메토트렉세이트에 대한 숨겨진 질문들

이상원 ( Sang Won Lee ) 대한류마티스학회 2012 대한류마티스학회지 Vol.19 No.1

Since the 1950`s, methotrexatehas been the most widely used for the treatment of rheumatoid arthritis among various disease-modifying anti-rheumatic drugs (DMARDs). In this review, several hidden questions on methotrexate were discussed. First, so far, methotrexate has been considered to improve rheumatoid arthritis by inhibiting cell proliferation through the reduction of synthesis regarding purine and pyrimidine. Recently, a new concept was proposed that methotrexate could increase the release of adenosine, which subsequently decreases the inflammatory function of immune cells, and can finally quench the inflammation in affected joints of rheumatoid arthritis. Second, there were only three clinical trials done to directly compare the efficacy between methotrexate and biologics. With these results, methotrexate showed comparable therapeutic efficacy to biologics, but did not prevent radiological progression. In the future, clinical trials to directly compare the efficacy of methotrexate to biologics will be needed. Third, measuring the serum concentration of methotrexate is not appropriate, since circulating methotrexate is rapidly cleared by cellular uptake or renal excretion. Methotrexate polyglutamate is a more stable compound than methotrexate and it is more likely to relate to efficacy or adverse effects of methotrexate. Recently, the efforts to measure methotrexate polyglutamate in red blood cells have been done to increase therapeutic efficacy and reduce its adverse effects. Fourth, NSAIDs can decrease the excretion of methotrexate though renal tubular cells and it may increase the serum concentration of methotrexate and the risk of its toxicity, suggesting that physicians should pay close attention to dose adjustments concerning methotrexate combined with NSAIDs.

Diclofenac과 methotrexate 병합 경구 투여한 백서에서의 급성 장관손상과 장내세균전위

김정욱 ( Jeong Wook Kim ) 대한내과학회 2007 대한내과학회지 Vol.73 No.3

목적: 비스테로이드성 항염제와 methotrexate는 전장관에 걸쳐 손상을 일으키고 감염성 합병증인 장내세균전위를 유발한다. 하지만 비스테로이드성 항염제의 장관손상과 장내세균전위에 대한 methotrexate의 영향에 대해서는 아직 알려진 바가 없다. 이번 연구에서는 실험동물에서 비스테로이드성 항염제의 장관손상과 장내세균전위에 대한 methotrexate의 영향을 알아보았다. 방법: 백서를 정상 대조군, methotrexate 단독 투여군, diclofenac 단독 투여군, 그리고 methotrexate와 diclofenac 병합투여군으로 나누고 methotrexate는 20 mg/kg 용량으로 일회 경구투여하고 diclofenac은 80 mg/kg 및 120 mg/kg로 일회 경구투여 하였다. 약물 투여 2일 후 장관손상을 알아보기 위하여 20시간 동안 장투과성검사와 배변횟수를 측정한 후 장관유착도도 관찰하였다. 원위부 회장과 맹장에서 호기성 및 그람음성 장내세균수와 장간막 림프절, 간, 비장, 신장과 심장에서의 그람음성균수를 측정하였으며, 실험기간 동안 식이량과 체중변화도 관찰하였다. 결과: Diclofenac이나 methotrexate 단독 투여에 의하여 장투과성과 장관유착도가 증가하고 배변횟수가 감소하였으며 장내세균의 과증식와 장내세균전위가 발생하였다. Diclofenac과 methotrexate 병합투여군에서는 diclofenac이나 methotrexate 단독 투여군보다 장투과성과 장관유착도가 증가하고 배변횟수가 감소하였다. 또한 diclofenac 80 mg/kg 투여에서 diclofenac 단독투여군보다 그람 음성 장내세균수가 감소하였고, diclofenac의 투여용량과 상관없이 간, 비장, 신장과 심장에서 장내세균전위가 감소하였다. 식이투여량과 체중감소는 연구 결과에 영향이 없었다. 결론: 백서에서 methotrexate는 비스테로이드성 항염제에 의한 장관손상을 증가시키지만 간, 비장, 신장과 심장에서의 장내세균전위는 감소시킨다. Background: NSAIDs and methotrexate induce gut damage and bacterial translocation (BT). However, there is no study examining the combined effects of methotrexate and NSAID on gut damage and BT. We examined the combined effects of methotrexate and NSAID-induced enteropathy and bacterial translocation in an experimental animal model. Methods: Rats received either no drug, NSAID alone (diclofenac 80 mg/kg and 120 mg/kg per os), methorexate alone (20 mg/kg per os) or NSAID with methotrexate. Gut barrier dysfunction, the degree of intestinal adhesion, stool pellet number, bacterial number of total aerobes and Gram negatives in the distal ileal and cecal contents and the number of Gram negatives in the mesenteric lymph nodes, liver, spleen, kidney and heart were measured. Results: Administration of diclofenac or methotrexate alone caused an increase in gut barrier dysfunction and intestinal adhesion and a decrease in stool pellet number. Administration of diclonfenac alone induced enteric bacterial overgrowth and increased BT to the mesenteric lymph nodes, liver, spleen, kidney and heart. Administration of methotrexate alone induced enteric bacterial undergrowth and BT to the mesenteric lymph nodes, liver, spleen but not to the kidney and heart. The supplements with methotrexate increased the NSAID-induced gut barrier dysfunction and intestinal adhesion, and decreased the stool pellet number. However, the reduced NSAID-induced enteric Gram negative bacterial overgrowth (with a dose of diclofenac of 80 mg/kg) and BT to the liver, spleen, kidney and heart. Conclusion: Methotrexate increases NSAID-induced intestinal damage, but reduces NSAID-induced BT to the liver, spleen, kidney and heart in experimental animals.(Korean J Med 73:258-266, 2007)

