Prospective six year follow up of patients withdrawn from a randomised study comparing parenteral gold salt and methotrexate.
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OBJECTIVE: To confirm the impression of a better outcome of patients withdrawn from parenteral gold salt therapy compared with those withdrawn from methotrexate. METHODS: Patients with early, active, and erosive RA were randomised for a double blind trial to receive either weekly 15 mg intramuscular methotrexate or 50 mg goldsodiumthiomalate. If the drug had to be withdrawn because of side effects treatment was continued with the other drug in still active disease. Patients with insufficient response were treated with a combination of both drugs. All patients were followed up by an extended clinical and radiographic evaluation. RESULTS: 64 patients each were allocated to methotrexate and gold treatment. After 72 months a complete record was available for 88% of patients. Within the first 36 months 38 patients withdrew from gold treatment (95% because of side effects) and 23 patients withdrew from methotrexate (57% because of side effects). A significant 40% to 70% improvement of all parameters (erythrocyte sedimentation rate, C reactive protein, swollen and tender joints, radiological progression) compared with baseline was observed in patients completing their randomised treatment with gold or methotrexate. The same improvement over three years was seen in patients who withdrew from gold treatment, while patients withdrawing from methotrexate experienced a deterioration of their disease. CONCLUSION: Withdrawals represent the majority of patients in long term drug trials. Patients with early RA stopping gold because of side effects show almost the same sustained improvement as patients continuing gold or methotrexate. Patients withdrawn from methotrexate experience a reactivation of their disease. (+info)
Increased transport of pteridines compensates for mutations in the high affinity folate transporter and contributes to methotrexate resistance in the protozoan parasite Leishmania tarentolae.
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Functional cloning led to the isolation of a novel methotrexate (MTX) resistance gene in the protozoan parasite Leishmania. The gene corresponds to orfG, an open reading frame (ORF) of the LD1/CD1 genomic locus that is frequently amplified in several Leishmania stocks. A functional ORF G-green fluorescence protein fusion was localized to the plasma membrane. Transport studies indicated that ORF G is a high affinity biopterin transporter. ORF G also transports folic acid, with a lower affinity, but does not transport the drug analog MTX. Disruption of both alleles of orfG led to a mutant strain that became hypersensitive to MTX and had no measurable biopterin transport. Leishmania tarentolae MTX-resistant cells without their high affinity folate transporters have a rearranged orfG gene and increased orfG RNA levels. Overexpression of orfG leads to increased biopterin uptake and, in folate-rich medium, to increased folate uptake. MTX-resistant cells compensate for mutations in their high affinity folate/MTX transporter by overexpressing ORF G, which increases the uptake of pterins and selectively increases the uptake of folic acid, but not MTX. (+info)
Electrical stimulation prolongs the survival days of leukemic mice treated with methotrexate.
(27/4604)
To investigate effects of electrical stimulation on survival days of leukemic mice treated with methotrexate (MTX), L1210-bearing mice were treated by MTX and calcium folinate (leucovorin) rescue therapy (MTX: 400 mg/kg, followed by leucovorin at the dose of 7.5 mg/kg at 8, 15 and 24 hr after MTX) under electrical stimulation (foot shock: shock amplitude, 0.4 mA; voltage, 60-100 V/cm; shock duration, 5 sec; frequency, 0.5 Hz) of various lengths. The survival days were significantly prolonged by 6-hr electrical stimulation in combination with MTX, while plasma MTX concentrations and pharmacokinetic parameters such as the area under the curve (AUC-12 hr) and clearance (CL) were not significantly altered. Psychological stress did not alter the efficacy of MTX in the communication box paradigm. Amplified efficacy of MTX was shown in a length-dependent manner when electrical stimulation of various lengths were applied to L1210-bearing mice. (+info)
Clonal selection and in vivo quantitation of protein interactions with protein-fragment complementation assays.
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Two strategies are described for detecting constitutive or induced protein-protein interactions in intact mammalian cells; these strategies are based on oligomerization domain-assisted complementation of rationally designed fragments of the murine enzyme dihydrofolate reductase (DHFR; EC 1.5.1.3). We describe a dominant clonal-selection assay of stably transfected cells expressing partner proteins FKBP (FK506 binding protein) and FRAP (FKBP-rapamycin binding protein) fused to DHFR fragments and show a rapamycin dose-dependent survival of clones that requires approximately 25 molecules of reconstituted DHFR per cell. A fluorescence assay also is described, based on stoichiometric binding of fluorescein-methotrexate to reconstituted DHFR in vivo. Formation of the FKBP-rapamycin-FRAP complex is detected in stably and transiently transfected cells. Quantitative rapamycin dose-dependence of this complex is shown to be consistent with in vitro binding and distinguishable from a known constitutive interaction of FKBP and FRAP. We also show that this strategy can be applied to study membrane protein receptors, demonstrating dose-dependent activation of the erythropoietin receptor by ligands. The combination of these clonal-selection and fluorescence assays in intact mammalian cells makes possible selection by simple survival, flow cytometry, or both. High-throughput drug screening and quantitative analysis of induction or disruption of protein-protein interactions are also made possible. (+info)
Granisetron (Kytril) suppresses methotrexate-induced nausea and vomiting among patients with inflammatory arthritis and is superior to prochlorperazine (Stemetil).
