Misonidazole with dexamethasone rescue: an escalating dose toxicity study.
Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, we reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. Furthermore, in that study we have observed that DEXA did not alter the plasma pharmacokinetics of misonidazole. We are presently investigating the use of DEXA (2 mg t.i.d. during treatment), with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO ranging from 13.5 to 17.5 gm/M2 given in 9 equally divided doses over 3 weeks. DEXA, 2 mg t.i.d. is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M2. One grade I PN occurred in the first four patients receiving 15.5 gm/M2. Six additional patients were entered at this dose level and no further incidence of PN was observed. Patients are being entered at the next step of 17.5 gm/M2.
D000293:Adolescent; D000328:Adult; D000368:Aged; D003907:Dexamethasone / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008875:Middle Aged; D008920:Misonidazole / Q000627:therapeutic use / Q000633:toxicity*; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control; D009593:Nitroimidazoles / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use / Q000633:toxicity*
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D003907:Dexamethasone; D008920:Misonidazole