Methotrexate pharmacokinetics in patients with rheumatoid arthritis

Few studies have evaluated the pharmacokinetics of low dose oral methotrexate (MTX) therapy. MTX pharmacokinetics were studied in 10 patients with classic rheumatoid arthritis (RA) after a single 7.5 mg oral dose. MTX was rapidly absorbed. Peak concentrations varied considerably, ranging from 0.31-0.72 microM. Measurable drug concentration was found in all patients at 24 h after the dose. CL/F-MTX = 145 +/- 52 ml/min/1.73 m2 and elimination half-life was 4.5 +/- 0.89 h. Oral MTX given as a single weekly dose has predictable pharmacokinetics. Further studies to examine what relationship exists, if any, with efficacy and toxicity of MTX in RA must be undertaken.     

Methotrexate: mechanism of action, pharmacokinetics, clinical indications, and toxicity

Methotrexate has become a standard therapy for the treatment of rheumatoid arthritis. This review summarizes the recent literature on low-dose methotrexate in the rheumatologic illnesses. The effect of methotrexate on in vivo rheumatoid factor production and suppression of ex vivo leukotriene B4 generation is reviewed. New information on drug interactions and pharmacokinetics is highlighted. The efficacy and toxicity of the drug in rheumatoid arthritis and other diseases are further defined. The effects of methotrexate on liver histology are also summarized.     

胰岛素肠溶胶丸人体药代动力学、药效动力学及生物利用度研究

目的 以正规胰岛素皮下注射制剂为参比,进行胰岛素肠溶胶丸人体药代动力学、药效动力学及相对生物利用度研究。方法 20例健康受试者,男14例,女6例,年龄21～41（28．64-5．2）岁,BMI18．0～22．0（21．24-1．1）kg／m^2,在正常血糖葡萄糖钳夹技术平台上,按随机顺序分别接受受试制剂（50IU）和参比制剂（15IU）两次试验。每个试验日经2h平衡后给药,采29个时点血样测血清胰岛素水平,同时记录12h中每5分钟的葡萄糖输注率,以计算药代动力学和药效动力学参数。结果 受试制剂与参比制剂的血药浓度峰值分别为（22．1±8．0）m／U／L和（118．6±25．2）mlU／L,达峰时间分别为（255．8±142．2）min和（115．5±43．4）min。葡萄糖处置率峰值（GIRmax）分别为（3．56±0．85）mg·kg^-1·min^-1和（4．87±1．26）mg·kg^-1·min^-1,GIRmax达峰时间分别为（166．3±75．9）min和（148．0＋40．8）min。受试制剂相对生物利用度为（7．42±3．25）％,相对有效性为（24．78±0．08）％。结论 胰岛素肠溶胶丸可经胃肠道吸收入血,相对生物利用度与相对有效性差别大,充分体现了口服胰岛素制剂模拟内源胰岛素分泌生理过程所带来的益处。其药代、药效特点为进一步临床研究提供可靠的依据。     

胰岛素粉雾剂人体药代动力学及生物利用度研究

目的与皮下注射正规胰岛素制剂比较，研究胰岛素粉雾剂人体药代动力学及药效动力学特征及其相对生物利用度。方法18名健康受试者（男14名，女4名），平均年龄（24．9±1．7）岁（21～33岁），体重指数为（20．6±1．2）kg／m^2（18．2～23．0kg／m^2），在正常血糖葡萄糖钳夹技术平台上，按随机顺序分别接受吸入胰岛素粉雾剂（80U）和皮下注射正规胰岛素（15U）两次试验。于给药后0、20、30、40、50、60、70、80、90、100、110、120、135、150、165、180、195、210、225、240、270、300、330、360、390、420、450、480min取血测血清胰岛素水平，同时记录8h中每5min的葡萄糖输注率，以计算药代动力学和药效动力学参数。结果受试制剂胰岛素粉雾剂及参比制剂皮下注射正规胰岛素的血药浓度峰值Cmax分别为（57．9±17．8）和（114．5±29．7）mU／L，达峰时间Tmax为（46．7±45．6）和（107．8±33．7）min。葡萄糖处置率峰值GIRmax为（3．35±0．98）和（5．17±1．75）mg·kg^-1·min^-1，其达峰时间TGIRmax为（88．3±17．0）和（151．9±34．6）min。相对生物利用度为（10．26±2．25）％，相对生物有效性为（14．33±7．26）％。结论胰岛素粉雾剂可经肺吸收入血，其吸收及降糖作用均较皮下注射正规胰岛素快。其药代、药效特点为进一步临床研究提供可靠的依据。     

