Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “METHOTREXATE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1987

Methotrexate and 7-hydroxy-methotrexate pharmacokinetics following intravenous bolus administration and high-dose infusion of methotrexate.

The pharmacokinetics of methotrexate and 7-hydroxy-methotrexate were studied in patients undergoing very high-dose methotrexate monotherapy. The patients received, first, two methotrexate intravenous bolus test doses (50 mg/m2) one with and one without concomitant administration of folinic acid (15 mg every 6 h) in a random sequence, and, second, an 8 h infusion, individualized to achieve a peak plasma concentration of 5 X 10(-4) M methotrexate (infusion rates greater than 1000 mg/h). Methotrexate and 7-hydroxy-methotrexate concentrations were measured by specific radioimmunoassays and the data were analysed simultaneously by an integrated pharmacokinetic model. Following test dose administration, methotrexate and 7-hydroxy-methotrexate plasma concentration kinetics were best described by assuming that methotrexate elimination (and 7-hydroxy-methotrexate formation) occurred from a peripheral compartment reaching rapid equilibrium with the plasma. Folinic acid administration did not influence the disposition of either compound. Following the infusion, a significant (P less than 0.01) decrease of methotrexate total plasmatic clearance occurred without modification of 7-hydroxy-methotrexate formation and elimination.

Adolescent↗
PubMed1987

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate after methotrexate infusions.

Methotrexate was administered by IV infusion, 2g (1.19 +/- 0.05 g/m2) over 24 hours, to a homogeneous group of patients undergoing treatment for breast cancer. Three courses were given at three week intervals. Methotrexate and 7-hydroxy-methotrexate plasma and urine pharmacokinetics were investigated. The average terminal half-lives of methotrexate and 7-hydroxy-methotrexate in plasma were 15.02 and 15.19 hours respectively. The area under concentration-time curve was 723.8 +/- 196.4 microM x h for methotrexate and 598.1 +/- 212.5 microM x h for 7-hydroxy-methotrexate. The total average urinary excretions of methotrexate and 7-hydroxy-methotrexate over a 96 hour period were 52% and 5.4% respectively. Urinary clearance of methotrexate was 3.46 +/- 1.4 1/h. In contrast, urinary excretion of 7-hydroxy-methotrexate was not linear. These results confirm the protein binding of metabolite to serum albumin and may suggest that distribution of 7-hydroxy-methotrexate is different from unchanged drug or that the metabolite can be eliminated by another route, such as bile.

Aged↗
PubMed1981

A randomized prospective comparison of intermittent methotrexate, methotrexate with leucovorin, and a methotrexate combination in head and neck cancer.

A randomized prospective clinical trial involved 259 cases of advanced recurrent Stage III and IV epidermoid cancers of the head and neck. The cases were randomized among three treatment programs evaluating two dose schedules and a combination treatment of methotrexate. The treatments consisted of: weekly methotrexate, biweekly methotrexate with leucovorin rescue (ML), and biweekly ML combined with cyclophosphamide and cytosine arabinoside (MLCC). Equivalent overall drug-related toxicity was produced with a 5% drug-related fatality rate. Methotrexate alone produced significantly more skin and mucosal toxicity, and the combination (MLCC) resulted in more hematologic toxicity than other treatments. Complete and partial objective responses were achieved in 26%, 24%, and 18% by each treatment. Methotrexate alone produced a median duration of response and 105 days compared with 42 and 49 days from the other treatments. Duration of response was significantly longer and survival was better in the methotrexate-alone group. Response was markedly stage dependent; 40% of Stage III patients achieved response, whereas only 17% of Stage IV patients responded. Presence of visceral metastases decreased response rates and the likelihood of response was particularly compromised by pulmonary metastatic spread; only seven of 54 such patients responded. Decreased survival was related to non-ambulatory performance status, disease-free intervals of less than one year and weight loss. Survival differences between Stage III and IV patients could not be shown. This study demonstrates the therapeutic superiority of weekly i.v. treatment with methotrexate but failed to support claims of an improved therapeutic index for high-dose methotrexate with leucovorin rescue. As the only randomized prospective clinical trial of chemotherapy in advanced head and neck cancer, this study reinforces the weekly i.v. schedule of methotrexate as the standard against which other drug schedules and drug combinations should be compared.

