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At least 19 recordsLinked to original sources
PubMed1977

[The carrier potential of liposomes for methotrexate. Changing of the tissue levels of methotrexate in the organs of mice (author's transl)].

Drugs entrapped in liposomes (artificial lipid vesicles) exhibit different pharmacokinetics after intravenous application than drugs injected in a free form. The folidacidantagonist methotrexate can be entrapped in liposomes in a therapeutically useful concentration (0.5 mg MTX/ml) and can be stored with high stability of entrappment. After intravenous injection into the tail vein of mice liposomes entrapped methotrexate is found more enriched in cell systems with high rate of endocytosis and not eliminated by the kidneys within 3 h like free methotrexate. It can be shown, that for the organs liver, spleen, kidney, gut, lung, and blood over a 6 h period liposomes entrapped methotrexate is enriched in the tissues and that for example after 6 h the methotrexate level in the liver is 20 fold higher in comparison to free injected methotrexate.

Animals↗
PubMed1978

Direct administration of methotrexate into the central nervous system of primates. Part 2: Distribution of 3H methotrexate after intrathecal lumbar injection.

The kinetics of distribution of 3H methotrexate (3HMTX) in the central nervous system, plasma, and urine after intraventricular, lumbar percutaneous puncture, and spinal catheter injections were compared. Levels of 3HMTX in whole brain after lumbar percutaneous injection were 40 times less than after intraventricular injection. Injection of 3HMTX via a spinal catheter increased the level of 3HMTX in whole brain but this was still tenfold less than after direct intraventricular instillation. Also, it was found that a disproportionately high amount of 3HMTX was in the brain-stem-cerebellum region which would further reduce the concentration of methotrexate in the cerebral hemispheres. Both intraventricular and lumbar spinal catheter administration of 3HMTX produced 3HMTX levels greater than 10(-6)M (moles/kg wet weight) in spinal cord tissue as measured by 3H specific activity between 2 to 8 hours after injection. Administration by lumbar percutaneous puncture, however, rarely resulted in this suggested therapeutic level of 10(-6)M. Initial 3HMTX levels in plasma after lumbar percutaneous instillation was 24 times greater than after intraventricular or lumbar spinal catheter injections. This indicated significant and unavoidable extradural leakage after lumbar percutaneous puncture, which may account for the substantially lower levels of 3HMTX in the brain and spinal cord tissue. It is concluded that intraventricular instillation of methotrexate is the best route of administering the drug to achieve therapeutic levels of methotrexate in both whole brain and throughout the spinal cord.

Animals↗
PubMed1977

Purification and properties of dihydrofolate reductase from methotrexate-sensitive and methotrexate-resistant Chinese hamster ovary cells.

We have previously described methotrexate-resistant Chinese hamster ovary cells which appear to contain normal levls of a structurally altered dihydrofolate reductase (EC 1.5.1.3) (Flintoff, W.F., Davidson, S.V., and Siminovitch, L. (1976) Somatic Cell Genet.2,245-261). By selecting for increased resistance form these class I cells, class III resistant cells were isolated which appeared to possess an increased activity of the altered enzyme. In the report, we describe the purification and several properties of the reductase from wild-type cells, two independently selected class I cells, and class III resistant cell. The reductases from wild-type and resistant cells had similar specific activities using folate and dihydrofolate as substrates, and similar molecular weights as determined by sodium dodecyl sulfate gel electrophoresis. The mutant enzymes, however, were about six- to eight-fold more resistant to inhibition by methotrexate than the wild-type enzyme, suggesting a decreased affinity of the mutant reductases to methotrexate-binding. Small differences between various enzymes were also seen in other physicochemical properties such as pH optima and Km values for folate, and in their heat stabilities, which suggest that different structural alterations may lead to the same mutant phenotype. As expected from earlier studies with crude extracts, class III cells did produce a higher (about 10-fold) yield of the reductase than the class I or wild-type cells.

Cell Line↗
PubMed1979

Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, adriamycin, methotrexate, 5-fluorouracil (CAMF) versus sequential cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and adriamycin.

Seventy-eight advanced breast cancer patients with hormone-resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF leads to A). C was given at 50 mg/m2, po, days 1-14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28-day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses-62% vs. 49%; stabilizations-23% vs. 31%). Responses by site of metasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.

Antineoplastic Agents↗
PubMed1979

Methotrexate-induced oral mucositis and salivary methotrexate concentrations.

