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PubMed2004

Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.

BACKGROUND: Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. METHODS: In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. FINDINGS: Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. INTERPRETATION: The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.

Antirheumatic Agents↗

PubMed1987

Alteration of methotrexate metabolism in rats by administration of an elemental liquid diet. II. Reduced toxicity and improved survival using cholestyramine.

The administration of an elemental, chemically defined liquid diet to rats significantly enhanced gastrointestinal toxicity associated with methotrexate administration compared with rats fed a regular chow diet. Chemotherapy induced enteritis is potentially enhanced by the abrasive effect of bile acids on the susceptible cells of the small bowel mucosa. This study evaluated the interactions of methotrexate and cholestyramine in vitro. An additional goal was to evaluate the effects of cholestyramine on animal survival and drug pharmacokinetics in rats given an elemental, chemically defined liquid diet. In vitro binding of cholestyramine to methotrexate increased in a linear fashion at varying concentrations of both drugs in phosphate buffer solution (r greater than 0.84, P less than 0.001) and in bile which was not influenced by pH (range 5-8). The addition of cholestyramine to an elemental liquid diet significantly improved survival following methotrexate administration (20 mg/kg IP bolus) compared with rats fed an elemental liquid diet alone (P less than 0.02). Both elemental liquid diets, either with or without cholestyramine, delayed serum and biliary clearance of methotrexate up to 72 hours compared with rats fed a regular chow diet. However, rats fed an elemental liquid diet with added cholestyramine had significantly lower levels of methotrexate in serum from the systemic and portal venous circulation at 48 hours (P less than 0.03) and in bile at 48 (P less than 0.02) and 72 hours (P less than 0.05) following methotrexate administration. The addition of cholestyramine to an elemental liquid diet improves survival and reduces gastrointestinal toxicity following methotrexate administration, by binding methotrexate in bile and reducing the delay in systemic clearance of the drug. By binding to intraluminal bile acids, cholestyramine may also have a locally protective effect on the mucosal cells of the small intestine following methotrexate administration. Cholestyramine may be of clinical benefit in patients receiving high-dose methotrexate regimens as an adjunct to leucovorin rescue.

Animals↗

PubMed2005

Methotrexate for induction of remission in refractory Crohn's disease.

BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, approximately 20% of patients who respond relapse when steroids are withdrawn and become steroid dependent (Binder 1985). Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine/6MP therapy. The evidence for its effectiveness has not been subjected to a systematic review. OBJECTIVES: To conduct a systematic review of the evidence for effectiveness of methotrexate for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. SEARCH STRATEGY: A computer-assisted search of MEDLINE and EMBASE for relevant studies published in English, French, Spanish, Italian and German between 1966 and July 2004. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. The Cochrane Controlled Trials Register and the IBD Review Group Specialized Trials Register were also searched. SELECTION CRITERIA: Randomized controlled trials involving patients of age > 17 years with refractory Crohn's disease defined by conventional clinical, radiological and endoscopic criteria, which was categorized as being active (Crohn's disease activity index >150). DATA COLLECTION AND ANALYSIS OUTCOME MEASURES: The outcome measure was the rate of induction of remission and complete withdrawal from steroids in the treatment and control groups after > 16 weeks of treatment. A secondary outcome was induction of remission with reduction in steroid dose of at least 50%. Selection of trials: The results of the searches above were reviewed independently by two observers and relevant studies selected according to the predefined selection criteria. Any disagreement among reviewers was resolved by consensus. The same two reviewers assessed the methodological quality of each trial (details of randomization method, including whether intention-to-treat analysis was possible from the published data, number of patients lost to follow-up, and if a blinded outcome assessment was used). A standard data extraction form was used. Appropriateness of combining results: Trials were first reviewed to assess the clinical comparability of trial protocols and study populations. MAIN RESULTS: Five randomized trials were identified. The five studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to combine the data statistically. Three small studies which employed low doses of methotrexate orally showed no statistically significant difference between methotrexate and placebo/control medication treated patients. One small study which used a higher dose of intravenous/oral methotrexate showed no statistically significant difference between methotrexate and azathioprine. A larger study which employed a higher dose of methotrexate intramuscularly showed substantial benefit (number needed to treat, NNT=5). Adverse effects were more common with high dose intramuscular methotrexate therapy than with placebo. AUTHORS' CONCLUSIONS: There is evidence from a single large randomized trial on which to recommend the use of methotrexate 25 mg intramuscularly weekly for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Although adverse effects were more common than with placebo, they were not severe. There is no evidence on which to base a recommendation for use of lower dose oral methotrexate.