Adult↗
PubMed1983

Methotrexate and methotrexate polyglutamates in human sarcoma metastases after high-dose methotrexate therapy.

The methotrexate concentrations in the lungs or cutaneous metastases of patients with osteogenic or soft-tissue sarcoma were determined at different times after a high-dose methotrexate therapy. The levels in the metastases were 0.964 to 2.96 X 10(-7) molar six to nine days after the end of MTX infusion. They were thus 7.8 to 28 times higher than the corresponding serum levels. At the same time, an appreciable rise of dihydrofolate reductase activity was observed in the metastases. After chromatographic separation over Sephadex G15, MTX polyglutamates could be demonstrated in all tumor samples investigated so far; these amounted up to 68.3% of the total MTX. Taking into account the slower efflux of MTX polyglutamates compared to unchanged MTX, a new hypothesis for the principle of action of high-dose methotrexate therapy is discussed: the very high MTX doses lead to such high intracellular MTX concentrations even in transport-resistant tumor cells that at least part of the MTX is converted into MTX polyglutamates. Unchanged MTX flows relatively rapidly out of the cells, whereas the MTX polyglutamates only break down very slowly and thus can be cytostatically effective over a long period of time.

Biotransformation↗
PubMed1986

Renal excretion and pharmacokinetics of methotrexate and 7-hydroxy-methotrexate following a 24-h high dose infusion of methotrexate in children.

In children with lymphoid malignancies 18 courses of methotrexate (18-200 mg/kg) administered as a 24-h infusion were monitored. Plasma concentrations and renal excretion rates of methotrexate (MTX) and 7-hydroxymethotrexate (7-OHMTX) were determined. A low correlation was found between the administered dose of MTX and the body exposure to MTX or 7-OHMTX. Although 84% of the MTX eventually recovered from the urine was excreted during the 24 h of the infusion, the renal clearance of MTX was markedly lower during the time of the infusion than after it. There were courses with a low and others with a high renal clearance of MTX during the infusion, despite the same urine flow. A low MTX renal clearance was correlated with a high body exposure to MTX. As the same variations were also seen in the same patient during successive courses, pharmacokinetical characterization of patients appears questionable. The renal clearance of 7-OHMTX was significantly lower than the renal clearance of MTX, and the body exposure to 7-OHMTX ranged from 2-40% of the MTX body exposure. Treatment courses with a low or a high body exposure to 7-OHMTX were not associated with different urinary recoveries of the metabolite. Differences in MTX hydroxylation could not be substantiated. Because the concentration of 7-OHMTX is high soon after the end of an infusion, a specific method of MTX determination should be chosen for controlling treatment.

Child↗
PubMedDate not supplied

Oral mucositis in children with acute lymphoblastic leukemia after high-dose methotrexate treatment without delayed elimination of methotrexate: relation to pharmacokinetic parameters of methotrexate.

