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PubMed1987

[Interaction of muscle glycogen phosphorylase B with methotrexate, folic and folinic acids].

The interaction of rabbit skeletal muscle glycogen phosphorylase b with methotrexate, folic and folinic acids has been studied. Microscopic dissociation constant for the glycogen phosphorylase b--methotrexate complex determined by analytical ultracentrifugation is 0.43 mM. A subunit of glycogen phosphorylase b is shown to have two sites for methotrexate binding. AMP and FMN diminish the affinity of glycogen phosphorylase b to methotrexate, whereas glycogen does not influence the methotrexate binding to the enzyme. Methotrexate, folic and folinic acids are found to be inhibitors of the muscle glycogen phosphorylase b. The inhibition is reversible and characterized by positive kinetic cooperativity (the Hill coefficient exceeds one unity). The value of the pterin concentration causing two-fold diminishing of the enzymatic reaction rate increased in the order: folic acid (0.65 mM), methotrexate (1.01 mM), folinic acid (3.7 mM). The antagonism between methotrexate, folic and folinic acids, on the one hand, and AMP and FMN, on the other, is revealed for their combined action.

Adenosine Monophosphate↗

PubMed1987

Prevention of methotrexate-induced gastrointestinal toxicity by glucose.

The effect of administration of glucose on methotrexate-induced body weight loss and gastrointestinal toxicity in mice was investigated. Using the everted sac technique, control rates (mumol/g/hr) of transport of D-glucose and L-tyrosine were 35.0 and 10.0, respectively. In animals pretreated with methotrexate (25 mg/kg/day i.p. for 4 days), these rates decreased to 10.9 and 6.3 mumol/g/hr, respectively. However, when intestinal sacs from untreated mice were exposed to MTX (10(-3) M), the drug had no significant effect on rates of transport of D-glucose or L-tyrosine. Methotrexate pretreatment in vivo also caused a 15% loss in animal body weights. Administration of glucose (0.5/g/kg. i/p.) 1 hour prior to methotrexate prevented the inhibition of transmucosal transport of both glucose and tyrosine. Glucose also reduced the body weight loss caused by methotrexate. Similar treatment with the nonmetabolizable sugar, 3-O-methylglucose, had no significant effect on the methotrexate-induced toxicity. The data suggest that coadministration of glucose with methotrexate may have a potential clinical value, since glucose may alleviate the toxic effects of methotrexate in patients receiving this drug.

Animals↗

PubMed1985

Cytotoxic effects of folate antagonists against methotrexate-resistant human leukemic lymphoblast CCRF-CEM cell lines.

A human T-lymphoblast cell line, CCRF-CEM/R1, resistant to methotrexate by virtue of increased dihydrofolate reductase activity, was grown in stepwise increasing concentrations of methotrexate. This additional selection pressure resulted in a cell line, CCRF-CEM/R2, resistant to methotrexate by virtue of both an elevation of dihydrofolate reductase activity and a marked decrease in methotrexate transport. The R1 and R2 cells were approximately 70- and 350-fold more resistant to methotrexate than were the parent cells. The effects of three folate antagonists were studied on these cell lines and also on CCRF-CEM/R3 cells, characterized by impaired methotrexate transport but normal levels of dihydrofolate reductase. The elevated reductase subline CCRF-CEM/R1 was cross-resistant to triazinate [Baker's antifol, NSC 139105; ethanesulfonic acid compounded with alpha-(2-chloro-4-[4,6-diamino-2,2-dimethyl-S-triazine-1-(2H)-yl] phenoxyl)-N,N-dimethyl-m-toluamide (1:1)] and trimetrexate (NSC 249008, JB-11, TMQ; 2,4-diamino-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline), two nonclassical folate antagonists. In contrast, the transport defective subline, CCRF-CEM/R3 was not cross-resistant to these two compounds. In cells resistant to MTX by virtue of both mechanisms, CCRF-CEM/R2, triazinate, and trimetrexate were partially cross-resistant. All three methotrexate-resistant sublines showed minor cross-resistance to isoaminohydroxyquinazoline (IAHQ, NSC 289517; 5,8-dideazaisopteroylglutamate), a folate antagonist inhibitor of thymidylate synthase. These data demonstrate that methotrexate-resistant tumor cells may be effectively inhibited by antifolates with different route of entry into cells or with different enzyme targets.

