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PubMed1975

A rapid and specific radioimmunoassay for methotrexate.

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

Animals↗

PubMed1976

Multidrug chemotherapy in pulmonary treatment of osteosarcoma.

Forty-three patients with osteosarcoma were treated with amputation and adjuvant chemotherapy utilizing a four-drug combination of cyclophosphamide, vincristine, phenylalanine mustard, and adriamycin (CONPADRI-I regimen). Twenty-four patients (56 per cent) remained free of metastases twelve to sixty-one months after diagnosis. Ten of the twenty-four have been disease-free for more than three years. Another group of thirty patients was treated with amputation and a five-drug adjuvant chemotherapy program which included the administration of massive doses of methotrexate with citrovorum factor (COMPADRI-II regimen). Twenty of the thirty (67 per cent) remained free of metastases from twelve to twenty-six months after amputation (median, sixteen months). Two deaths related to methotrexate toxicity occurred. Late metastases developed in three patients (at sixteen, nineteen, and twenty-six months after operation) in the group treated with the COMPADRI-II regimen.

Adolescent↗

PubMed2000

Trans-stimulation effects of folic acid derivatives on methotrexate transport by rat renal organic anion transporter, OAT-K1.

We examined the pharmacological role of the renal organic anion transporter OAT-K1, which localizes predominantly in the brush-border membranes of proximal straight tubules, in the urinary excretion of methotrexate and the possibility of its contribution to "folinic acid rescue." With Madin-Darby canine kidney (MDCK) cells stably transfected with OAT-K1 cDNA, OAT-K1-mediated methotrexate accumulation was inhibited in the presence of various folic acid derivatives. These derivatives included aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid (citrovorum factor, leucovorin), and folic acid with apparent inhibition constant values of 0.5, 1.2, 1.8, 8.2, and 14.1 microM, respectively. In contrast, 10 microM taurocholic acid and sulfobromophthalein did not inhibit OAT-K1-mediated methotrexate accumulation. In addition, methotrexate efflux was stimulated in the presence of inwardly directed gradients of aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid, and folic acid, but not of uric acid, taurocholic acid, and glutathione, indicating that OAT-K1-mediated methotrexate efflux is stimulated by a folic acid derivatives exchange. In conclusion, OAT-K1 was suggested to enhance the apical efflux of highly accumulated methotrexate in tubular epithelial cells and contribute at least in part to folinic acid rescue by exchanging intracellular methotrexate for extracellular folinic acid.

Aminopterin↗

PubMed1979

Improved double-antibody enzyme immunoassay for methotrexate.

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

Cross Reactions↗

PubMed1976

Methotrexate in blood, urine, and cerebrospinal fluid of children receiving high doses by infusion.

Methotrexate was determined in plasma (31 patients), urine (eight patients), and cerebrospinal fluid (two patients) after high doses (35 to 150 mg/kg) by infusion, with citrovorum factor rescue. Concentrations in plasma were proportional to dose at 6, 24, 72 h after beginning treatment, but this trend was very minimal for samples obtained at 48 h. Clinical toxicity probably will not be serious if the methotrexate concentration in the serum is less than 4.5 X 10(-6) mol/liter at 48 h after the start of a 6-h infusion. In both of the two patients so examined, therapeutic concentrations appeared in cerebrospinal fluid after intravenous infusion of the drug. A kinetic enzymic method, radioassay, and radioimmunoassay all yielded similar results for drug concentrations.

Child↗

PubMed2003

[Efficacy and side effects of methotrexate in the treatment of ectopic pregnancy].

OBJECTIVE: To study the efficacy and side effects of methotrexate with different protocols in the treatment of ectopic pregnancy (EP). METHODS: Total of 648 patients who had EP and were treated only with MTX were analysed. Patients were divided into six groups according to protocol: Group 1, 100 mg intravenously (IV); Group 2, 100 mg, IV, followed by citrovorum factor; Group 3, 20 mg, IV every day for five days; Group 4, 20 mg intramusculary (IM) every day for five days; Group 5, 75 mg, IV; Group 6, 75 mg, IM. RESULTS: The rates of repeated MTX injection in group 1 - 6 because of inadequate decrease of hCG were 23.3%, 25.0%, 21.4%, 20.6%, 24.4% and 22.4% respectively. Success rates were 87.4%, 85.4%, 90.5%, 92.6%, 86.3% and 91.4% respectively. Rates of liver dysfunction were 10.3%, 8.3%, 64.3%, 69.1%, 8.7% and 31.0%. CONCLUSION: Single-dose of 75 mg MTX IV injection may be the best regimen in the treatment of EP because of the same efficacy but the least side effects.

