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with a combinationof syntheticantimalarials(83 cases).Presse Med 1969;77:1995. 14. SugiharaH. Therapeutic result using aurothioglucoseon bronchial asthma. Diagn Treat 1965;53(4):750. 15. Fairris GM, Dewhurst AG, White JE, Campbell MJ. Methotrexate dosage in patients over 50 with psoriasis. Br Med J 1989;289:801-2. 16. Rose CD, Singsen BH, Eichenfield AH, et al. Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 1990;117:653-9. 17. WallaceCA, Bleyer WA, Sheny DD, et al. Toxicity and serum level of methotrexatein children with juvenile rheumatoid arthritis. Arthritis Rheum 1989;32:677-81. 18. Healey LA. The current status of methotrexate in rheumatic diseases.Bull Rheum Dis 1986;36(4):l-10.

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19. Bleyer WA. Clinical pharmacologyand therapeuticdrug monitoring of methotrexate. Am Assoc Clin Chem 1985;6:1-14. 20. Willkens RF. Reappraisal of the use of methotrexate in rheumatic disease.Am J Med 1983;75(suppl4B):19-25. 21. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthmaand after bronchial provocation. Am Rev Respir Dis 1989;139:806-17. 22. Finucane KE, Greville HW, Brown PJE. Irreversible airflow obstruction: evolution in asthma. Med J Aust 1985;142: 602-4. 23. Wilske KR, Healey LA. Why save our best drugs for last? Contemp Int Med 1990;July/August:8-9.

in bronchial

asthma -

Eduardo Calderbn, MD,* Ronald G. Coffey, PhD,** and Richard F. Lackey, MD*** Tampa, Flu.

MTX, a folic acid antagonist, has antineoplastic activity basedon the inhibition of DHFR, which reduces folate to tetrahydrofolate. Inhibiting the formation of tetrahydrofolate causesa major disruption of cellular metabolism by inducing an acute intracellular deficiency of folate coenzymes, particularly in transmethylation pathways. The de novo synthesisof purine nucleotidesandof thymidylate ceaseswith subsequentinterruption of the synthesisof DNA andRNA (as well as other vital metabolic reactions).’ MTX has been used in high doses (50 to 150 mg/week) as a cytotoxic agent in treatment of neoplasms. Lower dosages(5 to 25 mg/week) have been an effective treatment in inflammatory diseases,such as psoriatic arthritis, RA, polymyositis, and systemic lupus erythematosus. MTX has also been effective and safe in low doses(7.5 to 50 mg/ week) for severe asthmaas an adjunct to glucocorticoids. Although the mechanism of action of MTX in asthmahas not been established, it is unlikely that it dependson inhibition of DHFR, given that (1) it reFrom the *,***Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida College of Medicine; Section of Allergy and Immunology, JamesA. Haley Veterans Administration Hospital; and **Department of Pbarmacology and Therapeutics, College of Medicine, Tampa, Fla. Supportedin partby Veteran Affairs ResearchFunds. Reprint requests:Richard F. Lackey, MD, ResearchService (151), Bldg. 2, Rm. 208, James A. Haley Veterans Administration Hospital, 13000Bruce Downs Blvd., Tampa, FL 33612. l/1/30305

274

Abbreviations used

MTX: DHFR: PMNL: RA: LTB,: EOS: IL- 1:

Methotrexate Dihydrofolatereductase Polymorphonuclear leukocyte Rheumatoidarthritis LeukotrieneB, Eosinophil Interleukin-1

tains its anti-inflammatory action at doses of 15 mg/ week evenafter supplementationwith folinic acid (1 mg of folinic acid per 1 mg of MTX)’ and (2) DHFR is either absent or is present at very low concentrations in leukocytes,3 which are the major cell types in the inflammation of chronic asthma, and (3) low-dose MTX does not causeleukopenia. Alternatively, since asthmais an inflammatory disease, the following pharmacologic actions of MTX, observed in the laboratory and also in patients with psoriasisor RA treated with low dosesof MTX, may explain its mechanismof action in asthma: (1) inhibition of chemotaxis of PMNLs,“~ (2) inhibition of activity of IL-1,9 and (3) inhibition of histamine release by basophils.lo EVIDENCE AND COMMENTS Inhibition of chemotaxis of PMNLs

Temowitz and Herlin4 studied chemotaxis of PMNLs and monocytesin three groups of individuals: (1) 15 patients with psoriasis receiving long-term