Antineoplastic Agents↗

PubMed1986

Transport of folate compounds in L1210 cells: kinetic evidence that folate influx proceeds via the high-affinity transport system for 5-methyltetrahydrofolate and methotrexate.

Folate is transported into L1210 mouse leukemia cells by the same system that mediates the uptake of methotrexate and reduced folate compounds. This conclusion is supported by the following observations: (a) methotrexate competitively inhibits the influx of folate and the Ki is comparable to the Kt for methotrexate influx; (b) the profile for inhibition of folate influx by methotrexate is monophasic and complete inhibition is achieved at high concentrations of the competitor; (c) folate inhibits the influx of methotrexate and the Ki is comparable to the Kt for folate influx; (d) the N-hydroxysuccinimide ester of methotrexate, a potent and specific irreversible inhibitor of the reduced folate system, also blocks the influx of folate; (e) folate and methotrexate influx are both inhibited by low concentrations of p-chloromercuriphenylsulfonate; and (f) folate influx fluctuates with the anionic composition of the medium in the same fashion as the influx of methotrexate. Measurements of folate influx can be complicated by the fact that the 3H-labeled substrate is susceptible to decomposition and that labeled breakdown products at concentrations as low as 1% contribute appreciably to the observed uptake. Of these products, 6-hydroxymethylpterin appears to account for most of the extraneous uptake. Impurities can be eliminated by subjecting the [3H]folate to preparative thin-layer chromatography immediately prior to use.

Animals↗

PubMed1983

In situ methotrexate polyglutamate formation in rat tissues.

Rats given a single i.p. injection of 10 mg/kg of methotrexate rapidly accumulate drug in several tissues, including liver, kidneys, testes, brain and red cells. Using a tissue extraction procedure which minimizes the breakdown of methotrexate polyglutamate derivatives and molecular sieve high-performance liquid chromatography, we examined the formation of methotrexate polyglutamates in these tissues throughout a period of 1 week after a single dose of drug. Higher polyglutamates (n greater than 3) were found in the brain, liver, kidneys and testes as early as 3 hr. The percentage of methotrexate polyglutamates increases slowly in the liver, kidney, testis and brain during the course of the week, concomitant with a decline of unconjugated tissue methotrexate and a low plasma concentration of drug. This is in contrast to the blood cells, which have little polyglutamate formation and a rapid half-life for methotrexate. The consistently high levels of methotrexate polyglutamate levels found in the liver, kidneys, testes and brain are in agreement with data showing little or no disappearance of methotrexate from these tissues for up to 26 days.

Animals↗

PubMed1978

Thymidine rescue of high-dose methotrexate in humans.

Thymidine rescue was administered following 63 courses of high-dose methotrexate in 20 patients. In the first part of this study, the methotrexate was given as a 24-hr infusion and the dose was escalated from 0.14 to 8.54 g/sq m; in the second part, methotrexate was infused to maintain a serum concentration of 15 micrometer for 30, 36, or 40 hr. Thymidine rescue was started immediately after the end of the methotrexate infusions, and consisted of 8 g/sq m/day for 3 days or until serum methotrexate was below a toxic level. Mucositis and myelosuppression were the major toxicities. Neither was dose related. Serum methotrexate levels were proportional to the logarithm of the methotrexate dose. There was a mean 6-fold increase in thymidine concentration during rescue. However, thymidine levels prior to and during rescue were not related to the incidence of subsequent toxicity. Recovery of DNA synthesis in bone marrow cells was evident by nucleoside precursor incorporation at 24 hr after the start of rescue. Two of 16 evaluable patients achieved partial responses. This study indicates that thymidine is an effective rescue agent for high-dose methotrexate in humans.