Abdominal Pain↗

PubMed1992

[Transient subacute encephalopathy induced by high-dose methotrexate treatment in children with acute lymphoblastic leukemia and malignant lymphoma].

Transient subacute encephalopathy was detected in 4 of 83 patients undergoing treatment with high-dose methotrexate (HD-MTX) and citrovorum factor rescue for childhood acute lymphoblastic leukemia and malignant lymphoma from 1984 to 1991. Subacute encephalopathy occurred in relatively older patients and early in the course of treatment with HD-MTX. The average interval between the HD-MTX course and the onset of the neurologic disturbance was 6.5 days. All 4 patients treated had no neurological sequelae. Laboratory evaluations disclosed nontoxic plasma MTX levels at onset of symptom and not detected in liquor. CT in 4 patients disclosed no abnormality, but MR images revealed abnormal signal intensity patterns of cerebral white matter in 2 cases. In one case the abnormal MR finding resolved after 3 months. The pathogenesis of this neurologic symptom remains unknown, but further HD-MTX treatment may be acceptable in follow-up of MR image, because the prognosis of subacute encephalopathy seems favorable.

Adolescent↗

PubMed1990

Methotrexate therapy for persistent ectopic pregnancy after conservative laparoscopic management.

Persistent ectopic pregnancy is a recognized complication of conservative laparoscopic surgery. Three such cases were treated successfully with methotrexate and citrovorum factor rescue. All three patients experienced mild lower abdominal pain for a maximum of 36 hours; no other adverse effects were noted. More experience with this therapy will be necessary before subsequent fertility rates can be determined.

Abdominal Pain↗

PubMed1990

[Alternative chemotherapy of malignant bone neoplasms in children].

The authors propose alternative chemotherapy of osteosarcoma and Ewing's sarcoma in children. The aim of this proposal was elaboration of effective and, at the same time, less expensive and less toxic therapeutic regimens. The authors recommend open surgical biopsy with doxorubicin for 3 consecutive days as a protection against the released circulating neoplastic cells. After completion of histopathologic examination, one of two types of chemotherapy is chosen randomly. In osteosarcoma, there was induction chemotherapy for 4 or 9 weeks (according to the type of operation--conservative amputation or limb salvage surgery). In the I type of induction chemotherapy, high doses of methotrexate with vincristine and citrovorum factor rescue are administrated weekly, in the II type--the combination of BCD (bleomycin, cytoxan, actinomycin D) and CDDP (cisplatin). On the regimen of intensification chemotherapy decides the degree of tumour response to induction chemotherapy assessed as tumour necrosis in histopathologic examination. Maintenance chemotherapy is the same in two types of regimen and is continued for the period up to 2 years. The authors elaborated concomitantly the regimen of high methotrexate doses administration with rescue procedure in the case of elevated serum methotrexate levels, and regimen of cisplatin administration aiming at maximal patients protecting against the toxic effects of both drugs. In Ewing's sarcoma the randomisation differentiates between T-9 Rosen's regimen of chemotherapy and own modification of Memphis group regimen. The primary tumour is treated by radiotherapy with lower doses adjusted to the tumor response to induction chemotherapy (30-50 Gy or 50 Gy) and the irradiation port limited to the residual bone lesion plus a 2-3 centimeter margin. Surgical excision of bone with tumor depends on special tumor localisation as the clavicula, rib or fibula. The results of discussed treatment regimens will be subsequently published.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

[Early neurotoxicity of high-dose of methotrexate and tetrahydrobiopterin deficiency].

Transient neurologic dysfunction associated with high-dose methotrexate and citrovorum factor rescue (MTX-CF) has been previously reported. At the biochemical level, there are at least two important pathways in central nervous system metabolism which might be disturbed by MTX: MTX may deplete the cell of the de novo synthesis of purine nucleotides and thymidylate through its action on dihydrofolate reductase (DHFR), and also inhibit dihydropteridine reductase (DHPR), an enzyme maintaining the cofactor of phenylalanine-hydroxylase in its active tetrahydrogenated form (tetrahydrobiopterin), and hence interfere with the supply of the neurotransmitters derived from tyrosine and tryptophan. We describe such a neurologic disease in a patient with acute lymphoblastic leukemia (ALL) receiving chemotherapy. Significant increase in cerebrospinal fluid biopterins supports the hypothesis of an inhibition of dihydropteridine reductase by MTX, and provides additional suggestions in terms of etiology, diagnosis and treatment.