Crohn Disease↗

PubMed1983

Methotrexate polyglutamates in cultured human cells.

Cultured human fibroblasts accumulated methotrexate polyglutamates to levels far in excess of the dihydrofolate reductase binding capacity. After four days in methotrexate-free medium the intracellular drug level dropped by 70% but nearly 80% of the remaining methotrexate was in the form of polyglutamates. Reduced folates prevented the accumulation of polyglutamates and the effects of methotrexate on deoxyuridine incorporation into DNA and cell growth if present along with methotrexate from the beginning of the incubation. However, the reduced folates were less effective if added to cells after a long exposure to methotrexate alone. Thymidine, glycine, and adenosine (GAT) prevent methotrexate toxicity only if maintained in the incubation medium. However, preincubation with methotrexate and GAT permits continued synthesis and accumulation of polyglutamates so that when the GAT and methotrexate were removed, toxicity from the retained methotrexate polyglutamates could be expressed. (2,4-diamino-5-(3'4'-dichlorophenyl)-6 methyl pyrimidine (DDMP), an antifol that does not form polyglutamate derivatives, inhibited deoxyuridine incorporation into DNA as long as the DDMP remained in the culture medium. Compared to what was seen with longer exposures to methotrexate, removal of DDMP resulted in a greater reversal of the inhibition of deoxyuridine incorporation.

Adenosine↗

PubMed1983

Methotrexate metabolism by bone marrow cells from patients with leukemia.

Bone marrow cells from children with leukemia in remission and lymphoblasts and myeloblasts from children with early and late-stage leukemia all accumulated methotrexate during short-term culture and converted it to poly-gamma-glutamyl derivatives. This metabolism was time and dose-dependent. Leukemia cells from two patients with chronic myelocytic leukemia also synthesized methotrexate polyglutamates. Patients varied one from another in the quantity of total non-exchangeable methotrexate and methotrexate polyglutamates present in cells, but highest levels of each of these were seen in late acute lymphoblastic leukemia and in acute myeloblastic leukemia. Co-incubation of leukemic cells with both methotrexate and a ten-fold excess of folinic acid decreased accumulation and polyglutamylation of methotrexate to the same extent as achieved by reducing methotrexate concentration ten-fold. Co-incubation with methotrexate and a ten-fold excess of vincristine did not increase total cell methotrexate and methotrexate polyglutamates in leukemic cells in culture. Such an increase had been anticipated from earlier studies with other cells. Indeed, levels of methotrexate and its derivatives were modestly reduced.

Bone Marrow↗

PubMed1980

K+-induced alterations of energetics and exchange diffusion in the carrier-mediated transport of the folic acid analog, methotrexate, in Ehrlich ascites tumor cells.

The bidirectional fluxes and energetics of methotrexate transport in Ehrlich ascites tumor cells were profoundly altered in a high [K+], low [Na+] buffer (K+ buffer). Incubation of cells for 30 min in K+ buffer reduced influx by 27% and the efflux rate constant by 53%. This asymmetrical inhibition of bidirectional fluxes increased the net exchangeable intracellular methotrexate level per cell, but the actual intracellular methotrexate concentration at the steady state was similar to that in Na+ buffer, since the high [K+] caused an increase in intracellular water. Because cells exposed to K+ buffer were depolarized, the apparent electrochemical potential difference for methotrexate was markedly reduced. However, the steady-state intracellular methotrexate level was still related to the extracellular concentration by an absorption isotherm, indicating asymmetry in the bidirectional fluxes similar to that observed in Na+ buffer and thus predicting that transmembrane gradients would be produced at very low extracellular methotrexate concentrations. Glucose, which had little effect on bidirectional fluxes and reduced the steady-state level of methotrexate in Na+ buffer, stimulated influx, inhibited efflux and rapidly increased the steady state in K+ buffer similar to the effects of glucose in the presence of glucose in the presence of iodoacetate in Na+ buffer. Finally, cells exposed to k+ buffer exhibited trans-stimulation of [3H]methotrexate influx when loaded with non-labeled methotrexate, a phenomenon not observed in Na+ buffer. The results indicate that although methotrexate transport is not affected by transient changes in the cationic composition of the extracellular compartment, prolonged exposure of cells to a high [K+], low [Na+] environment markedly alters the physical properties of the cells and the transport parameters for methotrexdate and reveals characteristics of the methotrexate carrier system that are not evident in other buffer systems.

