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PubMed2005

Methotrexate for primary biliary cirrhosis.

BACKGROUND: Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous. OBJECTIVES: To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY: Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS: We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate. AUTHORS' CONCLUSIONS: Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.

Folic Acid Antagonists↗

PubMed1978

Hemoperfusion for methotrexate removal.

Removal of methotrexate by Amberlite XAD-4 hemoperfusion was determined in a patient with metastatic breast carcinoma. During 4 hr of hemoperfusion the plasma concentration of methotrexate fell from 5.5 x 10(-7) M TO 3.1 x 10(-7) M. After hemoperfusion methotrexate concentration increased as a consequence of multicompartmental pharmacokinetics to 5.5 x 10(-7) M and then slowly declined. Plasma methotrexate clearance decreased from 79 ml/min 30 min into hemoperfusion to 28 ml/min at the conclusion. In vitro clearance of methotrexate by 17 artificial kidneys, Amberlite XAD-4, and uncoated charcoal was determined. Uncoated charcoal had the greatest clearance of methotrexate of all the devices tested. We conclude that: (1) Amberlite XAD-4 transiently reduces plasma methotrexate concentration; (2) in vitro, charcoal hemoperfusion is more effective than XAD-4 in removing methotrexate; (3) as a consequence of the multicompartmental pharmacokinetics of methotrexate a postperfusion rebound in plasma methotrexate concentration is to be expected.

Charcoal↗

PubMed2000

Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate: a case study of five patients with treatment-resistant inflammatory bowel disease.

INTRODUCTION: This study reports the clinical outcome, toxicity, and methotrexate pharmacokinetics after the addition of low-dose cyclosporine to methotrexate in patients with ulcerative colitis or Crohn's disease. METHODS: Three patients with steroid-refractory ulcerative colitis and two patients with steroid refractory Crohn's disease who failed monotherapy with subcutaneous methotrexate 25 mg/week for 16 weeks were treated with the combination of methotrexate and low-dose oral cyclosporine (3 mg/kg/day) for an additional 16 weeks. Clinical response was measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate were also determined. RESULTS: Both patients with Crohn's disease withdrew from the study for toxicity (headaches, seizure). The three patients with ulcerative colitis experienced clinical improvement with a mean increase in the IBDQ score from 164 to 190 points, p = 0.01. The mean serum creatinine in the three patients who completed the study increased from 0.9 mg/dL at baseline to 1.2 mg/dL at week 16. p = 0.04. One patient developed hypertension. There was no significant change from baseline in the concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate. CONCLUSIONS: Combination therapy with methotrexate and low-dose oral cyclosporine did not alter methotrexate pharmacokinetics and resulted in high rates of cyclosporine-associated toxicity.

Colitis, Ulcerative↗

PubMed1977

Choline antagonism of methotrexate liver toxicity in the rat.

Because of the frequent reports of hepatic toxicity associated with long-term administration of methotrexate, a rat model was developed utilizing daily methotrexate administration. This model revealed an incidence of fatty metamorphosis of over 80 percent, atrophy and necrosis of 30 percent, and fibrosis of 10 percent. Fatty liver changes did not differ substantially from control animals in those animals receiving long-term thydroxyurea, an agent which, like methotrexate, inhibits DNA synthesis but unlike methotrexate, does not impair methylation reactions. Because choline has a lipotropic effect and because its synthesis requires methylation, an attempt was made to block the liver toxicity of methotrexate by simultaneous administration of choline. Animals so treated did not show the pathologic changes in the liver characteristic of methotrexate treatment alone. Furthermore, the accumulation of triglycerides in the liver which was characteristic of methotrexate administration was markedly reduced in those animals receiving choline. These data strongly suggest that, in the rat model, methotrexate produced liver toxicity by virtue of an effect other than inhibition of DNA synthesis; and that this toxicity can be blocked without impairing methotrexate effect on bone marrow by the administration of choline, a lipotropic agent requiring methylation for its synthesis. It is suggested that these results may have implications for human therapeutic situations involving long-term administration of methotrexate.

Animals↗

PubMed1999

Methotrexate sequestration in an ovarian cyst.

