• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.6
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• pp.1576-1583
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• 2006

In order to investigate the effect of Goamshimshinhwan(GASSW) on SD rats with deteriorated immunity caused by methotrexate. Methotrexate was fed to the SD rats once a day for 4 days. After the immune responses of the at a dosage 1,000, 500 and 250mg/kg/10ml. and the changes on body weight and gains, spleen weight, total blood leukocyte numbers, total lymphocyte numbers, the percentage of B-cell, T-cell, CD3+CD+4 T-cell, CD3+CD8+ T-cell and CD4+/CD8+ T-cell ratios in the bolld and spleen were observed. In addition, the serum IL-2 levels and productivity of IL-2 of splenic cells were also demonstrated in this study. The changes on body weight were increased significantly in 100 and 500mg/kg of GASSW groups and the changes on body gain were increased significantly in 1000mg/kg of GASSW groups as compared with control group. The changes on the spleen weight (absolutely or relatively) were increased significantly in all GASSW groups as compared with control group. The total blood leukocyte numbers were increased significantly in 1000 and 500mg/kg of GASSW groups as compared with control group. The total lymphocyte numbers were increased significantly in all GASSW groups in the blood and increased significantly in 1000 and 500mg/kg of GASSW goups in spleen as compared with control group. The percentage of B-cell and T-cell were increased significantly in 1000mg/kg of GASSW groups in the blood and increased significantly in 1000 and 500mg/kg of GASSW groups in spleen as compared with control group. The percentage of CD3+CD4+ T-cell and the serum IL-2 levels and productivity of IL-2 of splenic cells were increased significantly in 100 and 500 mg/kg of GASSW groups in the blood and spleen as compared with control group. The percentage of CD3+CD8+ T-cell were increased significantly in 1000mg/kg of GASSW groups only in spleen as compared with control groups. The CD4+/CD8+ T-cell ratios were increased significantly in 1000 and 500mg/kg of GASSW groups only in the blood as compared with control group. Goamshimshinhwan(GASSW) has immuno-stimulating effect on SD rats with deteriorated immunity caused by methotrexate.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1553-1556
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• 2012

Introduction: Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration. Patients and Methods: Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5´UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms. Results: Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population. Conclusion: Pharmacogenetics might contribute to tailored therapy.

• Journal of Yeungnam Medical Science
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• v.28 no.1
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• pp.60-69
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• 2011

Due to its efficacy and tolerability, low dose oral methotrexate (MTX) therapy has been widely used for treatment of rheumatoid arthritis (RA). However, it can rarely cause serious, life-threatening hematologic toxicities, such as pancytopenia. We report here on two patients with chronic kidney disease (CKD), who developed severe pancytopenia after 5 years (cumulative dose 1,240 mg) and 4 years (cumulative dose 1,320 mg) of low dose MTX therapy for treatment of RA, respectively. Both patients presented with renal insufficiency, hypoalbuminemia, concurrent use of nonsteroidal anti-inflammatory drugs, and elevated mean corpuscular volume of red blood cells (RECs), all of which are known as risk factors of MTX-induced pancytopenia. Despite receiving treatment, which included REC and platelet transfusions, antibiotic therapy, granulocyte colony stimulating factor, and leucovorin rescue, one patient died of sepsis. Based on our case study, prompt investigation of risk factors associated with MTX toxicity is required for all patients receiving MTX therapy. MTX treatment, even at a low dose, should be discontinued in patients with advanced CKD.

• The Journal of Internal Korean Medicine
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• v.25 no.4
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• pp.117-128
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• 2004

