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PubMed1986

The influence of route of administration on the hepatic uptake of methotrexate.

The present study was designed to determine if the hepatic toxicity of chronic low-dose methotrexate could be circumvented by administering the drug systemically, avoiding high initial hepatic drug exposure resulting from absorption of an oral dose into the portal circulation. Hepatic concentrations of methotrexate were determined in rats following chronic administration of 1 mg/kg by either the intraperitoneal (absorbed via the portal circulation) or subcutaneous route. Plasma drug profiles of methotrexate administered by the two routes were similar. The mean (+/- S.D.) hepatic methotrexate concentration following intraperitoneal administration was 3.12 +/- .47 nmol/gm wet weight and following subcutaneous administration it was 2.68 +/- .52 (p = .06). Renal methotrexate concentrations in the 2 groups were 1.23 +/- .27 and 1.26 +/- .49 nmol/gm wet weight, respectively (p = .88). The results of this study suggest that that oral administration does not lead to greater accumulation of methotrexate in the liver compared to systemic administration.

Animals↗

PubMed1990

Isolation and characterization of a variant dihydrofolate reductase cDNA from methotrexate-resistant murine L5178Y cells.

Dihydrofolate reductase (DHFR) cDNA sequences were isolated from a methotrexate-resistant mouse L5178Y cell line previously shown to contain methotrexate-resistant dihydrofolate reductase enzyme activity. Specifically-primed reverse transcription products were amplified using the polymerase chain reaction and then cloned into a mammalian expression plasmid. Candidate clones were identified by restriction analysis and then functionally tested by transfection into mouse 3T3 fibroblasts, selecting for methotrexate-resistant colonies. Sequence analysis of the cDNA clones demonstrated the substitution of tryptophan (TGG) in place of the wild-type phenylalanine (TTC) at codon 31. Sequencing of PCR-amplified genomic DNA extracted from the drug-resistant L5178Y cells confirmed the tryptophan codon at position 31. Transfection of mammalian tissue culture cells with expression plasmids containing the trp31 DHFR sequence resulted in substantial methotrexate-resistant colony formation. Recombinant trp31 DHFR enzyme activity expressed in stably-transfected Chinese hamster ovary cells was approximately 20-fold less sensitive to methotrexate inhibition than wild-type mouse DHFR enzyme activity. We conclude that the cloned Trp31 DHFR sequence encodes an enzyme substantially resistant to methotrexate which confers a drug-resistance phenotype to cells in which it is expressed.

Amino Acid Sequence↗

PubMed2006

Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease.

BACKGROUND: Although methotrexate is highly bound to albumin, it is thought to be removed by hemodialysis and not by peritoneal dialysis. We are not aware of any direct comparison in the same patient. CASE REPORT/METHODS: A 60-year-old patient on continuous ambulatory peritoneal dialysis was admitted to the East Alabama Medical Center for stomatitis and pancytopenia after being given 10 mg of methotrexate for his rheumatoid arthritis. Measurements of total methotrexate levels were made before, during, and after sequential peritoneal and hemodialysis treatments. RESULTS: We found that the clearance of methotrexate measured in the dialysate was equal in the first hour of dialysis for both types of dialysis, although serum levels were markedly lower in hemodialysis compared to peritoneal dialysis. CONCLUSION: Methotrexate was cleared by peritoneal dialysis in the first hour of an exchange and was not associated with a rebound in serum levels. Hemodialysis was associated with lower serum levels; however, there was also a significant rebound 2 hours after the procedure ended. Since neither procedure was able to preclude the death of the patient, other more effective means of methotrexate elimination should be employed.

Arthritis, Rheumatoid↗

PubMed2004

Defining the appropriate dosage of folinic acid after high-dose methotrexate for childhood acute lymphatic leukemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system.

Neurotoxicity after the administration of methotrexate continues to worry physicians. However, inadequate folinic acid rescue is often not considered as a cause of this complication. To clarify whether adequate folinic acid rescue prevents methotrexate-induced neurotoxicity without reducing the cure rate in childhood ALL, published evidence that supported or refuted this claim was investigated. A literature search was conducted and the authors of the relevant studies were contacted. The published data supported the contention that neurotoxicity can be prevented by adequate folinic acid rescue even after very high doses of methotrexate. The safe minimum dose of folinic acid can be defined in terms of the dose of methotrexate given; the time to start of rescue is probably less important. There was no evidence that higher doses of folinic acid, such as those used after methotrexate in the treatment of osteosarcoma, rescue leukemia cells. No change in cure rate was found in relation to changes in scheduling or clinically relevant doses of folinic acid rescue. The accumulation of folinic acid in the cerebrospinal fluid did not seem to be of clinical relevance. No studies indicate that doses of folinic acid after high-dose methotrexate administration interfere with the killing of leukemia cells, nor that delaying the start of rescue beyond a certain point increases the antileukemic effect; neurotoxicity will, however, be increased. Review of current protocols that use low-dose folinic acid rescue and are associated with neurotoxicity is highly recommended.