Adult↗

PubMed1984

Role of the cellular oxidation-reduction state in methotrexate binding to dihydrofolate reductase and dissociation induced by reduced folates.

5-Formyltetrahydrofolate promotes the net dissociation of methotrexate bound to dihydrofolate reductase in the Ehrlich ascites tumor (L. H. Matherly et al., Cancer Res., 43: 2694-2699, 1983). Treatment of Ehrlich tumor cells with glucose or inhibitors of electron transfer stabilized the association of the antifolate with dihydrofolate reductase as reflected by a 2-fold increased fraction of dihydrofolate reductase-bound methotrexate and an abolition of the 5-formyltetrahydrofolate-induced dissociation of the inhibitor-enzyme complex. Glucose and azide were also found to increase the intracellular ratio of reduced nicotinamide adenine dinucleotide phosphate (NADPH) to oxidized nicotinamide adenine dinucleotide phosphate (NADP+) in the tumor approximately 8- and 11-fold, respectively. However, other agents which enhanced the association between methotrexate and its target enzyme were less effective in increasing the intracellular level of NADPH relative to NADP+. Micromolar concentrations of NADPH promoted methotrexate binding to the purified Ehrlich tumor dihydrofolate reductase. Bound methotrexate could be dissociated from the purified enzyme by 5-methyltetrahydrofolate but less readily by 5-formyltetrahydrofolate and only in the presence of reduced levels of NADPH relative to NADP+. The tetraglutamate derivative of 5-methyltetrahydrofolate was even more effective than the underivatized compound in dissociating methotrexate from dihydrofolate reductase. These findings suggest a critical role for the cellular oxidation-reduction state in determining the affinity of dihydrofolate reductase for methotrexate and thus the cellular sensitivity to the antifolate. In addition, the data are consistent with the possibility that dihydrofolate reductase is a key locus for intracellular competitive interactions between reduced folates and methotrexate during leucovorin rescue from the pharmacological effects of the antifolate.

Animals↗

PubMed1981

5-Methyltetrahydrofolate transport by hepatoma cells and methotrexate-resistant sublines in culture.

The properties of the folate transport system in H35 hepatoma cells have been studied by measuring the transport of (+)-5-methyltetrahydrofolate. Using initial rates of uptake, it has been demonstrated that the uptake is saturable, carrier mediated, and shared by methotrexate. The accumulation of (+)-5-methyltetrahydrofolate is concentrative, demonstrating the presence of an active transport process. A previous study suggested that methotrexate-resistant sublines (H35R) acquired methotrexate insensitivity because of an impaired capacity for transport. This postulate was substantiated in the present investigation by several observations. The initial uptake and steady-state level of (+)-5-methyltetrahydrofolate were markedly reduced in the resistant sublines as was the case with methotrexate. Triazinate (2-(chloro-4-[4,6-diamino-2,2-dimethyl-S-triazine-1(2H)-ylphenoxyl])-N,N-dimethyl-m-toluamide . ethanesulfonic acid) an inhibitor of dihydrofolate reductase which enters the cells by a pathway independent of the folate coenzyme, was equally toxic to H35 cells and to an H35 subline resistant to 0.3 microM methotrexate. Resistant sublines that are insensitive to methotrexate up to 1 microM display a transport defect but have normal levels of dihydrofolate reductase. Sublines resistant to higher levels of methotrexate showed not only defective transport but also commensurate increases in dihydrofolate reductase. Attempts to demonstrate carried-dependent transport of (+)-5-methyltetrahydrofolate or methotrexate in resistant sublines were negative, suggesting the lack of a functional carrier. These properties were readily demonstrated in H35 cells and included temperature dependence, competition for uptake with analogs, and transstimulation.

Animals↗

PubMed1981

Intrathecal methotrexate-induced neurotoxicities.