OBJECTIVE: Methotrexate has been documented to accumulate in pleural effusions and ascitic fluid, resulting in severe local and systemic toxicity. In the following case report, we publish results of intraoperative measurements of methotrexate levels in serum and an ovarian cyst and attempt to determine if ovarian cysts similarly act as a depot for methotrexate. METHODS: After determining intraoperative measurements of serum and ovarian cystic levels of methotrexate, we compared demonstrated pharmacokinetics to those expected by using pharmacokinetic systems analysis software. RESULTS: Intraoperative measurement of methotrexate levels on day 3 of a 5-day methotrexate regimen revealed a serum methotrexate concentration of 1.6 x 10(-7) M and a concentration of 3.1 x 10(-7) M within the 166.4 ml ovarian cyst. CONCLUSIONS: The measured levels demonstrate that methotrexate is sequestered within an ovarian cyst resulting in higher local drug levels. Our pharmacokinetic analysis suggests that methotrexate doses less than 100 mg/m2 can be safely administered to patients with small ovarian cysts. However, computed simulations support the possibility of local and systemic toxicity arising from large ovarian cysts when using high doses of methotrexate.

Adult↗

PubMed1984

Pharmacokinetics of methotrexate in erythrocytes in psoriasis.

The intraerythrocytic levels of folate and methotrexate were measured in 25 patients on long-term methotrexate therapy for recalcitrant psoriasis. The mean steady state concentration of methotrexate in erythrocytes was 85 nmol/l and the mean erythrocyte folate concentration was 729 nmol/l. A linear correlation was not observed between these parameters, but the greatest methotrexate accumulation was found in cells at the lower end of the erythrocyte folate concentration range. In 5 patients started on methotrexate therapy the erythrocyte concentrations of methotrexate and folate were followed over 6 months. 3-4 days after the first dose, methotrexate had been accumulated against a concentration gradient in the erythrocytes. The methotrexate concentration increased steadily until the steady state level was reached after 4-6 weeks. The steady state level was maintained during the 6 month observation period. The erythrocyte folate concentration did not change during this period. The data suggest that methotrexate polyglutamate synthesis within the circulating erythrocyte is a major cause of methotrexate accumulation in these cells.

Adult↗

PubMed1985

Characterization of the multiple transport routes for methotrexate in L1210 cells using phthalate as a model anion substrate.

o-Phthalate is actively transported into L1210 cells and the primary route for cell entry is the same transport system which mediates the influx of methotrexate and other folate compounds. The identity of the influx route has been established by the following observations: (A) Phthalate influx is competitively inhibited by methotrexate and the inhibition constant (Ki) is comparable to the Kt for half-maximal influx of methotrexate: (B) Various anions inhibit the influx of phthalate and methotrexate with comparable Ki values; (C) The influx of phthalate and methotrexate both fluctuate in parallel with changes in the anionic composition of the external medium; and (D) A specific covalent inhibitor of the methotrexate transport system (NHS-methotrexate) also blocks the transport of phthalate. In contrast, the efflux of phthalate does not occur via the methotrexate influx carrier, but rather by two separate processes which can be distinguished by their sensitivities to bromosulfophthalein. Efflux via the bromosulfophthalein-sensitive route constitutes 75% of total efflux and is enhanced by glucose and inhibited by oligomycin. The inability of phthalate to exit via the methotrexate influx carrier is due to competing intracellular anions which prevent phthalate from interacting with the methotrexate binding site at the inner membrane surface.

Animals↗

PubMed2003

Insulin-induced enhancement of antitumoral response to methotrexate in breast cancer patients.

PURPOSE: It has been reported that insulin increases the cytotoxic effect in vitro of methotrexate by as much as 10,000-fold. The purpose of this study was to explore the clinical value of insulin as a potentiator of methotrexate. PATIENTS AND METHODS: Included in this prospective, randomized clinical trial were 30 women with metastatic breast cancer resistant to fluorouracil + Adriamycin + cyclophosphamide and also resistant to hormone therapy with measurable lesions. Three groups each of ten patients received two 21-day courses of the following treatments: insulin + methotrexate, methotrexate, and insulin, respectively. In each patient, the size of the target tumor was measured before and after treatment according to the Response Evaluation Criteria In Solid Tumors. The changes in the size of the target tumor in the three groups were compared statistically. RESULTS: Under the trial conditions, the methotrexate-treated group and the insulin-treated group responded most frequently with progressive disease. The group treated with insulin + methotrexate responded most frequently with stable disease. The median increase in tumor size was significantly lower with insulin + methotrexate than with each drug used separately. DISCUSSION: Our results confirmed in vivo the results of previous in vitro studies showing clinical evidence that insulin potentiates methotrexate under conditions where insulin alone does not promote an increase in tumor growth. Therefore, the chemotherapy antitumoral activity must have been enhanced by the biochemical events elicited in tumor cells by insulin. CONCLUSIONS: In multidrug-resistant metastatic breast cancer, methotrexate + insulin produced a significant antitumoral response that was not seen with either methotrexate or insulin used separately.

