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PubMed2001

Successful rescue with leucovorin and thymidine in a patient with high-dose methotrexate induced acute renal failure.

A 54-year-old patient with primary cerebral lymphoma was treated with two 4-weekly cycles of high-dose intravenous cytarabine (12 g/m2) and methotrexate (3 g/m2). The administration of the first course proceeded without notable complications. Before the administration of methotrexate in the second cycle blood cell counts and chemistry showed no abnormalities except for slightly increased alkaline phosphatase and gamma-glutamyl-transpeptidase levels which was attributed to diphantoin comedication. The patient developed symptoms of acute renal failure 7 h after methotrexate infusion which resulted in a very high serum methotrexate level (39.84 micromol/l) at 20 h after infusion. Rescue therapy was intensified: the leucovorin dosage was increased (1,200 mg continuous i.v. infusion every 24 h) and combined with thymidine rescue therapy (8 g/m2 per day continuous i.v. infusion every 24 h). Urine alkalinization was increased and diphantoin therapy was stopped. Leucovorin eye drops and mouth washes were started 5 days after methotrexate administration to prevent conjunctivitis and mucositis as a result of high methotrexate levels (>2.4 micromol/l). In spite of the fact that serum methotrexate levels remained persistently higher than 0.1 micromol/l for 12 days, the patient experienced no further short-term systemic toxicity except for anaemia (grade 3 according to NCI Common Toxicity Criteria). After day 12 intensified rescue therapy and the frequency of alkalinization were decreased to standard procedures and stopped on day 19. It is concluded that i.v. administration with high-dose methotrexate can result in unpredictable acute toxicity. In our patient, acute methotrexate toxicity was treated successfully by intensification of classical leucovorin rescue therapy in combination with thymidine infusion. In addition, leucovorin mouth washes and eye drops may have prevented mucositis and conjunctivitis, respectively.

Acute Kidney Injury↗

PubMed2000

Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration.

PURPOSE: Intrathecal methotrexate achieves high concentrations in cerebrospinal fluid (CSF), but drug distribution throughout the subarachnoid space after an intralumbar dose is limited. The objective of this study was to quantify methotrexate distribution in CSF after intraventricular and intravenous administration and to identify factors that influence CSF distribution. METHODS: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received methotrexate by bolus injection (0.5 mg) and infusion (0.05 to 0.5 mg/day over 24 to 168 h) into the lateral ventricle, as well as intravenous infusions. CSF was sampled from the lumbar space, fourth ventricle and the subarachnoid space at the vertex. Methotrexate in CSF and plasma was measured with the dihydrofolate reductase inhibition assay. RESULTS: After bolus intraventricular injection, methotrexate exposure in lumbar CSF ranged from 11% to 69% of that achieved in the fourth ventricle. During continuous intraventricular infusions, methotrexate steady-state concentrations (C(ss)) in lumbar CSF and CSF from the vertex were only 20% to 25% of the ventricular CSF C(ss). The dose, duration of infusion, and infusate volume did not influence drug distribution to the lumbar CSF, but probenicid increased the lumbar to ventricular C(ss) ratio, suggesting the involvement of a probenicid-sensitive transport pump in the efflux of MTX from the CSF. During the intravenous infusions, the ventricular methotrexate C(ss) was lower than the lumbar C(ss) and the C(ss) in CSF from the vertex. CONCLUSION: Methotrexate CSF distribution after intraventricular injection was uneven, and at steady-state CSF methotrexate concentrations were lower at sites that were more distant from the injection site.

Animals↗

PubMed1982

Randomized study of high-dose versus low-dose methotrexate in the treatment of extensive small cell lung cancer.

Forty patients with extensive small cell lung cancer randomly received either high-dose or low-dose methotrexate with leucovorin rescue in combination with cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of VP-16, vincristine, and hexamethylmelamine. Nineteen patients were treated with the high-dose methotrexate regimen, and 21 received the low-dose methotrexate treatment protocol; both treatment groups were similar in median age, performance status and spread of disease. Response rates (74 percent for high-dose therapy; 67 percent for low-dose therapy), median survival (nine months versus nine months), and overall survival were similar for the two treatment groups. Myelosuppression was equivalent in both treatment groups but moderate to severe mucositis developed more often when patients were treated with the high-dose methotrexate regimen as compared with low-dose methotrexate therapy (p less than 0.001). Central nervous system recurrences developed after three patients received high-dose methotrexate therapy. This study indicates that when used with other antineoplastic agents, high-dose methotrexate therapy does not improve the remission rate or survival nor does it decrease central nervous system metastasis in patients with small cell lung cancer when compared with standard doses of methotrexate; high-dose methotrexate is associated with greater cost and toxicity.