Oral mucositis is a common problem after high-dose methotrexate (HD-MTX) treatment. Our purpose was to identify factors associated with the development of mucositis in children with ALL who had no delayed elimination of methotrexate (MTX) according to the conventional criteria (p-MTX at 42 hours < 1 mumol/L and at 66 hours < 0.2 mumol/L). Pharmacokinetic studies of MTX and the metabolite 7-hydroxymethotrexate (7-OHMTX) in plasma and saliva were carried out in 13 children treated with HD-MTX (5-8 g/m2 intravenously over 24 hours for a total of 44 courses). Oral mucositis was evaluated according to the criteria of the World Health Organization. Mucositis was observed in 52% of the infusions. In 28 infusions with no delayed elimination of MTX 39% developed mucositis, which was found to correlate significantly with low systemic clearance of MTX during the infusion and a low p-7-OHMTX/p-MTX ratio at 66 hours after the start of infusion. The MTX concentration in saliva did not show any correlation with the development of mucositis. The present conventional criteria for high-risk MTX concentrations might need to be reevaluated because a high percentage of patients still suffer from oral toxicity despite "normal" elimination. A reduced ratio between the simultaneous concentrations of 7-OHMTX and MTX in plasma may be a possible mechanism of this "unpredictable" oral toxicity.

Antimetabolites, Antineoplastic↗
PubMed1985

Role of methotrexate polyglutamates in methotrexate- and sequential methotrexate-5-fluorouracil-mediated cell kill.

The synthesis of methotrexate (MTX) polyglutamates has been investigated in a human leukemia cell line, CCRF-CEM. An increase in either the extracellular MTX concentration (0.1-10 microM) or exposure time (4-24 h) allowed a greater accumulation of polyglutamate derivatives. The species which predominated (di-, tri-, or tetraglutamate) was also time and concentration dependent. Derivatives up to the pentaglutamate were readily detectable, with hexaglutamate present under some conditions. Polyglutamate derivatives were preferentially retained when the cells were transferred to drug-free medium. MTX itself rapidly exited the cells under these conditions. In the absence of extracellular MTX, the performed intracellular MTX polyglutamates continued to be elongated. Accumulation of MTX polyglutamates, particularly triglutamate and longer species, positively correlated with cytotoxicity to CCRF-CEM cells as measured by a clonogenic assay. Investigation of the methotrexate-fluorouracil interaction revealed no effect of 5-fluorouracil on MTX polyglutamate accumulation under various conditions where widely different degrees of cytotoxicity were found. The synergy observed when MTX precedes fluorouracil treatment is therefore not an effect on MTX polyglutamylation. MTX polyglutamates may, however, play an indirect role in this synergy.

Cell Survival↗
PubMed1986

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving low-dose oral methotrexate.

The absorption, distribution, and elimination kinetics of low-dose p.o. methotrexate (MTX) were repeatedly studied in 19 children during maintenance treatment of childhood acute lymphoblastic leukemia. Plasma concentrations, urinary elimination, and bone marrow concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were monitored during 24 h following a routine p.o. dose (30 mg/m2) using high-pressure liquid chromatography. Significant interindividual variability was found in time to peak concentration (30-180 min), peak concentration (0.41-2.77 microM), and to a lesser extent the half-lives (t1/2 alpha: 32.8-86.1 min; t1/2 beta: 43.6-350.0 min; t1/2 absorption: 25.2-60.3 min) and plasma area under the concentration-time curve from zero to infinity (195.6-818.5 microM.min). Significant amounts of 7-OH-MTX were detected in plasma, with a mean area under the concentration-time curve from zero to infinity of 208 microM.min compared with 365.6 microM.min for MTX. High concentrations of 7-OH-MTX were present in bone marrow 24 h after oral MTX (15/19 patients) and were at least five fold those in plasma and three fold the concentration of MTX in bone marrow. In four patients occasionally neither MTX nor metabolite could be detected. Repeated examination of these pharmacokinetic parameters in plasma and bone marrow showed that the intraindividual variability was small.

Administration, Oral↗
PubMed2003

High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL).