Adult↗

PubMed2006

Low-dose methotrexate inhibits lung metastasis and lengthens survival in rat osteosarcoma.

Lung metastasis is the most crucial event affecting the treatment of osteosarcoma and is dependent on tumor angiogenesis. To improve the prognosis for patients with osteosarcoma, prevention of lung metastasis is essential. Low-dose methotrexate is a useful drug for treating a variety of diseases. Low-dose methotrexate reportedly plays a role in antiangiogenesis for the synovial blood vessels in rheumatoid arthritis. However, whether low-dose methotrexate is correlated with tumor angiogenesis and metastasis is unclear. We investigated the inhibitory effect of methotrexate on lung metastasis in a rat osteosarcoma cell line with high metastatic potential, S-SLM. Two weeks after inoculation of S-SLM cells into male Fischer 344 rats, low-dose methotrexate (1.2 mg/kg once or twice a week) or saline was intraperitonealy injected for 4 weeks and the antimetastatic effect was evaluated. Low-dose methotrexate significantly reduced the number of lung metastatic nodules and the wet weight of the lungs. Immunohistochemical staining showed a decrease in microvessel density in the metastatic nodules. We also evaluated the effect of methotrexate on the proliferation of endothelial cells and S-SLM osteosarcoma cells in vitro. Methotrexate significantly inhibited the proliferation of endothelial cells at a lower concentration than that of S-SLM osteosarcoma cells. These data suggest that low-dose methotrexate inhibited lung metastasis of osteosarcoma through its antiangiogenic activity. Our results indicate that low-dose methotrexate is a promising drug for tumor dormancy therapy in patients with osteosarcoma and lung metastasis.

Animals↗

PubMed1976

Differential distribution of liposome-entrapped [3H]methotrexate and labelled lipids after intravenous injection in a primate.

Positive liposomes consisting of phosphatidylcholine, cholesterol and stearylamine and negatively charged liposomes consisting of phosphatidylcholine, cholesterol and phosphatidylserine, were double labelled with either 3H-labelled dipalmitoyl phosphatidylcholine and [14C]cholesterol or with [14C]cholesterol and [3H]methotrexate entrapped in the aqueous phase. The plasma levels and urinary excretion of radioactivity from sonicated and non-sonicated liposomes were then compared with the levels of radioactivity from free [3H]methotrexate during a 4 h experimental period after an initial intravenous injection in cynomolgous monkeys. Tissue uptake at the completion of the 4 h experimental period was also measured. It was found that plasma radioactivity from [3H]methotrexate and [14C]cholesterol in sonicated positive liposomes was cleared more slowly than from comparable non-sonicated liposomes, and considerably slower than from free [3H]methotrexate. Radioactivity from sonicated negative liposomes was cleared more rapidly than from positive sonicated liposomes. Positive liposomes captured considerably more [3H]methotrexate than negative liposomes and showed very low permeability to [3H]methotrexate in in vitro studies, even in the presence of high concentrations of serum. [14C]Cholesterol radioactivity was cleared more rapidly from plasma than 3H-radioactivity from liposome-entrapped [3H]methotrexate for double-labelled sonicated liposomes and generally showed greater uptake into tissues and red blood cells. 3H-labelled dipalmitoyl phosphatidylcholine in sonicated positive liposomes was cleared faster than [14C]cholesterol during the first 3 h. The more rapid disappearance of [14C]cholesterol from the plasma was complemented by greater uptake into a number of tissues, and positive non-sonicated liposomes were taken up to a greater extent by the spleen than equivalent sonicated liposomes. Renal excretion of 3H from liposome-entrapped [3H]methotrexate was considerably less than that of 3H from free [3H]methotrexate. There was insignificant excretion, however, of 14C from cholesterol in the urine. Entrapment in liposomes completely prevented the otherwise considerable breakdown of free methotrexate to 3H-containing products in plasma and partially prevented its breakdown in tissues. These studies indicate marked differences in the distribution of liposomes in vivo due to surface charge and size, and some degree of exchange of the lipid components of the liposome bilayer independent of the distribution of the entrapped species. They also show that entrapment in liposomes can reduce metabolic degradation of a drub, maintain high plasma levels and reduce its renal excretion.