Objectives : To examine the effects of Gojineumja on white rats which deteriorated immunity caused by Methotrexate(MTX), first of all, MTX was fed to the rats once a day for 4 day. Methods : After the immune response of the rats are deteriorated, dried extracts of Gojineumja(GJE) mixed in water was fed to the white rats once a day for l4days. The next conclusion was made by examining the rates of B-cells and T-cells of the peripheral blood and the changes in rates of CD4+ T-cells and CD8+ T -cells of the blood sampled from the spleen and peripheral region. Especially the count of CD3+ CD4+ T-cells of the peripheral blood and the count of CD3+ CD4+ T-cells of the spleen the count of CD4+/ CD8+ T-cell of the peripheral blood and the spleen proved the significant effect of increasing immune responses statistically. Results :(1) The following are the summary of the results. (2) The percentage of B lymphocyte of peripheral blood was increased significantly in GJE group as compared with control group. (3) The percentage of CD3+ CD4+ T-cell of peripheral blood was increased significantly in GJE group as compared with control group. (4) The percentage of CD3+ CD8+ T-cell of peripheral blood was not different statistically. (5) The percentage of CD4+/ CD8+ T-cell of peripheral blood was increased significantly in GJE group as compared with control group. (6) The percentage of CD3+ CD4+ T-cell of spleen was increased significantly in GJE group as compared with control group. (7) The percentage of CD3+ CD8+ T-cell was not different statistically. (8) The percentage of CD4+ /CD8+ T-cell was not different statistically. Conclusions : Gojineumja has an effect of increasing immune responses on white rats with deteriorated immunity caused by MTX.

• Clinical and Experimental Reproductive Medicine
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• v.41 no.1
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• pp.33-36
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• 2014

Objective: To estimate the failure rate of medical treatment and to identify variables associated with treatment failure in patients with tubal pregnancy and an initial serum level of human chorionic gonadotropin (HCG) over 10,000 IU/L. Methods: The inclusion criteria were tubal pregnancy diagnosed using ultrasonography, primary treatment of intramuscular methotrexate injection at one of the four institutions between January 2003 and December 2011, a serum HCG level within two days before treatment >10,000 IU/L, and follow-up data to determine treatment success or failure. Exclusion criteria were other primary treatments besides intramuscular methotrexate injection. The clinicopathologic data of 36 patients were collected and analyzed. Results: Medical treatment failed and surgery was performed in 19 (53%) patients. In univariable analysis, age, parity, and size of the gestational sac were associated with treatment failure, but none of the variables were associated with treatment failure in multivariable analysis. The failure rate in the subgroup with age<33 years and size of gestational sac ${\geq}1.1cm$ was significantly higher than those of the other subgroups (82% vs. 41% [mean of the other subgroups], respectively). Conclusion: Patients with a serum HCG level >10,000 IU/L who received medical treatment had a high failure rate. Among them, patients aged<33 year and with a gestational sac ${\geq}1.1cm$ had an extremely high failure rate.

• Korean Journal of Clinical Pharmacy
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• v.29 no.2
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• pp.101-108
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• 2019

Background: High doses of methotrexate (MTX) are often used in various chemotherapy protocols to treat acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) in children, but its delayed elimination increases the occurrence of adverse events, such as bone marrow suppression. The aim of this study was to investigate the elimination of MTX at 24 and 48 hours. Methods: We retrospectively analyzed electronic medical records of ALL or NHL pediatric patients who received $5g/m^2$ MTX infusion over 24 hours (between June, 2012 and July, 2018) at the Yonsei University Health System, Korea. The delayed elimination of MTX concentrations was assessed with 100 or $150{\mu}M$ MTX at 24 hours, and 2 or $5{\mu}M$ at 48 hours. Results: Among the 85 MTX cycles administered, 23 cycles were classified in delayed elimination group, and 62 cycles showed normal elimination. At 24 hours, the delayed elimination group with MTX concentration > $100{\mu}M$ showed higher percentage than group with MTX concentration < $100{\mu}M$ (45.8% vs. 19.7%, p = 0.015). However, no differences were observed at $150{\mu}M$ MTX (p = 0.66). At 48 hours, the delayed elimination was higher than the normal elimination at both concentration baselines (p < 0.001 at $2{\mu}M$, p = 0.024 at $5{\mu}M$). Conclusions: MTX concentrations greater than $100{\mu}M$ show high probability of delayed elimination at 24 hours. When MTX levels are above normal, leucovorin and hydration regimens should be continued to prevent delayed elimination.

