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PubMed1985

Glutamylation of methotrexate in hepatoma cells in vitro: regulation and the development of specific inhibitors.

Methotrexate is glutamylated in cultured hepatoma cells to derivatives that contain a total of 2 to 5 gamma-glutamyl residues. The rate of polyglutamate formation and extent of accumulation are saturable with respect to both medium concentration of methotrexate and time. Maximal rates of glutamylation and accumulation of methotrexate polyglutamates at steady state occur at approximately 10 microM extracellular methotrexate. Inclusion of physiologic concentrations of insulin or removal of folate from the medium each cause a doubling of the rate of glutamylation, and these effects are additive. Insulin and folate restriction also enhance the accumulation of methotrexate polyglutamates. In combination they result in a doubling in the intracellular methotrexate polyglutamate pool at steady state and a shift in the polyglutamate distribution to longer-chain-length species. The importance of the longer-chain-length polyglutamates is apparent from the 6-hr retention of the polyglutamate species: Glu2, 15%; Glu3, 21%; Glu4, 50%; and Glu5, 83%. In probing the glutamylation reaction, a new series of inhibitors have been initiated. These are based upon replacing the incoming glutamate with 4-fluoroglutamate or synthesizing methotrexate with the glutamate replaced by 4-fluoroglutamate. The 4-fluoroglutamyl analogs of methotrexate are effective inhibitors of dihydrofolate reductase but cannot be glutamylated. They will be utilized to probe the role of glutamylation in antifolate activity and folate metabolism.

Animals↗

PubMed1985

Effect of methotrexate on the immune response in children with acute lymphatic leukaemia.

Lymphocyte count, lymphocyte subpopulations identified by monoclonal antibodies and mitogen stimulation assays with phytohaemagglutinin, concanavalin A, pokeweed mitogen and staphylococcal protein A, were used to quantitate the effect of methotrexate on the immune response in children with acute lymphatic leukaemia on maintenance therapy. Methotrexate exerted a profound but apparently short-term effect on these parameters as it is prescribed in current maintenance schedules for childhood acute lymphatic leukaemia. A significant drop in lymphocyte count, affecting all subpopulations, was observed 4 h after oral or intramuscular administration of methotrexate which had reverted to pre-methotrexate values one week after the drug was given. Lymphocyte function was markedly affected, with a major decrease in mitogen responsiveness 1 h after methotrexate and a reversion to pre-methotrexate values by 48 h. A selectivity of suppressor T cells to methotrexate is proposed as being responsible for early recovery. Scheduling of methotrexate in current maintenance programmes would therefore appear to allow adequate time for recovery of immunoresponsiveness between doses.

Age Factors↗

PubMed1993

Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis.

BACKGROUND: The conventional treatments for gastrointestinal symptoms associated with methotrexate therapy for psoriasis are unsatisfactory. OBJECTIVE: Our purpose was to determine the frequency, severity, and dose-relationship of gastrointestinal symptoms induced by methotrexate therapy for psoriasis and the response to folate supplementation. METHODS: Seventy-eight patients with psoriasis receiving low-dose, once-weekly oral methotrexate therapy were studied for the development of gastrointestinal symptoms. The effect of supplementation with folic acid, 5 mg daily, on gastrointestinal symptoms was examined. RESULTS: Gastrointestinal symptoms occurred in 32% of patients; nausea accounted for 80% of symptoms. The onset and severity of symptoms were related to the weekly dose of methotrexate but not to the cumulative dose or to the duration of methotrexate therapy. The symptoms were eliminated by folate supplementation; this did not interfere with the therapeutic effect of methotrexate. CONCLUSION: Gastrointestinal symptoms occur frequently with methotrexate therapy for psoriasis and can be adequately controlled with folate supplementation, apparently without compromising the therapeutic efficacy of methotrexate.

Adult↗

PubMed1995

Treatment of dermatomyositis with methotrexate.