Animals↗

PubMed1987

Augmentation of methotrexate cytotoxicity in human colon cancer cells achieved through inhibition of thymidine salvage by dipyridamole.

In HCT 116 cells, a human colon cancer cell line, the levels of thymidine (0.6 microM) and hypoxanthine (9 microM) contributed to the tissue culture medium by the fetal bovine serum significantly reduced the growth inhibition and lethality produced by 0.1 microM methotrexate. Dipyridamole, an inhibitor of nucleoside transport, potentiated the growth inhibitory effects of methotrexate when the cells were grown in medium that was changed daily. However, when the medium was supplemented with dialyzed serum, methotrexate cytotoxicity was not increased by dipyridamole. Similarly, in cloning experiments, dipyridamole increased the cell killing produced by methotrexate. The potentiation of methotrexate toxicity produced by dipyridamole was mediated through inhibition of thymidine uptake. The uptake of 1 microM thymidine was inhibited 50% by 0.12 microM dipyridamole but neither hypoxanthine nor guanine uptake was decreased by dipyridamole (5 microM). As a result, the decrease in dTTP pools produced by methotrexate was augmented by dipyridamole. In contrast, dipyridamole did not influence the effect of methotrexate on ribonucleoside triphosphate pools. HCT 116 cells avidly salvaged low concentrations of thymidine, and methotrexate increased this capacity. Conversion of 0.11 microM thymidine to thymidine triphosphate was increased by 55%, from 16.6 to 25.7 pmoles/10(6) cells, following exposure to 1.0 microM methotrexate. Dipyridamole blocked this pool expansion. This study suggests that the salvage of physiological levels of thymidine may diminish the cytotoxic effects of methotrexate on human colon cancer cells. Inhibition of thymidine uptake by dipyridamole may be an effective strategy to increase the cytotoxicity of methotrexate.

Cell Line↗

PubMed2006

Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion.

OBJECTIVES: To develop clinical practice guidelines for the use of methotrexate in rheumatoid arthritis (RA), using the evidence-based approach and expert opinion. METHODS: A scientific committee used a Delphi procedure to select five questions, which formed the basis for developing recommendations. Evidence providing answers to the five questions was sought in the Cochrane databases, PubMed, and proceedings of meetings of the French Society for Rheumatology, European League Against Rheumatism, and American College of Rheumatology. Using this evidence, a group of rheumatologists developed and validated the recommendations. For each recommendation, the level of evidence and the extent of agreement among experts were specified. RESULTS: The recommendations were as follows: 1: The starting dosage for methotrexate in patients with RA should not be less than 10 mg/week and should be determined based on disease severity and patient-related factors; 2: When a patient with RA shows an inadequate response to methotrexate, the dosage should be increased at intervals of 6 weeks, up to 20 mg/week, according to tolerance and patient-related factors; 3: When starting methotrexate treatment in a patient with RA, preference should be given to the oral route. A switch to the intramuscular or subcutaneous route should be considered in patients with poor compliance, inadequate effectiveness, or gastrointestinal side effects; 4: At present, there is no evidence indicating that a change in methotrexate dosage is in order when a TNF antagonist is given concomitantly; 5: The investigations that are mandatory before starting methotrexate therapy in a patient with RA consist of a full blood cell count, serum transaminase levels, serum creatinine with computation of creatinine clearance, and a chest radiograph. In addition, serological tests for the hepatitis viruses B and C and a serum albumin assay are recommended. In patients with a history of respiratory disease or current respiratory symptoms, lung function tests with determination of the diffusing capacity for carbon monoxide are recommended; 6: Investigations that are mandatory for monitoring methotrexate therapy in patients with RA consist of full blood cell counts and serum transaminase and creatinine assays. These tests should be obtained at least once a month for the first 3 months then every 4-12 weeks; 7: Folate supplementation can be given routinely to patients treated with methotrexate for RA. In practice, a minimal dosage of 5 mg of folic acid once a week, at a distance from the methotrexate dose, is appropriate; 8: In the event of respiratory symptoms possibly related to methotrexate toxicity, the drug must be stopped and symptom severity evaluated. Should evidence of serious disease be found, the patient should be admitted immediately or advice from a pulmonologist should be obtained immediately. CONCLUSION: Recommendations about methotrexate therapy for RA were developed. These recommendations should help to improve practice uniformity and, ultimately, to improve the management of RA.

