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PubMed1997

Tacrolimus and methotrexate for the prophylaxis of acute graft-versus-host disease in allogeneic bone marrow transplantation in patients with hematologic malignancies.

We conducted a study to evaluate the efficacy of the combination of tacrolimus and short-course methotrexate for the prevention of acute GVHD in patients with hematologic malignancies. Patients received preparative regimens specific for their disease category. Twenty-six out of 28 received HLA-identical sibling transplants and the two remaining patients received one-antigen mismatched transplants from a family member. With a median follow-up of 14 months, the Kaplan-Meier estimate of event-free survival was 50 +/- 9%. The probability of grade II-IV GVHD was 15 +/- 7%. Four patients developed GVHD: two had grade II and one each developed grade III and IV GVHD. Administration of methotrexate was associated with severe mucositis and there was no correlation between the distribution of the GVHD grade and the cumulative dose of methotrexate given. Thirteen patients have died; nine from transplant-related complications and four from relapse. The major toxicity of tacrolimus was renal. Nine out of 28 patients (32%) developed renal dysfunction attributed to tacrolimus. The combination of tacrolimus and methotrexate is an effective regimen for GVHD prophylaxis but associated with significant renal and mucosal toxicity. Further studies of tacrolimus as a single agent or in combination with either steroids or with a lower dose of methotrexate or with other antiproliferative drugs to modify the adverse events may improve the therapeutic index of this useful and promising agent.

Acute Disease↗
PubMedDate not supplied

Placenta accreta and methotrexate therapy: three case reports.

Placenta accreta is a complication that is rising in incidence. The reported experience of methotrexate treatment in the conservative management of placenta accreta is scant. Three cases of placenta accreta managed with methotrexate are presented. Case 1: A woman had an antenatal diagnosis of placenta percreta. A successful manual placental removal occurred on post-cesarean day 16. Case 2: A woman had retention of a placenta accreta after a term vaginal delivery. Successful dilation and curettage were performed on postpartum day 37. Case 3: A woman had an antenatal diagnosis of placenta previa-percreta with bladder invasion. A simple hysterectomy was performed on post-cesarean day 46. Conservative management and methotrexate treatment resulted in uterine preservation in two of our three patients; however, this treatment did not prevent significant delayed hemorrhage. In view of the rapid resolution of vascular invasion of the bladder, methotrexate may have an important role in the management of placenta percreta with bladder invasion. The utility of methotrexate treatment with the conservative management of placenta accreta requires further evaluation.

Adult↗
PubMed1998

Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia.

The purpose of this study was to determine the incidence of and pharmacokinetic parameters associated with the development of transient encephalopathy following the administration of high-dose methotrexate and intrathecal chemotherapy in children with acute lymphoblastic leukemia (ALL). Two hundred and fifty-nine children with newly diagnosed ALL treated on one of two consecutive trials were analyzed. Presenting features in patients who developed transient encephalopathy were compared with those of patients who did not experience this event. For each patient who developed transient encephalopathy, methotrexate pharmacokinetic parameters were compared with those of matched controls. The cumulative incidence of acute encephalopathy was 3% (SE 1%) at 1 year and was associated with age greater than or equal to 10 years at diagnosis. Pharmacokinetic data did not differ between patients who developed transient encephalopathy and those who did not. The majority of patients had no long-term sequelae and were able to receive further courses of methotrexate without modification. Transient focal neurologic deficits occur in about 3% of children with ALL following the administration of intravenous and intrathecal methotrexate. These events cannot be predicted by pharmacokinetic parameters Of methotrexate disposition. However, these events are generally benign, suggesting that patients who experience acute encephalopathy should continue to receive this important chemotherapeutic agent.

Adolescent↗
PubMed2000

Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia.