BACKGROUND: No published data exist on the incidence of liver fibrosis in patients with dermatomyositis treated with methotrexate. OBJECTIVE: Our purpose was to examine the efficacy, steroid-sparing potential, and side effects of methotrexate in patients with dermatomyositis and to report liver biopsy results in four patients. METHODS: A retrospective review of all cases of dermatomyositis treated with methotrexate in a dermatology and rheumatology referral practice was conducted. RESULTS: Of the 10 cases reviewed, seven were of dermatomyositis whereas three were of amyopathic dermatomyositis (ADM). Nine patients received oral methotrexate. One patient received intravenous methotrexate. Improvement of cutaneous disease occurred in seven (100%) of the patients with dermatomyositis and in two (66%) of those with ADM; myositis improved in four (57%) of the patients with dermatomyositis. The initial prednisone dose was halved after an average of 18 weeks of methotrexate therapy in the patients with dermatomyositis and 13 weeks in the patients with ADM. Methotrexate-related side effects occurred in six (86%) of the patients with dermatomyositis and in one (33%) of the patients with ADM. Of the four patients who had liver biopsies, two (50%) showed mild hepatic fibrosis, resulting in discontinuation of the drug. Both patients in whom fibrosis developed had preexisting steroid-induced diabetes mellitus. CONCLUSION: Although methotrexate is an effective treatment for dermatomyositis, side effects are common. Patients with diabetes mellitus should be closely monitored for toxic effects on the liver.

Adult↗

PubMed1984

Influence of concomitant infusion of thymidine and inosine on methotrexate activity in normal and P388-bearing mice.

Combinations of thymidine and inosine (ranging from 0 to 7.5 mg/hr) were co-administered during a 72-hr continuous i.v. infusion of 3 micrograms/hr methotrexate in normal and P388 solid tumor-bearing DBA/2 mice. Methotrexate alone was lethal to all normal mice. Inosine at 1.0-7.5 mg/hr could reverse toxicity up to 100% while thymidine at 0.5-7.5 mg/hr was less effective (less than or equal to 86% survival). Combinations of the nucleosides averted toxicity more effectively than either compound alone and in a synergistic manner. From P388 tumor-bearing mice 27% survived methotrexate and eventually died of tumor. Co-infusion of thymidine or inosine decreased the percentage of toxic deaths and caused an increase in life span of more than 50% as compared to untreated tumor-bearing mice. However, the diminishing effect on survival with thymidine and inosine doses above 0.5 mg/hr indicated loss of the antitumor effect of methotrexate. This was also observed with combinations of the nucleosides. The influence of thymidine on the antitumor effect of methotrexate was compared in L1210- and P388-bearing mice (both in ascites) with 13 micrograms/hr methotrexate for 48 hr and 4 mg/hr thymidine for 96 hr. The increase in life span for L1210-bearing mice (8.6 days, 96%) was significantly longer than that with P388-bearing mice (6.1 days, 56%), probably due to biochemical differences between these tumors. It is concluded that co-administration of inosine and/or thymidine allows the use of methotrexate doses otherwise not tolerated, though with loss of anti-tumor effect. The choice of the tumor model may greatly influence the outcome of in-vivo studies on the modulation of methotrexate action by nucleosides.

Animals↗

PubMed1985

Targeting of liposomes containing methotrexate towards Tetrahymena pyriformis cells.