We examined the plasma and saliva levels of methotrexate (MTX) achieved during the treatment and rescue periods of ten patients receiving 42-h MTX infusions followed by citrovorum rescue. Saliva MTX levels were generally 1%--2% of the simultaneous plasma levels. Four patients developed severe oral mucositis; three patients developed mild to moderate oral toxicity, and three others had no evidence of mucositis. MTX levels in the patients with severe mucositis were not higher and did not persist longer than the levels achieved in patients with mild or absent toxicity. Attempts at reducing the severity of oral mucositis with topical citrovorum mouthwashes or with atropine to suppress salivation were unsuccessful. MTX-induced oral mucositis is not related to salivary MTX concentrations, and the use of topical citrovorum therapy or the suppression of salivation does not appear to ameliorate this toxicity.

Humans↗
PubMed1978

Direct administration of methotrexate into the central nervous system of primates. Part 1: Distribution and degradation of methotrexate in nervous and systemic tissue after intraventricular injection.

Levels of methotrexate (MTX) measured by both 3H radioactivity and dihydrofolate reductase assays were determined in cerebrospinal fluid (CSF), plasma, urine, and both neural and non-neural tissues at varying times after a single intraventricular injection into Cynomolgus monkeys (Macaca fascicularis). Clearance of the MTX from CSF was rapid after injection. A relatively constant level of 3HMTX was reached in plasma 2 1/2 hours after injection, and about 30% of the 3HMTX dose was excreted in the urine within 4 hours after injection. Maximum levels in CNS tissues were obtained by 4 hours after injection, and average concentrations of 10(-6) M MTX (moles/kg wet weight) were maintained in CSF for up to 12 hours and in brain for up to 24 hours after injection. Conversion of MTX to non-MTX products was detected in CSF between 4 and 12 hours, and in brain tissue between 12 and 24 hours after injection, and the amount of these products increased with time. Regional distribution studies in the cerebrum showed a U-shaped distribution curve for 3HMTX up to 12 hours after injection, which closely followed the 14C inulin distribution. Thus, the levels in deep cerebral tissue were less than the average level for brain, and this suggests that treatment of CNS tumors by intraventricular injection may have variable results, partly due to complex tissue distribution patterns.

Animals↗
PubMed1977

[Serum methotrexate determination by microbiological assay in patients receiving high-dosage methotrexate (author's transl)].

Microbiological assay according to Burchenal (modified by Mehta) is used for the determination of the serum methotrexate (MTX) level. Fifty cycles of high-dose MTX therapy were monitored in 11 patients with osteogenic sarcoma. The results showed close correlation with the clinical course of the therapy. The serum level of MTX was elevated in patients with symptoms of toxicity.

Bone Neoplasms↗
PubMed1975

Liver biopsy in methotrexate-treated psoriatics-a re-evalution.

Two-hundred and eighty-six liver biopsies were performed in 139 psoriatics on treatment or considered for treatment with methotrexate. In 56 psoriatics included in this study both pre- and post-methotrexate biopsies were performed, the average methotrexate dose being 936 mg. None of the data showed statistically significant differences between pre- and post-methotrexate biopsies, with the exception of an increase in fattly infiltration, found when comparing all pre-methotrexate biopsies with the total number of latest post-methotrexate samples. As expected, alcohol seemed to be significantly associated with liver fibrosis in pre-methotrexate biopsies. An patients, although potassium arsenite alone has not been proved to be the cause of liver damage among psoriatics included in this study. While only 1 of 22 psoriatics with a total normal biopsy had been on arsenite, 6 of 18 of the same group of psoriatics who had fibrosis had been on this drug earlier. Although no statistically significant differences related to fibrosis and cirrhosis could that in three cases liver cirrhosis did appear in a biopsy from a methotrexate-treated psoriatic who had signs of fibrosis of cirrhosis in a pre-methotrexate biopsy. This incidence is low in relation to the total number of patients treated. The relatively low incidence of cirrhosis found in the present study, as in earlier studies by our group is believed to be due to the use of an intermittent dosage schedule. The study showed that early fibrosis and cirrhosis seem to appear, with very minor abnormalities in laboratory results. This finding indicates the necessity of performing liver biopsies in the control of psoriatics on long-term methotrexate therapy. The difference between biopsies from psoriatics and liver biopsies from control patients may indicate that severity of disease may be a complicating factor in the pathogenesis of the liver damage.