The pharmacokinetics, therapeutic index, neurotoxicities, methods of administration, and dosages of intrathecal methotrexate are reviewed. The intrathecal administration of methotrexate can provide therapeutic concentrations in the cerebrospinal fluid (CSF) without the use of high-dose intravenous methotrexate. Major neurologic complications have been reported to occur in 3--40% of patients following intrathecal methotrexate. The development of neurotoxicity is related to dose, concentration of methotrexate in the CSF, age of the patient, anatomical and physiological abnormalities in the CNS, type of dilutional vehicle, intracranial radiation, and intravenous methotrexate. Substantial evidence is lacking that chemical preservatives and methotrexate breakdown products are risk factors. The use of intrathecal methotrexate is a reasonably safe and effective chemotherapeutic modality when proper administrative techniques are observed.

Humans↗

PubMedDate not supplied

Renal function and methotrexate clearance in children with newly diagnosed leukemia.

STUDY OBJECTIVES: To determine whether glomerular filtration rate (GFR) changes during induction chemotherapy in children with leukemia, and to examine GFR as a determinant of pharmacokinetic variability of methotrexate clearance. DESIGN: Prospective, unblinded observational study in consecutive patients. SETTING: A research hospital. PATIENTS: Thirty-eight children newly diagnosed with acute lymphoblastic leukemia. INTERVENTIONS: The patients received either high-dose methotrexate 1 g/m2 intravenously over 24 hours or low-dose methotrexate 30 mg/m2 orally every 6 hours for six doses; both regimens were followed by an intensive six-drug chemotherapy regimen given over 6 weeks. Glomerular filtration rate was determined in each subject before and at the conclusion of induction therapy. MEASUREMENTS AND MAIN RESULTS: The GFR was determined from 99mTc-DTPA serum clearance in all patients, and methotrexate clearance was estimated from serial serum concentrations in 18 of these children who received high-dose methotrexate. Median values for GFR at diagnosis (131 ml/min/1.73 m2) and after induction therapy (120 ml/min/1.73 m2) were not significantly different (p = 0.26) but were highly variable (range 49-274 ml/min/1.73 m2). Body size, age, and serum creatinine were correlated significantly with GFR at diagnosis. Amphotericin B therapy (6 patients) significantly decreased GFR (p = 0.046) without a corresponding increase in serum creatinine. Methotrexate clearance (58-155 ml/min/m2) was significantly (p = 0.007) correlated with GFR, but GFR accounted for only 37% of the variability of methotrexate clearance. CONCLUSIONS: The GFR was normal but highly variable in these children with leukemia and was significantly altered by amphotericin. Our results explain little of the intersubject variability in methotrexate clearance.

Administration, Oral↗

PubMed1995

Methotrexate loaded acrylic cement in the management of skeletal metastases. Biomechanical, biological, and systemic effect.

Skeletal metastases occur commonly, and frequently are complicated by the development of an impending or pathologic fracture. In the majority of instances, these patients are best treated by internal stabilization, frequently supplemented by methylmethacrylate, to relieve pain and maintain the patient's mobility. The underlying tumor may continue to grow, and if this occurs the progressive lysis may result in loosening and subsequent failure of the implant. To prevent additional local growth, postoperative radiotherapy is recommended, and many patients also receive endocrine or chemotherapy, but the adjuvant therapy is not always successful in preventing progressive local tumor induced osteolysis. It is possible that the addition of chemotherapeutic agents to the methylmethacrylate may inhibit local growth. This study was performed to determine the biomechanical, biologic, and systemic effects of adding methotrexate to methylmethacrylate. The results show that the addition of methotrexate in as much as a concentration of 2 g methotrexate per 40 g cement did not significantly alter the biomechanical characteristics of the bone cement. The incorporated methotrexate was released continuously from the loaded bone cement, and in the amount and concentration used did not have any toxic effects on the host animal. The methotrexate did not appear to be affected by the heat of polymerization and had a significant systemic effect. There was a significant reduction in pulmonary metastases with methotrexate loaded cement as compared with unloaded cement, the effect being dependent on the concentration of methotrexate in the cement. The results of these studies indicate that methotrexate loaded cement may have an important role to play as part of the orthopaedic management of impending and pathologic fractures.