The uptake of liposomes containing methotrexate by Tetrahymena pyriformis cells was investigated with the aim of producing liposome-cell association enabling methotrexate to be introduced into the cytoplasm of intact cells. Incubation of liposomes containing methotrexate with tetrahymena pyriformis cells resulted in a time and concentration-dependent uptake of entrapped methotrexate by the cells. The uptake by Tetrahymena pyriformis cells (at 1 hr) of liposomes prepared by phospholipids and gangliosides extracted from Tetrahymena pyriformis cells was approximately three fold higher than that of liposomes prepared by commercial phospholipids. Approximately 90% of liposome uptake could be inhibited by cytochalasin B and also by NaN3 and 2-deoxyglucose. This was consistent with the uptake being the result of endocytosis. The remaining uptake was probably the result of adhesion of liposomes to the cell membrane. The rate of efflux vs time of methotrexate entrapped in liposomes was much slower than that of free methotrexate which reinforces the concept that endocytosis is the main mode of liposomes uptake by the cells. Liposomes containing methotrexate at concentrations as low as 4.5 microM effectively inhibited the activity of dihydrofolate reductase which was used as a function parameter in this study. Similar inhibition of the enzyme activity by free methotrexate was achieved only at concentrations as high as 880 microM. The influence of liposomes lipid composition on the targeting of liposomes to Tetrahymena pyriformis cells was discussed.

Animals↗

PubMed1993

Toxicity of paracetamol in cultured chick hepatocytes treated with methotrexate.

Cultured chick hepatocytes were used to investigate the hepatotoxicity of methotrexate alone and in combination with paracetamol. Treatment with methotrexate alone at concentrations as high as 1 mg/ml resulted in no toxicity in cultured chick hepatocytes, as indicated by no detachment of cells and no effect on protein synthesis or on release of the intracellular enzyme lactate dehydrogenase. However, treatment with methotrexate alone resulted in a 30% decrease in reduced glutathione levels. Combined treatment with methotrexate and paracetamol was toxic, but only in cells preinduced for cytochrome P450 1A by treatment with beta-naphthoflavone. Under these conditions, methotrexate lowered the threshold concentration of paracetamol at which toxicity was observed. This methotrexate-mediated increase in paracetamol toxicity was associated with decreased formation of the glucuronide, sulfate and thiol metabolites of paracetamol and with increased covalent binding of radiolabeled paracetamol to macromolecules. In cells pretreated with beta-naphthoflavone, additional treatment with either methotrexate or buthionine sulfoximine, an inhibitor of glutathione synthesis, together with paracetamol, was associated with decreased restoration of glutathione levels. These results suggest that methotrexate increased paracetamol toxicity by decreasing the amount of glutathione available for conjugation with reactive metabolites of paracetamol.

Acetaminophen↗

PubMed2004

Influence of p53 and caspase 3 activity on cell death and senescence in response to methotrexate in the breast tumor cell.

The influence of p53 function and caspase 3 activity on the capacity of the antifolate, methotrexate, to promote senescence arrest and apoptotic cell death was investigated in breast tumor cells. In p53 wild-type, but caspase 3 deficient MCF-7 breast tumor cells, death of approximately 40% of the cell population was observed immediately after acute exposure to 10 microM methotrexate (the IC80 value for a 2 h drug exposure). There was no evidence of either DNA fragmentation, a sub G0 population or morphological alterations indicative of apoptosis; however, PARP cleavage was detected. Cell death was succeeded by growth arrest for at least 72 h--where arrest was characterized by expression of the senescence marker, beta-galactosidase. The response to methotrexate in MCF-7/E6 cells with attenuated p53 function was also primarily growth arrest--but lacking characteristics of senescence. In contrast, MCF-7 cells which expressed caspase 3 demonstrated a gradual and continuous loss of cell viability and unequivocal morphological evidence of apoptosis. DNA fragmentation indicative of apoptosis was also detected after exposure to methotrexate in p53 mutant MDA-MB231 breast tumor cells which also express caspase 3. Methotrexate-induced both p53 and p21waf1/cip1 in MCF-7 cells within 6 h; however, no significant DNA strand breakage was evident before 18 h, suggesting that the induction of p53 reflects a response to cellular stress other than DNA damage, such as nucleotide depletion. Overall, these studies suggest that the nature of the cellular response to methotrexate depends, in large part, on p53 and caspase function. p53 appears to be required for methotrexate-induced senescence, but not apoptosis, caspase 3 is required for DNA fragmentation and the morphological changes associated with apoptosis, while neither p53 nor caspase 3 are required for methotrexate-induced growth arrest. Furthermore, the senescence phenotype may occur in the absence of direct DNA damage.

