An approach to preventing methotrexate prescribing errors in rheumatoid arthritis

Methotrexate is an effective treatment for rheumatoid arthritis and is fairly well tolerated by patients when used appropriately. However, errors do occur due to a lack of awareness of the normal dosage range and potentially serious dose related side effects of methotrexate among physicians, pharmacists, and nurses. The approach taken by one hospital to prevent methotrexate prescribing errors includes daily monitoring of methotrexate by a pharmacist, building caution flags in the order loading program of the pharmacy computer system, and educating healthcare professionals to heighten awareness when prescribing, dispensing, and administering methotrexate for rheumatoid arthritis. At the hospital, since the institution of these policies and education of pharmacists, nurses, and physicians, there have been no incidents of methotrexate prescribing errors.     

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。     

The use of methotrexate in rheumatoid arthritis

The use of methotrexate in rheumatoid arthritis is reviewed. Methotrexate, a folic acid antagonist, is sometimes employed in an attempt to symptomatically control patients whose disease does not respond adequately to conventional therapies. Systemic administration of 7.5-15 mg/wk in a "pulse" fashion appears to be effective without precipitating severe adverse effects. However, concern over potentially serious side effects and a lack of well-controlled clinical trials have limited its use to severe, refractory disease. Further studies are needed before its role in rheumatoid arthritis can justifiably be expanded.     

Clinical pharmacogenetics of methotrexate

It is well known that interindividual variability can affect the response to many drugs in relation to age, gender, diet, and organ function. Pharmacogenomic studies have also documented that genetic polymorphisms can exert clinically significant effects in terms of drug resistance, efficacy and toxicity by modifying the expression of critical gene products (drug-metabolizing enzymes, transporters, and target molecules) as well as pharmacokinetic and pharmacodynamic parameters. A growing body of in vitro and clinical evidence suggests that common polymorphisms in the folate gene pathway are associated with an altered response to methotrexate (MTX) in patients with malignancy and autoimmune disease. Such polymorphisms may also induce significant MTX toxicity requiring expensive monitoring and treatment. Although the available data are not conclusive, they suggest that in the future MTX pharmacogenetics could play a key role in clinical practice by improving and tailoring treatment. This review describes the genetic polymorphisms that significantly influence MTX resistance, efficacy, and toxicity.     

Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients

The pharmacokinetics and bioavailability of low-dose methotrexate (MTX) (10 mg/m2) were evaluated in 41 subjects who had definite or classical rheumatoid arthritis as defined by the American Rheumatism Association criteria. Subjects received 10 mg/m2 (to the nearest 2.5 mg) of MTX in a single oral dose and a single intravenous (iv) dose one week apart. Serum concentrations for this low-dose regimen were monitored using a radiochemical ligand binding assay. The results indicate the MTX is cleared from the plasma at a rate of 84.6 mL/min/m2. The terminal half-life was approximately 6 h. The volumes of distribution at steady state and for the central compartment were 22.2 and 13.5 L/m2, respectively. The mean residence time in the body, in the systemic circulation, and in the periphery were estimated to be 4.7, 3.0, and 1.7 h, respectively, with a peripheral single-pass mean transit time of 6.0 h and an intrinsic mean residence time in the periphery of 7.9 h. The mean absorption time was 1.2 h and the oral bioavailability was 0.70. The ratio of synovial fluid concentration to serum concentration 4 and 24 h after a dose was found to be approximately 1.0, indicating that at least within that time range serum and synovial fluid concentrations are approximately equal. Because of conflicting results and insufficient data from previous high-dose pharmacokinetic studies, it is difficult to say whether or not low-dose MTX pharmacokinetics differs from those of high-dose MTX.     

Methotrexate in rheumatoid arthritis: an update

Methotrexate, a folic acid antagonist, is being employed more frequently in an attempt to control rheumatoid arthritis that has not responded adequately to conventional therapies. Systemic administration of 7.5-15 mg weekly in a pulse fashion appears to be effective without precipitating serious adverse effects. Concern over potentially serious adverse effects and lack of well-controlled clinical trials have limited its use to severe, refractory disease. Its use in the future is likely to increase in these patients because of its ease of administration and the high response rate noted in clinical studies.     

Monitoring methotrexate therapy in patients with rheumatoid arthritis

OBJECTIVE: The aim of this work was to study methotrexate (MTX) kinetics and their relation to the effectiveness of the therapy in patients with rheumatoid arthritis (RA). Other aims were to analyze the influence of MTX on liver, kidney, hematopoietic function and to determine the possibility of using early drug concentrations to predict the subsequent value of the treatment. MATERIAL AND METHODS: The observations were carried out in 49 patients with RA after the first dose of MTX and after 7 months of treatment. Methotrexate concentrations in blood serum and urine were determined using fluorescence polarization immunoassay applying a TDx Abbott analyzer. RESULTS: No correlation between concentrations, pharmacokinetic parameters and the duration of the disease, its activity, clinical symptoms, observations pertaining to the disease made by physician and patients and morning stiffness of joints was seen. Of those tests for the evaluation of liver, kidney and hematopoietic function, only the mean activity of N-acetyl-beta-D-glucosaminidase (NAG) in urine was significantly elevated both before and after treatment with MTX when compared to corresponding values in the control group of healthy subjects. We have formulated equations allowing for the early recognition of patients with a risk of adverse effects due to impaired elimination of MTX from the body. CONCLUSION: Our results show that monitoring MTX therapy using concentrations in patients with RA does not significantly improve the effectiveness of the treatment, but it can play an important role in increasing the safety of this drug.     