Carcinoma, Small Cell↗

PubMed1992

Transport of methotrexate in basolateral membrane vesicles from rat liver.

Transport of the antifolate cancer drug methotrexate was studied in vesicles isolated from the basolateral membrane of rat liver. Transport of methotrexate by basolateral membrane vesicles (BLMVs) was mostly via uptake into an osmotically active intravesicular space, with some binding (approximately 9%), as shown by initial uptake studies and by varying medium osmolarity with increasing concentrations of sucrose. Methotrexate transport was linear for the first 20 s of incubation. Transport was not affected by imposition of a Na+ gradient across the vesicular membrane. Transport of methotrexate displayed a broad pH optimum: at an intravesicular pH of 7.5, the initial rate of uptake was not significantly different at extravesicular pH values ranging from 5.5 to 7.5, but uptake was less at extravesicular pH of 5.0 or 8.0. Methotrexate transport was saturable: Km = 0.15 +/- 0.05 microM and Vmax = 11.4 +/- 1.1 pmol 10 s-1 mg-1 protein. Methotrexate uptake into BLMVs was not inhibited by 5-methyltetrahydrofolate nor by 5-formyltetrahydrofolate but was weakly inhibited by folic acid in a concentration-dependent manner. Uptake was also inhibited by anion-exchange inhibitor 4,4'-diisothio-cyanostilbene-2,2'-disulfonic acid (DIDS), and by the structurally unrelated anions ATP, ADP, Cl-, SO4(2-), and oxalate2-. Adenosine (no negative charge) had no effect on transport. When vesicles were preloaded with anions (ADP, SO4(2-), oxalate2-) such that an anion gradient existed from the intra- to the extravesicular compartment, and methotrexate uptake was measured, no stimulation of uptake was seen. Methotrexate uptake into rat liver BLMVs was electrogenic as shown by stimulation of the initial rate of uptake by a valinomycin-imposed K+ diffusion potential across the vesicular membrane. These results suggest that methotrexate is transported into the hepatocyte across the basolateral membrane by an electrogenic, multispecific anion carrier system.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1984

Kinetics of methotrexate binding to dihydrofolate reductase from Neisseria gonorrhoeae.

The kinetics of methotrexate inhibition of dihydrofolate reductase from Neisseria gonorrhoeae have been investigated. Methotrexate was shown to be a tight-binding inhibitor (Kt = 13 pM) competitive with dihydrofolate. However, "stoichiometric" or "pseudoirreversible" inhibition could not be demonstrated. Progress curves of inhibited assays quickly attained steady state regardless of the order of substrate addition, indicating that methotrexate association and dissociation processes were rapid. Kinetic techniques were used to measure the rate of methotrexate dissociation from the enzyme-NADPH-methotrexate ternary complex. At 30 degrees, the first-order off-rate constant (koff) was calculated to be 0.56 min-1. This value is approximately 40-fold greater than the dissociation rate constant of methotrexate for Escherichia coli dihydrofolate reductase. At lower temperatures, progress curves of methotrexate-inhibited gonococcal enzyme assays displayed marked increases in both curvature and the time to reach steady state. At 9 degrees, the methotrexate dissociation rate was slow enough (koff = 0.04 min-1) so that initial velocities of the reaction could be measured, and under these conditions methotrexate inhibition was shown to be "stoichiometric".

Folic Acid Antagonists↗

PubMed1993

MK-801 and memantine protect cultured neurons from glutamate toxicity induced by glutamate carboxypeptidase-mediated cleavage of methotrexate.

