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PubMed2000

Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group.

BACKGROUND: Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. METHODS: We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. RESULTS: The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response. CONCLUSIONS: In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.

Antibodies, Monoclonal↗

PubMed2001

The role of caspases in methotrexate-induced gastrointestinal toxicity.

BACKGROUND: Enterocolitis is the major toxicity of methotrexate-based cancer chemotherapy, which limits its clinical applications. Methotrexate induces gut mucosal apoptosis in vivo; however, little is known about the molecular mechanism involved. The effectors of apoptosis include the caspase family of proteases, which are selectively activated in a stimulus-specific and tissue-specific fashion. The aims of this study were (1) to establish an in vitro model of methotrexate-induced gut apoptosis and (2) to determine the role of caspases in methotrexate-induced apoptosis in intestinal epithelial cells. METHODS: Rat intestinal epithelial cells (RIE-1) were treated with methotrexate in the absence or presence of ZVAD-fluoromethyl ketone, a general caspase inhibitor. Apoptosis was quantified by means of deoxyribonucleic acid (DNA) fragmentation assays and Hoechst nuclear staining. Caspase activation was measured with the use of fluorogenic substrates. RESULTS: Methotrexate induced apoptosis and decreased cell number in RIE-1 cells. DNA fragmentation was preceded by the sequential activation of caspases 9, 2, and 3, whereas caspases 1 and 8 remained inactive. ZVAD-fluoromethyl ketone inhibited methotrexate-induced caspase activation, DNA fragmentation, and nuclear condensation. CONCLUSIONS: These results indicate that methotrexate activates specific caspases and induces apoptosis in RIE-1 cells. Furthermore, caspases may play an important role in methotrexate-induced apoptosis in RIE-1 cells and may be potential therapeutic targets to attenuate methotrexate-induced enterocolitis.

Amino Acid Chloromethyl Ketones↗

PubMed1996

Transvaginal intratubal methotrexate treatment of ectopic pregnancy. Report of 100 cases.

Between November 1988 and December 1993, 100 patients with a common, unruptured ectopic pregnancy were treated with 1 mg/kg injection of intratubal methotrexate under transvaginal sonographic control. Patients were not excluded from this series on the basis of the size of the adnexal mass, the term of ectopic pregnancy or initial beta-human chorionic gonadotrophin (HCG) concentrations. Patients were excluded following uncertain diagnosis, signs of a ruptured ectopic pregnancy, or a significant haemoperitoneum on ultrasound scans. The mean age of the patients was 29.5 years (range 20-41). The mean gestational age and initial HCG concentration were 7.5 weeks (5-11) and 11,614 mIU/ml (192-105,000 respectively). Of the 100 patients, 22 (22%) had an ectopic pregnancy with active cardiac activity. Complete resolution was obtained in 78 out of these 100 ectopic pregnancies. Of these, 66 patients (85%) needed only one intratubal methotrexate injection, and 12 patients (15%) required a second i.m. methotrexate injection of 1 mg/kg. In this study, local treatment with one single intratubal methotrexate injection was successful in only 66% of patients. The mean resolution time for reduction of beta-HCG concentrations was 23.5 days (range 7-40). There was no statistically significant correlation between initial beta-HCG concentrations and outcomes after methotrexate treatment of ectopic pregnancy in our study. Where embryonal heart beats were observed, the success rate of the procedure was 40.9% (nine out of 22 cases). In the absence of cardiac activity, or when ultrasound examination showed no embryo, the success rate achieved was 84.6% (66 out of 78 cases) (P < 0.01). In all, 34 patients were considered to be incompletely cured after only one intratubal methotrexate injection: 12 patients required a second i.m. injection, a stagnation of beta-HCG concentrations was observed in 15 patients, abdominal pain occurred in six patients, and one patient suffered tubal rupture with haemoperitoneum. A total of 22 patients required secondary surgical management (salpingectomy). No biochemical or clinical side-effects of methotrexate treatment occurred. Tubal alteration ascribable to methotrexate injection occurred in one patient in our study. Out of 75 patients in this series who wished to conceive, 21 (28%) became pregnant within 1 year with the following outcomes: 11 pregnancies at term, three miscarriages, one induced abortion and six recurrent ectopic pregnancies (four occurred on the same side). Our findings suggest that treatment of common unruptured ectopic pregnancy without prior selection of patients, by a single intratubal methotrexate administration was associated with a 66% success rate. This was dependent only on the presence of embryonal heart beats and there was no correlation between the success rate and initial beta-HCG concentrations. Successful outcome after methotrexate administration for ectopic pregnancy could be perfected by way of an improved selection of patients based on inactive embryonal hearts and absence of a visualized embryo.