Central Nervous System Neoplasms↗

PubMed1999

Plasma and rectal adenosine in inflammatory bowel disease: effect of methotrexate.

In animal models, the antiinflammatory mechanism of action of methotrexate has been attributed to elevation of the extracellular concentration of the endogenous autocoid, adenosine. Our goal was to determine if methotrexate elevates adenosine concentrations in plasma and at the site of disease in patients with inflammatory bowel disease. In 10 patients with Crohn's disease or ulcerative colitis, rectal adenosine and plasma adenosine concentrations were measured before and immediately after a subcutaneous injection of methotrexate, 15 or 25 mg. The mean predose rectal adenosine concentration of 2.4 mumol/l was not significantly different from the postdose concentration of 2.1 mumol/l, p = 0.17, (paired two-tailed t test). Rectal adenosine concentration tended to correlate with rectal endoscopic disease activity, r = 0.59, p = 0.067 (Spearman rank order correlation). After methotrexate injection, neither the mean daily plasma adenosine concentration, nor the plasma adenosine at any individual time point, were significantly different from preinjection values. In patients with inflammatory bowel disease, an injection of methotrexate in the clinically effective dose range does not raise rectal or plasma adenosine concentrations. A role for adenosine as the mediator of the antiinflammatory action of methotrexate is not supported.

Adenosine↗

PubMed2004

A rare drug reaction to methotrexate after treatment for ectopic pregnancy.

BACKGROUND: Ectopic pregnancies are commonly diagnosed and treated in physicians' offices. In the hemodynamically stable patient, therapy often includes treatment with methotrexate. Well-known adverse effects of this drug include mucositis, abdominal cramping, and malaise. We report a case of a rare drug reaction after treatment with methotrexate. CASE: A 34-year-old, gravida 2, para 0, at 7 weeks of gestation by last menstrual period was diagnosed with an ectopic pregnancy and treated with methotrexate. The patient had an anaphylactoid reaction shortly after administration of methotrexate. CONCLUSION: Methotrexate is a commonly used therapy for ectopic pregnancies in the outpatient setting. Practitioners should be aware of the potential adverse reactions to methotrexate.

Abortifacient Agents, Nonsteroidal↗

PubMed2006

A cautionary tale: fatal outcome of methotrexate therapy given for management of ectopic pregnancy.

BACKGROUND: Medical therapy with methotrexate is a standard practice for the commonly encountered problem of ectopic pregnancy. Methotrexate is excreted predominantly by the kidney and should be used with extreme caution in renal insufficiency. All physicians who administer methotrexate must understand its mechanism of action, distribution, and elimination to minimize potential risks to the patient. CASE: A young, dialysis-dependent woman received a standard dose of methotrexate for an ectopic pregnancy. Prolonged methotrexate exposure resulted. The consequences-pancytopenia, desquamation, acute respiratory distress syndrome, and profound bowel ischemia-ultimately led to her death. CONCLUSION: Methotrexate, even at extremely low doses, can be fatal in patients with renal insufficiency. Alternative means of therapy should be sought for women with ectopic pregnancy and renal failure.

Abortifacient Agents, Nonsteroidal↗

PubMed2004

Low-voltage electrochemotherapy with low-dose methotrexate enhances survival in mice with osteosarcoma.

Methotrexate plays a key role in adjuvant chemotherapy for treatment of osteosarcoma, but is used at a high dose because it can pass through a cell membrane only with difficulty. Therefore, if the drug delivery of methotrexate to the tumor could be enhanced, antitumor effect and survival would improve. We examined whether enhancement of the antitumor effect of electrochemotherapy was feasible by using low-dose methotrexate in mice with osteosarcoma. The tumor-bearing mice were divided into four groups: no treatment, methotrexate treatment alone, electroporation alone, and methotrexate treatment followed by electroporation. In single-treatment series, the size of the tumors in mice treated with electrochemotherapy decreased substantially 6 days after treatment, whereas continuous growth was observed in the other groups. In the series of treatments repeated three times at 6-day intervals, the original tumors in the electrochemotherapy group decreased consistently and the tumors disappeared in four of seven animals within 16 days. In the other groups, the tumors continued to grow and all host animals died within 58 days. These results show the usefulness of electroporation to enhance the effects of low-dose methotrexate and the potential benefits of electrochemotherapy for the treatment of human osteosarcoma.