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88 2

treatment (mean, 3 years) with MTX at dosesof 7.5 to 15 mg/week, (2) 10 patients with psoriasis with no treatment, and (3) 21 healthy control subjects. A profound depression of PMNLs and monocyte chemotaxis was observed in group “a” within the first 48 hours after the intake of MTX, but the chemoractic activity recovered its initial values during the 7 days after MTX was stopped.O’Callaghan et al5 compared PMNL chemotaxis migration in 10 patients with RA who received a single dose of MTX (10 mg) with a matched group of patients with RA who did not receive MTX and with four healthy, untreated control subjects. There was significant inhibition of PMNL chemotaxis only in the group receiving MTX. Waldsdorfer et a1.6studied the chemotactic activity of peripheral PMNLs in six patients with psoriasis treated with MTX, 20 mg. Chemotactic activity was depressed in vitro when the PMNLs were stimulated with the chemoattractants, C5a and N-forrnyl-Lmethionyl-L-leucyl-phenylalanine. The reduced chemotaxis occurred within the first 24 hours after MTX administration, persistedthe following 24 hours, and returned to normal after 7 days. An inhibition of PMNL migration reducesthe number of EOSs,basophils, and neutrophils at the inflammation site that could account, at least in part, for MTX action in asthma. EOSs are major cellular participants in the pathophysiology of asthma, and basopmldegranulation, mediatedby IgE or other stimuli, results in releaseof histamine, leukotrienes, chemotactic peptides, and other potent chemical mediators of inflammation, Basophils have an active role in both early and late-phase asthmatic responses, and neutrophils accumulate in many tissues that are the sites of acute IgE-dependent allergic reactions. It is possible that neutrophils contribute to these reactions and that a network of mediators, releasedby the IgEantigen interaction, results in the later accumulation of inflammatory cells. Van de Kerkhof et a1.7applied a solution of LTB, to selected areas of the backs of three patients with psoriasis receiving long-term MTX therapy (10 to 12.5 mg/ week), of three untreatedpatients with psoriasis, and of three control subjects. The sites of the three dosesof LTB, (10, 50, and 500 ng) were each covered with an impermeable dressing that was removed after 24 hours: at that time, a biopsy was obtained from each site. There was no appreciabledifference in the degreeof PMNL infiltration of normal and untreatedpatients with psoriasis, but there was a significant decreasein patients treatedwith MTX. The PMNL infiltrations were significantly reduced in MTX-treated patients, presumablybecauseof a direct effect of MTX. The administration of MTX to mice in doses that would be equivalent to 9 mgl week in

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275

man induced significant inhibition of LTB,- and C5ainduced neutrophil chemotaxis.’ MTX may reduce other actions of LTBI, such as chemotaxis of mononuclear leukocytes and, to a lesser degree, of EOSs, adherenceof neutrophils to endothelial surfaces, aggregation and degranulation of neutrophils, and vascular permeability. The suppressionof these actions may also contribute to MTX mechanismsof action in asthma, since LTB, appearsto play an important role in the pathophysiology of asthma. Inhibition

of IL-I activity

Segal et a1.9studied the effects of MTX on the production and activity of IL-l from human mononuclear cells obtainedfrom nine patients with RA who had received 10 to 15 mg/week of MTX. MTX inhibited IL- 1 activity without affecting IL- 1 production or secretion. Since IL-1 has an important role in the processof inflammation, the inhibition of its activity could be one of the mechanismsby which MTX exerts its beneficial clinical effect in asthma and other inflammatory diseases. Although the role of cytokines, such as IL-l, in allergic asthma has received considerable attention becauseof its potent proinflammatory activities, only a limited numberof studiesare available. Studieshave been made of the presenceof this cytokine in bronchoalveolar lavage fluid and of the capability of alveolar macrophagesand human bronchial epithelial cells to produceIL- 1. The paucity of studies,however, makes it difficult to ascertain the potential role of cytokines in lung inflammation. Key to the IL-l action on several of the inflammatory cell types is its stimulation of arachidonic acid releaseand metabolism by either the cyclooxygenase or the lipoxygenase pathway to yield prostaglandins or leukotrienes, respectively.” In vitro, IL-l induces the releaseof mediators from human basophils, mast cells, and endothelial cells, facilitates the influx of granulocytes at the tissue sites through the expression of adhesionmolecules,promotesthe synthesisof other cytokines with inflammatory properties, and potentiates the effects of cytokines on T cells. Inhibition

of basophil

histamine

release

Nolte and Skov” studied histamine releasedby human basophils from whole blood from four healthy control subjects, four atopic patients, and 10 patients with breast cancer under treatment with cyclophosphamide, MTX, and 5-fluorouracil. The patients had been administered neither radiotherapy nor chemotherapy immediately before the study. The patients received40 mg/ m2of MTX asa bolus injection. Their basophils were preincubatedfrom 1 to 20 hours alone or in the absenceor presenceof MTX or MTX plus