Cleavage of methotrexate into glutamate and diaminomethylpteroate by intrathecal glutamate carboxypeptidase is a new approach to the treatment of acute methotrexate neurotoxicity. The simulation of glutamate carboxypeptidase rescue from high-dose methotrexate in neuron astrocyte cocultures of rat cerebellum or cerebral cortex resulted in a selective, concentration-dependent neurotoxicity. The neurotoxicity was caused by the enzymatic release of glutamate from methotrexate at lower concentrations of methotrexate, and by both glutamate and diaminomethylpteroate at concentrations of methotrexate exceeding 200 microM. The good neuroprotection afforded by MK-801 and memantine suggested that glutamate toxicity was mediated by N-methyl-D-aspartate receptors. Methotrexate alone was not toxic to astrocytes, neurons, or the neurite networking. [3H]thymidine and [3H]deoxyuridine incorporation studies showed that astrocyte proliferation in the presence of methotrexate was maintained by the reutilization of pyrimidine bases for DNA synthesis. N-methyl-D-asparate receptor antagonists should be coadministered in future experimental and clinical trials examining intrathecal glutamate carboxypeptidase rescue of methotrexate toxicity.

Animals↗

PubMed2006

Beta-glucan ameliorates methotrexate-induced oxidative organ injury via its antioxidant and immunomodulatory effects.

Methotrexate is an antifolate that is widely used in the treatment of rheumatic disorders and malignant tumors. The efficacy of methotrexate is often limited by severe side effects and toxic sequelae, where oxidative stress is noticeable. In the present study, the possible protective effect of beta-glucan in methotrexate-induced toxicity was investigated. Following a single dose of methotrexate injection (20 mg/kg), either saline or beta-glucan (50 mg/kg; orally) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the ileum, liver and kidney were removed to measure tissue malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content, as well as histological examination. Methotrexate caused a significant decrease in GSH levels, while MDA levels, MPO activity and collagen content were increased in all the tissues (P<0.05-0.001). On the other hand, administration of beta-glucan following methotrexate abolished the depletion of GSH and inhibited the increases in MDA, MPO activity and collagen content, while the histological analysis revealed that beta-glucan attenuated the tissue damage. Stimulation index, an indicator of oxidative burst in the neutrophils, was decreased by methotrexate (P<0.001), while beta-glucan abolished this effect. Furthermore, increased leukocyte apoptosis and cell death in methotrexate-treated animals were inhibited by beta-glucan (P<0.05). Thus, the findings of the present study suggest that beta-glucan, through its antioxidant and immunoregulatory effects, may be of therapeutic value in alleviating the leukocyte apoptosis, oxidative tissue injury and thereby the intestinal and hepatorenal side effects of methotrexate treatment.

Animals↗

PubMed1999

Efficacy of methotrexate treatment in viable and nonviable cervical pregnancies.

OBJECTIVES: This retrospective study examined the overall efficacy of methotrexate chemotherapy in the treatment of cervical pregnancy and attempted to determine whether differences in the response to methotrexate therapy exist between patients with viable and nonviable cervical pregnancies. STUDY DESIGN: A MEDLINE database search and a bibliographic review of the relevant literature were conducted to find reported cases of cervical pregnancy treated with methotrexate administration during the period from 1983 to 1997. Clinical and demographic characteristics, methotrexate regimen, concomitant invasive procedures, complications, and outcomes in viable and nonviable pregnancy groups were analyzed and compared. RESULTS: A total of 62 reported cases of cervical pregnancy were assessed. There were no statistically significant differences in demographic data, transfusion rate, and human chorionic gonadotropin remission time between viable and nonviable cervical pregnancy groups. Among the 35 cases of viable pregnancy 63% of women received systemic injection alone or a combination of systemic and local (intra-amniotic or intracervical) injection with methotrexate or potassium chloride and 37% had local injection of methotrexate (with or without potassium chloride) alone. Among the 23 cases of nonviable cervical pregnancy 96% of women received systemic methotrexate injection only. The need for >/=1 concomitant surgical procedure (such as simple curettage, dilation and curettage, cervical blocking, or uterine artery embolization) in conjunction with methotrexate therapy was significantly higher (P =.021) in the viable pregnancy group (43%) than in the nonviable pregnancy group (13%). The 94% success rate of preservation of the uterus in the viable pregnancy group was not significantly different from the 91% preservation rate in the nonviable pregnancy group. All patients who had successful uterine preservation returned to normal menstrual patterns. CONCLUSION: This retrospective study found that conservative treatment with methotrexate chemotherapy of patients with either viable or nonviable cervical pregnancies at <12 weeks' gestation carries a 91% success rate for preservation of the uterus. The structure of the cervix was restored and menstruation returned for all patients in whom the uterus was preserved after treatment. There was no evidence to suggest that the reproductive performance of these patients was affected by the treatment.