Animals↗

PubMed1993

Determinants of the disparate antitumor activities of (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate and methotrexate toward human lymphoblastic leukemia cells, characterized by severely impaired antifolate membrane transport.

We previously reported (Matherly et al., J Biol Chem 267: 23253-23260, 1992) that impaired methotrexate transport in a drug-resistant CCRF-CEM variant (CEM/MTX) involved the synthesis of a structurally altered isoform of the "classical" carrier for methotrexate and related derivatives. Although CEM/MTX cells were highly resistant (162- to 300-fold) to assorted antifolate substrates for the classical transporter, including methotrexate, aminopterin, 10-ethyl-10-deazaaminopterin, ICI D1694, and 1843U89, they were only 3.6-fold resistant to (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate (DDATHF). These divergent antifolate sensitivities were not associated with appreciable differences in the levels of dihydrofolate reductase, thymidylate synthase, and 5'-phosphoribosylglycinamide (GAR) transformylase, or the expression of a high affinity membrane folate binding protein receptor in either line. The initial rate of [14C]DDATHF influx was increased 2.9-fold over that for [3H]methotrexate in parental cells (at 2 microM). Whereas [14C]DDATHF initial uptake was, likewise, increased over [3H]methotrexate in CEM/MTX cells (5.3-fold), influx of both compounds was impaired substantially (95-97%). For the parent, influx of [14C]DDATHF was inhibited by substrates for the classical transporter including unlabeled DDATHF, methotrexate, (6R,S)-5-formyl tetrahydrofolate, 10-ethyl-10-deazaaminopterin, ICI D1694, 1843U89, and folic acid. The synthesis of a modified transporter in CEM/MTX cells was accompanied by significant changes in the binding of all these transport substrates. In spite of its impaired transport, [14C]DDATHF (at 2 microM), unlike methotrexate, continued to accumulate in CEM/MTX cells, eventually reaching 62% of the parental drug levels after 4 hr. At this time, 53% (parent) and 71% (CEM/MTX) of the intracellular radioactivity from [14C]DDATHF was identified as polyglutamates. DDATHF polyglutamates in CEM/MTX cells after 4 hr reached 90% of the levels measured in parental cells. While significant levels of methotrexate polyglutamates were detected in the parental line, methotrexate polyglutamylation was negligible in intact CEM/MTX cells. The specific activity of folylpolyglutamate synthetase was measured in cell-free extracts from parental and CEM/MTX cells using aminopterin, methotrexate, and DDATHF as substrates; in each case, CEM/MTX cells showed 2-fold higher enzyme activity than parental cells. These data show that even for tumor cells with severely impaired antifolate transport, the extensive conversion of DDATHF to polyglutamyl forms required for GAR transformylase inhibition preserves high levels of antitumor activity.

Antineoplastic Agents↗

PubMed1996

Comparison of methotrexate polyglutamylation in L1210 leukemia cells when influx is mediated by the reduced folate carrier or the folate receptor. Lack of evidence for influx route-specific effects.