Although high-dose methotrexate has been extensively studied in children with newly diagnosed acute lymphoblastic leukemia (ALL), there are fewer data in children with relapsed ALL, many of whom have been heavily pretreated and have subclinical kidney dysfunction. We characterized the pharmacokinetics of adaptively controlled methotrexate given as a 24-h infusion during consolidation therapy in 24 children with relapsed ALL. To achieve the target steady-state concentration of 65 microM, dosage adjustments were required in 14 patients, with doses ranging from 2854 to 6700 mg/m2 per course. The mean steady-state plasma concentration (Cpss) of 68.0 microM was different (P = 0.025) than the predicted Cpss (mean = 87.4 microM; range 35.7-184 microM) had no adjustment in dose been made. The coefficient of variation in Cpss was reduced from 41% to 18% by individualizing doses. Predisposing factors that correlated with decreased methotrexate clearance were female sex (P = 0.03), age greater than 6 years (P = 0.01), and prior history of heavy amphotericin B treatment (>30 mg/kg) (P = 0.03), but no factor predicted low clearance as well as the measured initial methotrexate clearance during the infusion (P < 0.0001). There was no life-threatening toxicity with the regimen. We conclude that dosage individualization decreases interpatient variability and avoids potentially toxic methotrexate exposures in heavily pretreated ALL patients.

Adolescent↗
PubMed2001

Efficacy of parenteral methotrexate in refractory Crohn's disease.

BACKGROUND: Methotrexate is steroid-sparing in short-term trials for refractory Crohn's disease. This study assesses the impact of dosing and administration on the long-term utility of methotrexate in Crohn's disease. METHODS: The efficacy and tolerability of methotrexate were assessed in all refractory Crohn's disease patients treated at the University of Chicago from 1 September 1989 to 6 June 1997. RESULTS: Seventy-six patients were identified: 43% male, mean age 35 years, mean Crohn's disease duration 9.5 years. Mean methotrexate duration was 55 weeks; mean dose was 20 mg/week. Drug administration was parenteral (78%), oral (13%), or combination (8%). Improvement occurred in 63% after a mean of 9 weeks, for a mean duration of 65 weeks. Remission occurred in 37% after a mean of 22 weeks, for a mean duration of 59 weeks. Improvement and remission were highest with parenteral therapy, but dose-independent. Parenteral therapy maintained remission in 46%. Improvement (P=0.05) and remission (P=0.01) were more likely for patients under 40. Improvement rates were higher with concurrent steroids (P=0.02) or antibiotics (P=0.01). Side-effects occurred in 46%, resulting in discontinuation in 18%. Prednisone was decreased in 78%, and stopped in 40%. CONCLUSIONS: Long-term therapy with methotrexate in Crohn's disease is safe, effective, steroid-sparing, and most efficacious in younger patients and when given parenterally.

Administration, Oral↗
PubMed2002

Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission.

BACKGROUND: The role of azathioprine and methotrexate in inducing and maintaining remission in patients with ulcerative colitis is still controversial. AIM: To evaluate the efficacy and tolerability of these two drugs in a series of patients with steroid-dependent or steroid-resistant active ulcerative colitis. METHODS: Forty-two patients were treated with a daily dose of azathioprine (2 mg/kg) and, if intolerant or not responding, with methotrexate (12.5 mg/week intramuscularly), and their efficacy was established by clinical, endoscopic and histological examinations at 6 months. Patients achieving clinical remission continued with treatment and were followed up. RESULTS: Of the 42 patients on azathioprine, 10 experienced early side-effects requiring withdrawal from treatment, 22 (69%) achieved complete remission, six (19%) achieved improvement and four (12%) obtained no substantial benefit. Methotrexate, administered to eight patients intolerant to and two patients resistant to azathioprine, induced complete remission in six patients (60%) and improvement in four (40%). During follow-up, a larger number of patients on azathioprine relapsed in comparison with patients on methotrexate [16/28 (57%) vs. 2/10 (20%), respectively; P < 0.05]. Only minor side-effects were observed on both treatments. CONCLUSIONS: Azathioprine is effective in patients with steroid-dependent or steroid-resistant ulcerative colitis. Methotrexate seems to be a good alternative in patients intolerant to or not responding to azathioprine.

Adult↗
PubMed1986

Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.

We treated 93 patients who had acute nonlymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate postgrafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival.

Acute Disease↗
PubMed2000

Effect of methotrexate on the temporomandibular joint and facial morphology in juvenile rheumatoid arthritis patients.

