Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The glutathione transferases comprise a family of isoenzymes, one or more of which are involved in the conjugation of alkylating agents to glutathione (GSH). Increased GSH transferase activity has been shown to underlie acquired resistance to several alkylating agents. Ethacrynic acid inhibits the isoenzymes of GSH transferase with 50% inhibitory concentration values ranging from 0.3 to 6.0 microM and has been shown to restore sensitivity to alkylating agents in drug-resistant animal tumor models. We entered 27 previously treated patients with advanced cancer on a study of ethacrynic acid (25 to 75 mg/m2 p.o. every 6 h for 3 doses) and thiotepa (30 to 55 mg/m2 i.v. 1 h after the second dose of ethacrynic acid). The major toxicity of ethacrynic acid was diuresis, which was observed at every dose level; in addition, severe metabolic abnormalities occurred at 75 mg/m2. At 50 mg/m2, the diuretic effects were manageable. Myelosuppression was the most important effect of the combination. Two of seven courses of ethacrynic acid, 50 mg/m2, and thiotepa, 55 mg/m2, were associated with grade 3 or 4 neutropenia and/or thrombocytopenia. Nausea/vomiting greater than or equal to grade 2 was observed in 16% of courses. GSH transferase activity was assayed spectrophotometrically in the peripheral mononuclear cells of all patients. At each dose level, activity decreased following ethacrynic acid administration, with recovery by 6 h. Administration of ethacrynic acid, 50 mg/m2, resulted in a mean nadir of transferase activity of 37% of control. The pharmacokinetics of thiotepa and its principal metabolite TEPA were studied in 23 patients. The plasma disappearance of thiotepa fit a two-compartment open model with a terminal half-life of approximately 2 h. Plasma TEPA levels peaked at a mean of 2.16 h following thiotepa administration. The harmonic mean terminal half-life of TEPA was 10.4 h, and the TEPA area under the curve (AUC) did not increase with increasing thiotepa dose. The AUC of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA was lower than that previously observed. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA. The severity of the platelet toxicity was correlated with the AUC of thiotepa, but not with that of TEPA. This combination of thiotepa and ethacrynic acid will be tested further in Phase II trials.
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PMID:Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. 193 69

A prospective study of combined modality therapy of non-AIDS related lymphomatous meningitis was carried out. Lymphomatous meningitis is diagnosed increasingly as anti-lymphoma therapies become more effective and result in prolonged patient survival. Twenty-two patients (range 38-69 years; median 60) with lymphomatous meningitis due to metastatic non-AIDS related non-Hodgkins lymphoma were treated. Neurologic presentation included: headache (n=13); cranial neuropathies (n=9); ataxia (n=5); cauda equina syndrome (n=3); myelopathy (n=1); and meningismus (n=1). All patients underwent radiographic evaluation of the extent of central nervous system disease (CNS) followed by radiotherapy (n=8) and sequential intraventricular chemotherapy (methotrexate in 22 patients; cytarabine in 12; thio-TEPA in 5). CNS imaging demonstrated: interrupted CSF now (n=8); intra-cranial subarachnoid nodules (n=2); hydrocephalus (n=2); spinal subarachnoid nodules (2); nerve root enhancement (n=2); and epidural spinal cord compression (n=1). Cytologic responses were seen in 16 patients (73%) to first-, 7 (58%) to second- and 2 (40%) to third-line chemotherapy. Treatment-related toxicity included 14 patients (64%) with aseptic meningitis and 12 patients (55%) with thrombocytopenia or neutropenia (all unrelated to intraventricular chemotherapy). Median survival was 10 months (range: 3-24 months). Fourteen patients (64%) died of their systemic disease, 3 patients (14%) died of progressive lymphomatous meningitis, 4 patients (19%) died of progressive combined systemic disease in lymphomatous meningitis and 1 patient (5%) is disease-free. Fourteen patients (64%) received concurrent systemic chemotherapy and no differences were seen in outcome within this group of patients including 6 patients treated with dose intensive chemotherapy and autologous bone marrow transplantation. Lymphomatous meningitis in patients with non-AIDS related non-Hodgkin's lymphoma may be palliated with combined modality therapy, however, despite the application of standard or dose intensive systemic chemotherapy, therapy remains non-curative.
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PMID:Lymphomatous meningitis in immunocompetent patients. 2159 Feb 44