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OBJECTIVE: Methotrexate (MTX) is an increasingly popular anti-rheumatic drug with its usefulness limited by toxicity, most commonly gastrointestinal (GI). The aim of the study was to study the effectiveness of the 5-HT3 receptor antagonist granisetron (GR) in the therapy of MTX-induced nausea. METHODS: A single-blind 8 week pilot study with random allocation to either GR 1 mg or prochlorperazine (Stemetil; PCh) 10 mg was undertaken in 13 patients who were taking or had taken MTX for either rheumatoid arthritis (10) or psoriatic arthritis (3). RESULTS: One in six patients treated with PCh completed the 8 week study compared to 7/7 treated with GR. After switching of symptomatic patients, 11 completed the study on GR and median improvement was by two grades (P < 0.001) with a significantly better visual analogue scale score for patient satisfaction compared to PCh. CONCLUSION: Treatment with GR may be useful in establishing and maintaining some patients on MTX where GI toxicity would have precluded such therapy. (+info)
High-dose leucovorin as sole therapy for methotrexate toxicity.
(30/4604)
PURPOSE: Hemodialysis, hemoperfusion, thymidine, and carboxypeptidase have been recommended together with high-dose (HD) leucovorin (LV) to treat patients at risk for methotrexate (MTX) toxicity. To elucidate the efficacy of high LV rescue as the sole salvage modality for severe MTX intoxication, we studied 13 patients who were treated in this fashion at Memorial Sloan-Kettering Cancer Center (New York, NY). PATIENTS AND METHODS: To identify patients at high risk for severe MTX toxicity, we performed a retrospective review of all patients with MTX levels greater than 100 micromol/L at 24 hours and greater than 10 micromol/L at 48 hours after HD MTX. RESULTS: A total of 13 patients were identified. The median MTX concentration was 164 micromol/L at 24 hours (range, 102 to 940 micromol/L), 16.3 micromol/L at 48 hours (range, 10.5 to 190 micromol/L), and 6.2 micromol/L at 72 hours (range, 1.35 to 39 micromol/L). MTX levels remained greater than 0.1 micromol/L for an average of 11 +/- 3 days (mean +/- SD) (range, 7 to 17 days). In addition to supportive treatment with hydration and sodium bicarbonate administration, all patients were treated solely with HD LV, which was started within the first 24 hours in nine patients, 48 hours in three patients, and 72 hours in one patient in doses that varied from 0.24 to 8 g/d. Significant neutropenia (neutrophil count < 1,000/ microL) occurred in eight patients and lasted for 1 to 5 days. Thrombocytopenia (platelet count < 100,000/microL) occurred in seven patients and lasted for 5 to 10 days. Other toxic manifestations included mucositis of varying degrees, diarrhea, and neutropenic fever, but all patients recovered. CONCLUSION: In the range of MTX levels observed, HD LV can be used as a sole therapy for MTX toxicity without the need for extracorporeal removal and with tolerable morbidity. (+info)
Use of a five-agent GVHD prevention regimen in recipients of unrelated donor marrow.
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A five-agent GVHD prophylaxis programme consisting of cyclosporin A, methotrexate, anti-thymocyte-globulin, pentaglobin and metronidazol was given to 48 recipients of unrelated donor marrow with chronic myelogenous leukemia, acute leukemia, myelodysplastic syndromes, and familiar lymphocytic hemophagocytosis of an average age of 33.5 (0.6-56) years. GVHD grades II-IV occurred in 18 patients (39%) and grades III-IV in five patients (11%). Chronic GVHD developed in nine patients (23%), three limited and six extensive. Fifteen patients died. Clinical relapse was detected in eight patients. Four patients died as a consequence of the underlying disease and subsequent treatment, 11 patients died of transplant-related causes. After a median follow-up of 19 months, the overall and disease-free survival are 67% and 62%, respectively. Survival by age is as follows: 0-19 years: 12/13 patients; 20-39 years: 14/25 patients; 40-59 years: 7/10 patients. The five-agent GVHD prophylaxis regimen is effective. Matched-unrelated donor transplants can be carried out safely in patients younger than 50 years of age. The results in patients younger than 20 years of age should encourage matched-unrelated donor transplants at earlier stages of the disease. (+info)
Long-term follow-up results of a Pilot Phase II study of multidrug chemotherapy (MVP-CAB) in patients with advanced urothelial cancer.
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BACKGROUND: To determine the long-term effects and toxicity of multidrug chemotherapy for advanced urothelial cancer. METHODS: Forty patients with metastatic urothelial cancer were treated with a new combination chemotherapy, MVP-CAB (methotrexate, doxorubicin, vincristine, cyclophosphamide, bleomycin and cisplatin every 28 days). Of the 40 patients, 26 had not undergone prior chemotherapy or radiotherapy; the remaining 14 patients had undergone prior cisplatin-based chemotherapy. RESULTS: The clinical response rate to MVP-CAB therapy for all 40 patients was 63% [complete response (CR), six patients; partial response (PR), 19 patients]. The median duration of the effects was 22 and 13 months in the patients with CR and PR, respectively. The clinical response rate for the 26 patients without prior chemotherapy was 77% (CR, four patients; PR, 16 patients). The rate for the 14 patients with prior chemotherapy was 36% (CR, two patients; PR, three patients). The response rate according to metastatic site was highest for the liver (80%), followed by the lymph nodes (74%) and lungs (67%). The effect on bone metastasis was poor (22%). There was good compliance with the MVP-CAB chemotherapy regimen and toxicity was tolerable. The 1-, 3- and 5-year overall survival rates were 42.5, 10 and 5%, respectively. CONCLUSIONS: MVP-CAB combination chemotherapy was found to be effective for the treatment of advanced urothelial cancer, especially for liver metastasis. (+info)