Arthritis, Rheumatoid↗

PubMed1998

Methotrexate effects on trophoblast and the corpus luteum in early pregnancy.

OBJECTIVE: Our purpose was to determine whether methotrexate affects the trophoblast or corpus luteum when administered for abortion. STUDY DESIGN: A randomized controlled trial was performed in women requesting an abortion up to 49 days' gestation. Twenty patients were treated with intramuscular methotrexate 50 mg/m2 (10 women) or 60 mg/m2 (10 women). Serum beta-human chorionic gonadotropin, progesterone, and 17-hydroxyprogesterone levels were determined at baseline and then serially after methotrexate administration for the first 24 hours, then every 24 hours for 7 days. On the seventh day misoprostol 800 microg was administered vaginally. RESULTS: Serum beta-human chorionic gonadotropin increased at a lower rate than occurs in normal pregnancy. Progesterone levels averaged 56.9 +/- 19.8 nmol/L at baseline and 45.5 +/- 20.5 nmol/L (P = .01) 1 week after methotrexate. Progesterone decreased in 16 women over the 7 days and increased in the other 4; these latter women all aborted after a single dose of misoprostol. Levels of 17-hydroxyprogesterone plateaued during the first day after methotrexate administration; both progesterone and 17-hydroxyprogesterone declined simultaneously between the third and fourth day after methotrexate. CONCLUSIONS: Methotrexate most likely primarily affects trophoblast production of human chorionic gonadotropin, as evidenced by a blunting of the expected increase in serum beta-human chorionic gonadotropin resulting in less support for the production of progesterone by the corpus luteum. However, changes in progesterone levels after methotrexate administration were inconsistent and are unlikely to represent the ultimate effect of methotrexate in abortion. The less-than-normal increase in serum beta-human chorionic gonadotropin levels after methotrexate administration is most likely a result of disruption of cytotrophoblast syncytialization. This disruption may be the true effect of methotrexate in destabilizing the implantation site of an early pregnancy.

17-alpha-Hydroxyprogesterone↗

PubMed2002

Methotrexate-induced apoptosis in hepatocytes after partial hepatectomy.

To investigate apoptosis induced by methotrexate in hepatocytes in vivo, rats received a single injection of methotrexate immediately after partial hepatectomy and apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and gel electrophoresis of DNA. Characteristic DNA fragmentation was obvious at 2 h and peaked at 4 h after partial hepatectomy with methotrexate injection. TUNEL-positive staining was observed in nuclei and nuclear fragments of hepatocytes in the methotrexate-injected liver (partial hepatectomy with methotrexate), with negligible background staining in the control (partial hepatectomy only) and in the methotrexate-injected normal (normal with methotrexate) rat liver. The involvement of the c-Jun N-terminal kinase (JNK) activator protein 1 (AP-1) pathway and p53 in apoptosis was also examined. The activity of JNK increased at 15 min and peaked at 1 h after partial hepatectomy. This increase was repressed by methotrexate injection. Western blot analysis showed that the levels of c-Fos and c-Jun protein expression, which increased at 1 h after partial hepatectomy, were also reduced by methotrexate. The levels of p53 protein were markedly increased after partial hepatectomy with methotrexate injection. The increase in p53 protein was followed by an up-regulation of p21(WAF1/CIP1) protein at 2 h after partial hepatectomy. These results suggested that the inhibition of the JNK-AP-1 pathway and concurrent up-regulation of p53 and p21(WAF1/CIP1) were involved in hepatocyte apoptosis induced by partial hepatectomy with methotrexate.

Animals↗

PubMed2002

A synthetic analog of prostaglandin E(1) prevents the production of reactive oxygen species in the intestinal mucosa of methotrexate-treated rats.