PURPOSE: The objectives of the present study were to determine the relationship between methotrexate (MTX) elimination time and various aspects of renal function and to evaluate the prognostic value of elevated serum MTX and creatinine for delayed MTX elimination. PATIENTS AND METHODS: The majority of the 264 children were being treated for ALL. According to the NOPHO-92 protocol, 5 or 8 g MTX/m(2) was administered over 24 h. Serum creatinine was assessed daily. In 11 patients from one centre, renal function was studied in more detail using serum cystatin C, iohexol clearance, and urinary albumin, IgG and protein HC. RESULTS: Increased serum creatinine correlated significantly with the elimination time of MTX, whereas no indications were found of tubular or barrier function damage. Of the 1164 courses, 44 had delayed elimination of MTX (>/=120 h). Serum MTX >150 microM at the end of infusion had a sensitivity of 0.27 and a specificity of 0.94 to predict delayed MTX elimination, and >/=50% increase in serum creatinine during the first treatment day (creatinine ratio) had a sensitivity of 0.32 and a specificity of 0.99. The corresponding risk ratios were 5 and 19 for MTX >150 micro M and creatinine ratio, respectively. In courses with a normal elimination time (<72 h), 99% of the courses had a rise in serum creatinine of less than 50%. CONCLUSIONS: Elevation of serum creatinine by more than 50% is a better predictor of delayed elimination than the level of serum MTX at the end of MTX infusion, especially if information on previous creatinine measurements is used to reduce the impact of an occasionally low serum creatinine value before the start of the MTX infusion.

Adolescent↗
PubMed2003

Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared with methotrexate alone.

OBJECTIVE: To study the pharmacokinetics of methotrexate (MTX) plus cyclosporin A (CSA) in patients with rheumatoid arthritis (RA). METHODS: On day 1 of the study, patients with RA receiving stable doses of MTX had blood and urine levels of MTX and its metabolite 7-hydroxymethotrexate (7-OH-MTX) measured post oral dosing of the drug. MTX was then discontinued and CSA therapy was started on day 8. On day 20, blood levels of CSA and CSA metabolites were measured post drug dosing. On day 23, MTX therapy was restarted and levels of MTX, CSA and their metabolites were again measured as described above. RESULTS: In the 30 patients, coadministration of CSA and MTX led to a 26% increase in mean peak plasma MTX concentration (P < 0.01), an 18% increase in the mean plasma MTX concentration area under the curve (AUC, P=0.01) and an 80% decrease in plasma 7-OH-MTX AUC (P < 0.01). In 13 patients receiving a 10 mg MTX dose, CSA reduced urinary 7-OH-MTX excretion by 87% (P < 0.01) without altering MTX excretion. MTX did not alter the pharmacokinetics of CSA or its metabolites. CONCLUSION: CSA may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy.

Administration, Oral↗
PubMed1996

Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil.

PURPOSE: To compare sequential methotrexate (M) and fluorouracil (F) (M-->F) with surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13) and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with estrogen receptor (ER)-negative tumors and negative axillary nodes. PATIENTS AND METHODS: A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates. RESULTS: A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M-->F (69% v 56% [P = .006] in those or= 50 years). A survival advantage was evident in older patients (89% v 80%; P = .03). In B-19, through 5 years, an overall DFS advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were evident with CMF. The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater in women aged F or CMF after lumpectomy and breast irradiation resulted in a low probability of ipsilateral breast tumor recurrence (IBTR). In B-13, the frequency of IBTR was 2.6% following M-->F versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in B-19. Toxicity >or= grade 3 was more frequent among CMF patients in B-19. The age-related difference in CMF benefit was not related to amount of drug received. CONCLUSION: M-->F and CMF are effective for node-negative patients with ER-negative tumors. The incidence of local-regional or distant metastases and IBTR decreased after either therapy. The benefit from either therapy was evident in all patients, but the CMF advantage was greater in those F may be used in patients with medical problems that would preclude CMF administration.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport.