Abortifacient Agents, Nonsteroidal↗

PubMed2002

Weekly pulse therapy of methotrexate improves survival compared with its daily administration in MRL/lpr mice.

The purpose of this study was to determine whether weekly pulse therapy was superior to daily administration of methotrexate in MRL/lpr mice. Oral methotrexate was given to 6-week-old MRL/lpr mice at doses of 0.3, 1.0, or 3.0 mg/kg 5 days a week or at a dose of 15.0 mg/kg once a week until 35 weeks of age. The effects of methotrexate on physical, serological, and pathological findings were assessed. The survival rate and articular destruction on X-ray films were also evaluated. Both weekly pulse therapy and daily administration of methotrexate at the same weekly dose improved nephropathy and articular destruction of MRL/lpr mice when compared with control. However, weekly pulse therapy with methotrexate prolonged the survival of MRL/lpr mice when compared with the daily administration of the same weekly dose of methotrexate and control. Methotrexate did not suppress the increase in anti-DNA antibody and rheumatoid factor. Daily administration of methotrexate reduced the red and white blood cell counts, whereas weekly pulse therapy caused little reduction. In conclusion, weekly pulse therapy was superior to daily administration of methotrexate with respect to the survival rate, possibly due to a reduction in toxicity.

Animals↗

PubMed2002

Comparison of abortions induced by methotrexate or mifepristone followed by misoprostol.

OBJECTIVE: To compare the effectiveness, side effects, and acceptability of medical abortions induced by methotrexate and misoprostol with abortions induced by mifepristone and misoprostol. METHODS: This was a multicenter, randomized, nonblinded, controlled trial comparing 50 mg/m(2) of methotrexate followed 4-6 days later by 800 microgram of vaginal misoprostol with 600 mg of oral mifepristone followed 36-48 hours by 400 microgram of oral misoprostol. RESULTS: There were 518 women in the methotrexate group and 524 women in the mifepristone group. In the methotrexate group, 21 women required suction curretage, two for continuing pregnancy, eight because of physician request (usually for excessive bleeding), and 11 because of patient request. In the mifepristone group, 22 women needed surgical termination, 17 because of physician request, and five because of patient request. By day 8, only 386 (74.5%) in the methotrexate group had completed the abortion compared with 474 (90.5%) in the mifepristone group, and the mean number of days from beginning to completion was 7.1 for methotrexate and 3.3 for mifepristone (P </=.001). There were no differences in complications, and side effects were similar. Acceptance was slightly higher with mifepristone (88.0%) than with methotrexate (83.2%). CONCLUSION: Abortions induced with mifepristone completed faster than those induced with methotrexate, but the overall success rates, side effects, and complications were similar. Acceptance rates were slightly higher with mifepristone than methotrexate (P =.03).

Abortifacient Agents, Nonsteroidal↗

PubMed1999

Methotrexate compared with mercaptopurine for early induced abortion.