Administration of methotrexate to rats results in severe enterocolitis and death. Previous our studies showed that a synthetic analog of prostaglandin E(1), OP-1206 [17S, 20-dimethyl-trans-Delta(2)-prostaglandin E(1)] ameliorated the anticancer agent-induced enterocolitis of rats. In the current study, we have focused on the biochemical effect of OP-1206 on the methotrexate-induced intestinal inflammation implicating reactive oxygen species (ROS). Methotrexate (15 mg/kg body weight) was orally administered to rats once daily for 5 days. OP-1206 (0.5 microg/kg body weight) was orally administered to rats twice a day for 5 days. On the 6th day, the chemiluminescence from the jejunum was measured to evaluate the generation of ROS. Spontaneous chemiluminescence from the jejunum of the methotrexate-treated rats increased significantly, compared with the control. Luminol-enhanced chemiluminescence from inflamed mucosal scrapings from the jejunum of the methotrexate-treated rats indicated more remarkable enhancement than the control rats. The treatment of OP-1206 with methotrexate showed significantly lower chemiluminescence of both the jejunum and mucosal scrapings than those of the methotrexate-treated rats. The alkaline phosphatase (ALP) activity, as a marker of small intestinal differentiation, in the intestinal mucosa of the methotrexate-treated rats decreased remarkably, but that of the methotrexate and OP-1206-treated rats was significantly higher than that of the methotrexate-treated rats. Thus, OP-1206 may possibly help the anticancer chemotherapy by protecting the small intestine from the methotrexate-induced damage.

Alprostadil↗

PubMed2000

Methotrexate use in rheumatoid arthritis. A Clinician's perspective.

Aminopterine, a precursor of methotrexate (MTX), was first used for the treatment of rheumatoid arthritis (RA) in 1951 [Gubner, R., 1951. Therapeutic suppression of tissue reactivity: I. Comparison of the effects of cortisone and aminopterin. Am. J. Med. Sci. 221, 169-175; Gubner, R., August, S., Ginsberg, V., 1951. Therapeutic suppression of tissue reactivity: II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221, 176-182.]. Corticosteroids, and to some extent cyclophosphamide, took MTX out of the rheumatologist's armamentarium until the late 1970s-early 1980s when the toxic profile of these compounds became apparent. By the mid 1980s, four randomized clinical trials (RCTs) had proven beyond doubt the beneficial effects of MTX when administered to patients with established disease who had failed to respond to other compounds such as gold salts and D-penicillamine [Thompson, R.N., Watts, C., Edelman, J., Esdaile, J., and Russell, A.S., 1984. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J. Rheumatol. 11, 760-763; Andersen, P.A., West, S.G., O'Dell, J.R., Via, C.S., Claypool, R.G., and Kotzin, B.L., 1985. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann. Intern. Med. 103, 489-496; Weinblatt, M.E., Coblyn, J.S., Fox, D.A., Fraser, P.A., Holdsworth, D.E., Glass, D.N., and Trentham, D.E., 1985. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818-822; Williams, H.J., Willkens, R.F., Samuelson, C.O.J., Alarcón, G.S., Guttadauria, M., Yarboro, C., Polisson, R.P., Weiner, S.R., Luggen, M.E., Billingsley, L.M., Dahl, S.L., Egger, M.J., Reading, J.C., and Ward, J.R., 1985. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 28, 721-730.]. Subsequently, these four trials were included in a meta-analysis and the drug was approved by the Food and Drug Administration for use in RA [Health and Public Policy Committee, H.P.P.C. and American College Physicians, A.C.P., 1987. Methotrexate in rheumatoid arthritis. Ann. Intern. Med. 107, 418-419; Paulus, H.E., 1986. FDA Arthritis Advisory Committee meeting: Methotrexate; guidelines for the clinical evaluation of antiinflammatory drugs; DMSO in scleroderma. Arthritis Rheum. 29, 1289-1290; Tugwell, P., Bennett, K., and Gent, M., 1987. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann. Intern. Med. 107, 358-366.]. Since then, rheumatologists have become aware of what Pincus et al. have called "the side effects" of RA comparing the morbidity and mortality caused by RA with that potentially caused by medications used to treat this disease [Pincus, T. and Callahan, L.F., 1993. The "side effects" of rheumatoid arthritis: joint destruction, disability and early mortality. Br. J. Rheumatol. 32, 28-37.]. Thus, during the 1990s the use of MTX for the treatment of RA became generalized [O'Dell, J.R., 1997. Methotrexate use in rheumatoid arthritis. Rheum. Dis. Clin. N Am. 23, 779-796 (a); Bannwarth, B., Vernhes, J., Schaeverbeke, T., and Dehais, J., 1995. The facts about methotrexate in rheumatoid arthritis. Rev. Rhum. 62, 471-473 (b); Bologna, C., Jorgensen, C., and Sany, J., 1997a. Methotrexate as the initial second-line disease modifying agent in the treatment of rheumatoid arthritis patients. Clin. Exp. Rheumatol. 15, 597-601; Bologna, C., Viu, P. (ABSTRACT TRUNCATED)