ABCG2 is a plasma membrane efflux pump that is able to confer resistance to several anticancer agents, including mitoxantrone, camptothecins, anthracyclines, and flavopiridol. The antimetabolite methotrexate (MTX) was inferred recently to be an additional substrate of the pump based on the analysis of ABCG2-overexpressing cell lines. However, the transport characteristics of the pump with regard to this agent have not been determined. In addition, physiological substrates of ABCG2 have not been identified. Here we examine the in vitro transport properties of the pump using membrane vesicles prepared from HEK293 cells transfected with ABCG2 expression vector. In so doing it is shown that MTX is a high capacity low affinity substrate of the pump, with K(m) and V(max) values of 1.34 +/- 0.18 mM and 687 +/- 87 pmol/mg/min, respectively. Unlike previously characterized multidrug resistance protein family members, ABCG2 is also able to transport MTX diglutamate and MTX triglutamate. However, addition of even one more glutamyl residue is sufficient to completely abrogate ABCG2-mediated transport. By contrast with the wild-type protein (ABCG2-R482), two ABCG2 variants that have been identified in drug selected cell lines, R482T and R482G, were unable to transport MTX to any extent. Similarly, folic acid was subject to efflux by the wild-type protein but not by the two mutants. However, transport of the reduced folate leucovorin was not detected for either the wild-type or the mutant proteins. Finally, it is shown that ABCG2 is capable of transporting E(2)17betaG with K(m) and V(max) values of 44.2 +/- 4.3 micro M and 103 +/- 17 pmol/mg/min, respectively. These results indicate that ABCG2 is a component of the energy-dependent efflux system for certain folates and antifolates, but that its transport characteristics with respect to polyglutamates and reduced folates are not identical to those of multidrug resistance protein family members. In addition, it is demonstrated that R482 mutations observed in drug-resistant cell lines have profound effects on the in vitro transport properties of the pump.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1993

Methotrexate and gamma-tert-butyl methotrexate transport in CEM and CEM/MTX human leukemic lymphoblasts.

In a continuing investigation of determinants of their 200-fold methotrexate resistance and their collateral sensitivity to gamma-tert-butyl methotrexate, the ability of CEM/MTX cells to transport the two drugs was analyzed and compared with that of CEM cells. The Km and Vmax values for the influx of methotrexate into CEM cells did not differ significantly from those of CEM/MTX cells, and this was the case for gamma-tert-butyl methotrexate as well. Surface binding and influx rates were proportional to cell surface area, but differences in efflux rates and methotrexate uptake were too large to be explained on this basis. Neither methotrexate nor trimetrexate competed with gamma-tert-butyl methotrexate influx in CEM cells. However, both drugs perturbed the gamma-tert-butyl methotrexate steady state in CEM cells, resulting in slightly less uptake than with gamma-tert-butyl methotrexate alone. However, the major difference between the two cell types was in the methotrexate uptake plateau, which was much greater in the case of the parental cell line. A related observation was the more rapid efflux of methotrexate from CEM/MTX cells than from CEM cells. The poor uptake, the associated meager capacity to polyglutamylate methotrexate and the enhanced methotrexate efflux appear to be responsible for its decreased activity against CEM/MTX cells. Half-lives for gamma-tert-butyl methotrexate efflux were the same in both cell lines, allowing the drug to accumulate to cytotoxic levels despite its inability to form polyglutamates.

Cell Line↗
PubMed1993

Methotrexate Resistance in Datura innoxia (Uptake and Metabolism of Methotrexate in Wild-Type and Resistant Cell Lines).