Adult↗

PubMed1998

Mifepristone in combination with methotrexate for the medical treatment of tubal pregnancy: a randomized, controlled trial.

In the search for a more potent alternative to a single i.m. injection of methotrexate for ectopic pregnancy, a randomized trial was organized. The efficacy of a combination of methotrexate and mifepristone was compared with methotrexate alone in the treatment of unruptured tubal pregnancies. The diagnosis of an unruptured tubal pregnancy was confirmed laparoscopically in 50 patients during a 2 year period. Women were randomized to receive a single i.m. injection of 50 mg/m2 methotrexate alone or a single dose of 600 mg oral mifepristone in combination with the same dose of methotrexate. Both treatment protocols were successful in achieving the resolution of unruptured ectopic pregnancy (18/25 in the methotrexate group and 22/25 in the combination group) following the initial intervention. A second injection was needed in four (16%) cases in the methotrexate group and in one (4%) case in the combination group. Overall, a complete resolution was achieved in 22/25 and 23/25 cases respectively. Unruptured ectopic pregnancy resolved faster in women given the combination of methotrexate and mifepristone compared to women given methotrexate only (P = 0.01). The effect of the methotrexate and mifepristone combination was more pronounced in women with higher human chorionic gonadotrophin concentrations.

Adult↗

PubMed2002

Investigation of the chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests.

OBJECTIVE: Methotrexate has a well-recognized side-effect of acute hypersensitivity pneumonitis. There is concern about whether chronic pulmonary toxicity can occur with methotrexate treatment. Our objective was to compare chest high-resolution computed tomography (HRCT) findings and serial pulmonary function tests in rheumatoid arthritis (RA) patients on methotrexate with findings for a control group of patients with RA who were not being treated with methotrexate. METHODS: Study patients had an initial chest radiograph, full pulmonary function tests and chest HRCT. Pulmonary function tests were then performed regularly over a 2-yr period. RESULTS: Fifty-five RA patients on methotrexate and 73 control patients with RA were enrolled for the study. Mean dose of methotrexate was 10.7 mg/week (S.D. 2.5 mg/week) and mean duration of treatment at entry into the study was 30 (20) months. Twenty per cent of patients with RA treated with methotrexate had pulmonary fibrosis (PF) on initial HRCT compared with 23% in the control group. When the patients with and without PF were compared, there was no statistical difference in the duration (mean difference -4.18 months, P=0.237) or dose (mean difference -0.8 mg/week P=0.52) of methotrexate therapy. Mean changes after 2 yr in forced expiratory volume, forced vital capacity, diffusion capacity for carbon monoxide and residual volumes were not different in the methotrexate group compared with the control group. CONCLUSION: There is no evidence to suggest clinically, from HRCT assessment or serial pulmonary function tests, that low-dose methotrexate is associated with chronic interstitial lung disease.

Administration, Oral↗

PubMed2003

Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis.

OBJECTIVES: To analyse whether the beneficial effects of methotrexate in rheumatoid arthritis (RA) could be due to inhibition of inflammatory cytokine production. METHODS: Cytokine production was studied using whole blood (WB) and mononuclear cells (MNC) of healthy volunteers and RA patients. Cultures were stimulated with either bacterial products such as lipo-oligosaccharide (LOS) or Staphylococcus aureus Cowan I (SAC) to activate monocytes or with monoclonal antibodies to CD3 and CD28 to induce polyclonal T-cell activation. We analysed the effect of methotrexate on cytokine production in these systems. RESULTS: We showed that methotrexate inhibits production of cytokines induced by T-cell activation. Among the cytokines inhibited were interleukin 4 (IL-4), IL-13, IFN gamma, tumour necrosis factor-alpha (TNF alpha) and granulocyte-macrophage colony-stimulating factor. Inhibition was seen at concentrations easily achieved in plasma of RA patients taking the drug. IL-8 production was hardly influenced by methotrexate. Furthermore, inhibition was dependent on the stimulus; IL-6, IL-8, IL-1 beta and TNF alpha production induced by LOS or SAC was only slightly decreased by methotrexate. The addition of folinic acid or thymidine and hypoxanthine reversed the inhibitory effects of methotrexate on cytokine production. Concentrations of methotrexate required for inhibition varied between donors. Oral intake of 10 mg methotrexate by RA patients led to marked inhibition of cytokine production in blood drawn after 2 h. CONCLUSIONS: Methotrexate turns out to be an efficient inhibitor of cytokine production induced by T-cell activation in freshly drawn blood. This is due to inhibition of the de novo synthesis of purines and pyrimidines. Cytokines produced by monocytes are hardly affected by methotrexate.