Animals↗

PubMed1997

Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients.

Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the participants of this trial to evaluate the possibility that an interaction of FK506 and methotrexate was the explanation for the clinical findings. Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patients. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses. Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attributable to pharmacologic interactions with methotrexate.

Adolescent↗

PubMed1999

A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: The optimum initial dose of methotrexate for steroid-requiring inflammatory bowel disease is not known. AIM: To compare directly the efficacy and toxicity of methotrexate 15 and 25 mg/week, and to explore the value of methotrexate blood levels as predictors of outcome. METHODS: A 16-week randomized single-blind comparison of subcutaneous methotrexate 15 or 25 mg/week was performed in 32 patients with steroid-requiring Crohn's disease or ulcerative colitis. Patients who did not respond to methotrexate 15 mg/week were further studied for an additional 16 weeks on methotrexate 25 mg/week. Blood was drawn every 2 weeks for methotrexate levels. RESULTS: After 16 weeks, 17% of patients in each group achieved remission; 39% of patients randomized to 15 mg/week and 33% of patients randomized to 25 mg/week improved (P=N.S. ). Clinical status improved in four out of 11 patients after methotrexate dose escalation from 15 to 25 mg/week. Toxicity was not different between the treatment groups. Methotrexate blood levels did not predict efficacy or toxicity. CONCLUSIONS: For induction of remission in steroid-requiring inflammatory bowel disease, subcutaneous methotrexate at initial doses of 15 and 25 mg/week are equally efficacious. At these doses, response is not associated with blood methotrexate concentrations.

Adult↗

PubMed2001

Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells.

The molecular basis of methotrexate resistance was studied in human MDA-MB-231 breast cancer cells, which are inherently defective in methotrexate uptake and lack expression of the reduced folate carrier (RFC). Transfection of MDA-MB-231 cells with RFC cDNA restored methotrexate uptake and increased methotrexate sensitivity by approximately 50-fold. A CpG island in the promoter region of RFC was found to be methylated in MDA-MB-231 cells, but was unmethylated in RFC expressing, methotrexate-sensitive MCF-7 breast cancer cells. Chromatin immunoprecipitation with antibodies against acetylated histones H3 and H4 showed that the RFC promoter was enriched for acetylated histones on expressed, unmethylated alleles only. Treatment of MDA-MB-231 cells with 5-aza-2'-deoxycytidine restored RFC expression but also led to increased methotrexate efflux and did not reverse methotrexate resistance. This suggests that 5-aza-2'-deoxycytidine up-regulates both methotrexate uptake and some methotrexate-resistance mechanism(s). Reverse transcription-polymerase chain reaction analysis showed increased expression levels of several ATP-dependent efflux pumps in response to 5-aza-2'-deoxycytidine treatment, including P-glycoprotein and members of the multidrug resistance-associated protein family. Up-regulation of P-glycoprotein in response to 5-aza-2'-deoxycytidine was associated with demethylation of a CpG island in the MDR1 promoter, whereas the mechanism(s) for 5-aza-2'-deoxycytidine-induced up-regulation of multidrug resistance-associated proteins is probably indirect. Dipyridamole inhibited methotrexate efflux and reversed methotrexate resistance in 5-aza-2'-deoxycytidine-treated MDA-MB-231 cells.

Acetylation↗

PubMed2000

High-dose methotrexate in childhood all.