Juvenile rheumatoid arthritis is a disease characterized by chronic inflammation in one or more joints; it affects children and adolescents up to 18 years of age. This disease may cause significant skeletal joint destruction, and the temporomandibular joint, like other joints, may become severely affected resulting in aberrant mandibular growth, abnormal dentofacial development, and/or altered orofacial muscle function. Methotrexate is the most common remittive agent used in juvenile rheumatoid arthritis to modify the course of inflammatory destruction of peripheral joints. The purpose of this study was: (1) to evaluate the effect of methotrexate therapy on the prevalence of temporomandibular joint lesions and aberration in craniofacial development in children afflicted with juvenile rheumatoid arthritis; (2) to further examine the relationship between the temporomandibular joint/cephalometric findings and rheumatologic data (ie, age at onset, duration of disease); and (3) to evaluate further pauciarticular- and polyarticular-onset disease in juvenile rheumatoid arthritis and the prevalence of temporomandibular joint lesions and facial dysmorphology. The following information was obtained from 45 patients with juvenile rheumatoid arthritis: (1) routine rheumatologic clinical examination data; (2) anamnestic temporomandibular joint evaluation data; (3) clinical temporomandibular joint examination data; (4) lateral cephalometric measurement data; (5) posteroanterior cephalometric measurement data; and (6) individually corrected axial tomographic data. The results demonstrated the following: (1) radiographic evidence of condylar degeneration was apparent in 63% of all patients with juvenile rheumatoid arthritis with pauciarticular patients showing less temporomandibular involvement than polyarticular patients; (2) polyarticular juvenile rheumatoid arthritis patients receiving methotrexate showed less severe temporomandibular joint involvement than the polyarticular patients not receiving methotrexate; (3) the craniofacial structure was affected to a greater extent in the polyarticular form of the disease; (4) the craniomandibular index scores were significantly greater in the polyarticular group; (5) vertical height asymmetry and chin deviation were noted in more than 50% of the patients; and (6) there was a correlation between the severity of condylar lesions and cephalometric findings (ie, mandibular retroposition, posterior rotation, smaller ramus and mandibular dimensions) and the onset and duration of the disease. In conclusion, under the conditions of this study, methotrexate therapy was effective in minimizing temporomandibular joint destruction and craniofacial dysmorphology in juvenile rheumatoid arthritis patients with the polyarticular form of the disease.

Adolescent↗
PubMed1995

Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers.

Although substitution of tyrosine, phenylalanine, tryptophan, or arginine for leucine 22 in human dihydrofolate reductase greatly slows hydride transfer, there is little loss in overall activity (kcat) at pH 7.65 (except for the arginine 22 variant), but Km for dihydrofolate and NADPH are increased significantly. The greatest effect, decreased binding of methotrexate to the enzyme-NADPH complex by 740- to 28,000-fold due to a large increase in the rate of methotrexate dissociation, makes these variants suitable to act as selectable markers. Affinities for four other inhibitors are also greatly decreased. Binding of methotrexate to apoenzyme is decreased much less (decreases as much as 120-fold), binding of tetrahydrofolate is decreased as much as 23-fold, and binding of dihydrofolate is decreased little or increased. Crystal structures of ternary complexes of three of the variants show that the mutations cause little perturbation of the protein backbone, of side chains of other active site residues, or of bound inhibitor. The largest structural deviations occur in the ternary complex of the arginine variant at residues 21-27 and in the orientation of the methotrexate. Tyrosine 22 and arginine 22 relieve short contacts to methotrexate and NADPH by occupying low probability conformations, but this is unnecessary for phenylalanine 22 in the piritrexim complex.

Amino Acid Sequence↗
PubMed1996

Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kidney.

We have cloned a cDNA coding for a novel member of organic anion transporter, designated OAT-K1, expressed specifically in the kidney of rats. The rat OAT-K1 cDNA (2788 base pairs) had an open reading frame encoding for a 669-amino acid protein (calculated molecular mass of 74 kDa) which shows 72% identity with the cloned rat liver organic anion transporter, oatp. Northern hybridization and reverse transcription-coupled polymerase chain reaction revealed that the rat OAT-K1 messenger RNA transcript is expressed predominantly in the kidney. By use of stable LLC-PK1 cell monolayers transfected with the rat OAT-K1 cDNA, the transporter was suggested to mediate basolateral uptake of methotrexate, an anionic anticancer drug, but not taurocholate, p-aminohippurate, prostaglandin E2, and leukotriene C4. The methotrexate transport by rat OAT-K1 was unaffected by the presence of Na+ or Cl- gradient. The methotrexate accumulation by the OAT-K1-expressing cells showed saturability with the apparent Km value of 1.0 microM. Folate, sulfobromophthalein, and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited the methotrexate accumulation markedly. These findings suggest that the rat OAT-K1 is localized in the basolateral membranes of renal tubules, where it mediates renal clearance of methotrexate from the blood.