Apoptosis↗

PubMed2004

Methotrexate differentially affects growth of suspension and adherent cells.

The effects of low concentrations of methotrexate (MTX) on the growth of suspension (FM3A, 2B4 and THP-1) and adherent (NIH3T3 and V79) cells were compared. The concentration of methotrexate to cause the inhibition of cell growth was lower in suspension cells than in adherent cells. The IC(50) for FM3A, 2B4, THP-1, NIH3T3 and V79 cells were 3.5, 5, 9, 30 and 50 nM, respectively. The inhibition of cell growth was reversed completely by tetrahydrofolate and was fully or significantly reversed by adenosine and thymidine, suggesting that the effects of low concentrations of methotrexate result from the inhibition of biosynthesis of purines and pyrimidines. In suspension cells but not in adherent cells there was a decrease in the levels of S-adenosylmethionine and polyamines after methotrexate treatment. Growth of suspension but not adherent cells was significantly recovered by treatment with S-adenosylmethionine. However, treatment with spermidine did not reverse the effects of methotrexate in any of the cell lines. The preferential inhibitory effect of methotrexate in suspension cells versus adherent cells was due mainly to a more rapid uptake of methotrexate. This may be relevant to the in vivo effects of low doses of methotrexate, which have immunosuppressive and anti-inflammatory effects, because lymphocytes are suspension cells.

Adenosylmethionine Decarboxylase↗

PubMed2004

Previous ectopic pregnancy as a predictor of failure of systemic methotrexate therapy.

OBJECTIVE: To investigate whether a history of previous ectopic pregnancy is an independent risk factor for failure of methotrexate therapy in subsequent ectopic pregnancies and whether the previous treatment method influenced failure. SETTING: Inner-city teaching hospital. DESIGN: Retrospective case review. PATIENT(S): Five hundred four consecutive patients treated with "single-dose" methotrexate for ectopic pregnancy. Nine patients electing surgery after beginning medical therapy were excluded from analysis. INTERVENTION(S): Systemic methotrexate 50 mg/m(2). MAIN OUTCOME MEASURE(S): Failure of methotrexate therapy. RESULT(S): Twenty-one (18.6%) of 113 of previous ectopic patients and 26 (6.8%) of 382 first-time ectopic patients failed methotrexate therapy (odds ratio, 3.12). The overall success rate was 90.5% (448/495 patients). Univariant analysis showed that treatment hCG and progesterone (P) levels and ectopic cardiac activity were significantly different between successful and failed therapy. Logistic regression analysis for these four variables showed that only hCG and history of previous methotrexate remained significant risk factors for failure of methotrexate therapy. The likelihood of failure in patients with a previous ectopic was not influenced by previous treatment with salpingostomy, salpingectomy, or medical treatment. CONCLUSION(S): A history of previous ectopic pregnancy appears to be an independent risk factor for failure of systemic methotrexate treatment, but failure is not affected by previous treatment method.

Adult↗

PubMed2004

Methotrexate therapy for ocular cicatricial pemphigoid.