青藤碱和甲氨蝶呤联合治疗类风湿关节炎

目的 :观察青藤碱和甲氨蝶呤联合治疗类风湿关节炎的疗效和不良反应。方法 :对照组 32例 (男性 6例、女性 2 6例 ,年龄 4 6a±s3a ,病程 4 .1a± 1.0a) ;青藤碱组 32例 (男性 7例 ,女性 2 5例 ,年龄 4 6a± 4a ,病程 4 .6a± 1.6a)。 2组原有非甾类抗炎药 (吲哚美辛、双氯芬酸 )继续应用。对照组加服甲氨蝶呤 15mg ,qw ;青藤碱组加服青藤碱 2 0mg ,tid +甲氨蝶呤 7.5mg ,qw。 3d后无不良反应 ,青藤碱加至 4 0mg ,tid。 2组于 1mo时非甾类抗炎药减半 ,2mo停用。 3mo为一个疗程。结果 :对照组显效 31% ,有效 56% ,改善 13% ;青藤碱组显效 38% ,有效 59% ,改善 3%。不良反应对照组4 7% ,青藤碱组 12 %。结论 :联合用药可减少治疗类风湿关节炎的用药剂量 ,增加病人治疗的顺应性和减少不良反应     

甲氨蝶呤治疗类风湿关节炎作用机制的研究进展

甲氨蝶呤(methotrexate,MTX)是一种细胞毒药物,广泛用于抗肿瘤治疗,从20世纪50年代开始,MTX被试用于治疗类风湿关节炎(rheumatoid arthritis,RA),并取得良好疗效.至今,虽然有许多新药出现,但MTX便宜、服药简便、副作用少,仍被广泛用于治疗RA及其他自身免疫性疾病.现在,MTX作为治疗RA的首选药被写入我国新出台的RA诊治指南(草案),然而它的抗炎机制还不是非常明确,本文就近年来MTX治疗RA的作用机制研究进展作一综述.     

正清风痛宁联合甲氨喋呤治疗类风湿关节炎

目的评价正清风痛宁缓释片联合甲氨喋呤(MTX)治疗类风湿关节炎(RA)的疗效。方法RA患者69例,随机分成2组,正清风痛宁缓释片联合MTX治疗组35例,采用正清风痛宁缓释片2粒,每日2次口服,同时服用MTX10mg,每周1次;对照组34例,MTX10mg口服,每周1次,于治疗8周后,观察两组疗效。结果正清风痛宁组35例,其中显效21例,占60%,有效14例,占40%,无效0例,总有效率为100%;对照组34例,其中显效7例,占20.6%,有效24例,占70.6%,无效3例,占8.8%,总有效率为91.2%。两组疗效相比,经秩和检验,有显著性差异(P<0.05)。治疗组和对照组关节疼痛、肿胀、压痛、晨僵、血沉、C-反应蛋白、类风湿因子治疗后均明显低于治疗前(P<0.01或P<0.05)。治疗后正清风痛宁组与对照组晨僵、关节疼痛、肿胀、压痛、握力、ESR、CRP、PLT相比有显著差异(P<0.05)。结论正清风痛宁口服联合MTX治疗类风湿关节炎的疗效优于单用MTX组。     

来氟米特和甲氨蝶呤联合治疗类风湿关节炎(英文)

目的 :观察小剂量来氟米特和甲氨蝶呤联合应用治疗类风湿关节炎的疗效和安全性。方法 :64例类风湿关节炎病人随机分入 2组 ,各 32例。 2组病人于治疗前 1wk停用非甾体类抗炎镇痛药。试验开始时来氟米特 +甲氨蝶呤组 (Lef +MTX)给予来氟米特 2 0mg ,po ,qd +甲氨蝶呤 (MTX) 7.5mg po ,qw ,服 4wk后来氟米特 10mg ,po ,qd +MTX 7.5mg ,po ,qw ;MTX组服甲氨蝶呤 15mg ,po ,qw ,2组均以 2 4wk为一个疗程。治疗前、治疗后wk 12 ,2 4均做体检及实验室检查 ;治疗前后摄双手正位片。结果 :Lef +MTX组显效 88%( 2 8/32例 ) ,MTX组 38%( 12 /32例 )。Lef +MTX组不良反应 4例占 12 %,主要为皮疹、恶心 ;MTX组 14例占 4 3%,主要为恶心、呕吐、口腔溃疡、脱发、ALT升高、心悸、月经不调等。结论 :来氟米特与甲氨蝶呤联合治疗起效快、疗效佳、不良反应率低。     