Biopterins↗

PubMed1991

Delayed hemorrhage of a persistent ectopic pregnancy following laparoscopic salpingostomy and methotrexate therapy.

This report describes the first known case of delayed hemorrhage of a persistent ectopic pregnancy following surgical and medical therapy. A 2.5-cm ampullary pregnancy without cardiac activity was removed by laparoscopic salpingostomy. The serum beta-hCG level before laparoscopy was 1542 mIU/mL, increasing to 3163 mIU/mL by the eighth postoperative day. Administration of methotrexate and citrovorum factor caused a 48% decline in the level of serum beta-hCG over 72 hours, but did not prevent delayed hemorrhage by the tubal gestation. This case emphasizes that close surveillance during the treatment of persistent ectopic pregnancy should continue until serum beta-hCG is undetectable.

Adult↗

PubMed1990

[The influence of liver and renal functions on the changes in serum methotrexate (MTX) level in high-dose MTX therapy].

Sixty times of high dose methotrexate (MTX) with citrovorum factor rescue (HDMTX-CF) therapy were applied for 15 patients with osteosarcoma. The serum level of MTX was measured at every 24 hr. by FPIA (Fluorescence Polarization Immuno Assay) method and blood analysis was performed at the same time. Fourtysix parameters were measured in each HDMTX-CF therapy and examined by multiple parameter statistical analyses by a personal computer. In the results, the number of performed chemotherapy, rescue time, serum GOT and creatinine level at 24 hr. were the most relative factors for the change of serum MTX level.

Adolescent↗

PubMedDate not supplied

[Treatment of ectopic pregnancy using methotrexate].

The authors applied the conservative treatment of ectopic pregnancy with methotrexate in a prospective study comprising 22 patients. Out of this number, 14 patients had intact ectopic pregnancy and 8 showed the signs of initial tubal abortion (as proved by the hematocele finding). This group of 8 patients insisted to be given the same therapy, although they were informed of the possible failure in cases of initial tubal abortion. In all these cases methotrexate was administered locally, injected into the gestational sac under ultrasonic monitoring. In addition to the local application, 13 patients systemically received the same drug in pills (2.5 mg). At the same time, all the patients were given the antidote (Citrovorum factor). This method of treatment appeared to be successful in 16 patients (72.7%), four of them also having hematocele. Surgical treatment was applied afterwards in six patients (27.3%).

Female↗

PubMed1990

[Fulminant hepatic failure induced by intermediate dose methotrexate in a case of non-Hodgkin's lymphoma].

Methotrexate (MTX) is frequently used as an antifolics agent in many malignant neoplasms such as leukemia, lymphoma and osteosarcoma. The major side effects of MTX are liver and renal damages, bone marrow suppression and so on. But careful management and citrovorum factor rescue could decrease the incidence and degree of these side effects. In this report, we described a patient with non-Hodgkin's lymphoma who developed and died of fulminant hepatic failure soon after the administration of intermediate dose MTX. Serological tests for HB virus were not changed throughout, and lymphocyte stimulation test for MTX was strongly positive. His autopsy revealed no inflammatory cell infiltration into the liver, but marked biliary congestion which is a distinctive feature of drug induced hepatitis. From above results, it was suggested that nature of this fulminant hepatic failure was an allergic reaction to MTX. There is no previous report which is concerning about MTX and fetal drug related hepatic failure.

Adult↗

PubMed1986

Telangiectatic osteogenic sarcoma. Improved survival with combination chemotherapy.

Since the inception of adjuvant chemotherapy for osteogenic sarcoma (OS), 25 patients were treated for telangiectatic osteogenic sarcoma (TOS) from 1973 through 1980. This represented 12% of all patients with primary OS of an extremity seen during this time period. Tumors that demonstrated only focal areas of TOS with areas of other subtypes were designated not as TOS but as "mixed" subtypes of OS. In the 25 patients with pure TOS, surgery included 18 amputations and seven resections for the primary tumor. Ten patients were treated on the first chemotherapy protocol (T-4) including high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR), Adriamycin (ADR), and cyclophosphamide (CYC). Of those 10 patients, five have been free of disease for seven to ten years from the time of diagnosis. Nine patients were treated on the second protocol (T-7) including HDMTX with CFR, ADR, and the combination bleomycin, cyclophosphamide, and dactinomycin (BCD). Six of those nine patients are disease-free survivors 63 to 88 months (median, 63 months) from diagnosis. Six were treated on the third chemotherapy protocol (T-10) including HDMTX with CFR, ADR, BCD, and the substitution of cisplatinum for those not having a complete response to preoperative chemotherapy with HDMTX. All six of the latter are disease-free survivors 42 to 56 months (median, 49 months) from the start of treatment. Toxicity included two HDMTX-related drug deaths in patients started on treatment prior to 1977. Of the entire group, 17/25 (68%) have remained free of disease at a mean follow-up time of over five and one-half years. This study demonstrates that TOS is responsive to chemotherapy and is potentially curable. Some prior reports of the uniformly poor prognosis of this variant of OS should not discourage attempts of curative therapy by chemotherapy and surgery.