Investigation of bioavailability, pharmacokinetics and safety of new pediatric formulations of artesunate and mefloquine

The bioavailability/pharmacokinetics of dihydroartemisinin and mefloquine following the oral doses of 4 mg/kg body weight artesunate (Cambodian Pharmaceutical Enterprise) given concurrently with 10 mg/kg body weight oral mefloquine artesunate (Cambodian Pharmaceutical Enterprise) were investigated in 15 healthy Cambodian male volunteers. Both formulations were generally well tolerated. Both produced satisfactory plasma/blood concentration-time profiles. Oral artesunate and mefloquine were rapidly absorbed from gastrointestinal tract with marked inter-individual variation. For the dihydroartemisinin, the median (95% Cl) Cmax of 748 (304-1,470) ng/ml was observed at 1.5 (0.3-3.0) hours (tmax) after drug administration. The median (95% CI) values for AUC0-infinity, lambda(z) and tl/2z were 1.673 (1.08-2.88) microg.h/ml, 0.54(0.24-1.1)/hour and 1.3 (0.6-2.9) hours, respectively. For mefloquine, a median (95% Cl) Cmax of 1,000 (591-1,500) ng/ml was observed at 4 (2-6) hours (tmax) after drug administration. The median (95% CI) value for AUC0-168h was 3.92 (2.88-7.02) microg.h/ml.     

Methotrexate in pregnancy: reply

We would like to thank Lloyd and colleagues for their interestin our recent case report. We would certainly agree that anypatient exposed to any dose of methotrexate during pregnancyor in the 6 months prior to conception is at risk of fetal abnormality.Our advice     

Methotrexate and histologic hepatic abnormalities: A meta-analysis

STUDY OBJECTIVE: To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis. DESIGN: A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis. PATIENTS: A total of 636 patients from 15 studies. RESULTS: The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3%, p = 0.02). CONCLUSIONS: The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.     

Methotrexate.

The folic acid antagonists, aminopterin and then methotrexate, have been the primary systemically administered drugs for the treatment of severe psoriasis for 25 years. Methotrexate was finally approved by the FDA 5 years ago and was recently estimated to be used for approximately 25,000 psoriatic patients annually. With the small but chronic doses used for psoriasis, methotrexate has been relatively safe, except for a limited occurrence of significant hepatotoxicity. The good to excellent results obtained in most patients must, therefore, be weighted against the small risk of liver damage. Methotrexate has also been used with some effectiveness in several other dermatologic conditions, including mycosis fungoides, dermatomyositis, pityriasis rubra pilaris, and others, although they are not yet FDA-approved indications. The recent successful introduction of photochemotherapy (psoralen and ultraviolet light) for moderate and severely affected psoriatics will probably lead to a substantial decrease in the number of patients requiring methotrexate.     

Methotrexate in Crohn's disease: long-term efficacy and toxicity

OBJECTIVE: A 16-wk, placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn's disease. The long-term efficacy and safety of this antimetabolite drug, however, are not yet well established and are assessed in this study. METHODS: A total of 49 patients with Crohn's disease who were treated with methotrexate for > or =6 months were studied. All patients had been chronically treated with steroids; but at the time of initiation, only 27 were still on steroids. Of the 49 patients, 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure. Clinical remission was defined as a Harvey-Bradshaw index of <4. RESULTS: In all, 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months (range, 7-59 months). In these patients the probabilities of relapse were 29%, 41%, and 48% at 1, 2, and 3 yr, respectively. A higher rate of relapse was observed in women and in patients with ileocolitis. Adverse reactions were recorded in 24 patients, requiring discontinuation of methotrexate in five. A liver biopsy was performed in 11 patients; a mild steatosis was found in five, a slight dilation of the sinusoids in one, a granulomatous hepatitis with a mild portal fibrosis in one, and a slight periportal fibrosis in one patient. CONCLUSIONS: This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn's disease, with side effects that are usually only moderate.     

Methotrexate misadventure: a case for counselling

SIR, Methotrexate (MTX), a broad-spectrum anti-cancer agent,is used to treat a number of autoimmune diseases, includingrheumatoid arthritis and psoriasis. Oral MTX carries particularrisks of serious illness through inappropriate prescribing anddispensing errors. The majority of reported medication errorshave been due either to the dispensing of the wrong strength,or the patient taking the wrong strength [1–4]. The riskof misadventure is increased when a patient has supplies ofboth strengths, as may be needed to provide a particular dose.Counselling patients receiving low-dose oral MTX is essentialat each consultation and dispensing. We report