Dtsch Med Wochenschr 2000; 125(47): 1435-1438
DOI: 10.1055/s-2000-8490
Der Arzneistoff
© Georg Thieme Verlag Stuttgart · New York

Methotrexat

Further Information

Publication History

Publication Date:
31 December 2000 (online)

Methotrexat (MTX) wird seit Ende der 40er Jahre in der Chemotherapie maligner Erkrankungen verwandt. Seit den 80er Jahren findet MTX als Basistherapeutikum der rheumatoiden Arthritis (RA) eine zunehmende Verbreitung [1]. Das Wissen über Nutzen und Risiko einer langfristigen Behandlung und über den molekularen Wirkmechanismus nimmt stetig zu. Chemisch ist MTX der Folsäure nahe verwandt [Abb. 1].

Literatur

  • 1 Songsiridej N, Furst D E. Methotrexate - the rapidly acting drug.  Bailliere’s Clin Rheumatol. 1990;  4 575-593
  • 2 Cronstein B N. Molecular therapeutics. Methotrexate and its mechanism of action.  Arthritis Rheum. 1996;  39 1951-1960
  • 3 Yukioka K, Wakitani S, Yukioka M, Furumitsu Y, Shichikawa K, Ochi T, Goto H, Matsui-Yuasa I, Otani S, Nishizawa Y, Morii H. Polyamine levels in synovial tissues and synovial fluids of patients with rheumatoid arthritis.  J Rheumatol. 1992;  19 689-692
  • 4 Flescher E, Bowlin T L, Ballester A, Houk R, Talal N. Increased polyamines may downregulate interleukin 2 production in rheumatoid arthritis.  J Clin Invest. 1989;  83 1356-1362
  • 5 Nesher G, Moore T L. The in vitro effects of methotrexate on peripheral blood mononuclear cells: Modulation by methyl donors and spermidine.  Arthritis Rheum. 1990;  33 54-959
  • 6 Baggot J E, Vaughn W H, Hudson B B. Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5‘-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide.  Biochem J. 1986;  236 193-200
  • 7 Cronstein B N, Eberle M A, Gruber H E, Levin R I. Methotrexate inhibits neutrophil function by stimulatin adenosine release from connective tissue cells.  Proc Natl Acad Sci USA. 1991;  88 2441-2445
  • 8 Cronstein B N, Daguma L, Nichols D, Hutchison A J, Williams M. The adenosine/neutrophil paradox resolved: Human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 - generation, respectively.  J Clin Invest. 1990;  85 1150-1157
  • 9 Cronstein B N, Levin R I, Philips M, Hirschhorn R, Abramson S B, Weissmann G. Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors.  J Immunol. 1992;  148 2201-2206
  • 10 Parmely M J, Zhou W W, Edwards CK I II, Borcherding D R, Silverstein R, Morrison D C. Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-α production and protect mice against endotoxin challenge.  J Immunol. 1993;  151 389-396
  • 11 Bouma M G, Stad R K, van den Wildenberg F AJM, Buurman W A. Differential regulatory effects of adenosine on cytokine release by activated human monocytes.  J Immunol. 1994;  153 4159-4168
  • 12 Sajjadi F G, Takabayashi K, Foster A C, Domingo R C, Firestein G S. Inhibition of TNF-α expression by adenosine: Role of A3 adenosine receptors.  J Immunol. 1996;  156 3435-3442
  • 13 Le Moine O, Stordeur P, Schandene L, Marchant A, De Groote D, Goldman M, Deviere J. Adenosine enhances IL-10 secretion by human monocytes.  J Immunol. 1996;  156 4408-4414
  • 14 Boyle D L, Sajjadi F G, Firestein G S. Inhibition of synoviocyte collagenase gene expression by adenosine receptor stimulation.  Arthritis Rheum. 1996;  39 923-930
  • 15 Marrill J T, Shen C, Schreibman D, Coffey D, Zakharenko O, Fisher R, Lahita R G, Salmon J, Cronstein B N. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: A mechanism for methotrexate-induced nodulosis in rheumatoid arthritis.  Arthritis Rheum. 1997;  40 1308-1315
  • 16 Falcini F, Taccetti G, Ermini M, Trapani S, Calzolari A, Franchi A, Cerinic M M. Methotrexate-associated appearance and rapid progression of rheumatoid nodules in sysemic-onset juvenile rheumatoid arthritis.  Arthritis Rheum. 1997;  40 175-178
  • 17 Segal R, Caspi D, Tishler M, Fishel B, Yaron M. Accelerated nodulosis and vasculitis during methotrexate therapy for rheumatoid arthritis.  Arthritis Rheum. 1988;  31 1182-1185
  • 18 Wagener P. Die Häufigkeit einer akralen Nodulosis unter Methotrexat-Langzeittherapie bei Patienten mit entzündlich-rheumatischen Erkrankungen. Z.  Rheumatol. 1994;  53 346-350
  • 19 Herman R A, Veng-Pedersen P, Hoffman J, Koehnke R, Furst D E. Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients.  J Pharm Sci. 1989;  78 165-171
  • 20 Lebbe C, Beyeler C, Gerber N J, Reichen J. Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis.  Ann Rheum Dis. 1994;  53 475-477
  • 21 Claudepierre P, Urien S, Chevalier X, Chassany O, Larget-Piet B, Tillement J -P. Methotrexate serum binding in rheumatoid arthritis.  Int J Clin Pharmacol Ther. 1994;  32 113-115
  • 22 Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin.  Pharmacokinet. 1996;  30 194-210
  • 23 Kremer J M, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates.  Arthritis Rheum. 1986;  29 832-835