An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m2. The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m2. The highest dose, 33.6 g/m2, has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m2) was used, and only two (2.2%) of 89 ALL cases showed CNS relapse, both of reversible kind. In the United Kingdom, a randomized controlled study was started in 1990. Results published so far are based on a segment of cases characterized by standard risk and white blood cell count below 50 x 10(9); a 4% reduction in CNS relapse was found for high-dose methotrexate in comparison to those treated only with long-term intrathecal methotrexate. The use of methotrexate unalterably warrants some precautions. Rescue therapy with folinic acid is usually started 36 h after initiating the methotrexate infusion. Steps are also taken to secure adequate intake of fluids and alkalinization of the urine. Provided irradiation is avoided, neurotoxicities rarely occur. For regular high-dose methotrexate adverse effects mostly involve mucositis and myelosuppresion.

Antimetabolites, Antineoplastic↗

PubMed1998

Effects of methotrexate on trophoblast proliferation and local immune responses.

Methotrexate is a folic acid analogue that has been used successfully for the treatment of ectopic pregnancy and, in conjunction with misoprostol, for medical abortions of early intrauterine pregnancies. To administer the most efficacious treatment requires knowledge of the mechanism underlying the induction of methotrexate-induced abortion. This study was designed to ascertain trophoblast integrity, proliferation and differentiation following administration of methotrexate. In addition, to determine if methotrexate affects the local uterine immune response, we ascertained the numbers and identities of decidual leukocytes following treatment. Ten women with undesired intrauterine pregnancies of 42-49 days gestation were recruited to receive methotrexte 50 mg/m2 i.m. A suction aspiration was performed 7 days later. Tissues from gestational age-matched elective surgical abortions were used as controls. Additionally, specimens from women who received methotrexate and misoprostol for abortion in a clinical trial of oral methotrexate in combination with misoprostol, who had a suction abortion because of continued embryonic cardiac activity 14 days after the methotrexate, were evaluated. Immunoreactivity to proliferating cell nuclear antigen and cyclin D3 antibodies was used to demonstrate a marked reduction in the proliferation index of cytotrophoblasts from methotrexate-treated abortions. Methotrexate treatment failures and non-treated pregnancies had a much higher proliferation index. There was no direct destruction of the syncytiotrophoblast, as indicated by the continued presence of human placental lactogen and beta-human chorionic gonadotrophin proteins. A decrease in the total number of leukocyte cells was observed in the decidua of methotrexate-treated samples, with the large granular lymphocyte (LGL) cells showing the greatest decline in numbers. Our conclusions from this study are that methotrexate acts primarily to derail the normal developmental programme of the trophoblast stem cell population, as well as to decrease LGL cell numbers in the decidua.

Adult↗

PubMed2004

Experience with the use of low-dose methotrexate for inflammatory bowel disease.

BACKGROUND: Thiopurine drugs (azathioprine and 6-mercaptopurine) are well established in the treatment of patients with inflammatory bowel disease. However, some patients are intolerant or resistant to thiopurine drugs and their management remains a challenge. Several studies have suggested methotrexate is effective for the induction and maintenance of remission in Crohn's disease. OBJECTIVE: This study was conducted because the overall data on clinical efficacy of methotrexate in inflammatory bowel disease remain limited and there are no data regarding fistulating Crohn's disease or concomitant use of methotrexate with thiopurine drugs in inflammatory bowel disease. METHODS: This study was a retrospective review of medical notes. Clinical response was defined as sustained withdrawal of oral steroids or fistula improvement. New episodes of steroid therapy, infliximab or surgery during the first 6 months were considered as failure to achieve clinical response. RESULTS: Seventy-two patients were studied (66 Crohn's disease and six ulcerative colitis). The mean dose of methotrexate used was 18.2 mg/week. Clinical response was achieved in 22 of 54 patients (40.7%) who completed 6 months of methotrexate treatment. For patients with Crohn's disease, fistula improvement was achieved in eight of 18 (44.4%) patients compared with 11 of 30 (36.7%) receiving methotrexate for steroid withdrawal. Clinical response was achieved in six of 15 patients (40%) treated with methotrexate and azathioprine at the same time compared with 16 of 39 patients (41%) treated with methotrexate alone. CONCLUSIONS: Methotrexate is reasonably effective in clinical practice as a steroid sparing agent in inflammatory bowel disease. The efficacy in fistulating Crohn's disease justifies its use as an immunomodulator in these patients. Combined azathioprine and methotrexate treatment appears to offer no advantage over methotrexate alone.

Adolescent↗