Animals↗

PubMed1999

Pulmonary function changes in patients with psoriasis on methotrexate therapy.

Methotrexate is known to induce pulmonary fibrosis. The present study was undertaken to assess pulmonary toxicity, if any, in psoriasis patients on methotrexate therapy and correlate the dose and duration of the treatment with any changes in pulmonary function. Ten patients who had taken methotrexate for one year and ten patients receiving methotrexate were included in the present study. Detailed lung function studies including arterial blood gas analysis were carried out. In both groups, the only pulmonary function abnormalities detected were FEF200-1200, FEF25-75%, residual volume (RV), and RV/TLC%, which showed a decline after six months of treatment. However, this was not significant. No changes were detected in the arterial blood gas values following methotrexate therapy. Therefore, the present study did not find any significant deterioration of lung functions in psoriasis patients on methotrexate therapy.

Adult↗

PubMed2006

Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate.

BACKGROUND: Methotrexate is an effective treatment in Crohn's disease, which may induce liver fibrosis with high cumulative doses. Transient elastography (FibroScan, Echosens, Paris, France) is a new non-invasive rapid, allowing assessment of liver fibrosis by measurement of liver stiffness. AIM: A prospective study to evaluate liver fibrosis with FibroScan and non-invasive biochemical methods in Crohn's disease patients treated with methotrexate. METHODS: Consecutive Crohn's disease patients had evaluation of liver fibrosis with non-invasive methods. Two subgroups of patients were compared: cumulative dose of methotrexate of more than 1500 mg (group 1) and naive for methotrexate (group 2). Liver biopsy was performed in patients with persistent liver enzyme abnormalities or FibroScan value >8.7 kPa. RESULTS: Fifty-four consecutive Crohn's disease patients were fully investigated (45 females, mean age 41 +/- 14 years). Median FibroScan values were similar in group 1 (n = 21) and in group 2 (n = 33), 5.5 and 4.5 kPa, respectively. FibroScan values were not correlated with the cumulative dose of methotrexate. CONCLUSION: In Crohn's disease patients treated with a high dose of methotrexate, significant liver fibrosis is rare and not accurately detected with liver enzymes abnormalities. FibroScan could be recommended and liver biopsy could be performed only with patients with high values and/or with chronic liver enzymes abnormalities.

Adult↗

PubMed1976

The effect of trimethoprim on cellular transport of methotrexate and its cytotoxicity to human lymphoblastoid cells in vitro.

A study has been made of the effects of the antifolate drug trimethoprim (2,4-diamino-5-(3'4',5'-trimethoxybenzyl)pyrimidine) on the cellular transport of natural folates and of methotrexate in a human lymphoblastoid cell line grown in culture. The results indicated that cellular uptake of 5-methyltetrahydrofolate, folic acid and methotrexate could be inhibited by trimethoprim; the inhibition, for methotrexate at least, was competitive, but it was in every case rather weak. Calculations showed that under conditions used during therapy with methotrexate, trimethoprim could be employed as an antibacterial agent without the cellular uptake of methotrexate being impaired by more than 1%. The cytotoxic effect of trimethoprim against the cell line used was 2000 times less, on a molar basis, than that of methotrexate. However, the degree of growth inhibition caused by the two agents in combination was greater than the sum of the individual toxicities. Again, this effect was not large at clinically useful concentrations of trimethoprim.

Biological Transport↗

PubMedDate not supplied

Intralesional methotrexate for keratoacanthoma of the nose.

