International journal of radiation oncology, biology, physics
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Int. J. Radiat. Oncol. Biol. Phys. · Sep 1984
Randomized Controlled Trial Clinical TrialNeuropathy of nitroimidazole radiosensitizers: clinical and pathological description.
The dose limiting toxicity of the nitroimidazole radiosensitizers is peripherial neuropathy. Improved pharmacology of newer drugs has eliminated the encephalopathy. Peripheral neuropathies are predominently mild to moderate paresthesias of both hands and feet. ⋯ Sural nerve biopsies from patients indicate progressive axonal degeneration affecting both large and small caliber myelinated fibers. Axonal damage appears to be more severe in the distal portion of the nerves. More data are needed for correlation of clinical and pathological changes.
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Int. J. Radiat. Oncol. Biol. Phys. · Sep 1984
Clinical TrialIs misonidazole neurotoxicity altered by the use of phenytoin and/or dexamethasone in RTOG 79-18 and RTOG 79-16?
An analysis of Misonidazole (MISO) neurotoxicity in RTOG 79-16 and RTOG 79-18 was undertaken to evaluate the incidence of neurotoxicity relative to dexamethasone dose and phenytoin use. MISO was administered as follows: 79-16 arm A, 1 gm/m2 5 days a week for a total of 10 gm/m2 in 2 weeks; 79-16 arm B, 2 gm/m2 twice weekly for a total of 12 gm/m2 in 3 weeks; and 79-18, 2.5 gm/m2 once a week for a total of 15 gm/m2 in 6 weeks. Practically all patients were on dexamethasone, and 240 out of 550 were on phenytoin for seizures. ⋯ There was no correlation between dexamethasone dose and incidence of neurotoxicity within each study. However, the incidence of (PN) for the combined studies was 6.4% (35/550) which is lower than 18.9% (85/449) for non-brain Phase III protocols where patients are rarely, if ever, on dexamethasone or other corticosteroids. Four hour and 24 hour plasma MISO levels, and 24 hour/4 hour MISO ratios did not correlate with toxicity.
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Int. J. Radiat. Oncol. Biol. Phys. · Sep 1984
Clinical Trial Controlled Clinical TrialMisonidazole 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. ⋯ 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.
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Int. J. Radiat. Oncol. Biol. Phys. · Sep 1984
Enhanced tumor responses through therapies combining CCNU, MISO and radiation.
Studies were performed to determine whether the radiation sensitizer misonidazole (MISO) could enhance the tumor control probability in a treatment strategy combining radiation and the nitrosourea 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). In initial experiments KHT sarcoma-bearing mice were injected with 1.0 mg/g of MISO simultaneously with a 20 mg/kg dose of CCNU 30-40 min prior to irradiation (1500 rad). These timings were chosen to maximize the effectiveness of MISO both as a chemopotentiator and radiosensitizer. ⋯ These results were not due to the radiation-CCNU sequence but rather reflected the ability of the sensitizer to act as a chemopotentiator when CCNU is given 0 to 6 hr after the MISO-radiation combination. This was not the case when the MISO-radiation combination was administered 18 or 24 hr prior to CCNU. The data therefore indicate that 1) improved tumor responses may be achieved when MISO is added to a radiation-chemotherapy combination and 2) MISO may be more effective in such a protocol when utilized as a chemopotentiator.
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Int. J. Radiat. Oncol. Biol. Phys. · Aug 1984
The effect of vitamin B6 on the neurotoxicity and pharmacology of desmethylmisonidazole and misonidazole: clinical and laboratory studies.
The clinical usefulness of misonidazole (MISO) and desmethylmisonidazole (DMM) is severely limited by neurotoxicity. Based on theoretical considerations and on laboratory data suggesting that pyridoxine (PN) decreased MISO toxicity in mice, we attempted to ameliorate the clinical neuropathy of DMM using oral PN. Pharmacokinetic analysis suggested interaction of PN and DMM but no protection against neuropathy was observed. ⋯ Dexamethasone did not alter MISO toxicity in mice, contrary to the clinical findings. We conclude that vitamin B6 is not useful in preventing clinical neurotoxicity of MISO or DMM. Furthermore, this mouse model of neurotoxicity assessment has produced results inconsistent with those seen clinically.