caa a22 4500 465790054 CHVBK 20180323112021.0 cr unu---uuuuu 170327e19900501xx s 000 0 eng 10.1007/BF00177266 doi (NATIONALLICENCE)springer-10.1007/BF00177266 Clinical toxicity associated with tiazofurin [Elektronische Daten] [Jean Grem, Larry Rubinstein, Susan King, Bruce Cheson, Michael Hawkins, Dale Shoemaker] Summary: Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23-36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (≥ grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 uM) and prolonged exposure to plasma levels exceeding 50 uM may result in a higher incidence of serious non-hematologic toxicity. Kluwer Academic Publishers, 1990 tiazofurin nationallicence IMP dehydrogenase nationallicence phase I trials nationallicence Grem Jean Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut Rubinstein Larry Biometric Research Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut King Susan Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut Cheson Bruce Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut Hawkins Michael Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut Shoemaker Dale Regulatory Affairs Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut Investigational New Drugs Kluwer Academic Publishers 8/2(1990-05-01), 227-238 0167-6997 8:2<227 1990 8 10637 https://doi.org/10.1007/BF00177266 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00177266 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Grem Jean Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Rubinstein Larry Biometric Research Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- King Susan Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Cheson Bruce Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Hawkins Michael Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Shoemaker Dale Regulatory Affairs Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA aut NATIONALLICENCE 773 0- Investigational New Drugs Kluwer Academic Publishers 8/2(1990-05-01), 227-238 0167-6997 8:2<227 1990 8 10637 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer