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PubMed1999

[Low-dose weekly methotrexate therapy for progressive neuro-Behçet's disease].

Among a variety of central nervous system (CNS) manifestations of Behçet's disease, the most serious one is progressive dementia. However, there has been no effective treatment to prevent the progression of dementia. The present studies have examined the efficacy of low-dose weekly methotrexate therapy for the progressive dementia in Behçet's disease. Six patients with the progressive type of neuro-Behçet's disease were treated with low-dose weekly methotrexate (7.5-15 mg/week). Neurological findings, psychological findings, brain MRI and IL-6 in cerebrospinal fluid were evaluated at the start and one year after the initiation of the therapy. All the 6 patients were refractory to the conventional therapy for neuro-Behçet's disease. The progression of neuropsychological abnormalities such as dementia was not recognized after one year from the initiation of methotrexate therapy. Consistently, IL-6 levels in cerebrospinal fluid were significantly decreased after one year from the initiation of therapy. Six months after the discontinuation of low-dose weekly methotrexate, progression of neuropsychological abnormalities such as dementia was recognized, and IL-6 levels in cerebrospinal fluid were significantly increased. These findings may suggest the suppression of the ongoing inflammatory process in the intracranial lesions by methotrexate. These results suggest that low-dose weekly methotrexate therapy may be a new promising method for the treatment of the progressive type of neuro-Behçet's disease.

Behcet Syndrome↗

PubMedDate not supplied

Lack of effect of methotrexate on human head and neck tumours transplanted in athymic nude mice.

Human head and neck tumour tissues derived from 16 different patients were transplanted in athymic nude mice. Treatment of tumour-bearing animals with methotrexate had little or no effect on the doubling time of the xenografts. Included were three tumour lines derived from patients in whom methotrexate did demonstrate antitumour activity. These results are also in contrast to clinical experience with methotrexate, showing remissions in 50% of patients with head and neck cancer. It is unlikely that this lack of effect of methotrexate is attributed to a difference in drug pharmacokinetics between man and nude mouse, since a xenografted rat tumour was found to be sensitive. With regard to possible resistance mechanisms underlying methotrexate inactivity, we found no evidence of increased dihydrofolate reductase activity in the methotrexate-insensitive human xenografts. It is possible that in this model a selection occurs favouring the outgrowth of a resistant subpopulation of tumour cells.

Animals↗

PubMed1996

Effects of methotrexate, sulphasalazine and aurothiomalate on polymorphonuclear leucocytes in rheumatoid arthritis.

The aim of the study was to evaluate the effects of treatment with methotrexate, sulphasalazine and aurothiomalate on polymorphonuclear leucocytes (PMN) in rheumatoid arthritis (RA). Circulating PMNs from 58 RA patients treated with either methotrexate (n = 27), sulphasalazine (n = 16) or aurothiomalate (n = 15) were assayed for their chemotactic capacity and generation of superoxide anions. The expression of CD18/CD11b was measured for 17 RA patients treated with methotrexate. Chemotaxis and generation of superoxide anions were not affected by any of the three drugs. We found no difference in the expression of CD18/CD11b in RA patients treated with methotrexate compared to healthy subjects. Further methotrexate and aurothiomalate did not in vitro alter chemotaxis, generation of superoxide anion or expression of CD18/CD11b on normal PMNs. In conclusion we found no evidence that the effect of methotrexate, aurothiomalate or sulphasalazine in RA can be explained by modulation of chemotactic ability or superoxide anion generation of peripheral circulating PMNs.

Adult↗

PubMed1992

Chronopharmacology of methotrexate pharmacokinetics in childhood leukemia.

Survival has been shown to improve when maintenance therapy for acute lymphocytic leukemia in children is given at night rather during the day. We examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In a crossover study, we determined the pharmacokinetics of intravenous methotrexate at 10:00 and 21:00 h in six children with standard or high-risk leukemia. During the study, children refrained from concomitant drugs (6-mercaptopurine and trimethoprim sulfamethoxazole). There was a significant fall in methotrexate plasma clearance at night (from 5.6 +/- 3 ml/min/kg to 4.7 +/- 2.3 ml/min/kg p < 0.05). Renal clearance of methotrexate tended to decrease at night and unbound renal clearance decreased significantly (from 17.5 +/- 1.7 ml/min/kg to 8.5 +/- 3.6 ml/min/kg p < 0.05). Creatinine clearance did not exhibit diurnal variation, when comparing two 12-h collections, but there was a significant decrease in the nonglomerular clearance of methotrexate (from 14.8 +/- 5.2 to 6 +/- 4 ml/min/kg). Because it is a weak organic acid, the tubular secretion of methotrexate depends on urinary pH. At night urinary pH is more acidic. This may result in more reabsorption and hence reduced renal clearance.