276 Calderbn et al.

folinic acid. After preincubation, the basophils were stimulated with anti-IgE, allergensor the calcium ionophore A23187 plus 25 rig/ml of 12-O-tetradecanoylphorbol 13-acetate.The exposure of human basophils to MTX and folinic acid for >9 hours leads to a loss of the histamine-releaseresponseregardless of which stimulus is used. Nolte and Skov concluded that MTX, with or without the addition of folinic acid, is a potent inhibitor of histamine release. Although the authors used cytotoxic dosesand observed 100% inhibition at serum concentrations of 500 kg/ml of MTX, evensubmicrogramconcentrations(0.5 kg/ml) produced significant inhibition of histamine release. Histamine induces someof the inflammatory changes characteristic of asthma and may contribute to bronchomotor tone in bronchial asthma. CONCLUSION The use of folinic acid with low-dose MTX of arthritic patients did not alter the effectivenessof MTX, suggestingthat the major mechanismof action of lowdose MTX is not related to the inhibition of DHFR’ or hematopoiesis.8Accordingly, MTX at low dose in the treatment of asthma is also probably not related to inhibition of DHFR. There has been no evidence of a role for this enzyme in smooth muscle contraction, cellular infiltration, mucussecretion, and airway inflammation and edema. It is more likely that the action of MTX in severe asthma results, at least in part, from its capacity to inhibit attraction of PMNLs and other responsesto LTB, and IL- 1. Its efficacy may also be partly due to inhibition of histamine release from basophils and, possible, mast cells.

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REFERENCES 1 Calabresi P, Parks RE. Chemotherapy of neoplastic diseases. In: Gilman A, Goodman LS, Rall TW, Murad F, eds. Goodman & Gilman’s the pharmacologic basis of therapeutics. 7th ed. New York: Macmillan Publishing, 1985: 1264. 2 Buckley LM, Cooper SM, Vacek PM. The use of leucovorin after low-dose methotrexate in patients with rheumatoid arthritis [Abstract]. Arthritis Rheum 1988;31:R3. 3. The erythrocyte and iron metabolism: leukocyte composition and metabolism. In: White A, Handler P, Smith EL, eds. Principles of biochemistry. 5th ed. New York: McGraw-Hill, 1973:876. 4. Temowitz T, Herlin T. Neutrophil and monocyte chemotaxis in methotrexate-treated psoriasis patients. Act Dennatol Venemol (Stockh) 1985;12O(suppl):23-6. 5. O’Callaghan JW, Forrest MJ, Brooks PM. Inhibition of neutrophil chemotaxis in methotrexate-treated rheumatoid arthritis patients. Rheumatol Int 1988;8:41-5. 6. Walsdorfer U, Christophers E, Schroder JM. Methotrexate inhibits polymorphonuclear leukocyte chemotaxis in psoriasis. Br J Dermatol 1983;108:451-6. I. van de Kerkhof PC, Bauer FW, Maassen-de Grood RM. Methotrexate inhibits the leukotriene B,-induced intradermal accumulation of polymorphonuclear leukocytes. Br J Dermatol 1985;113:251a-5a. 8. Smlrez CR, Pickett WC, Bell DH, et al. Effect of low-dose methotrexate on neutrophil chemotaxis induced by leukotriene B, and complement C5a. J Rheumatol 1987;14:9-11. 9. Segal R, Mozes E, Yaron M, Tartakovsky B. The effects of methotrexate on the production and activity of interleukin- 1. Arthritis Rheum 1989;32:370-7. 10. Nolte H, Skov PS. Inhibition of basophil histamine release by methotrexate. Agents Actions 1988;23:173-6. 11. Mizel SB. The interleukins. FASEB J 1989;3:2379-88.

Methotrexate in bronchial asthma.

Mullarkey J. ALLERGY with a combinationof syntheticantimalarials(83 cases).Presse Med 1969;77:1995. 14. SugiharaH. Therapeutic result using aurothio...
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