Amino Acid Sequence↗
PubMed2003

Methotrexate as a first-line corticosteroid-sparing therapy in a cohort of uveitis and scleritis.

PURPOSE: To evaluate the clinical experience with methotrexate as a first-line corticosteroid-sparing drug in patients with resistant ocular inflammation. METHODS: We retrospectively studied 39 consecutive patients with uveitis (n = 36) or scleritis (n = 3) who were treated with methotrexate following inadequate control with corticosteroids lasting five years. Criteria for initiating treatment with methotrexate and defining outcome were strictly defined. RESULTS: The cohort included 21 females and 18 males, all Caucasians, with a mean age of 26.6 years (range: 3-73 years). Patients were followed up for 21.5 +/- 12.6 months. Treatment was discontinued due to side effects in 10 patients (26%). Of the remaining 29 patients, full or partial control of inflammation was achieved in 23 (79%). Response to treatment was observed after a mean of 2.4 +/- 0.8 months. Ten patients were fully controlled and discontinued methotrexate therapy after a mean of 20.9 +/- 9.2 months, with no recurrence of inflammation. Use of topical and systemic corticosteroids was markedly reduced in responsive patients. CONCLUSIONS: Methotrexate is recommended as a first-line adjunct to or replacement of systemic corticosteroids in the treatment of ocular inflammation.

Adolescent↗
PubMed1999

Leflunomide versus methotrexate: a comparison of the European and American experience.

This paper compares and contrasts the results of two major Phase III clinical trials that compared the efficacy and safety of leflunomide, a new disease-modifying antirheumatic drug (DMARD), and methotrexate. In both the American trial (US301) and the multinational trial (MN302), patients with active rheumatoid arthritis (RA) were given either leflunomide (20 mg/day after a loading dose of 100 mg/day for 3 days) or methotrexate (7.5-15 mg/week) for 52 weeks. US301 was also placebo-controlled. Folate supplementation was mandatory in US301 but was given to < 10% of the patients in MN302. In US301, American College of Rheumatology (ACR) 20% response rates and improvement in tender and swollen joints were significantly better than placebo in both treatment groups, but were not significantly different from each other. Both treatments significantly retarded radiographically assessed progression of RA compared to placebo, but the degree of retardation was significantly greater with leflunomide. In MN302, the ACR response rate and improvement in tender and swollen joints with leflunomide were similar to those seen in US301. The ACR response rate and improvements in all efficacy variables with methotrexate were significantly greater than with leflunomide, however. Radiographically assessed disease progression was not statistically different with the two treatments. Use of methotrexate without folate in MN302 was associated with a higher incidence of clinically significant elevations of liver enzyme levels. These results indicate that both leflunomide and methotrexate are effective DMARDs. The symptomatic relief provided by both drugs is similar when they are given with folate supplementation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Methotrexate poisoning with acute hepatorenal dysfunction.

A 17-year-old girl receiving high-dose methotrexate for the treatment of osteosarcoma developed complications of acute renal failure and liver dysfunction with a coagulation disorder. The methotrexate concentrations were quickly reduced from 600 micromol/L to 50 micromol/L by treatment with plasma exchange and hemodialysis at 72 hours after discontinuation of the drug. After this reduction, continuous hemodiafiltration was initiated to further lower the methotrexate concentrations because of the persistently high and then the actual rebound in the plasma concentrations after plasma exchange and hemodialysis treatment. Continuous hemodiafiltration was able to reduce the concentrations without any rebound, despite its low column clearance. The rebound in plasma methotrexate concentrations seems to be corrected by plasma methotrexate after plasma exchange and/or hemodialysis.

Acute Kidney Injury↗
PubMed2002

In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6G and the use of a coated coil as a new drug delivery system.