PURPOSE: To report the use of methotrexate therapy as first-line systemic therapy in the treatment of ocular-cicatricial pemphigoid and drug-induced ocular-cicatricial pemphigoid. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Twelve patients with ocular-cicatricial pemphigoid and 5 patients with drug-induced ocular-cicatricial pemphigoid treated with low-dose oral methotrexate as the sole systemic agent. In 14 of the 17 patients, methotrexate was the first systemic agent used. METHODS: Clinical data abstracted from patient medical records. MAIN OUTCOME MEASURES: Visual acuity, conjunctival inflammation, progression of cicatrization, and treatment-related side effects. RESULTS: After a mean follow-up duration of 30.2 months (range, 6-78 months), complete control or suppression, or both, of conjunctival inflammation was achieved in 89% of eyes with ocular-cicatricial pemphigoid and in 100% of eyes with drug-induced ocular-cicatricial pemphigoid using methotrexate monotherapy as the first-line systemic agent. Progression of conjunctival cicatrization was prevented in 72% of eyes with ocular-cicatricial pemphigoid and 90% of eyes with drug-induced ocular-cicatricial pemphigoid. Visual acuity was maintained or improved in 85% of total eyes treated with methotrexate monotherapy, and a final visual acuity of 6/18 or better was achieved in 74% of the eyes. Methotrexate therapy was well tolerated, with 92% of patients maintained on continued treatment experiencing no side effects. The most common side effects were gastrointestinal (50%), and most (78%) were reversible on dose reduction. In 4 of 17 cases, methotrexate was ceased as a result of possible treatment-related side effects. CONCLUSIONS: Low-dose oral methotrexate monotherapy is both highly efficacious and well tolerated as the first-line systemic agent in the treatment of ocular-cicatricial pemphigoid and drug-induced ocular-cicatricial pemphigoid.

Aged↗

PubMed1999

Treatment of tubal pregnancy in the netherlands: an economic comparison of systemic methotrexate administration and laparoscopic salpingostomy.

OBJECTIVE: This study was undertaken to compare from a societal perspective the costs of systemic methotrexate administration with those of laparoscopic salpingostomy for the treatment of patients with tubal pregnancy. STUDY DESIGN: An economic evaluation was set up in tandem with a multicenter randomized clinical trial that compared systemic methotrexate administration and laparoscopic salpingostomy for the treatment of 100 hemodynamically stable patients with laparoscopically confirmed unruptured tubal pregnancy. Data on resources used for treatment and lost production time were prospectively collected and costs of both treatments were calculated by multiplying actual expenses for resource units at a single center and resource unit use measured in all centers. Costs were originally calculated in Dutch guilders and converted to US dollars at a rate of 1.67 guilders/$1. RESULTS: Because clinical outcomes of the trial were equivalent for the 2 strategies a cost-minimization analysis was done. Mean total costs per patient were $5721 for systemic methotrexate administration and $4066 for laparoscopic salpingostomy, with a mean difference of $1655 (95% confidence interval, $906-$2414). Costs of systemic methotrexate administration were similar to those of salpingostomy for patients in whom the initial serum human chorionic gonadotropin concentration was <1500 IU/L, a cutoff value that had not been previously hypothesized. In a scenario without a confirmatory laparoscopy, in which transvaginal ultrasonography and serial repeated serum human chorionic gonadotropin measurements were assumed to be as accurate as laparoscopy, systemic methotrexate therapy would have reduced total cost by $1500 for a patient with an initial serum human chorionic gonadotropin concentration of <1500 IU/L. In such a scenario total costs would have been similar for a patient with an initial serum human chorionic gonadotropin concentration in the range of 1500 to 3000 IU/L, whereas systemic methotrexate administration would be more costly for a patient with an initial serum human chorionic gonadotropin concentration of >3000 IU/L. CONCLUSIONS: Although systemic methotrexate administration is safe and effective for the treatment of tubal pregnancy, it does not necessarily reduce costs. Systemic methotrexate therapy could reduce costs if administered to patients with low initial serum human chorionic gonadotropin concentrations without confirmatory laparoscopy.

Chorionic Gonadotropin↗

PubMed2003

Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia.

BACKGROUND: Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells. METHODS: We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m(2) over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m(2), or high dose, 1 g/m(2) intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia. RESULTS: Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 +/- 14.7 micromol/L versus 23.5 +/- 18.0 micromol/L, P <.001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 +/- 0.66 pmol/5 x 10(6) cells versus 7.4 +/- 15.2 pmol/5 x 10(6) cells, P <.001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 +/- 13.5 micromol/L versus 3.8 +/- 2.5 micromol/L, P =.029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% +/- 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% +/- 35%) compared with those in patients receiving mercaptopurine alone (P <.0001). CONCLUSION: These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine.