자궁경관 임신에서 Methotrexate의 효능

고현선 ( Hyun Sun Ko ),김연희 ( Yeun Hee Kim ),안현영 ( Hyun Young Ahn ),박인양 ( In Yang Park ),이희중 ( Hee Joong Lee ),이영 ( Young Lee ),김사진 ( Sa Jin Kim ),김수평 ( Soo Pyung Kim ),신종철 ( Jong Chul Shin ) 대한주산의학회 2005 Perinatology Vol.16 No.1

목적 : 본 연구는 자궁경관임신의 보존 치료방법인 methotrexate의 치료 효과를 알아보고자 하였으며, 나아가 자궁경관 임신의 적절한 치료방법을 찾아보고자 하였다. 방법 : 1999년 1월부터 2004년 5월까지 가톨릭의과대학 부속병원에 입원한 환자 44예의 자궁경부 임신 환자 중 methotrexate 치료를 받은 35예의 환자들을 대상으로 하였다. 환자들의 임상적 특징, 치료방법, methotrexate 의 주입경로(전신, 국소, 혹은 복합요법), 소파술유무, 부작용 및 치료 성과를 중심으로 분석하였다. 통계적인 분석으로 unpaired t-test, Wilcoxon 순위 합검정, Fisher`s exact test를 이용하여 유의성을 검증하였으며, p값이 0.05 이하일 때 통계적으로 유의하다고 판정하였다. 결과 : Methotrexate에 의한 치료 성공율은 82.9%였고 태아 생존유무에 따라 유의한 차이는 없었다. 입원당시 혈중 beta-hCG 수치는 태아 심박동이 있는 경우 유의하게 높았다(p=0.0085). Methotrexate의 주입경로는 태아 심박동이 있는 경우와 심박동이 없는 경우 전신요법이 각각 37.5%, 81.5%에서 시행되었고, 복합요법은 각각 50.5%, 14.8%로 태아 심박동이 있는 경우 주로 복합요법이, 태아 심박동이 없는 경우 주로 전신요법이 시행되어 유의한 차이를 보였다(p=0.035). Methotrexate의 복합요법을 시행한 8예 모두 치료에 성공적이었다. Methotrexate의 주된 부작용은 간독성이었으나, 심각하지는 않았다. 결론 : 본 연구결과, methotrexate는 투여 경로에 따른 차이는 증명되지 않았으나, 임신 초기에 진단된 자궁경관 임신의 치료에 있어 효과적인 치료 방법이다. 또한, 전신요법과 양막강내 국소 주입의 복합요법은 자궁경관 임신에서 매우 효과적일 것으로 기대된다. Objectives : This retrospective study was performed to evaluate the overall efficacy of methotrexate chemotherapy and to determine its proper management protocol in cervical pregnancy. Method : From January 1999 to May 2004, 44 patients of cervical pregnancy admitted in hospitals attached to Catholic University Medical Center. Among those, data of 35 cases received methotrexate therapy were analyzed. Clinical characteristics, route of methotrexate administration, concomitant invasive procedures, complications, and outcomes were analyzed. Analysis was performed by unpaired t-test, Fisher`s exact test and Wilcoxon`s rank sum test. Results : The overall success rate of methotrexate was 82.9% and there was no significant difference according to viability, although initial beta hCG was significantly increased in viable pregnancy (p=0.0085). Major route of methotrexate was systemic in nonviable pregnancy and combined in viable pregnancy (p=0.035). In all patients who had a combination of systemic and local injection with methotrexate, treatment outcome was successful. Most common complication of methotrexate was liver toxicity, but not serious. Conclusion : Our results suggest that methotrexate treatment is effective as a therapeutic modality for early cervical pregnancy, but its administration route might be not related with efficacy. Furthermore, the combination of systemic and local intra-amniotic injection seems to be more effective.