OBJECTIVE: To compare the antimetabolites methotrexate and 6-mercaptopurine as single-agent medical abortifacients using clinical and immunohistochemical analyses. METHODS: Twenty-seven women with gestations less than 7 weeks from the last menstrual period (LMP) were randomized to receive intramuscular methotrexate, 50 mg/m2, or oral 6-mercaptopurine, 200 mg. Forty-six additional women received methotrexate after randomization was discontinued. Women returned at 2-week intervals. Those without fetal cardiac activity were followed until complete abortion. Those with fetal cardiac activity were considered failures and underwent suction abortions. Tissue collected at the time of suction abortion was analyzed with the cell-proliferation immunohistochemical assay Ki-67. RESULTS: All 12 women in the 6-mercaptopurine group had fetal cardiac activity at follow-up and underwent suction abortion; therefore, this arm of the study was discontinued. Six of the 61 women who received methotrexate had fetal cardiac activity at follow-up and also underwent suction abortion. Fetal cardiac activity was present after methotrexate in three of 55 women at less than 6 weeks from the LMP and in three of six between 6 and 7 weeks from the LMP (P < .01). Women who aborted after methotrexate started bleeding on day 19 (standard deviation [SD] 7.8), bled for 9 days (SD 4.0), and used minimal pain medications. Tissues exposed to methotrexate showed decreased Ki-67 activity compared with tissues exposed to 6-mercaptopurine (P = .003). CONCLUSION: In oral doses of 200 mg, 6-mercaptopurine did not induce early abortion. A single intramuscular dose of methotrexate used without prostaglandins induced abortion in most women at gestational ages of less than 6 weeks. Ki-67 activity was lower in a small sample of fetal tissues exposed to methotrexate than in tissues exposed to 6-mercaptopurine.

Abortifacient Agents↗

PubMed1999

Methotrexate and leflunomide: biochemical basis for combination therapy in the treatment of rheumatoid arthritis.

OBJECTIVES: Methotrexate is currently one of the most widely prescribed disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA). Combination therapy of methotrexate with other DMARDs increases the clinical success of low-dose methotrexate treatment. Leflunomide is a new DMARD that may have a high potential for success in combination therapy with methotrexate. This review compares the mode of action of methotrexate and leflunomide and speculates on how this contributes to therapeutic efficacy in RA when these agents are used singly or in combination. METHODS: A literature review of the biochemical mechanisms considered to be the basis for the therapeutic efficacy of methotrexate and leflunomide in treating RA is presented. RESULTS: Low-dose methotrexate inhibits cytokine production, purine biosynthesis, and, in an animal model, causes the release of adenosine, a potent antiinflammatory agent. Leflunomide, through inhibition of de novo pyrimidine biosynthesis, can regulate lymphocyte proliferation. CONCLUSIONS: The biochemical mechanisms underlying the therapeutic efficacy of low-dose methotrexate and leflunomide in the treatment of RA are quite different. The potentially complementary mechanisms of action of these two effective DMARDs should provide a rationale for their use in combination therapy for patients whose condition no longer responds to methotrexate alone.

Adenosine↗

PubMed1999

Improved high-performance liquid chromatography determination of methotrexate and its major metabolite in plasma using a poly(styrene-divinylbenzene) column.

A sensitive high-performance liquid chromatographic assay has been developed for measuring plasma concentrations of methotrexate and its major metabolite, 7-hydroxymethotrexate. Methotrexate and metabolite were extracted from plasma using solid-phase extraction. An internal standard, aminopterin was used. Chromatographic separation was achieved using a 15-cm poly(styrene-divinylbenzene) (PRP-1) column. This column is more robust than a silica-based stationary phase. Post column, the eluent was irradiated with UV light, producing fluorescent photolytic degradation products of methotrexate and the metabolite. The excitation and emission wavelengths of fluorescence detection were at 350 and 435 nm, respectively. The mobile phase consisted of 0.1 M phosphate buffer (pH 6.5), with 6% N,N-dimethylformamide and 0.2% of 30% hydrogen peroxide. The absolute recoveries for methotrexate and 7-hydroxymethotrexate were greater than 86%. Precision, expressed as a coefficient of variation (n=6), was <10% at each of five methotrexate concentrations in the range 2.5-50 ng/ml. The limits of quantitation of methotrexate were 1 and 2.5 ng/ml for methotrexate and 7-hydroxymethotrexate, respectively (using 1 ml plasma). A robust HPLC method has been developed for the reproducible quantitation of methotrexate in plasma of patients taking a weekly dose of methotrexate for rheumatoid arthritis.

Antimetabolites, Antineoplastic↗

PubMed1998

Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomized clinical trials.