Antirheumatic Agents↗

PubMed1996

Hodgkin's disease and lymphoproliferations resembling Hodgkin's disease in patients receiving long-term low-dose methotrexate therapy.

Recently, it has been shown that patients with rheumatologic diseases who are treated with methotrexate can develop immunosuppression-associated lymphoproliferative disorders. Although a variety of lymphoproliferations have been described in the setting of methotrexate therapy, only rare cases of Hodgkin's disease (HD) have been reported. In this study, we provide a more complete characterization of the spectrum of lymphoproliferations that resemble HD or show features diagnostic of HD that occur in patients receiving long-term low-dose methotrexate therapy. Eight patients were receiving methotrexate for various disorders. Four cases were considered to represent lymphoproliferations resembling HD; the other four cases were diagnosed as HD because they showed diagnostic morphologic and immunophenotypic features. All three patients with lymphoproliferations resembling HD on whom follow-up was available experienced tumor regression with methotrexate withdrawal or with methotrexate withdrawal and steroids; none of these three patients required further therapy. All three patients with HD on whom follow-up was available are alive and free of disease following chemotherapy or radiation therapy. In two of these patients, the tumor persisted or progressed despite discontinuation of methotrexate with observation; the third patient received chemotherapy at the same time methotrexate was stopped. Our findings indicate that a spectrum of lymphoproliferations resembling HD or diagnostic of HD can occur in patients receiving long-term low-dose methotrexate therapy. Recognition of these lymphoproliferative disorders is clinically important because a subset of these neoplasms will completely resolve with discontinuation of methotrexate, thereby obviating the need for chemotherapy or radiation therapy.

Aged↗

PubMed1991

Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study.

Five patients with documented recurrences of glioblastoma multiforme were given continuous infusions of methotrexate delivered intratumorally using implantable catheters and subcutaneous refillable pumps. A continuous infusion of methotrexate (1 mg/d) was begun with concomitant oral administration of folinic acid. The methotrexate dose was increased every 2 weeks to 3, 10, 30, and, ultimately, 75 mg/d in two patients. Samples of serum and ventricular cerebrospinal fluid (CSF) were obtained to determine the levels of methotrexate and total bioactive folates, and brain tissue was obtained from two patients for determination of methotrexate concentration. The patients survived from 7 to 49 weeks after the implantation of the infusion device. Neither the clinical examination nor sequential radiological studies gave clear evidence of reduction in tumor size. Pneumonia developed in one patient, and mild hepatitis and increased seizure frequency in another. Methotrexate was stable in the delivery system over 12 days, and ventricular CSF reached steady-state levels by 5 days. Steady-state ventricular CSF levels of methotrexate were higher than serum levels in some patients, while the reverse was true in others. Levels of total bioactive folates in the CSF did not increase above the normal range. Methotrexate concentrations were highest at the center of the tumor, but measurable amounts of methotrexate were detectable in all areas of the brain. At autopsy in four patients, variable liquefactive necrosis of the brain tumors was seen, and viable tumor was found at the periphery of the tumor bed. These preliminary results suggest that it is technically feasible to infuse methotrexate into brain tumor cavities, and show that little central nervous system or systemic toxicity was encountered in five patients. Better delineation of the safety and efficacy of this therapeutic approach will require further clinical trials.

Brain Chemistry↗

PubMed1991

Methotrexate disposition following disruption of the blood-brain barrier.