Child↗

PubMed1996

Increased matrix proteins, collagen and transforming growth factor are early markers of hepatotoxicity in patients on long-term methotrexate therapy.

BACKGROUND: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often limits the use of long-term low dose methotrexate for psoriasis and autoimmune diseases. Standard light microscopy lacks sensitivity for early fibrosis. DESIGN: This is a retrospective study of immunohistochemical markers of early fibrosis including laminin and fibronectin, collagen deposition and lipocyte activation in hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to five years, at an average dose of 20 mg/week. Biopsies before initiation of methotrexate (n = 36) showed minimal immunohistochemical expression of desmin, transforming growth factor alpha, matrix proteins, and collagen. Expression of laminin, fibronectin, collagens III and IV increased significantly and progressively over baseline values after cumulative doses of 1.5 +/- 0.25 g (n = 20) and 3 +/- 0.5 g methotrexate, respectively. Increases in desmin, smooth muscle actin and collagen type I also occurred but the changes were less consistent. Light microscopic abnormalities of hepatotoxicity were not detectable in any of these biopsies. CONCLUSIONS: Immunohistochemical quantification of matrix proteins and collagens type III and IV may be early, sensitive and dose responsive markers of methotrexate hepatotoxicity which progress with increasing cumulative doses of methotrexate.

Adult↗

PubMed1987

Methotrexate effects on heterotopic bone in rats.

We studied the effects of high-dose methotrexate on heterotopic bone formation induced by implants of demineralized bone matrix in the abdominal wall of growing rats. Methotrexate induced an arrest in normal weight gain of the animals, more pronounced the younger the animals were. The youngest animals had reduced ash weight and decreased isotope uptake in the tibiae and teeth. However, implants from these animals, given methotrexate 10 days before implantation of bone matrix, had a 33 per cent increase in ash content. When methotrexate was given at, or 10 days after, implantation, heterotopic bone formation was reduced by 40 and 22 per cent, respectively, whereas orthotopic bone was considerably less affected in these older animals. In a second experiment, no difference in elimination rates of 45Ca between methotrexate-treated and control rats in implants, teeth, or tibiae were found. It appears that a less detrimental effect of methotrexate on new bone formation can be expected if the drug is given before, or a substantial period after, surgery requiring bone formation for healing.

Animals↗

PubMed1991

Neutropenia due to low-dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal.

OBJECTIVE: To review experience with neutropenia related to low-dose methotrexate therapy in patients with psoriasis and rheumatoid arthritis. DESIGN: Retrospective review of medical records. SETTING: A 509-bed Melbourne teaching hospital. PATIENTS: Five patients admitted in 1987 and 1988, with neutrophil counts of less than 1 x 10(9)/L, given low doses of methotrexate for psoriasis or rheumatoid arthritis. MAIN OUTCOME MEASURES: Death, or length of hospital admission. FINDINGS: Four patients were women, and one a man; three had been treated for psoriasis, and two for rheumatoid arthritis. Ages ranged from 56 to 91 years. The eldest patients, aged 77, 81 and 91 years, died. The other two were discharged after 43 and 48 days. Prior to or shortly after admission, four patients were treated with penicillin antibiotics which may have interfered with methotrexate excretion. CONCLUSIONS: Methotrexate clearances (related to creatinine clearance rates and presumably low) were probably reduced sufficiently by concomitant therapy to result in neutropenia. Practitioners using methotrexate should be aware of drug interactions resulting in delayed methotrexate excretion. Blood counts should be monitored after changes in therapy, especially in patients with impaired renal function, such as the elderly.