  • 24 Schilsky R L. Methotrexate: An effective agent for treating cancer and building careers. The polyglutamate era.  Stem cells. 1996;  14 29-32
  • 25 Pourel J, Guillemin F, Fener P, Webanck L, Bene M C, Delorme N. Delayed methotrexate pneumonitis in rheumatoid arthritis.  J Rheumatol. 1991;  18 303-304
  • 26 Nuernberg B, Koehnke R, Solsky M, Hoffman J, Furst D E. Biliary elimination of low-dose methotrexate in humans.  Arthritis Rheum. 1990;  33 898-902
  • 27 American College of Rheumatology ad hoc Committee on Clinical Guidelines . Guidelines for the management of rheumatoid arthritis.  Arthritis Rheum. 1996;  39 713-722
  • 28 Felson D T, Andersson J J, Meenan R F. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: Results of two metaanalyses.  Arthritis Rheum. 1990;  33 1449-1461
  • 29 Boffa M J, Chalmers R JG. Methotrexate for psoriasis.  Clin Exp Dermatol. 1996;  21 399-408
  • 30 Kaye S A, Isenberg D A. Treatment of polymyositis and dermatomyositis.  Br J Hosp Med. 1994;  52 463-468
  • 31 Villalba L, Adams E M. Update on therapy for refractory dermatomyositis and polymyositis.  Curr Opin Rheumatol. 1996;  8 544-551
  • 32 Sneller M C, Hoffman G S, Talar-Williams C, Kerr G S, Hallahan C W, Fauci A S. An analysis of fourty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone.  Arthritis Rheum. 1995;  38 608-613
  • 33 Hoffman G S, Leavitt R Y, Kerr G S, Rottem M, Sneller M C, Fauci A S. Treatment of glucocorticoid-resistant or relapsing Takayasu arteriitis with methotrexate.  Arthritis Rheum. 1994;  37 578-582
  • 34 Van den Hoogen F HJ, Boerbooms A MT, Swaak A JG, Rasker J J, van Lier H JJ, van de Putte L BA. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: A 24 week randomized double blind trial, followed by a 24 week observational trial.  Br J Rheumatol. 1996;  35 364-372
  • 35 Schnabel A, Herlyn K, Burchardi C, Reinhold-Keller E, Gross W L. Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis.  Rheumatol Int. 1996;  15 195-200
  • 36 Schnabel A, Reinhold-Keller E, Gross W L. Risikoprofil von niedrigdosiertem Methotrexat in der Therapie der chronischen Polyarthritis.  Dtsch Med Wschr. 1992;  117 1116-1121
  • 37 Walker A M, Funch D, Dreyer N A, Tolman K G, Kremer J M, Alarcon G S, Lee R G, Weinblatt M E. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis.  Arthritis Rheum. 1993;  36 329-335
  • 38 Hilliquin P, Renoux M, Perrot S, Puechal X, Menkes C J. Occurence of pulmonary complications during methotrexate therapy in rheumatoid arthritis.  Brit J Rheumatol. 1996;  35 441-445
  • 39 Golden M R, Katz R S, Balk R A, Golden H E. the relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis.  J Rheumatol. 1995;  22 1043-1047
  • 40 Gutierrez-Urena S, Molina J F, Garcia C O, Cuellar M L, Espinoza L R. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis.  Arthritis Rheum. 1996;  39 272-276
  • 41 Schröder J O, Schwab U M, Schnabel A, Asbeck F, Zurborn K H, Gross W L, Euler H H. Häufung MTX-assoziierter Zytopenien bei älteren Patienten.  Dtsch Ärzteblatt. 1996;  93 321-322
  • 42 Bleyer W A. Methotrexate induced lymphoma? (Editorial).  J Rheumatol. 1988;  25 404-407
  • 43 Sibilia J, Cazals-Hatem D, Liote F, Balandraud N, Tebib J, Mariette X. Increased risk of Hodgkin’s disease but not of non-Hodgkin’s lymphoma in patients with rheumatoid arthritis treated with MTX. Results of a 3 year prospective study in France.  Arthritis Rheum. 1999;  42 S82
  • 44 Welch G N, Loscalzo J. Homocysteine and atherothrombosis.  New Engl J Med. 1998;  338 1042-1050
  • 45 Morgan S L, Baggot J E, Vaughn W H, Austin J S, Veitch T A, Lee J Y, Koopman W J, Krumdieck C L, Alarcon G S. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis.  Ann Intern Med. 1994;  121 833-841
  • 46 Shiroky J B, Neville C, Esdaile J M, Choquette D, Zummer M, Hazeltine M, Bykerk V, Kanji M, St-Pierre A, Robidoux L, Borque L. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis: Results of a multicenter randomized, double-blind, placebo-controlled trial.  Arthritis Rheum. 1993;  36 795-803
  • 47 Morgan S L, Baggott J E, Lee J Y, Alarcon G S. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention.  J Rheumatol. 1998;  25 441-446
  • 48 Van Meerten E, Verweij J, Schellens J HM. Antineoplastic agents. Drug interactions of clinical significance.  Drug Saf. 1995;  12 168-182
  • 49 Groenendal H, Rampen F H. Methotrexate and trimethoprim-sulphamethoxazole - a potentially hazardous combination.  Clin Exp Dermatol. 1990;  15 358-360

Dr. med. F. Schröder

Abteilung Kardiologie und Angiologie Medizinische Hochschule Hannover

Carl-Neuberg-Straße 1

30625 Hannover

Prof. Dr. med. J. O. Schroeder

2. Medizinische Klinik und Poliklinik der Christian-Albrechts-Universität

Chemnitzstraße 33

24116 Kiel

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