Intracarotid drug administration after osmotic blood-brain barrier disruption (BBBD) enhances drug delivery to brain tumors. Despite clinical use, the pharmacokinetics of drugs following BBBD has not been described to date. Since methotrexate exhibits a concentration-toxicity response relationship, methotrexate disposition was determined following BBBD and intracarotid administration in seven patients with nonoperable brain tumors. Following a 1.5-5 g intracarotid methotrexate injection, 12 blood samples and 9 urine collections were obtained. Methotrexate concentrations in serum and urine were determined by fluorescence polarization immunoassay. The serum concentration-time data were best described by a three-compartment model. Systemic and renal clearances were consistent with previous studies. However, a prolonged mean terminal half-life of 51.5 h was observed. Serum methotrexate concentrations at 72 h exceeded 0.1 mumol/L in five of seven patients. Stomatitis occurred in one patient. Relative to previous reports, prolonged methotrexate half-life and cytotoxic methotrexate concentrations were observed in the serum of patients receiving intracarotid methotrexate following BBBD. Due to the prolonged cytotoxic methotrexate concentrations observed, extended leucovorin therapy may be indicated following BBBD and intracarotid methotrexate.

Adult↗

PubMed1990

Methotrexate as an adjunct in the treatment of persistent mild cardiac allograft rejection.

Because methotrexate arrests inflammation in autoimmune disease, we studied its efficacy in persistent low-grade cardiac allograft rejection. Seventeen patients aged 39.5 +/- 0.9 years (mean +/- SE) had persistent rejection despite previous therapy with high dose corticosteroids. Maintenance immunosuppression consisted of prednisone, azathioprine, and cyclosporine. The rejection episode treated with methotrexate occurred 180 +/- 55.4 days posttransplantation. Patients had incurred 2.7 +/- 0.3 previous episodes of rejection with the first episode occurring 30.6 +/- 6.2 days post transplant. Methotrexate was administered orally in 3 doses to an average weekly dose of 12.8 +/- 0.8 mg. The duration of methotrexate therapy was 9.0 +/- 1.1 weeks. Sixteen of the seventeen persistent rejection episodes resolved by 22.8 +/- 3.2 days of methotrexate therapy. Using methotrexate, the prednisone dose was decreased from 22.4 +/- 4.8 mg/day at initiation of methotrexate to 9.7 +/- 1.4 mg/day at the completion of methotrexate therapy (P less than 0.01). Over a 306 +/- 35-day follow-up, 9 of 17 patients (53%) have remained rejection-free. Leukopenia, necessitating reduction in azathioprine occurred in 10 patients. One patient developed herpes zoster during therapy. These data indicate that methotrexate is effective in resolving persistent cardiac allograft rejection with minimal morbidity. In addition, the use of methotrexate for treatment of rejection allows reduction in maintenance corticosteroid doses.

Adult↗

PubMed2006

Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma.

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.

Adolescent↗

PubMed1989

Short-term methotrexate administration by low-dose infusion--does it influence clearance of psoriasis?

Twenty-four patients between them received 86 low-dose methotrexate infusions (given over 36 or 48 h) delivered by a Graseby syringe pump in addition to conventional topical therapy during hospital admission for treatment of severe psoriasis (either erythrodermic or severe widespread plaque-type). The average length of hospital stay, usually the time taken to achieve complete clearance, and the average relapse time in the group of patients overall showed no differences from a control group of 25 patients (matched for age and sex) having a similar severity of psoriasis treated without methotrexate. However, separation of the patients into three sub-groups (erythrodermic, severe and 'unstable' widespread plaque-type, and severe and 'stable' widespread plaque-type disease) revealed that erythrodermic patients, as expected, cleared significantly quicker when receiving methotrexate although severe and 'unstable' widespread plaque-type patients had their clearance times possibly prolonged by short-term methotrexate administration. Although methotrexate is commonly used for long-term management of patients with severe psoriasis, short-term methotrexate administered in this manner cannot necessarily be recommended for severe widespread plaque-type disease. Measurement of methotrexate levels in a further 24 patients with severe psoriasis receiving 47 low-dose infusions revealed relatively constant and predictable methotrexate concentrations. Acute side-effects of methotrexate given by the infusion method were minor and uncommon, the infusion being well tolerated by patients. However, the low-dose infusion technique did not, apparently, offer any advantage over conventional methotrexate administration.

Adult↗

PubMed2005

Methotrexate for psoriasis: current European practice. A postal survey.