Our objective was to determine whether methotrexate is an effective steroid-sparing agent for patients with severe asthma. Published reports of controlled trials assessing the use of methotrexate in asthma were identified by a search of the MEDLINE, EMBASE, CINAHL, Biological Abstracts on CD, and Current Contents databases. Bibliographies from identified studies and from review articles were manually searched. Published and unpublished reports in any language were identified and assessed for inclusion in the meta-analysis. We selected randomized, double-blind, placebo-controlled trials in which low-dose methotrexate was administered to corticosteroid-dependent asthmatics, and oral steroids were subsequently tapered according to the patients' clinical status. Data were extracted independently by two reviewers. For all eligible trials, the mean reduction in oral corticosteroid dose, the mean change in FEV1, and the standard deviations, were calculated for the treatment and control groups. Data concerning side-effects of therapy were also extracted. Data from 12 studies, reporting on a total of 250 patients, were pooled using a weighted average method, with weights proportional to the inverse of the variance of the treatment effect. Compared to placebo, the use of methotrexate was associated with a pooled 6.0% improvement in FEV1 (95% CI, 1.0-11%) and an 18.2% reduction in oral steroid use (95% CI, 11.7-24.7%). This corresponded to a 3.3 mg day-1 greater reduction in oral steroid use for patients taking methotrexate than for those taking placebo (95% CI, 2.1-4.4 mg day-1). Gastrointestinal complications and transient increases in liver enzymes were more common in patients randomized to methotrexate. Three potentially life-threatening side-effects (two pneumonias and one liver dysfunction) occurred in 159 patients randomized to methotrexate vs. none in those patients on placebo. It was concluded that methotrexate allowed a modest reduction in oral corticosteroid compared to patients receiving placebo. The benefit is relatively small, however, and should be balanced against the potential for side-effects associated with the use of methotrexate.

Asthma↗

PubMed1979

Methotrexate, a high-affinity pseudosubstrate of dihydrofolate reductase.

Investigations have been made of the slow, tight-binding inhibition by methotrexate of the reaction catalyzed by dihydrofolate reductase from Streptococcus faecium A. Quantitative analysis has shown that progress curve data are in accord with a mechanism that involves the rapid formation of an enzyme-NADPH-methotrexate complex that subsequently undergoes a relatively slow, reversible isomerization reaction. From the Ki value for the dissociation of methotrexate from the E-NADPH-methotrexate complex (23 nM) and values of 5.1 and 0.013 min-1 for the forward and reverse rate constants of the isomerization reaction, the overall inhibition constant for methotrexate was calculated to be 58 pM. The formation of an enzyme-methotrexate complex was demonstrated by means of fluorescence quenching, and a value of 0.36 muM was determined for its dissociation constant. The same technique was used to determine dissociation constants for the reaction of methotrexate with the E-NADP and E-NADPH complexes. The results indicate that in the presence of either NADPH or NADP there is enhancement of the binding of methotrexate to the enzyme. It is proposed that methotrexate behaves as a pseudosubstrate for dihydrofolate reductase.

Kinetics↗

PubMed2004

Systemic treatment with either cyclosporin A or methotrexate does not influence the T helper 1/T helper 2 balance in psoriatic patients.

Cyclosporin A and methotrexate are highly effective drugs in the treatment of psoriasis. It was hypothesized that these therapies might modulate T helper cell cytokine secretion patterns or T cell migration patterns. Flow cytometric determination of interferon-gamma (IFNgamma) and interleukin 4 (IL4) producing T helper cell frequencies, as well as of cutaneous lymphocyte associated antigen (CLA) expressing T cell frequencies was performed in patients suffering from severe psoriasis, before, during, and after a scheduled immunosuppressive regimen with either cyclosporin A or methotrexate. Both cyclosporin A and methotrexate treatment reduced the psoriasis area severity index score after 12 weeks of treatment. Cyclosporin A treatment reduced the frequencies of IL4-producing CD4(pos) T cells, without significantly affecting the T helper 1 to T helper 2 (Th1/Th2) balance but in conjunction with the decreasing number of peripheral blood eosinophil counts. In methotrexate-treated patients, the Th1/Th2 balance was unaffected. Cessation of both therapies resulted in increased numbers of IFNgamma- as well as IL4-producing CD4(pos) T cells as compared to before initiation of oral therapy. Methotrexate, but not cyclosporin A, treatment reduced the frequencies of circulating skin-homing CLA(pos) T cells. This effect was reversed by 4 weeks after withdrawal of methotrexate therapy. We conclude that (1) neither cyclosporin A nor methotrexate affects the balance between Th1 and Th2 cells; (2) exaggerated cytokine production by T helper cells after cessation of oral cyclosporin A or methotrexate drug treatment may contribute to the reappearance of psoriatic skin lesions; and (3) decrease of circulating skin-homing T cells may be responsible for part of the therapeutic effect of methotrexate in severe psoriasis.