Adolescent↗

PubMed1989

[Preventive effects of intra-arterial infusion chemotherapy of liver metastasis in non-resectable pancreatic cancer].

This is a study which evaluates intra-arterial chemotherapy for non-resectable carcinoma of the pancreas without liver metastasis (locally advanced). Twenty-one patients received ia-chemotherapy (MA-CP: Methotrexate + Angiotensin II----Citrovorum factor + Prostaglandin E1). They showed a 39% 1-year survival rate and 92% of 1-year cumulative rate of survival without liver metastasis. These incidences were significantly higher than those of (13%, 50%) 52 patients who underwent systemic chemotherapy (control). As the reason for such significant differences, we suspected that a high dose of chemotherapeutic view after MTX had been infused into the pancreatic-supplying arteries. This speculation was confirmed by the serial determination of the MTX concentration in the portal blood.

Alprostadil↗

PubMed1989

Evaluation of methotrexate containing chemotherapeutic regimens in the treatment of childhood undifferentiated non-Hodgkin's lymphoma and B cell acute lymphoblastic leukemia.

From September 1983 to October 1988, 13 undifferentiated non-Hodgkin's lymphomas (NHL) of Burkitt's or non-Burkitt's type and 3 B cell acute lymphoblastic leukemias were treated with various multiagent chemotherapy regimens containing modest to high dose methotrexate (HDMTX) infusions. All were children between the ages 2 years 8 months and 14 years 1 month. The group included 13 boys and 3 girls. The lymphomas were located primarily in the head and neck, 5; abdomen, 7; and lymph nodes, 1. The clinical stages at diagnosis were stage I, 1; stage II, 6; stage III, 3; and stage IV, 3. The MTX infusion dosage ranged from 300 to 4,285 mg/M2, and the total cumulative dose per patient ranged from 750 to 30,168 mg/M2. Citrovorum Factor Rescue was given following all MTX infusions, except for 62 of the 300 mg/M2 infusions. The serum MTX levels were monitored following all HDMTX. The chemotherapy related toxicities were graded and analysed. The clinical characteristics, which might predispose to HDMTX-related toxicities, were identified and are discussed. Our data reveals the inpatient and interpatient variations in the kinetics of MTX. There were no drug-related deaths, and the overall outcome of the patients was satisfactory. We conclude that MTX infusion continues to play an important role in the current management of childhood B cell malignancies; however, obstacles still remain, especially for those with widespread B cell disease.

Adolescent↗

PubMed1989

Outpatient chemotherapy of unruptured ectopic pregnancy.

This report describes an individualized, reduced dose, methotrexate (MTX) and citrovorum factor (CF) treatment regimen for outpatient management of unruptured ectopic pregnancy (EP). One hundred sixteen laparoscopically documented EPs, the majority (90%) of whom were symptomatic, were diagnosed from an Emergency Department population. Eighty of 116 (69%) were unruptured, 37 (46.3%) of whom were eligible for MTX-CF chemotherapy. One patient refused chemotherapy. Thirty-four of the 36 (94.4%) patients treated with MTX-CF had complete resolution of their ectopics, whereas 2 experienced rupture after chemotherapy, 1 of them 23 days after MTX initiation. While there were no major chemotherapy-related side effects, 3 of the 36 (8.3%) patients experienced minor side effects. The authors conclude that: (1) individualized dosing of outpatient MTX-CF chemotherapy for symptomatic EP can be safely managed, even in an indigent population; (2) rupture can occur up to 23 days after chemotherapy initiation; (3) fetal cardiac activity is an absolute contraindication to chemotherapy; (4) chemotherapy in patients with symptoms is of limited value because the disease is too far advanced; therefore, it is essential that the diagnosis of EP be established before symptom onset; and (5) chemotherapy offers no significant immediate advantages to outpatient laparoscopic surgery. However, increasingly reliable nonlaparoscopic diagnosis will soon give wider application to this approach.

Adult↗