• Journal of Chest Surgery
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• v.2 no.1
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• pp.25-40
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• 1969

Lung homotransplantation was performed in 15 pairs of dog. Methotrexate and R.E.S. blocking were used to prolong the survival time. Details of handling the transplant, operative technique and management of the recipient were discussed and following results were obtained: 1]. 7 dogs out of 15 dogs of homotransplantation of lung were survived beyond 3 days. In the group of dogs treated with methotrexate, the average survival was 8.5 days, and in the group of dogs treated with R.E.S. blocking, the average survial was 9.7 days with longest survival of 17 days. 2]. The causes of immediate postoperative death in homotransplantation of dogs were lung edema and disruption of bronchial anastomosis. 3]. The main causes of death in successful homotransplantation dogs which were survived beyond 3 days were infection of lung parenchyma and bronchial necrosis rather than the occurence of graft rejection. 4]. Graft rejection was not revealed even after 7 days of operation in the group treated with methotrexate as well as in the group treated with R. E.S. blocking. This finding made it suggest that the R. E.S. blocking may be effective to control the rejection reaction. 5]. Even though the pulmonary function of transplanted lung was revealed the evidence of severe impairment immediate after operation by bronchospirometry, it was increased gradually and 10 days after operation the minute ventilation and oxygen uptake were decreased 8%, 13% respectively less than pre-operative one.

• Archives of Pharmacal Research
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• v.12 no.3
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• pp.186-190
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• 1989

The release rates of methotrexate (MTX) from MTX-human serum albumin (HSA) conjugate, and 5-fluorouracil (5-FU) from 5-FU acetic acid (AA)-HSA conjugate were determined after incubation of the conjugates in various conditions. The concentrations of 5-FU released from the conjugate increased monoexponentially, however those of MTX increased biexponentially in all studies. It indicated that there are two distinct types of MTX-HSA linkage, weakly and tightly bound linkages. The release rates of 5-FU were lower than those of MTX in all studies indicating that the bond of 5-FU-AA-HSA conjugate is very stable, which is supported by the higher value of activation energy (39. 9 vs 10. 7 Kcal/mole) using Arrhenius equation. The release rates of MTX and 5 -FU from the conjugates increased with incubation temperatures. Proteolytic enzyme and liver homogenates accelerated significantly the release rates of MTX and 5-FU. Approximately 1.30 and 22.0% of MTX were released after 12 hours of incubation in the absence and presence of protease, respectively. The corresponding values for 5-FU were released after 12 hours of incubation with rat liver homogenates which were diluted 6 times with phosphate buffer of pH 6.0. The MTX-HSA and 5-FU-AA-HSA conjugates were very stable in rat plasma.

• The Journal of Korean Medicine
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• v.30 no.6
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• pp.69-79
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• 2009

Objective: In this study, the immunomodulatory activity of a mixture of wild Panax ginseng and red-mold rice extracts (MPR) on RAW 264.7 macrophage cells in the presence and absence of methotrexate (MTX), an anti-cancer drug, was investigated. Methods and Results: In the cell viability, MPR showed a significant cell proliferation and inhibited cell regression by red-mold rice (RMR) alone or MTX alone. MPR induced moderate increase in nitric oxide (NO) production. NO production and inducible nitric oxide synthase (iNOS) mRNA expression by LPS decreased after MPR treatment. In addition, MPR slightly induced COX-2 mRNA expression, but it did not affect the expression of COX-2 mRNA by LPS treatment. In RT-PCR analyses, MPR induced IL-$1{\alpha}$, IL-$1{\beta}$, IL-6, and TNF-$\alpha$ mRNA expression, but had no effect on IL-10 and TGF-$\beta$, regardless of MTX treatment. Furthermore, MPR did not interfere with the cytotoxicity of MTX against MCF-7 human breast carcinoma cells. Conclusions: MPR is efficacious in protecting against MTX-induced cell regression as a result of macrophage activation, resulting in induction of cytokine expression, implying that MPR could be considered an adjuvant in MTX-chemotherapy.

• Journal of Oral Medicine and Pain
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• v.40 no.2
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• pp.82-87
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• 2015

Methotrexate (MTX) is a chemotherapeutic agent that is used to treat a host of malignancies. But recently, MTX has also been used as a therapeutic agent for chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus. However, MTX is an antimetabolite that affects rapidly dividing normal cells such as oral mucosal epithelial cells, gastrointestinal epithelial cells, and bone marrow cells-which explains why oral mucositis is often an initial manifestation of MTX toxicity. Because oral lesions are frequently initially presented in dental clinics, dentists should consider the possibility of adverse drug reactions in the differential diagnoses of oral lesions through a meticulous collection of patients' medical histories. In this report, we examine patients who suffered from oral ulcerative lesions upon diagnosis of MTX-induced oral mucositis. Then, we suggest approaches for the diagnosis and treatment of MTX-induced oral mucositis through a review of literature.