We previously described a methotrexate-resistant L1210 cell line (MTXrA) that lacks a functional reduced folate carrier and does not appreciably express the folate receptor. In the present study, we utilized MTXrA cell lines stably transfected with cDNAs encoding either the folate receptor or the reduced folate carrier to investigate the influence of the route of folate influx on the rate and extent of methotrexate polyglutamylation. At an extracellular methotrexate concentration of 0.1 microM, influx in the folate receptor transfectant (MTXrA-TF1) and in the reduced folate carrier transfectant (MTXrA-R1) was equal and methotrexate polyglutamates accumulated at an identical rate, but the onset was delayed until dihydrofolate reductase was saturated with the monoglutamate (approxmately 3 hr). The onset of polyglutamate formation was immediate and identical among the lines in cells pretreated with the lipophilic dihydrofolate reductase inhibitor trimetrexate to block methotrexate binding to dihydrofolate reductase. The spectra of individual methotrexate polyglutamates that accumulated were similar, with the tetraglutamate present as the predominant form. A 100-fold higher methotrexate concentration was required to detect methotrexate uptake and polyglutamylation in the transport defective parent MTXrA line, demonstrating that diffusion or an unidentified low affinity route also supports polyglutamylation. Since the folate receptor and the reduced folate carrier achieve nearly identical rates of polyglutamylation despite very different mechanisms of methotrexate delivery, the data suggest that transport-mediated substrate channeling to folylpolyglutamate synthetase is unlikely to play a role in tetrahydrofolate metabolism. This study supports the notion that it is the intracellular concentration of methotrexate achieved within the cell that drives polyglutamylation irrespective of its route of entry.

Animals↗

PubMed1994

A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis.

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is a progressive disease with no accepted effective treatment. Because methotrexate was associated with clinical and histological improvement in two men with PSC, we conducted a prospective trial of methotrexate in PSC. METHODS: A prospective placebo-controlled, double-blind trial of methotrexate in PSC was performed. Twenty-four patients with PSC were randomized to receive methotrexate or placebo for a 2-year period. Seven of 12 taking methotrexate and five taking placebo had cirrhosis. Serial liver biopsies, endoscopic retrograde cholangiopancreatography (ERCP), and biochemical tests of liver function were followed. RESULTS: There were no significant changes in liver histological results, ERCP findings, tests of liver function (other than alkaline phosphatase), or outcome between the two groups. Mean alkaline phosphatase levels decreased by 152 IU in the methotrexate group and increased by 30 IU in the placebo group (P = 0.032). Patients taking methotrexate were more likely to reduce or discontinue cholestyramine than patients taking placebo. CONCLUSIONS: This study does not support efficacy for methotrexate in the treatment of PSC. On the basis of this study, the empiric use of methotrexate in patients with PSC is not recommended. However, methotrexate is being further evaluated in patients with precirrhotic PSC.

Adolescent↗

PubMed1989

Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid patients.

The significance of hepatic changes in methotrexate-treated RA patients is unclear at this time. In our group of RA patients, there was a slight increase in the incidence of triaditis and fat during methotrexate therapy. Disease duration greater than or equal to 10 years was associated with increased hepatic triaditis before treatment. Age greater than 50 years was associated with increased hepatic fat before and after treatment. It appears that patients' ages and duration of underlying RA account for some changes, independent of methotrexate therapy. Several of our patients changed from higher to lower histologic grade or had an apparent decrease in fibrosis, fat, or triaditis on the pathologists' reports and the blind readings of the repeat biopsies. This may be explained by sampling error. More importantly, some of these changes may not be of clinical significance. One report of methotrexate-induced cirrhosis in patients with psoriasis demonstrated that in all but one of 14 patients who continued receiving methotrexate the cirrhosis decrease or did not progress. This may also be true of the hepatic fibrosis seen in RA after methotrexate treatment. In this study, there did not appear to be changes seen on pretreatment liver biopsy that were predictive of subsequent fibrosis or cirrhosis. Our data indicate that pretreatment biopsy is unwarranted in a population similar to ours. However, our practice has been to try to avoid methotrexate in patients with diabetes, prior liver disease, alcoholism, or obesity because of previous reports suggesting that these patients are at increased risk for the development of cirrhosis. Only the above-mentioned patient, eventually diagnosed as having cirrhosis, might have been handled differently. Including the study, none of the approximately 700 RA patients in the literature having liver biopsies after methotrexate therapy have developed cirrhosis consequent to its use. Most of these had received a total dose of approximately 1,500 mg in small weekly doses, and alcohol was prohibited. Below this cumulative dose the risk of clinically significant liver damage in carefully selected patients is very low. In view of this experience, the recommendation that RA patients have liver biopsies after 1,500 mg of methotrexate (a holdover from the psoriasis literature) may be too conservative in low-risk RA patients, provided methotrexate is administered weekly and alcohol is prohibited. Recognizing that the absolute need for biopsy is unproven, a more realistic milestone for those choosing biopsy might be after each 2,000 to 2,500 mg.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

PubMed1990

Role of hypoxanthine and thymidine in determining methotrexate plus dipyridamole cytotoxicity.