青霉胺和甲氨蝶呤联合治疗类风湿关节炎

目的：观察青霉胺和甲氨蝶呤联合治疗类风湿关节炎疗效。方法：试验分２组，治疗组７０例（男性１３例，女性５７例；年龄４７±ｓ１２ａ；病程３±４ａ）在原有非甾体抗炎镇痛药的基础上用青霉胺１２５ｍｇ／片，ｐｏ，ｑｄ和甲氨蝶呤７．５ｍｇ，ｐｏ，ｑｗ；对照组５５例（男性１７例，女性３８例；年龄５１±１２ａ；病程６±５ａ）只应用非甾体抗炎镇痛药。２组均３ｍｏ为一个疗程。结果：治疗组总有效率９４％，显效率６７％；对照组总有效率７６％，显效率９％，Ｐ＜０．０１。不良反应依次为１７％和１３％。结论：联合药物治疗的效果好。     

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。     

甲氨蝶呤对C反应蛋白在类风湿关节炎中致炎作用的影响

目的了解甲氨蝶呤(MTX)对C反应蛋白(CRP)在体外培养类风湿关节炎(RA)滑膜成纤维细胞(FLS)中的致炎作用的影响。方法体外培养人RAFLS和健康人滑膜成纤维细胞(HFLS)。分别设立空白对照组、CRP刺激组、MTX加CRP作用组,用实时荧光定量聚合酶链反应(RT-q PCR)和酶联免疫吸附试验(ELISA)检测各组白细胞介素(IL)-6、基质金属蛋白酶(MMP)-3、肿瘤坏死因子(TNF)-α的m RNA和蛋白表达。免疫印迹法检测各组磷酸化P65、IκB的表达。结果 CRP能明显上调RAFLS表达的IL-6、MMP-3、TNF-α的m RNA和蛋白表达水平(P<0.01),且比HFLS明显升高(P<0.05),提示CRP有促炎作用。CRP能使RAFLS的磷酸化P65水平明显增加,IκB明显减少,提示CRP能活化核因子(NF)-κB通路。在IL-1β诱导下,RAFLS中CRP的m RNA和蛋白表达明显升高,而MTX能降低RAFLS中CRP的表达(P<0.05)。MTX能拮抗CRP上调RAFLS表达IL-6、MMP3、TNF-α的m RNA和蛋白表达水平的作用(P<0.05),能拮抗CRP增加RAFLS的磷酸化P65水平和降解IκB的作用(P<0.05)。结论 MTX可以通过降低RAFLS表达的CRP,拮抗CRP活化NF-κB通路、促进IL-6、MMP3、TNF-α等炎症因子产生的作用,从而达到治疗控制RA炎症的作用。     

Potential role of pharmacogenetics in anti-TNF treatment of rheumatoid arthritis and Crohn's disease

Etanercept, infliximab and adalimumab have shown clinical benefit in immune-mediated inflammatory diseases; however, the outcome of treatment with these tumour-necrosis factor inhibitors remains insufficient in approximately 40-60% and approximately 25-40% of individuals with rheumatoid arthritis and Crohn's disease, respectively. Moreover, their use is accompanied by adverse events and unintentional immune suppression. Pharmacogenetics has the potential to increase efficacy and ameliorate adverse events and immune suppression, and its application might be of clinical benefit for patients with rheumatoid arthritis and Crohn's disease. Pharmacogenetic studies have shown associations between single nucleotide polymorphisms in genes encoding enzymes related to the pharmacodynamics of these drugs and treatment outcome. As we discuss here, replication and prospective validation are warranted before pharmacogenetics can be used in clinical practice.     

类风湿关节炎患者甲氨蝶呤中毒6例临床分析

目的探讨类风湿关节炎患者甲氨蝶呤中毒的临床特点、治疗及预后。方法回顾分析6例小剂量甲氨蝶呤引起中毒的类风湿关节炎患者的临床资料及诊治过程:其中5例为误服,1例是小剂量甲氨蝶呤引起的急性骨髓抑制。结果 5例患者出现口腔黏膜溃烂,2例出现口腔出血,1例便血,2例腹泻,1例皮肤破溃、瘀斑,1例全身散在皮疹伴瘙痒;血常规:白细胞(WBC)(0.77~5.11)×109/L,中性粒细胞(0.13~3.01)×109/L,血小板(PLT)(1~70)×109/L;2例肝功能损伤。治疗给予亚叶酸钙解救,应用造血因子、成分输血、早期经验性应用抗生素、保肝治疗、加强基础护理等综合救治措施。6例患者均康复出院。结论急性粒细胞缺乏、血小板减少、肝功能损伤是甲氨蝶呤严重的不良反应,处理及时、得当可取得良好疗效。     

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.