The aim of this survey was to determine current practice throughout Europe regarding use and monitoring of methotrexate therapy for psoriasis. A structured questionnaire with questions on methotrexate prescribing and monitoring was mailed to 150 dermatologists in 32 European countries in June 2002. Dermatologists' names were chosen at random from the 2001 European Academy of Dermatology and Venereology membership directory. A reply was received from 69 dermatologists of whom 59 prescribed methotrexate regularly. In those patients receiving systemic treatment for psoriasis, methotrexate was the most widely used drug (4.4 patients of every 10) followed by acitretin (3.2) and cyclosporin (1.6). Myelosuppression was the commonest reported fatal side-effect of methotrexate (eight of a total of 10 cases). None of the respondents routinely requested a baseline liver biopsy before starting methotrexate treatment and of every 10 of their patients on long-term methotrexate it was estimated that less than two had had a liver biopsy some time during treatment. Serum measurement of the amino-terminal peptide of type III procollagen (PIIINP) was used routinely to detect liver fibrosis by 12 (20%) of the 59 respondents who regularly prescribed methotrexate. This survey demonstrates that, despite the advent of new therapies, methotrexate retains a central role in the treatment of severe psoriasis in Europe. The responses demonstrated variation in, among others, the methotrexate dose regimen utilized and the use of folate supplementation, confirming the need for randomized controlled studies to address these issues.

Biopsy↗

PubMed2006

Methotrexate-induced renal oxidative stress in rats: the role of a novel antioxidant caffeic acid phenethyl ester.

The exact mechanisms of methotrexate-induced renal toxicity have not yet been determined. However, several hypotheses have been put forward, including oxidative stress. The aim of this study was to investigate the role of caffeic acid phenethyl ester (Caffeic Ester), a novel antioxidant, on methotrexate-induced renal oxidative stress in rats. Nineteen adult male rats were equally divided into three experimental groups as follows: control group, methotrexate-treated group, and methotrexate+Caffeic Ester-treated group. A single dose of methotrexate (20 mg/kg) was administered intraperitoneally (ip). Caffeic Ester (10 micromol/kg) was administered ip, once daily for seven days. Malondialdehyde (MDA) levels (an index of lipid peroxidation) were used as a marker of oxidative stress-induced renal injury. Similarly, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were determined to evaluate the changes of antioxidant status in renal tissue. Methotrexate administration to control rats increased MDA levels (P<0.0001), but decreased SOD, CAT and GSH-Px activities in renal tissue (P<0.0001). Caffeic Ester+ methotrexate treatment caused a significant decrease in MDA levels (P<0.001), and caused an increase in SOD, CAT and GSH-Px activities when compared with methotrexate treatment alone (P<0.001, <0.05, <0.0001, respectively). In conclusion, methotrexate leads to a reduction in antioxidant enzymatic defense capacity and causes lipid peroxidation in renal tissue. Similarly, Caffeic Ester exhibits protective effects on methotrexate-induced renal oxidative impairment in rats.

Animals↗

PubMed2003

Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the renal tubular secretion of methotrexate. However, the relative contribution of the active S- and inactive R-enantiomers is unknown. This study examined the effect of racemic ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney (IPK). Nineteen kidneys were divided between a control and three treatment groups. Controls were perfused with methotrexate alone (25 micrograms mL-1, n = 5) over three 30-min periods. Treatment groups were perfused with methotrexate (25 micrograms m-1) for the first period, followed by a second period of methotrexate (25 micrograms mL-1) plus R- (n = 5), S- (n = 5) or RS-ketoprofen (n = 4) at 25 micrograms mL-1, and a third period of methotrexate (25 micrograms mL-1) plus R-, S- or RS-ketoprofen (50 micrograms mL-1). Perfusate and urine were collected over 10-min intervals. Methotrexate was measured by HPLC and its binding in perfusate by ultrafiltration. The clearance ratio (CR) for methotrexate was obtained by dividing the renal clearance by the product of its fraction unbound and the glomerular filtration rate. During control experiments, there was no significant change in the CR over 90 min. R-, S- and RS-ketoprofen at 50 micrograms mL-1 reduced the CR of methotrexate significantly, but there was no difference between the three groups. While the enantiomers of ketoprofen reduced the renal excretion of methotrexate, the interaction was not enantioselective.

Animals↗

PubMed2006

Occurrence and impact of unanticipated variation in intravenous methotrexate dosing.