Antimetabolites, Antineoplastic↗

PubMed1999

Tamoxifen compared to methotrexate when used with misoprostol for abortion.

The purpose of this study was to compare tamoxifen to methotrexate, with respect to effectiveness, when followed by misoprostol to induce abortion. In the first phase, 198 women presenting for medical abortion at < 7 weeks gestation were randomized to receive either 40 mg of tamoxifen, followed 2 to 3 days later by 800 micrograms of misoprostol self-administered vaginally or 50 mg/m2 of methotrexate, followed 5 to 7 days later by the same dose of misoprostol. In the second phase, 200 women were randomized to receive 20 mg tamoxifen twice daily for 4 days, followed by 800 micrograms misoprostol or the same regimen of methotrexate and misoprostol as in phase 1. The main outcome measure was success rate determined by the number of women who aborted without surgery. In phase 1, the success rate was higher in the methotrexate group (93.0%) compared to the tamoxifen group (85.7%) (p = 0.045). In the tamoxifen group, nine of 98 women had incomplete abortions with symptoms requiring a surgical aspiration, compared to one of 100 women in the methotrexate group. In phase 2, the success rates were 90.9% in the methotrexate group compared to 84.7% in the tamoxifen group (p = 0.20). The side effects were less in the tamoxifen group in phase 1 but not in phase 2. When tamoxifen is given as a single dose, it is less effective than methotrexate but when it is given 20 mg twice daily for 4 days, there is no significant difference. Tamoxifen does not appear to have any benefits over methotrexate.

Abortion, Incomplete↗

PubMed1990

Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis.

Twenty-nine children with juvenile rheumatoid arthritis were studied to determine the safety and efficacy of methotrexate therapy. The initial dose of methotrexate averaged 7.1 mg/m2/wk and was given as a single, oral weekly dose or as three divided doses, each separated by 12 hours. Current antiinflammatory medications were continued; 25 of 29 children had had lack of efficacy, and 8 of 29 had toxic effects, with one or more prior drugs such as intramuscularly or orally administered gold, hydroxychloroquine, or D-penicillamine. Intolerable corticosteroid dependency or toxic effects were present in 18 of 29 cases. Methotrexate-treated patients were examined monthly; minimum treatment duration required to assess efficacy and toxicity was 6 months. The range of treatment duration was 8 to 39 months (mean 18.5 months). Efficacy was assessed by comparing pretreatment versus posttreatment fever and rash, swollen-joint counts, articular indexes, duration of morning stiffness, functional class, hemoglobin levels, and platelet counts. Treatment with methotrexate effectively controlled fever and rash in 83% of children with systemic juvenile rheumatoid arthritis, reduced morning stiffness by 63%, eliminated recalcitrant joint restriction in 48%, and reduced numbers of swollen joints and swelling indexes by 46% and 52%, respectively. No significant toxic effects were observed. Juvenile rheumatoid arthritis of long duration, or with major erosions, was more likely to be refractory to methotrexate therapy. We recommend earlier consideration of methotrexate in place of other slow-acting antirheumatic drugs for juvenile rheumatoid arthritis not responding well to usual therapy. Future studies should address potential methotrexate toxic effects in the lungs and reproductive system, as well as outcome after discontinuation of methotrexate treatment.

Adolescent↗

PubMed1983

Comparison of estramustine phosphate, methotrexate and cis-platinum in patients with advanced, hormone refractory prostate cancer.

In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were randomized to receive estramustine phosphate, methotrexate or cis-platinum. Response evaluations were done in 158 cases. Objective response rates (complete, partial or stabilization of disease) were 34 per cent for estramustine phosphate, 36 per cent for cis-platinum and 41 per cent for methotrexate. Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate. Probabilities of continued response indicated some advantage for methotrexate and median response durations at this time were twice as long for methotrexate (32 weeks) as for cis-platinum (16 weeks), with estramustine phosphate intermediate (23 weeks). Survival rates for the original treatment randomization groups were not different at this time. Side effects of estramustine phosphate consisted primarily of nausea and vomiting and/or anorexia but to a lesser extent than with cis-platinum. These effects were somewhat less for methotrexate, for which the major side effects were stomatitis and leukopenia, as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels. Other side effects of cis-platinum were less than for methotrexate (no stomatitis), except for signs of renal toxicity (elevations in blood urea nitrogen and serum creatinine), which were greater. Methotrexate had a relatively high level of activity against metastatic, progressive, hormone nonresponsive prostatic cancer, with side effects that were substantial but manageable.