류마티스관절염 동물모델에서 메토트렉세이트의 STAT3-TH17/STAT5-Treg Axis 조절을 통한 관절염의 치료효과

박은미 ( Eun Mi Park ),박미경 ( Mi Kyung Park ),이동건 ( Dong Gun Lee ),백승예 ( Seung Ye Baek ),우정원 ( Jung Won Woo ),곽승기 ( Seung Ki Kwok ),조미라 ( Mi La Cho ),박성환 ( Sung Hwan Park ) 대한류마티스학회 2013 대한류마티스학회지 Vol.20 No.2

Objective. Methotrexate is the first-line drug in treatment of rheumatoid arthritis (RA) exhibiting higher efficacy and better tolerability than most other DMARDs. To have a better understanding of the anti-arthritic mechanism of methotrexate, we investigated the effect of methotrexate on suppressing the autoimmune inflammatory and destructive arthritis in collagen-induced arthritis (CIA) mice. Methods. The effects of methotrexate on joint inflammation were assessed by clinical scoring and histologic analysis. Levels of cytokines and autoreactive antibodies were analyzed by immunohistochemistry and ELISA. The population of TH17 and Foxp3+ regulatory T (Treg) cells and phosphorylation of their critical transcription activators, STAT3 and STAT5, were examined by fluorescence microscopy and flow cytometry, respectively. Results. Treatment with methotrexate significantly alleviated joint inflammation and cartilage destruction in CIA. Serum levels of total immunoglobulins G, G1, G2a specific to type II collagen were also reduced considerably in methotrexate- treated mice. The drug inhibited the expression of proinflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-17 in arthritic joints ex vivo as well as by splenocytes in vitro. Moreover, methotrexate treatment resulted in reciprocal modulation of TH17 cells and Foxp3+ regulatory T (Treg) cells in spleen tissues, in which TH17 cells were decreased and Treg cells in number were increased. Subsequent analysis of CD4+T cells showed that phosphorylation of STAT3 was decreased whereas phosphorylation of STAT5 was increased in methotrexate-treated mice. Conclusion. Methotrexate treatment effectively suppressed autoimmune arthritis and restored homeostasis of the immune system by reciprocal regulation of TH17 and Treg cells in a mouse model of collagen-induced arthritis.

자궁경관 임신에서 자궁경관 흡입 소파술 및 국소 Methotrexate 주입술과 병합한 전신 Methotrexate의 단회요법과 다회요법의 비교

이일한 ( Il Han Lee ),한승수 ( Seung Su Han ),김동호 ( Dong Ho Kim ),이상훈 ( Sang Hoon Lee ) 대한산부인과학회 2008 Obstetrics & Gynecology Science Vol.51 No.9