Aged↗

PubMed1994

Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine the effect of two different weekly doses of folic acid on the toxicity and efficacy of low-dose methotrexate therapy for rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled study. PATIENTS: 79 persons between 19 and 78 years of age who fulfilled the American Rheumatism Association's criteria for rheumatoid arthritis. INTERVENTION: Participants were randomly assigned to visually identical placebo or to 5 mg or 27.5 mg of folic acid each week. MEASUREMENTS: Duration, intensity, and clinical severity of toxic events; efficacy (indices of joint tenderness and swelling and grip strength); plasma and erythrocyte folate levels; and other laboratory variables. RESULTS: Folic acid supplementation at either dose did not affect the efficacy of methotrexate therapy as judged by joint indices and patient and physician assessments of disease. Patients given folic acid supplements had lower toxicity scores than did participants given placebo (P < or = 0.001). Low blood folate levels and increased mean corpuscular volumes were associated with substantial methotrexate toxicity, whereas daily dietary intakes of more than 900 nmol (400 micrograms) of folic acid were associated with little methotrexate toxicity. CONCLUSIONS: Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.

Adult↗

PubMed2001

Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Corticosteroids remain the cornerstone of therapy for giant-cell arteritis, but relapse during dose tapering and corticosteroid-related adverse events often complicate management of this condition. Although several approaches, including combined therapy with cytotoxic agents, have been suggested to overcome these problems, no study has clearly shown benefits of alternate treatments. OBJECTIVE: To analyze the safety and efficacy of combined therapy with corticosteroids and methotrexate in giant-cell arteritis. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-based clinic. PATIENTS: 42 patients with new-onset giant-cell arteritis according to biopsy. INTERVENTION: High initial doses of corticosteroid were given; the dose was then tapered quickly until therapy was completely withdrawn. Methotrexate or placebo was given weekly from the start of corticosteroid therapy for 24 months. MEASUREMENTS: Number of relapses, cumulative dose of corticosteroid, and number of adverse events were assessed on completion of follow-up. RESULTS: Compared with combined prednisone and placebo therapy, treatment with prednisone and methotrexate reduced the proportion of patients who experienced at least one relapse (45% vs. 84.2%; P = 0.02) and the proportion of patients who experienced multiple relapses (P = 0.004). The mean cumulative dose of prednisone was 4187 +/- 1529 mg in the methotrexate group and 5489.5 +/- 1396 mg in the placebo group (mean difference, 1302 mg [95% CI, 350 to 2253 mg]; P = 0.009). Overall, the rate and severity of adverse events were similar between groups. Treatment was discontinued in 3 patients in the methotrexate group who experienced definite drug-related adverse events. In sensitivity analysis that included patients lost to follow-up, differences between groups in number of relapses and cumulative dose of prednisone were significant. CONCLUSIONS: Treatment with methotrexate plus corticosteroid is a safe alternative to corticosteroid therapy alone in patients with giant-cell arteritis and is more effective in controlling disease.

Adrenal Cortex Hormones↗

PubMed1993

An approach to preventing methotrexate prescribing errors in rheumatoid arthritis.

Methotrexate is an effective treatment for rheumatoid arthritis and is fairly well tolerated by patients when used appropriately. However, errors do occur due to a lack of awareness of the normal dosage range and potentially serious dose related side effects of methotrexate among physicians, pharmacists, and nurses. The approach taken by one hospital to prevent methotrexate prescribing errors includes daily monitoring of methotrexate by a pharmacist, building caution flags in the order loading program of the pharmacy computer system, and educating healthcare professionals to heighten awareness when prescribing, dispensing, and administering methotrexate for rheumatoid arthritis. At the hospital, since the institution of these policies and education of pharmacists, nurses, and physicians, there have been no incidents of methotrexate prescribing errors.

Arthritis, Rheumatoid↗

PubMed1999

[Efficiency of methotrexate in the treatment of cortico-dependent asthmatic patients].