Animals↗

PubMed1996

Methotrexate can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients.

BACKGROUND: Methotrexate has been used successfully to treat refractory or recurrent rejection in heart transplant recipients. We therefore conducted an open pilot study to determine whether methotrexate is useful in the treatment of chronic rejection after lung transplantation. METHODS: Between December 1993 and January 1995 methotrexate was prescribed to 10 patients with persistent or progressive bronchiolitis obliterans despite multiple attempts to control the chronic rejection with conventional treatment (pulse steroids or antilymphocyte products, or both). Data from the nine patients with a minimum of 6 months of follow-up were collected. RESULTS: No patients have died. The spirometry data of the eight patients with declining values of forced expiratory volume in 1 second are presented. Before initiation of methotrexate therapy the median decline in forced expiratory volume in 1 second was 1.4 +/- 0.8 L, or 43% +/- 17%, from the highest preinterventional forced expiratory volume in 1 second value during the preceding 12 months. At 6 months the median decline in forced expiratory volume in 1 second from the time methotrexate therapy was started was 0.1 +/- 0.2 L, or 3% +/- 11%. At 9 months (n = 6) the value was 0.2 +/- 0.2 L, or 6% +/- 12%. At 12 months (n = 5) the median decline was 0.4 +/- 0.3 L, or 9% +/- 16%. In two patients there has been no further decline in forced expiratory volume in 1 second since methotrexate therapy was started (one patient has had a slight but sustained improvement). Five patients have had a reduction in forced expiratory volume in 1 second of 10% or less at most recent follow-up, and only one patient has derived no apparent benefit from methotrexate therapy. Toxicity has been minimal. CONCLUSIONS: Methotrexate is a potentially promising therapeutic alternative in the therapy of bronchiolitis obliterans syndrome in lung transplant recipients.

Adult↗

PubMed2004

Costs of treatment in patients with moderate to severe plaque psoriasis: economic analysis in a randomized controlled comparison of methotrexate and cyclosporine.

OBJECTIVES: To document and compare the costs of treatment of psoriasis with 2 established systemic agents that differ substantially in their unit costs: methotrexate vs cyclosporine. DESIGN: Cost-minimization analysis within a randomized controlled trial. SETTING: Outpatient dermatology department at an academic hospital. PATIENTS: Adults with moderate to severe plaque psoriasis, with no previous methotrexate or cyclosporine treatment. INTERVENTION: Sixteen weeks of treatment with methotrexate or cyclosporine and an additional 36 weeks of follow-up. MAIN OUTCOME MEASURES: Direct and indirect medical and nonmedical costs associated with resource utilization during treatment and follow-up. RESULTS: Average cumulative total costs associated with 16 weeks of treatment were 1593 US dollars for methotrexate and 2114 US dollars for cyclosporine (521 US dollars less for methotrexate); during 36 weeks of follow-up, these costs were 2418 US dollars and 2306 US dollars, respectively. The overall difference in cumulative 1-year costs was 409 US dollars, or approximately 10% of the total costs. CONCLUSIONS: After 1 year, the overall difference in total costs between methotrexate and cyclosporine for 16 weeks of treatment and follow-up is relatively small. Systemic medication costs are only a fraction of the costs directly and indirectly generated by utilization of health care resources and associated with individual patients rather than with methotrexate or cyclosporine. Economic arguments can be supportive of but not decisive for individual patient decisions and guidelines for systemic therapy. Rational decision making for the treatment of psoriasis may include costs only within a long-term horizon and may consider the societal and patient benefits of different alternatives.

Administration, Oral↗

PubMed1998

Adult and two children with fetal methotrexate syndrome.