BACKGROUND: Studies using direct measurement suggest that the doses of up to 65% of drug infusions are outside industry standards. These preparation-associated errors occur despite routine safety procedures. As of April 5, 2006, the clinical impact of these errors had not been evaluated. OBJECTIVE: To measure the occurrence and associated clinical outcomes of variations in intravenous methotrexate dosing. METHODS: A prospective observational study was performed on 47 methotrexate infusions of 800 mg/m2 that were administered to 19 children with acute lymphoblastic leukemia. Serum methotrexate concentrations were measured at the end of the infusions, which were administered over 24 hours. The total methotrexate dose was determined by direct measurement of the concentration and the volume of each infusion. RESULTS: Dosing errors greater than or equal to 10% occurred in 11 (23%) infusions and ranged from -61% to 55% of the ideal dose. Repeated measures regression analysis found the measured total methotrexate dose was not significantly associated with the serum methotrexate concentration (p = 0.58) or with clinical toxicities. The methotrexate dose administered over the last hours of infusion (p = 0.006) and the serum creatinine level at diagnosis (p = 0.05) were the most significant predictors of the methotrexate concentration. High methotrexate concentrations were significantly associated with increased hepatic aminotransferase levels; however, the degree of elevation was of limited clinical relevance. CONCLUSIONS: While unexpected errors in drug dosing are more common than is suggested by other methods, the clinical impact observed in this model of methotrexate infusion was not demonstrably greater than medication errors described by other methods. Subsequent studies in this model of dosing error will require larger sample sizes, and other drugs should be evaluated.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Clinical pharmacokinetics of methotrexate in children.

Among the few antineoplastic agents investigated pharmacologically in children and adults, methotrexate has been clearly demonstrated to be handled differently in the two age groups. Age has in fact proved to be a major determinant, exerting an effect on both the pharmacokinetics and pharmacodynamics of methotrexate. Its pharmacokinetics, in turn, determine the drug toxicity. The beta-phase of methotrexate clearance, represented by the plasma drug concentration 48 hours from the start of a 6-hour infusion in a high dose treatment regimen, appears to be constant with age. In children, an increasing plasma drug concentration is apparent with increasing age, but whether this trend reflects a potential increase in the area under the plasma concentration-time curve of methotrexate has yet to be defined. Recent investigations have suggested that the drug is more completely distributed in the tissues of children than adults at the same infused dosage. This may explain the increased tissue toxicity caused by methotrexate. However, other observations suggest a faster drug turnover rate in the tissues of children. This may prevent the drug from concentrating in vital organs. Whether the metabolism of methotrexate, particularly the biosynthesis of methotrexate polyglutamates, plays a role in the biological effect of the drug is worthy of further investigation. The high brain tissue concentration after systemic methotrexate infusion and the slower efflux of methotrexate from brain tissues and cerebrospinal fluid make these tissues vulnerable to methotrexate toxicity.

Adolescent↗

PubMed1995

Methotrexate treatment of idiopathic granulomatous hepatitis.

OBJECTIVE: To test the efficacy and safety of low-dose oral pulse methotrexate therapy in patients with idiopathic granulomatous hepatitis who had complications of, did not respond to, or refused glucocorticoid therapy. DESIGN: Prospective case study. SETTING: Academic medical center hospital. PATIENTS: Seven patients with biopsy-proven, idiopathic granulomatous hepatitis who could not tolerate or were unresponsive to glucocorticoid therapy. INTERVENTION: Low-dose oral pulse methotrexate, 15 mg/wk. MEASUREMENTS: Temperature, symptoms, dose of concurrent glucocorticoids, biochemical tests of liver function, side effects of methotrexate, and assessment of liver biopsy specimens. RESULTS: All six febrile patients became afebrile within 3 months of starting methotrexate. Fatigue and anorexia improved in all patients. Glucocorticoid therapy was successfully discontinued within 6 months of starting methotrexate in four patients receiving prednisone at entry. Liver biopsy specimens were obtained again after methotrexate therapy and showed absence of granulomas in four of four patients. The minimum effective dose of methotrexate was 0.20 mg/kg body weight per week. No serious adverse effects and no failures to respond to methotrexate therapy were noted in this group of patients. In three patients, methotrexate therapy has been successfully tapered without signs or symptoms of recurrent disease. CONCLUSIONS: Low-dose oral pulse methotrexate was effective in treating patients with granulomatous hepatitis.

Administration, Oral↗