Aged↗

PubMed2000

Cost-effectiveness of single-dose methotrexate compared with laparoscopic treatment of ectopic pregnancy.

OBJECTIVE: To evaluate the cost-effectiveness of treatment with intramuscular (IM) methotrexate compared with fallopian tube-sparing laparoscopy for small unruptured ectopic pregnancy. METHODS: A decision-analytic model accounting for varying resolution rates, complication rates, and cost estimates was built to compare the use of methotrexate with laparoscopy. Meta-analysis results of studies identified by a MEDLINE search for IM methotrexate resolution rates and tube-sparing laparoscopy resolution rates were used in model estimation. A similar process was used to generate model complication rates. Data on associated resource use were derived from established clinical guidelines. Estimates of 1998 costs incurred by provider organizations were calculated using data from a large managed care organization. RESULTS: The average methotrexate resolution rate among the studies included was 87% (range 75-90%). The average laparoscopy resolution rate was 91% (range 72-100%). Complication rates for methotrexate ranged from 0% to 22%, with an average of 10% for minor complications, and from 0% to 11% for serious complications, with an average of 7%. Complication rates for laparoscopy ranged from 0% to 8% for intraoperative complications, with an average of 2%, and from 0% to 15% for postoperative complications, with an average of 9%. Baseline model estimates indicated an average cost saving of more than $3000 per resolved ectopic pregnancy with methotrexate treatment compared with laparoscopy. Results of extensive sensitivity analyses supported the finding of a cost saving with methotrexate treatment. CONCLUSION: Single-dose methotrexate is a cost-saving, nonsurgical, fallopian tube-sparing treatment for ectopic pregnancy.

Abortifacient Agents, Nonsteroidal↗

PubMed1995

Aminophylline for methotrexate-induced neurotoxicity.

Methotrexate, a mainstay treatment for children with acute lymphoblastic leukaemia, can cause neurotoxicity, with paralysis, seizures, somnolence, anorexia, and headaches. The pathophysiology of this reaction is unknown. It has been suggested that the anti-inflammatory effect of methotrexate in patients with arthritis is due to adenosine release brought on by inhibition of purine synthesis. Since adenosine is a central nervous system depressant, we wondered whether adenosine release in the central nervous system could account for some of the neurotoxicity due to methotrexate, and whether that toxicity could be lessened by displacement of adenosine from its receptor by aminophylline. 6 patients (age 3-16 years) who had methotrexate-induced neurotoxicity unresponsive to standard treatment received 2.5 mg/kg aminophylline. In addition, the concentration of adenosine in the cerebrospinal fluid (CSF) from 11 children completing a 24-h systemic methotrexate protocol was compared with that in 8 newly diagnosed patients and 12 who had not received any treatment for at least a week. 4 of 6 patients with toxic signs and symptoms attributed to methotrexate and unrelieved by steroids, epidural blood patch, promethazine, 5-hydroytryptamine antagonists, paracetamol, and narcotics, had complete resolution of neurotoxicity after or during a 1-h infusion of aminophylline; 2 others had a pronounced improvement but persistent nausea. CSF adenosine concentrations of patients receiving methotrexate, even when there was very slight or no toxicity, were greatly increased compared with control subjects (mean values of 217 and 51 nmol/L, median 175 and 52 nmol/L). Subacute methotrexate neurotoxicity may be mediated by adenosine and relieved by aminophylline.

Adenosine↗