목적: 자궁경관 임신에서 자궁경관 흡입 소파술및 국소 MTX주입과 병합한 전신 MTX의 단회요법과 다회요법의 효과를 비교하고자 하였다. 방법: 2000년1월에서 2006년 12월 사이 중앙대학교병원 산부인과에 내원하여 자궁경관 임신으로 진단받은 40명을 대상으로 하여 흡입소파술 및 국소적 MTX주입과 병합한 전신적 MTX 요법을 시행받은 환자들의 의무기록을 후향적으로 분석하였다. 단회요법은 MTX 1.0 mg/kg과 leucovorin 0.1 mg/kg을 1회씩 근주하였고 (Group 1, n=18), 다회요법은 MTX 1.0 mg/kg과 leucovorin 0.1 mg/kg을 4회 번갈아 근주하였다 (Group 2, n=22). 임상증상에 따라 적절한 시기에 국소흡입소파술 및 MTX 50 mg을 국소주입하였다. 치료시작 전 환자의 기초상태를 조사하였고 치료결과와 부작용 등을 비교분석하였다. 결과: 환자의 평균 나이는 28±2.8 vs 28.4±2.4세였고 진단시의 임신주수는 평균 49.4±8.3 vs 56.4±7.4일이었다. 진단 시의 β-hCG 농도는 3,242.2±189.2 vs 2,864.3±172.4 mIU/mL이었다. 단회요법군과 다회요법군간의 의미 있는 차이는 없었다. 치료 성공률은 단회요법군에서는 66.7% (12/18), 다회요법군에서는 95.5% (21/22)로 관찰되어 다회요법군에서 높은 성공률을 보였고 혈청 β-hCG가 감소되는 양상은 다회요법군에서 더욱 현격하였고 정상화 시기도 빠르게 관찰되었다. 부작용 발생빈도는 단회요법군에서 16.7% (3/18), 다회요법군에서 22.7% (5/22)로 다회요법군에서 약간 높았지만 경미하였다. 결론: 자궁경관 임신의 보존적 치료에서 흡입소파술및 국소 MTX 주입과 병합한 전신 MTX 단회요법과 다회요법은 안전하고 효과적인 치료법이다. 본 연구에서는 다회요법이 단회요법과 비교하여 중한 부작용 없이 더 효과적이었다. 향후 임상효과와 부작용, 임신율 등을 평가하기 위한 대단위 연구가 필요하다고 사료된다. Objective: To compare the clinical efficacy of systemic single-dose and multiple-dose methotrexate (MTX) regimens combined with aspiration curettage and local MTX in treatment of cervical pregnancy. Methods: Between January 2000 and December 2006, 40 cases of cervical pregnancies were treated with combined systemic and local methotrexate therapy at the Department of Obstetrics and Gynecology, Chung-Ang University Hospital. The patients were treated with either of the two regimens:a) Single dose regimen (Group 1): 1 mg/kg of intramuscular MTX with leucovorin treatment (18 cases).b) Multiple dose regimen (Group 2): four doses of 1 mg/kg of intramuscular MTX with leucovorin treatment (22 cases). Combination treatment with aspiration curettage and local MTX injection were done in all patients after clinically indicated.Baseline characteristics, regimens used and number of doses administered, treatment outcome, presence and severity of side effects were analyzed. Results: The mean age of the patients was 28±2.8 vs 28.4±2.4 years and gestational age at diagnosis was 49.4±8.3 vs 56.4±7.4 days. Initial level of serum β-hCG ranges was 3,242.2±189.2 vs 2,864.3±172.4 IU/mL. There were no significant differences in initial β-hCG values, gestational age between single-dose group and multiple-dose groups, The overall success rate of MTX management for an ectopic pregnancy was 82.5% (33/40) with 66.7% (12/18) and 95.5% (21/22) for single and multiple dose groups respectively. Multiple dose group had more rapid downward trend of hCG and more rapid stabilization. Side effects occurred in 20% (8/40) of the study group with 16.7% (3/18) and 22.7% (5/22) for single and multiple dose groups respectively but not significant. Conclusion: Systemic single-dose and multiple-dose MTX regimen combined with local MTX injection with aspiration curettage and local MTX injection is an effective and safe treatment modality for cervical pregnancies. In our study, multiple-dose regimen treatment is more effective, mild side effects comparable with single dose regimen. Further comparative studies with long-term follow-up are needed to evaluate reproductive outcome and to reduce side effects.

A Rare Case of Methotrexate Induced Pancreatitis in Ectopic Pregnancy

Jiwon Choi,Mina Kang,Young Min Hur,Young Ju Kim,Sunwha Park Ewha Womans University School of Medicine 2023 EMJ (Ewha medical journal) Vol.46 No.2

Ectopic pregnancy (EP) refers to blastocyst implantation outside the uterine endometrium. EP is major cause of maternal morbidity and mortality. Treatment options include surgery, medical therapy with methotrexate, or expectant management. Methotrexate is the primary regimen used in cases of early, unruptured ectopic pregnancies. Most side effects of methotrexate are minor, including nausea, vomiting, abdominal discomfort, and photosensitive skin reaction. Serious side effects, including bone marrow suppression, and pulmonary fibrosis, are invariably observed when methotrexate is administered in high doses with frequent dosing intervals, in chemotherapeutic protocols for malignancy. These side effects are uncommon with the doses used to treat ectopic pregnancies. Since cases of methotrexate-induced pancreatitis are rare, we report a case of pancreatitis in a patient with EP treated with methotrexate and expect to consider pancreatitis as a side effect of methotrexate in a patient with upper abdominal pain undergoing methotrexate chemotherapy.