Adult↗

PubMed1998

The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis.

AIMS: Methotrexate is considered by many practitioners to be the agent of choice in the treatment of rheumatoid arthritis. The pharmacokinetics of methotrexate have been reported to exhibit significant intersubject variability. Therefore, this study was undertaken to evaluate the population pharmacokinetics of methotrexate during long-term administration in adults with rheumatoid arthritis. METHODS: Methotrexate pharmacokinetics were evaluated in a 36 month study of 62 adults with rheumatoid arthritis. Patients received oral or intramuscular doses of methotrexate weekly with pharmacokinetic studies performed every 6 months. Data were analyzed with nonlinear mixed effects modeling. RESULTS: Three thousand two hundred and sixty post oral or intramuscular dose serum methotrexate concentrations comprising 425 individual concentration vs time profiles were modeled using NONMEM. Covariates that significantly (P < 0.005) influenced the disposition of methotrexate were age (AGE, years), body weight (BW, kg), creatinine clearance (CL(CR), 1 h(-1)), gender (GEN; 0 = male, 1 = female), dose (DOSE, micromol), and fed vs fasted state (FED; 0 = fasted, 1 = fed). The final model describing the biexponential disposition of methotrexate was clearance(CL, 1 h(-1)) = (0.0810*BW + 0.257*CL(CR))*(1-(0.167*GEN); central volume (Vc, 1) = 0.311*BW; peripheral volume (Vp, 1) = 0.469*BW-0.169*AGE; intercompartmental clearance (Q, 1 h(-1)) = 4.27*(1-0.355*GEN); oral absorption rate constant (ka(p.o.), h(-1)) = 4.70-0.0439*DOSE*(1-0.507*FED); intramuscular absorption rate constant (ka(i.m.), h(-1)) = 0.122*DOSE; relative bioavailability (F) = 93.4%; and oral absorption lag time (LAG(p.o.), min) = 13.5. Pharmacokinetic parameters (%CV) for a typical fasted male subject in this study were CL, 7.341 h(-1) (27%); Vc, 23.51 (28%); Vp, 25.31 (31%); Q, 4.25 1 h(-1) (41%); ka(p.o.), 3.67 h(-1) (77%); and ka(i.m.), 3.09 h(-1) (44%). CONCLUSIONS: The population pharmacokinetics of methotrexate in adults with rheumatoid arthritis were well described by this investigation. Substantial interpatient variability was explained by incorporating patient specific data into regression equations predicting pharmacokinetic parameters.

Adult↗

PubMed2002

A study of parenteral use of methotrexate in rheumatic conditions.

1. This paper reports the findings of a small pragmatic study to compare the safety and efficacy of methotrexate administered by intramuscular and subcutaneous injection, and to teach patients to self-administer methotrexate by the subcutaneous route. 2. Eight patients with rheumatic conditions, already receiving a stable weekly dose of methotrexate by intramuscular injection, were entered into this 13-week study. 3. Serum levels of methotrexate were measured on six consecutive occasions: three whilst patients received intramuscular methotrexate and then three after switching to the subcutaneous route. 4. Patients were taught to self-administer their methotrexate subcutaneously and were then discharged to perform this task at home. 5. Levels of disease activity and psychological scores were measured at the start and end of the study. Satisfaction with self-administration and teaching of injection techniques were assessed at 13 weeks. 6. Serum methotrexate levels were not significantly affected by the route of administration. All patients were able to perform self-injection safely and seven out of eight preferred self-administration at home. 7. This small study demonstrates that there is no difference in the safety and efficacy of methotrexate given by either parenteral route. Patients were able to administer safely methotrexate subcutaneously. Self-administration reduced hospital visits, was more convenient for patients and improved patient satisfaction.

Adult↗