PURPOSE: To determine the in vitro human scleral permeability of several dyes and drugdye combinations with varying molecular weights (MW) and lipid solubilities (fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein, and rhodamine). Coils coated with rhodamine were also evaluated for scleral permeability and sustained release. METHODS: Scleral sections excised from moist chamber stored human globes were mounted in a 2-compartment perfusion chamber. A small depot of drug/dye (100 microl of 10(-4) M fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein or rhodamine) or a coated coil in 100 microl of BSS was added to the episcleral surface while perfusing BSS to the choroidal side. The perfusate was collected and measured for fluorescence. Permeability was calculated as Ktrans from the flux measurements. RESULTS: Ktrans values (cm/sec, mean +/- SE) for the studied dyes and drug-dye combinations were 5.21 +/- 0.71 x 10(-6) for fluorescein, 1.64 +/- 0.17 x 10(-6) for dexamethasone-fluorescein, 3.36 +/- 0.62 x 10(-6) for methotrexate-fluorescein, 1.86 +/- 0.39 x 10(-6) for rhodamine and 2.18 +/- 0.23 x 10(-6) for the rhodamine from the coils. We found a significant difference between the permeability of the sclera to fluorescein and dexamethasone-fluorescein (P < 0.001), methotrexate-fluorescein (P < 0.05) and rhodamine (P < 0.001). Steady state flux was observed from the rhodamine coil. CONCLUSION: The rank order of scleral permeability to the studied dyes is as follows: fluorescein > methotrexate-fluorescein > rhodamine coil > rhodamine 6G > dexamethasone-fluorescein. Differences in scleral permeability are related to MW and lipid solubility. Prolonged transscleral diffusion of rhodamine delivered by solution and by coil are similar.

Coated Materials, Biocompatible↗
PubMed2003

Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer.

BACKGROUND: The purpose of this study was to carry out two randomised phase II trials of S16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results. PATIENTS AND METHODS: S16020 at either 80 or 100 mg/m2 was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m2, was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S16020 and 12 received methotrexate. RESULTS: A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the tumour sites and erythematous rash; consequently, both studies were stopped. CONCLUSIONS: Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

Adult↗
PubMed1989

Resistance to drugs associated with the multidrug resistance phenotype following selection with high-concentration methotrexate.

To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 10(2)- to greater than 10(5)-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications.

Antineoplastic Agents↗
PubMed1984

Expression of the mouse dihydrofolate reductase cDNA in B. subtilis: a system to select mutant cDNAs coding for methotrexate resistant enzymes.

With the aim to obtain a cDNA coding for a mammalian methotrexate resistant dihydrofolate reductase (Dhfr) a plasmid ( pQS1 ) harboring the mouse wild type Dhfr cDNA was constructed and used to transform a methotrexate sensitive bacteria: B. subtilis. A plasmid, pQS4 , expressing large amount of Dhfr in both E. coli and B. subtilis was isolated through a two steps selection with two substrate analogues, trimethoprim followed by methotrexate. This new plasmid has a 54 bp duplication including the beta-lactamase promoter and a deletion of 564 bp removing the 5' end of the beta-lactamase coding region. These changes create a new -35 region TTGAAA and a potentially stronger binding site for both E. coli and B. subtilis 16S ribosomal RNA. pQS4 transformed B. subtilis were then grown in the presence of high level of methotrexate and resistant mutants isolated. One of them, pQS6 , which codes for an enzyme about 50 times more resistant to methotrexate than the wild type Dhfr was sequenced. It shows that a point mutation replaces the glutamine residue at position 35 by a proline.

Animals↗
PubMed1996

Effect of age on the efficacy and tolerance of methotrexate in rheumatoid arthritis.

The objective of this study was to assess the influence of age on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Four hundred and sixty-nine patients were separated according to the age of onset of methotrexate treatment: before 65 yr (group 1, n = 416) and after 65 yr (group 2, n = 53). No difference was found in the evolution of clinical and biological parameters between the two groups. The number of patients in remission at the end of the study was equal. The frequency and type of side-effects were similar. No significant difference was found in the frequency and reasons for methotrexate withdrawal. We noted a trend towards lower therapeutic maintenance of methotrexate when prescribed after the age of 65 yr (P = 0.07, actuarial method). In conclusion, the age at initiation of methotrexate treatment probably did not influence its efficacy and toxicity in rheumatoid arthritis.

Actuarial Analysis↗