疗组有效率为63%,明显高于对照组的43%(P＜0.05),此外,对照组血清谷丙转氨酶和血清谷草转氨酶高于治疗组,不良反应治疗组发生率为8.01%.对照组发生率为13.52%.结论:羟氯喹和MTX联合应用能较好地缓解症状,患者症状改善的时间缩短,不良反应发生率低,患者耐受性好,值得临床推广.     

Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors

Cholinergic neurons degenerate in Alzheimer's disease, resulting in cognitive impairments and memory deficits, and drug development efforts have focused on selective M1 muscarinic agonists. 5-(3-Ethyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine trifluoroacetic acid (CDD-0102) stimulates M1 muscarinic receptors in rat brain [Messer, W.S., Jr., Abuh, Y.F., Liu, Y., Periyasamy, S., Ngur, D.O., Edgar, M.A., El-Assadi, A.A., Sbeih, S., Dunbar, P.G., Roknich, S., Rho, T., Fang, Z., Ojo, B., Zhang, H., Huzl, J.J., III, Nagy, P.I., 1997a. J. Med. Chem. 40, 1230-1246.] and improves memory function in rats with lesions of the basal forebrain cholinergic system. Moreover, CDD-0102 exhibits oral bioavailability, few side effects and low toxicity, and thus represents a viable candidate for clinical studies. Despite the development of functionally selective agonists such as xanomeline and CDD-0102, there is room for improvements in ligand affinity and selectivity. The high degree of amino acid homology within transmembrane domains has hindered the development of truly selective agonists. Site-directed mutagenesis, biochemical and molecular modeling studies have identified key amino acid residues such as Thr192 and Asn382 in the binding of agonist to M1 receptors [Huang, X.P., Nagy, P.I., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1999. Br. J. Pharmacol. 126, 735-745.]. Recent work has implicated residues at the top of transmembrane domain VI in the binding of muscarinic agonists and activation of M1 receptors [Huang, X.P., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1998. J. Pharmacol. Exp. Ther. 286, 1129-1139.]. Thus, residues such as Ser388 represent molecular targets for the further development of agonists with improved M1 receptor affinity, selectivity and activity.     

Autoimmune hepatitis after long-term methotrexate therapy for rheumatoid arthritis

Methotrexate (MTX) therapy may be effective in patients with rheumatoid arthritis (RA) or psoriasis due to its anti-inflammatory and immunosuppressive properties. Potential liver toxicity of MTX exists, but the incidence of MTX-specific lesions in liver biopsy of patients with RA and elevated serum transaminase levels is rare; however, severe hepatic damage may occurs unexpectedly in these patients. We describe the first documented case of an adult patient with RA who developed an acute flare of severe hepatitis after long-term therapy with MTX. Autoantibodies positivity, elevated serum IgG levels and compatible liver biopsy findings prompted us to diagnose autoimmune hepatitis, most probably triggered by a breakdown of immune tolerance induced by MTX. A complete remission was achieved in this patient with corticosteroids therapy.     

甲氨蝶呤和白芍总苷联用治疗类风湿关节炎的疗效观察

目的观察甲氨蝶呤（MTX）联合白芍总苷（TGP）治疗类风湿关节炎（RA）的临床疗效。方法59例患者分为2组,MTX组28例仅口服MTX治疗,TGP＋MTX组31例口服MTX加TGP治疗,疗程均3个月。结果治疗4、8、12周,TGP＋MTX组总有效率分别为87．1％、93．5％、96．8％,略高于MTX组（分别为82．1％、85．7％、96．4％）,但差异无统计学意义（P〉0．05）。2组均能显著降低红细胞沉降率（ESR）、C反应蛋白水平,但TGP＋MTX组更显著,且肝功能异常情况明显低于对照组。结论TGP＋MTX联合方案起效快、疗效稳定、不良反应较少,依从性更高,较适合老年RA患者。     

小剂量环磷酰胺在类风湿关节炎的临床应用

目的：探讨小剂量环磷酰胺治疗类风湿关节炎（RA）的可行性、有效性及安全性。方法：40例患者分为小剂量环磷酰胺组与甲氨蝶呤组,评价药物疗效及不良反应。结果：小剂量环磷酰胺治疗组患者耐受良好,临床指标有所改善,关节压痛数、肿胀数、晨僵时间、ESR和CRP明显降低P〈0．05．差异有显著性。治疗前后肝肾功能、血、尿常规比较均未见明显异常改变。结论：小剂量环磷酰胺治疗类风湿关节炎是一种简单、有效、安全的治疗方案。     

Pharmacokinetics,pharmacodynamics and toxicities of methotrexate in healthy and collagen‐induced arthritic rats

Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPG_n) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen‐induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post‐induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPG_n in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple‐doses, RBC MTX reached steady‐state (82.4 nm ) within 4 days. The MTXPG₂ and MTXPG₃ in RBC kept increasing until the end of the study, attaining 12.5 and 17.7 nm . Significant weight loss was observed after dosing with 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing with 0.3 mg/kg/2 days. A pharmacokinetic/pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX and RBC MTXPG_n concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. Methotrexate showed modest (I_maxd = 0.16) but sensitive (IC_50d = 0.712 nm ) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of the effects of methotrexate on rheumatoid arthritis. Copyright © 2013 John Wiley & Sons, Ltd.