Adult↗
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↗
PubMed1978

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.

Acute Disease↗
PubMed1978

Conjugation of methotrexate to poly(L-lysine) increases drug transport and overcomes drug resistance in cultured cells.

Methotrexate and [(3)H]methotrexate were conjugated through a carbodiimide-catalyzed reaction to a 70,000 molecular weight poly(L-lysine) in molar ratios of approximately 13 to 1. The cellular uptake of labeled conjugate was far in excess of the uptake of free drug in cells that were either proficient or deficient in methotrexate transport. The conjugate markedly inhibited the growth of PRO(-)3 Mtx(RII) 5-3 Chinese hamster ovary cells, which are known to be drug resistant by virtue of a deficient methotrexate transport. The cells, however, were not inhibited by the same concentrations of free poly(Lys) and free drug. The 100-fold difference in drug concentration needed to inhibit the mutant cells and their corresponding wild type was totally abolished by exposing the methotrexate-resistant cells to methotrexate-poly(Lys). That the drug is carried into the resistant cells as intact drug-poly(Lys) is evident also from the fact that the conjugate is rendered inactive by brief trypsinization in vitro. Because the conjugate fails to inhibit dihydrofolate reductase (5,6,7,8-tetrahydrofolate: NADP(+) oxidoreductase; EC 1.5.1.3) in vitro, it must be concluded that the strong growth inhibitory effect of the conjugate is due to the intracellular hydrolysis of its polymeric backbone, followed by the release inside the cell of a pharmacologically active form of methotrexate. Our date show that in methotrexate-resistant cells the intracellular release of active drug after uptake of conjugate is of the same order of magnitude as the uptake of free drug by transport-proficient cells and, hence, that the drug resistance due to deficient transport can be totally overcome.

Biological Transport↗
PubMed1978

Optimization of high-dose methotrexate with leucovorin rescue therapy in the L1210 leukemia and sarcoma 180 murine tumor models.

An analysis of dose and schedule dependence of calcium leucovorin rescue during high-dose methotrexate therapy of ascitic forms of l1210 leukemia and Sarcoma 180 is reported. Schedules with very delayed "low-dose" leucovorin rescue following lethal doses of methotrexate were highly effective in preventing toxicity and achieved a pronounced antitumor effect in both ascites tumor models. Best results were obtained on a schedule of methotrexate (400 mg/kg s.c.) followed 16 to 20 hr later by calcium leucovorin (12 mg/kg s.c.) given once every 2 hr for a total of 5 doses. Progressive increases in the calcium leucovorin dosage on any schedule reduced both toxicity and the antitumor effect of methotrexate in each model. Following a single course of therapy, essentially no toxicity was observed, and the antitumor effects were 2-fold (L1210 leukemia) and 4-fold (Sarcoma 180) greater than a single, maximally tolerated dose (24/kg s.c.) methotrexate alone. An increase in the methotrexate dosage to 800 mg/kg s.c. with or without an increase in calcium leucovorin dosages on the same schedule did not appreciably increase the antitumor effect observed. Two courses of high-dose methotrexate (400 mg/kg s.c.) with leucovorin rescue (24 mg/kg s.c. 16, 20, and 24 hr after drug) given with an 8-day interval between courses doubled the total antitumor effect in each model with no substantial increase in toxicity and gave long-term survivors with Sarcoma 180. The results, overall, are in close agreement with prior prediction for schedule and dose dependence made on the basis of related pharmacokinetic and biochemical studies in murine tumor models reported from this laboratory.

Animals↗
PubMed1977

Methotrexate-induced sudden fatal pulmonary reaction.

A teenage girl in bone marrow remission with acute lymphocytic leukemia died suddenly from pulmonary edema. She had taken her first oral dose of methotrexate and cyclophosphamide 10 hours previously when she was feeling well and was asymptomatic. One week previously she had received the last of four intrathecal injections of methotrexate. Autopsy showed marked pulmonary edema as well as chronic lung changes, as previously described in patients with methotrexate pneumonitis. There is usually at least a 12-day interval from the onset of administration of methotrexate to the onset of the lung toxicity. The authors suggest the patient was sensitized by the intrathecal methotrexate and then reacted with angioneurotic edema of the lung when given the first oral dose of methotrexate. Careful examination for infectious agents, including electron microscopy, was negative.

Adolescent↗
PubMed1978

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion.

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35--350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was less than 4.5 X 10(-6) M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.

Adolescent↗