OBJECTIVE: To evaluate the efficiency of low doses of methotrexate as corticosteroid sparing agent in asthmatic patients requiring long term corticosteroid therapy. METHODS: A prospective study was conducted with seven adult patients and one female pediatric patient suffering from corticosteroid-dependent bronchial asthma. The minimal stabilization time for each patient before initiating treatment with MTX was 3 months. The administered dose of methotrexate was 10 mg/week p.o. for adult patients and 15 mg/week for the pediatric patient. Dose tapering of methyl-prednisolone both during the stabilization and therapy periods was a 2 mg decrease every two weeks provided that no worsening in FEV1 higher than 5% occurred. RESULTS: For the group of adult patients, the stabilization time was 5.6 +/- 2.7 months. Methyl-prednisolone dose during the stabilization period could be decreased from 15.0 mg down to 25.4 +/- 12.0 mg (p = 0.013). The period of treatment of methotrexate was 7.3 +/- 3.4 months and the dose of methyl-prednisolone could be decreased from 25.4 +/- 12.0 mg down to 12.0 +/- 11.9 mg (p < 0.001). In the pediatric patient, the deflazacor dose was decreased from 60 down to 30 mg/day during treatment with methotrexate. In all patients a significant decrease could be obtained in the MP dose during treatment with methotrexate with no decrease in FEV1. No secondary effects were observed with the exception of a labial herpes in the pediatric patient. CONCLUSIONS: The administration of one single weekly dose of methotrexate 10 mg in adults and 15 in one pediatric patient allowed for a decrease of approximately 50% in the glucocorticosteroid dosage in this group of patients with corticosteroid-dependent bronchial asthma with no relevant adverse reactions during therapy.

Adolescent↗

PubMed1975

Consequences of methotrexate inhibition of purine biosynthesis in L5178Y cells.

Addition of 1 muM methotrexate to cultures of L5178Y cells results in an initial inhibition of thymidine, uridine, and leucine incorporation into acid-insoluble material followed, after about 10 hr, by a partial recovery in the extent of incorporation of these precursors. Acid-soluble adenosine triphosphate and guanosine triphosphate concentrations are greatly reduced initially, but guanosine triphosphate concentrations appear to recover partially by 10 hr. Acid-soluble uridine triphosphate and cytidine triphosphate concentrations initially increase after methotrexate treatment but then, with time, they too decline. Hypoxanthine and guanine are more effective than is adenine in overcoming the methotrexate-induced inhibition of thymidine incorporation. These results suggest that, in the presence of methotrexate, guanine nucleotides become limiting for nucleic acid synthesis before adenine nucleotides do. The block of purine de novo synthesis in L5178Y cells by methotrexate is almost complete and is not reversed with time. This suggests that the additional purine nucleotides that are available for nucleic acid synthesis 8 to 10 hr after addition of methotrexate are being derived from nucleic acid breakdown. Consistent with this is the observed reduction in the number of polyribosomes and hence, presumably in messenger RNA levels.

Adenine↗

PubMed1999

A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.

Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.

Adult↗

PubMed1975

A rapid and specific radioimmunoassay for methotrexate.

A sensitive and precise radioimmunoassay for methotrexate has been developed using antibody induced in rabbits, tritium-labeled methotrexate, and a nitrocellulose membrane separation technique. Antibody specificity was characterized by comparing the effectiveness of various related compounds to displace labeled methotrexate from the antibody-binding site. Assay of serum samples from persons receiving the drug was rapid and easy to perform. In a pharmacokinetic study of methotrexate, corresponding results were obtained when measurements were made by either enzymic assay or by radioimmunoassay. Drug concentrations could also be monitored in the cerebrospinal fluid and urine of patients on high-dose methotrexate therapy followed by citrovorum factor rescue. The system measured a little as 0.1 to 1 pmole of methotrexate, depending upon the antiserum used, and naturally occurring folates did not interfere with these determinations.

Animals↗

PubMed2000

Experiences and satisfaction with providing methotrexate-induced abortions among US providers.

OBJECTIVE: This study examined the acceptability of and experiences with methotrexate as an abortifacient among health care providers in the United States. METHODS: Seventy-six telephone interviews were conducted with providers (28% physicians, 13% midlevel providers, 29% administrators, and 30% counselors/other medical staff) of methotrexate-induced abortions during May and June of 1997. We examined provider satisfaction and several key operational issues relative to medical abortion, including: time spent with patients and staffing, training, and space needs. RESULTS: The majority of providers agreed that overall, more time was spent with methotrexate than with surgical abortion patients. Most agreed that the number of staff needed was the same for both methods, and that methotrexate required less office space. There were differing views on whether methotrexate required more, an equal amount of, or less training than surgical. Overall, providers were satisfied with methotrexate as an abortifacient. CONCLUSION: These data suggest that as knowledge of the method spreads, more providers will add this technique to their services.

Abortifacient Agents, Nonsteroidal↗

PubMed1979

Improved double-antibody enzyme immunoassay for methotrexate.