A wild-type Datura innoxia cell line (Px4) was used to select methotrexate-resistant cells through a stepwise procedure. Two independently selected cell lines, MTX161 and MTX132, were stable and shown to be 5 to 15 times more resistant to methotrexate than wild type. These methotrexate-resistant cells were similar to the wild-type cells in levels and kinetic properties of dihydrofolate reductase, the sensitivity of dihydrofolate reductase to methotrexate, the binding of [3H]methotrexate to soluble proteins, and the formation of methotrexate polyglutamate derivatives. High performance liquid chromatographic analyses indicated that methotrexate polyglutamylation is only slight and may not be significant in the toxicity of methotrexate to Datura cells. The uptake of methotrexate was also investigated in the wild-type and resistant cells. The Px4 cells exhibited a linear uptake that lasted for 1 to 7 h. The uptake was saturable, pH and energy dependent, and had a Km of 65.6 nM and a Vmax of 12.5 nmol h-1g-1 fresh weight. Neither MTX161 nor MTX132 exhibited the sustained uptake of methotrexate shown by the Px4 cells. As a result, there were greatly reduced concentrations of intracellular methotrexate in resistant cells. Resistant cell lines had 2- to 3-fold higher Km values for methotrexate uptake compared with Px4 cells. It is proposed that these cells became resistant as a result of a stable change in the membrane transport system for methotrexate.

Journal Article↗
PubMed1983

Role of methotrexate polyglutamylation and cellular energy metabolism in inhibition of methotrexate binding to dihydrofolate reductase by 5-formyltetrahydrofolate in Ehrlich ascites tumor cells in vitro.

5-Formyltetrahydrofolate was found to reverse the binding of methotrexate to dihydrofolate reductase in the Ehrlich ascites tumor in vitro. When cells pretreated with methotrexate were resuspended in methotrexate-free buffer containing 5-formyltetrahydrofolate (or 5-methyltetrahydrofolate), net dissociation of the antifolate from the enzyme was observed. Methotrexate associated with the enzyme under these conditions was below the enzyme binding capacity. However, glucose or azide increased the fraction of dihydrofolate reductase associated with methotrexate and abolished the effect of tetrahydrofolates on this intracellular component. Addition of 5-fluoro-2'-deoxyuridine had no effect on this response to the reduced folate, thereby precluding a direct role for the thymidylate synthase-dependent generation of dihydrofolate in this dissociation of methotrexate from dihydrofolate reductase. Enzyme-bound methotrexate could also be reduced by exposure to 5-formyltetrahydrofolate prior to uptake and efflux of free methotrexate. When cells were incubated under conditions which favored formation of methotrexate polyglutamate derivatives, subsequent treatment with 5-formyltetrahydrofolate had no effect on the binding of the conjugated antifolate to dihydrofolate reductase. These findings support a role for dihydrofolate reductase as a locus for competitive binding interactions between reduced folates and methotrexate that may be a basis for the ability of 5-formyltetrahydrofolate to prevent the biochemical effects of this antifolate. These data suggest that the presence of methotrexate polyglutamate derivatives and cellular energy metabolism may be critical determinants of the responsiveness of methotrexate-treated cells to reduced folates and may play important roles in the selectivity of 5-formyltetrahydrofolate rescue.

Animals↗
PubMed1996

Methotrexate osteopathy in long-term, low-dose methotrexate treatment for psoriasis and rheumatoid arthritis.

BACKGROUND: In dermatology and rheumatology, methotrexate is frequently prescribed in low dosages per week; in oncology, high dosages per week are prescribed. Methotrexate osteopathy was first reported in children with leukemia treated with high doses of methotrexate. In animal studies, low doses of methotrexate proved to have an adverse effect on bone metabolism, especially on osteoblast activity. OBSERVATIONS: Methotrexate osteopathy is a relatively unknown complication of low-dose methotrexate treatment. We describe three patients treated with low-dose oral methotrexate in whom signs and symptoms were present that were similar to those found in children treated with high doses of methotrexate. All three patients had a triad of severe pain localized in the distal tibiae, osteoporosis, and compression fractures of the distal tibia, which could be identified with radiographs, technetium Tc 99m scanning, and magnetic resonance imaging. CONCLUSIONS: Methotrexate osteopathy can occur in patients treated with low doses of methotrexate, even over a short period of time. As pain is localized in the distal tibia, it is easily misdiagnosed as psoriatic arthritis of the ankle, but the diagnosis can be correctly made by careful investigation and use of imaging techniques. The only therapy is withdrawal of methotrexate. It is important that more physicians become aware of this side effect of methotrexate therapy, which can occur along with arthritic symptoms.