A 56-year-old woman developed a nodule on her nose. A shave biopsy of the enlarging lesion was performed after 2 weeks and showed a keratoacanthoma. During the subsequent 4 weeks, the lesion continued to grow rapidly, and she was referred for excision of the lesion using the Mohs microscopically controlled technique. A tender 10x12 mm (120 mm2) erythematous nodule with a keratin-filled central umbilication was present on her left nasal ala (Figure 1). Treatment options were discussed. The left nasal ala was locally anesthetized with 1% lidocaine with 1:100,000 epinephrine and the keratoacanthoma was circumferentially infiltrated with 10 mg of methotrexate (0.8 mL of 12.5 mg/mL methotrexate) using a 30-gauge needle. The total amount of methotrexate injected was divided among several injection sites: the peripheral shoulder of the lesion (such that there was blanching of the entire rim) and under the center of the lesion at a depth clinically judged to be the deepest area of involvement. Within the next 7 days, the tumor began to decrease in size and ulcerate centrally. Examination 2 weeks after the initial injection showed a 71% reduction in the area of the tumor, which now measured 35 mm2 (7.0x5.0 mm). The tumor was injected in a similar manner as before with 5 mg of methotrexate. After another 2 weeks, the tumor had continued to shrink. It was flat without nodularity and measured 12 mm2 (4.0x3.0 mm); the tumor area was 66% less than 2 weeks earlier and 90% less than its original size. The residual tumor was again injected with 4.5 mg of methotrexate. There was complete clinical involution of the tumor when the patient returned for evaluation 6 weeks after her initial injection of methotrexate (Figure 2). A biopsy of the lesional area to confirm histologic resolution of the keratoacanthoma was not performed since there was no visible residual tumor. Periodic follow-up examination has been performed and there has been no subsequent recurrence of the keratoacanthoma.

Antimetabolites, Antineoplastic↗

PubMed1994

Effect of three lipophilic methotrexate derivatives upon mediator release by lipopolysaccharide-stimulated rat peritoneal macrophages.

The ability of methotrexate and three lipophilic derivatives (methotrexate-gamma-dimyristoylphosphatidylethanolamine (M gamma D), methotrexate-alpha-dimyristoylphosphatidylethanolamine (M alpha D) and methotrexate-alpha-gamma-di-dimyristoylphosphatidylethanolamine (M alpha gamma D) to modulate mediator release by lipopolysaccharide-stimulated rat peritoneal macrophages was investigated. At nontoxic concentrations, approximately 10 nmol/10(5) cells, M alpha D and M gamma D produced 11.06 +/- 1.0 and 75.6 +/- 5.2%, respectively, inhibition of tumour necrosis factor (TNF) release (mean +/- s.e.m., n = 4). At this same dose M alpha gamma D resulted in 68.8 +/- 2.1% inhibition of TNF but cellular ATP levels were reduced by 80%. The inhibitory activity of all three derivatives was dose-dependent. Non-derivatized methotrexate at a concentration of 25 nmol/10(5) cells had no inhibitory effect upon TNF release (14.7 +/- 0.8%, n = 3). Determination of prostaglandin E2 (PGE2) levels in the same samples demonstrated that all three conjugates were powerful inhibitors of prostaglandin release. At a quarter of the conjugate concentrations described above the monoamides M alpha (3.1 nmol/10(5) cells) and M gamma D (2.5 nmol/10(5) cells) maintained their effects on PGE2 production with 73 +/- 2.3 and 71 +/- 2.0% (n = 4) inhibition, respectively. At this lower concentration, however, the diamide M alpha gamma D (3.1 nmol/10(5) cells) was less effective in reducing the amount of PGE2 released from the macrophages (29 +/- 18%, n = 4). Maximal PGE2 inhibition by each of the conjugates was attained at approximately 5 nmol/10(5) cells. Unconjugated methotrexate (range of 2.5-20 nmol/10(5) cells) did not inhibit the release of PGE2 from lipopolysaccharide-stimulated macrophages.

Animals↗

PubMed1989

Complementation of a methotrexate uptake defect in Chinese hamster ovary cells by DNA-mediated gene transfer.

A methotrexate-resistant Chinese hamster ovary cell line deficient in methotrexate uptake has been complemented to methotrexate sensitivity by transfection with DNA isolated from either wild-type Chinese hamster ovary or human G2 cells. Primary and secondary transfectants regained the ability to take up methotrexate in a manner similar to that of wild-type cells, and in the case of those transfected with human DNA, to contain human-specific DNA sequences. The complementation by DNA-mediated gene transfer of this methotrexate-resistant phenotype provides a basis for the cloning of a gene involved in methotrexate uptake.

Animals↗

PubMed1987

Oral methotrexate is as effective as intramuscular in maintenance therapy of acute lymphoblastic leukaemia.

It has been postulated that variations in methotrexate absorption may influence the outcome of treatment in lymphoblastic leukaemia. One hundred and forty four children with acute lymphoblastic leukaemia not of the T cell type were randomised to receive continuing treatment with daily 6-mercaptopurine, vincristine, and prednisolone six weekly and methotrexate once weekly, either as a single oral dose or an intramuscular injection. Analysis of results with a minimum follow up of three and a half years has shown that the route of administration of methotrexate has had no influence on relapse at any site, but more children receiving intramuscular methotrexate died in remission. These results indicate that oral methotrexate is as effective as intramuscular methotrexate in continuing treatment of lymphoblastic leukaemia.