We report an enzyme immunoassay procedure for methotrexate measurement that takes less than 3 h to perform. beta-D-Galactosidase (EC 3.2.1.23) from Escherichia coli was conjugated to methotrexate by means of the mixed anhydride reaction. Bound and free labeled drug were separated by a preincubated cubic complex of first and second antibody. The enzyme activity of the bound fraction was measured with o-nitrophenyl-beta-D-galactopyranoside as substrate. The standard curve covered the range 1 to 10 micrograms of methotrexate per liter. One microgram of methotrexate per liter inhibited binding of the tracer by 17%. The assay is specific for methotrexate in the presence of folinic acid (citrovorum factor), folic acid, tetrahydrofolic acid, and other methotrexate metabolities. Intra- and inter-assay CVs were less than 5 and 10%, respectively. Results obtained with this enzyme immunoassay method agreed well with those obtained with an established radioimmunoassay method.

Cross Reactions↗

PubMedDate not supplied

Hospital resources used for ectopic pregnancy treatment by laparoscopy and methotrexate.

OBJECTIVE: To compare resources used in the medical and laparoscopic treatment of unruptured ectopic pregnancy. METHODS: We prospectively recorded all the medical resources required in the treatment of unruptured ectopic pregnancy. The study period ranged from January 1, 1995 to June 30, 1998. Single-dose intramuscular methotrexate injections were administered in 55 women (group I). This therapeutic option was provided on an outpatient basis in small EP (beta-HCG level < 5000 IU/L and hematosalpinx diameter < 3 cm). Serial clinical controls and biologic tests were performed until bHCG became negative. Forty women underwent a laparoscopic salpingostomy because they refused the methotrexate regimen or had "social" contra-indications (ie, predictable difficulties in the follow-up) (group II). Twenty-one patients underwent conservative laparoscopic treatment because of "medical" contraindications to methotrexate (group III). We recorded the resources used with the outpatient and inpatient treatment in each group (methotrexate consumption, operating room acts, length of hospital stay, clinical examinations, biological tests, and sonograms during the follow-up). RESULTS: We observed similar cure rates in each group, but it took significantly longer for beta-HCG to become negative in group 1. However, hospitalization was significantly less often required, and the length of hospital stay was shorter in this group. But length of follow-up, number of office visits, biological tests, sonograms, and subsequent readmissions were significantly more frequent after methotrexate. Despite more severe clinical presentations for patients in group III, we didn't find any significant differences in the hospital resources used in this group in comparison with those used in group II. CONCLUSIONS: The outpatient methotrexate option may result in low consumption of resources for a hospital because most of the follow-up can be performed by city practitioners and laboratories. For the laparoscopic option, efforts should be made to reduce the postoperative hospital stay.

Adult↗

PubMed2002

[Personal experience with methotrexate in the treatment of idiopathic juvenile arthritis].

Methotrexate was introduced in the treatment of juvenile idiopathic arthritis (JIA) about fifteen years ago. Today, methotrexate is the drug of choice in the basic treatment of JIA, especially for oligoarticular subtype The aim of this study is to show our experiences with this agent. In the period from 1996 to 2001 in the Pediatric Clinic--University of Zagreb 256 children with JIA were hospitalised--85 with polyarticular (33.2%) and 171 with oligoarticular subtype (66.8%). 34 of these patients (13.28%)--21 female and 13 male--16 with polyarticular and 18 with oligoarticular subtype were treated with methotrexate. The age at the beginning of the therapy was from 3 to 18 years (mean age 11.31 ys). The countinuos treatment with methotrexate lasted from 1 to 3 years. The dosage of methotrexate was 10-20 mg/m2, i.e. 0.3-0.5 mg/kg of body weight weekly. During patients' hospitalization the drug was administered parenterally, while at home it was continued to be given perorally. All of the patients took with methotrexate also nonsteroidal antiinflammatory drugs, and some corticosteroid therapy. All of the patients were submitted to regular physical therapy. The results of the treatment response were judged according to the global patients assessment (number of inflammated joints, degree of inflammation and functional disability), laboratory data (inflammation reactants, hemoglobin, RF). Statistically significant improvement of clinical and laboratory parameters (p < 0.01) was proved in 33 patients, while the improvement in one patient was minimal. Adverse reactions were rare and transitory.

Adolescent↗