The Advantage of Cyclosporine A and Methotrexate Rotational Therapy in Long-Term Systemic Treatment for Chronic Plaque Psoriasis in a Real World Practice

( Chong Won Choi ),( Bo Ri Kim ),( Jungyoon Ohn ),( Sang Woong Youn ) 대한피부과학회 2017 Annals of Dermatology Vol.29 No.1

Background: Psoriasis is a chronic inflammatory disease. In the treatment of psoriasis, cyclosporine is commonly prescribed systemic agents. However, long-term use of cyclosporine is not recommended because of side effects such as nephrotoxicity or hypertension. Objective: To ascertain the improved safety of rotational therapy using cyclosporine and methotrexate, we investigated the frequency of abnormal results in laboratory test after long term rotational therapy using cyclosporine and methotrexate. Methods: From January 2009 to June 2014, patients who were treated with cyclosporine or methotrexate were enrolled. The clinical data and usage of medications were reviewed. Laboratory tests were conducted before starting the treatment and regularly follow- up. The occurrences of any laboratory abnormalities during the treatments were investigated. Results: A total of 21 psoriatic patients were enrolled. The mean of medication period and cumulative dose of cyclosporine and methotrexate were 497.81±512.06 days and 115.68±184.34 g in cyclosporine and 264.19±264.71 days and 448.71±448.63 mg in methotrexate. Laboratory abnormalities were found in total two patients after rotational therapy: two patients (9.5%) in aspartate aminotransferase/alanine aminotransferase and one patient (4.8%) in uric acid. No laboratory abnormalities were found in renal function test. Conclusion: We found that the rotational approaches using cyclosporine and methotrexate reduced the possibility of the development of nephrotoxicity. In addition to other advantage such as quick switching from one agent to another, the rotational therapy using cyclosporine and methotrexate can minimize the adverse events during the systemic treatment of chronic plaque psoriasis. (Ann Dermatol 29(1) 55∼60, 2017)

Design, synthesis of methotrexate-diosgenin conjugates and biological evaluation of their effect on methotrexate transport-resistant cells

( Bangrong Cai ),( Aimei Liao ),( Kyung-ku Lee ),( Jae-sam Ban ),( Hyun-sam Yang ),( Young Jun Im ),( Changju Chun ) 전남대학교 약품개발연구소 2016 약품개발연구지 Vol.25 No.-

A series of methotrexate-diosgenin conjugates was designed and synthesized to enhance the passive internalization of methotrexate (MTX) in to transport-resistant cells. The inhibitory effects of these con-jugates on dihydrofolate reductase (DHFR), and their anti-proliferation behaviors against a transport-resistant breast cancer cell line, MDA-MB-231, were investigated. All of the synthesized conjugates retained an ability to inhibit DHFR after the diosgenin substitution. The MTX conjugates were much more potent against methotrexate-resistant MDA-MB-231 cells than MTX. Conjugate 18, containing a disulfide bond, exhibited the most potent anti-proliferative and DHFR inhibitory effects (IC₅₀=4.1 μM and 17.21 nM, respectively). Anti-proliferative activity was higher in the conjugate with a longer space linker (conjugate 21) than those with shorter linkers (conjugates 19 and 20). These results suggest that dios-genin conjugation of MTX may be an effective way to overcome its transport resistance in cancer cells. ⓒ 2016 Elsevier Inc. All rights reserved.

척수강내 Methotrexate과량 투여의 치료

남은미,이현경,이순남 大韓血液學會 1997 大韓血液學會誌 Vol.32 No.1

백서에서 Methotrexate에 의하여 유발된 장관장벽손상 및 장내세균전위와 중량 변화에 대한 글루타민의 효과

김은정,김정욱,Kim, Eun-Jeong,Kim, Jeong-Wook 대한약학회 2007 약학회지 Vol.51 No.1

The aim of this study was to examine whether administration of glutamine are able to prevent the methotrexate induced gut barrier damage, bacterial translocation, and weight changes. The animals with glutamine were fed with L-glutamine (1.2 and 2.4 mg/kg/day) for 7 days before methotrexate administration (20 mg/kg orally). 48 hour after methotrexate administration, intestinal permeability were measured for an assessment of the gut barrier dysfunction. Also, enteric aerobic bacterial counts, number of gram-negatives in mesenteric lymph node (MLN), liver spleen, kidney and heart were measured for an assessment of the enteric bacterial number and bacterial translocation. Amounts of food intake, body weight changes and organ weight changes of liver spleen, kidney and heart were measured. Methotrexate administration caused body and liver weight loss regardless amounts of food intakes. Methotrexate induced increasing intestinal permeability, enteric bacterial undergrowth and bacterial translocation to MLN, liver and spleen, but not kidney and heart. The supplements with glutamine reduced the intestinal permeability bacterial translocation, and not influences enteric bacterial number, and body and liver weight changes. This study suggested that glutamine might effectively reduce methotrexate induced intestinal damage and bacterial translocation, but not influence body and organ weight loss.