Administration, Oral↗

PubMed2005

Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study.

OBJECTIVE: To examine the efficacy and safety of infliximab combined with methotrexate compared with methotrexate alone in the treatment of ankylosing spondylitis (AS) using MRI and DXA to monitor its impact on bone. METHODS: In this single centre study 42 subjects with active AS were treated with methotrexate and were randomly assigned, in a ratio of 2:1, to receive five infusions of either 5 mg/kg infliximab or placebo over 30 weeks. The primary outcome was improvement in disease activity as shown by the BASDAI at week 30. MRI was used to assess the effect of treatments on sacroiliac and spinal enthesitis/osteitis and DXA to monitor bone mineral density. RESULTS: Both therapeutic agents were well tolerated with no dropouts due to adverse events. A significantly greater improvement in mean BASDAI score was seen in the infliximab arm at week 10 (p = 0.017) than in the placebo arm, but this was not maintained by week 30 (p = 0.195), 8 weeks after the last infusion, at which stage disease flares were reported by some subjects. MRI showed that the mean number of lesions resolving for each subject from week 0 to week 30 was significantly greater in the combination group than in the methotrexate monotherapy group (p = 0.016). CONCLUSIONS: Infliximab in combination with methotrexate was a safe and efficacious treatment in AS over 6 months and was associated with significant regression in enthesitis/osteitis as determined by MRI. However, disease flares were reported 8 weeks after the last infusion, indicating that addition of methotrexate failed to extend the infliximab dosing interval.

Absorptiometry, Photon↗

PubMed1993

Effects of methotrexate on glycosaminoglycan production by scleroderma fibroblasts in culture.

OBJECTIVE: To determine the effects of increasing concentrations of methotrexate on the proliferation and glycosaminoglycan (GAG) synthesis of cultured dermal fibroblasts from patients with scleroderma. METHODS: Cultured dermal fibroblasts from nine patients with scleroderma and nine normal volunteers were grown for 72 hours in media containing various concentrations of methotrexate. The GAG synthesis in each cell was measured after incubating the fibroblasts with [3H]glucosamine and [35S]sulphate. RESULTS: A negative correlation was found between the concentration of methotrexate and numbers of fibroblasts from patients with scleroderma and normal controls. A positive correlation was found between GAG synthesis in each cell, as measured by [3H]glucosamine and [35S]sulphate incorporation, and increasing methotrexate concentrations in fibroblasts from patients with scleroderma and normal controls. CONCLUSIONS: These data indicate increased GAG synthesis in scleroderma and normal fibroblasts with increasing concentrations of methotrexate. Therefore the reported beneficial effect of methotrexate on skin fibrosis in scleroderma is most probably not the result of direct inhibition of GAG synthesis by fibroblasts.

Adult↗

PubMed1997

Study of eight cases of cancer in 426 rheumatoid arthritis patients treated with methotrexate.

OBJECTIVE: To report cancer cases in 426 rheumatoid arthritis patients treated with methotrexate, and determine whether there was an increased incidence of cancer compared with patients never treated with methotrexate (rheumatoid controls) and to the whole regional population. METHODS: The duration of methotrexate treatment was 37.4 (SD 27.9) months. This population was compared with 420 rheumatoid arthritis controls and with a regional population of 812,344 people. Life table analysis was performed to compare the cancer incidence in the two rheumatoid populations. Adjustment for potentially confounding factors was done. The indirect standardisation methods was used to compare each rheumatoid population with the regional population. RESULTS: Eight cases of cancer (1.88%; 4.04 cases/1000 person years) were diagnosed in the methotrexate population v six (1.43%; 58.8 cases/1000 person years) in the rheumatoid controls. The life table method showed a higher incidence of cancer in the rheumatoid controls (P = 0.0001). In a multivariate analysis (Cox model), the only significant factor explaining this difference in the cancer incidence was age (P = 0.02). In the regional population there were 6418 new cases of cancer (0.79%; 2.85 cases/1000 person years). By the indirect standardisation method, the ratio of observed cases to expected cases of cancer in each of the rheumatoid populations was not significantly different from 1. CONCLUSIONS: In these eight cases, methotrexate was not found to be responsible for generating cancers. However, because of data regarding lymphomas and methotrexate, and because of the short follow up, especially in the control group, longer prospective studies are warranted.

Adult↗