Aged↗
PubMedDate not supplied

Treatment of ectopic pregnancy by systemic methotrexate, transvaginal methotrexate, and operative laparoscopy.

OBJECTIVE: To evaluate the efficacy of treatment of ectopic pregnancy by local administration of methotrexate, systemic methotrexate, and laparoscopy. METHODS: This study was a retrospective analysis from the department of Obstetrics and Gynecology of two university-affiliated hospitals. Medical records of 40 patients who were treated by methotrexate from January 1991 to October 1994 and 66 patients who were treated surgically by laparoscopy from April 1986 to June 1994 were reviewed. Among the methotrexate group, 19 patients were treated by ultrasound-guided injection and 31 others were treated by intramuscular administration. Success rate of the primary treatment and the duration of hospitalization were examined for each group. The cases of methotrexate failure were characterized and compared with the primary laparoscopic group. RESULTS: The success rate was similar between the local (79.8%) and the systemic (66.7%) methotrexate groups. The primary laparoscopy group had a significantly higher success rate (95.5%) than the methotrexate group (72.5%); P < .01. When patients who had laparoscopy as their primary treatment (n = 66) were compared with those who underwent surgery after failed methotrexate treatment (n = 11), the primary laparoscopic group were seen to have shorter hospitalization time, smaller tubal diameter at surgery, and higher pre-operative hemoglobin level (P < .05). More patients in the methotrexate failure group (45.5%) had hemoperitoneum of > 500 mL than those in the primary laparoscopy group (1.5%; P < .001). CONCLUSIONS: There is no difference in efficacy between local and systemic methotrexate administration. Laparoscopic treatment of ectopic pregnancy is associated with a higher success rate than methotrexate treatment. Patients treated by laparoscopy after methotrexate failure were sicker than those who were treated by laparoscopy as their primary treatment.

Adult↗
PubMed1982

Identification and quantitation of methotrexate and methotrexate metabolites in clinical high-dose therapy by high pressure liquid chromatography and field desorption mass spectrometry.

High-pressure liquid chromatography in combination with field desorption mass spectrometry as techniques of high specificity and sensitivity have been applied to the identification and quantitation of the anticancer drug methotrexate and its metabolites which occur in clinical high-dose therapy. Field desorption mass spectra of methotrexate and several methotrexate and folic acid derivatives, when investigated as free acids or ammonium salts, yield abundant protonated molecular ions and a consistent pattern of structurally significant fragments. High-pressure liquid chromatographic separation of methotrexate metabolites was performed on reverse-phase, C-18 columns using a volatile, ammonium bicarbonate/acetate containing mobile phase that was especially suited for the field desorption mass spectral analysis of isolated metabolites, and provided the definite identification of 7-hydroxymethotrexate and 4-[[2,4-diamino-6-pteridinyl]methyl]methylamino]-benzoic acid in serum and urine of patients treated with high-dose methotrexate. The high intensity and stability of the [MH]+ ions was found suitable for the quantitation of methotrexate and related folate analogues by field desorption mass spectrometry. A synthetic methotrexate derivative, methotrexate-gamma-(2-hydroxy)ethyl-amide was used as internal standard for the quantitative determination of methotrexate in serum and urine. In a study to comparatively assess the potential of specific quantitation methods, serum and urine levels of methotrexate and its major metabolite, 7-hydroxymethotrexate were determined by (i) an enzyme immunoassay, (ii) reverse phase high-pressure liquid chromatography and (iii) field desorption mass spectrometry. Results obtained from four patients with osteogenic sarcoma receiving high-dose methotrexate/leucovorin rescue therapy consistently show the sustained elimination of 7-hydroxymethotrexate over several days, thus indicating the utility of specifically monitoring this nephrotoxic metabolite, at massive methotrexate doses.

Adult↗