The folic acid antagonists, methotrexate and aminopterin, are known to be teratogenic in humans. The critical period for their teratogenecity is suspected to be between 6 to 8 weeks post-conception. Fetal exposure from 10 to 32 weeks weeks post-conception to methotrexate alone or in combination with other anti-cancer drugs has not resulted in obvious teratogenic effects. Methotrexate is often used to treat cancers but is occasionally used as an abortifacient. The long-term outcome of the fetal aminopterin syndrome has been published in only four adults. We report on a 28-year-old man with fetal methotrexate syndrome and two children with mild manifestations of the syndrome. One child was inadvertently exposed to methotrexate from 7 1/2 through 30 weeks post-conception because his mother was receiving it for treatment of breast cancer. The other was exposed from 11 weeks and 5 days through 25 weeks in an attempt to induce abortion. The 28-year-old man has craniofacial and digital anomalies, growth retardation but normal intelligence as noted in the previously reported cases. These cases remind us of the teratogenicity of methotrexate and should serve as a warning that if methotrexate is used as an abortifaciant and an abortion does not ensue, there is a teratogenic risk.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Dihydrofolate reductase synthesis in the presence of immobilized methotrexate. An approach to a continuous cell-free protein synthesis system.

Dihydrofolate reductase was synthesized in a batch system in the presence of the affinity ligand methotrexate, bound to various matrices. Two types of gel were used: commercial methotrexate-agarose with pores inaccessible for translation machinery and methotrexate-POROS with pores easily accessible for translation reaction mixture components. The transcription/translation reaction was not inhibited by either the immobilized methotrexate or the matrix. The enzyme was synthesized with a high yield and could simultaneously be removed from the reaction mixture by the affinity matrix during the synthesis. With methotrexate-POROS present the reaction probably proceeded mainly in the pores of the gel. Kinetic limitations to the reaction in the presence of the gel were not observed. Active dihydrofolate reductase was eluted from methotrexate-POROS. The activity recovered was higher than dihydrofolate reductase activity synthesized in free solution system. The influence of the presence of immobilized methotrexate on dihydrofolate reductase synthesis will be further studied in a novel type of a continuous protein synthesis system.

Bacterial Proteins↗

PubMed1987

A comparative study on the pharmacokinetics of methotrexate in a dose range of 0.5 g to 33.6 g/m2 in children with acute lymphoblastic leukemia.

Concentrations of methotrexate have been determined in the serum and cerebrospinal fluid after 406 infusions of methotrexate to 58 children with acute lymphoblastic leukemia. The dose of methotrexate varied between 500 mg/m2 and 33,600 mg/m2. Pharmacokinetic analysis of the data has been carried out. The effect of dose, age, and number of treatments on steady-state concentration, serum half-life, cerebrospinal fluid (CSF) serum distribution ratio, volume of distribution, systemic clearance of methotrexate was examined. The elevation of dose resulted in a nonproportional increase of the steady-state concentrations both in serum and CSF. The great inpatient and interpatient variations of steady-state concentrations caused only statistically not significant differences in the parameters of different subgroups of dosages. Correlation was found between concentrations of methotrexate in serum and CSF. One to 4 years old children were found to have lower steady-state concentrations of methotrexate in the serum and CSF, greater volume of distribution and faster clearance of the drug. Dose-dependency and age-dependency of methotrexate pharmacokinetics has been concluded.

Acute Disease↗

PubMed2003

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68.

OBJECTIVE: Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor(s) is involved in the modulation of acute inflammation by methotrexate and its nonpolyglutamated analog MX-68 (N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid). METHODS: We studied the effects of low-dose methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 5 weeks), MX-68 (2 mg/kg IP 2 days and 1 hour before induction of inflammation), dexamethasone (1.5 mg/kg IP 1 hour before induction of inflammation), or vehicle control on acute inflammation in an air-pouch model in A(2A) and A(3) receptor knockout mice. RESULTS: Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor alpha accumulation in the exudates of wild-type mice, but not in those of A(2A) or A(3) receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A(2A) knockout, A(3) knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68. CONCLUSION: These findings confirm that adenosine, acting at A(2A) and A(3) receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68.

2-Aminoadipic Acid↗

PubMed1993

Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate. METHODS: We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5-5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups. RESULTS: Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%, P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups. CONCLUSION: The methotrexate-leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.

Adolescent↗