The nucleoside transport inhibitor dipyridamole can potentiate the cytotoxicity of methotrexate by a mechanism that was thought to be related to the inhibition of thymidine salvage. In human ovarian carcinoma cells thymidine only partly reversed the in vitro cytotoxicity of methotrexate plus dipyridamole at sub-millimolar concentrations, above which the cytotoxicity of thymidine itself became evident. Hypoxathine with thymidine, or hypoxanthine alone at a higher concentration, completely reversed methotrexate and methotrexate plus dipyridamole cytotoxicity. The effects of dipyridamole on cellular cyclic adenosine monophosphate (cAMP) levels and on 3H-methotrexate efflux in 2008 cells were examined. At 10 mumol/l, dipyridamole did not alter cAMP content or methotrexate influx in ovarian carcinoma cells, but reduced the rate of efflux of 3H-methotrexate by 25%. In Chinese hamster ovary cells and their folylpolyglutamyl synthase-deficient variant AUX B1, the reduced methotrexate efflux by dipyridamole was not due to increased polyglutamation, since increased retention was observed in both cell lines. The data support the hypothesis that dipyridamole potentiated the activity of methotrexate by inhibiting the salvage of hypoxanthine, and to a lesser extent, that of thymidine. The ability of dipyridamole to increase the cellular retention of methotrexate was probably a non-specific action of dipyridamole on the cell membrane, and may have a role in the observed synergy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Folate supplementation during methotrexate therapy for patients with psoriasis.

Methotrexate is a folate antagonist that is a well-established therapy for autoimmune and inflammatory conditions. In some patients, methotrexate is associated with significant side effects and toxicity. Folate supplementation is often used to ameliorate methotrexate-associated side effects and toxicities. We sought to demonstrate that folate supplementation during methotrexate therapy reduces both toxicity and side effects without compromising efficacy. A MEDLINE search of the search terms "methotrexate," "folic acid," "folinic acid," and "leucovorin" was performed and literature relevant to the use of folates as a supplement to methotrexate was reviewed. According to studies reviewed, the use of folate supplements in patients treated with methotrexate reduces the incidence of hepatotoxicity and gastrointestinal intolerance without impairing the efficacy of methotrexate. Both folic acid and folinic acid are equally effective; however, folic acid is more cost effective. It must be noted that there are relatively few studies that have addressed folate supplementation with the use of methotrexate for the treatment of psoriasis. After examining the available data from the literature and drawing from clinical experience, we advise folate supplementation for every patient who receives methotrexate.

Drug Therapy, Combination↗

PubMed2002

Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study.

BACKGROUND: Methotrexate is the most frequent choice of disease-modifying antirheumatic therapy for rheumatoid arthritis. Although results of studies have shown the efficacy of such drugs, including methotrexate, on rheumatoid arthritis morbidity measures, their effect on mortality in patients with the disease remains unknown. Our aim was to prospectively assess the effect on mortality of methotrexate in a cohort of patients with rheumatoid arthritis. METHODS: Our cohort included 1240 patients with rheumatoid arthritis seen at the Wichita Arthritis Center, an outpatient rheumatology facility. Patients' details were entered into a computerised database at the time of their first clinic visit. We also obtained and recorded demographic, clinical, laboratory, and self-reported data at each follow-up visit (average interval 3.5 months). We estimated the mortality hazard ratio of methotrexate with a marginal structural Cox proportional hazards model. FINDINGS: 191 individuals died during follow-up. Patients who began treatment with methotrexate (n=588) had worse prognostic factors for mortality. After adjustment for this confounding by indication, the mortality hazard ratio for methotrexate use compared with no methotrexate use was 0.4 (95% CI 0.2-0.8). Other conventional disease-modifying antirheumatic drugs did not have a significant effect on mortality. The hazard ratio of methotrexate use for cardiovascular death was 0.3 (0.2-0.7), whereas that for non-cardiovascular deaths was 0.6 (0.2-1.2). INTERPRETATION: Our data indicate that methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality. This survival benefit of methotrexate would set a standard against which new disease-modifying antirheumatic drugs could be compared.

Antirheumatic Agents↗

PubMed1999

Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group.

BACKGROUND: Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate. METHODS: In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. FINDINGS: At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group. INTERPRETATION: During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.

Adult↗