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Journal of Neuro-oncology Nov 1988The frequency with which polyneuropathy developed was investigated in patients with cancer of the larynx and pharynx who participated in a double-blind trial of the... (Clinical Trial)
Clinical Trial
The frequency with which polyneuropathy developed was investigated in patients with cancer of the larynx and pharynx who participated in a double-blind trial of the radiosensitizing drug misonidazole. Fourteen of 36 patients receiving misonidazole (total dose of about 11 g/m2) developed neuropathy, while this occurred in only 2 of 34 patients in the placebo group. Vibration perception threshold increased in all patients who developed neuropathy, but also in 12 (5 misonidazole and 7 placebo treated) without other symptoms or signs of neuropathy. Pharmacokinetic studies of misonidazole revealed a correlation between development of neuropathy and a high 'peak plasma concentration/g misonidazole in each fraction' and especially a high 'area under plasma concentration curve/g misonidazole in each fraction'.
Topics: Adult; Aged; Aged, 80 and over; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Laryngeal Neoplasms; Male; Middle Aged; Misonidazole; Nervous System Diseases; Pharyngeal Neoplasms
PubMed: 3066854
DOI: 10.1007/BF00163705 -
British Medical Journal Oct 1980
Topics: Humans; Hyperbaric Oxygenation; Misonidazole; Neoplasms; Nervous System Diseases; Radiation-Sensitizing Agents
PubMed: 7427595
DOI: No ID Found -
Biochemical and Biophysical Research... May 1983The hydroxylamine derivative of misonidazole reacts with glutathione under physiological conditions to form two isomeric conjugates. Based on physical and chemical...
The hydroxylamine derivative of misonidazole reacts with glutathione under physiological conditions to form two isomeric conjugates. Based on physical and chemical properties, the two conjugates have been identified as 1-[2-amino-(4-glutathion-S-yl)-1-imidazolyl]-3-methoxypropanol and 1-[2-amino-(5-glutathion-S-yl)-1-imidazolyl]-3-methoxypropanol. The formation of the glutathione conjugates of reduced misonidazole offers a molecular mechanism for the depletion of GSH in mammalian cells after exposure to misonidazole under hypoxic conditions.
Topics: Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Glutathione; Magnetic Resonance Spectroscopy; Misonidazole; Nitroimidazoles; Oxidation-Reduction
PubMed: 6847675
DOI: 10.1016/0006-291x(83)91719-9 -
International Journal of Radiation... 1982In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed a initial peripheral neuropathy rate of 55%, despite a dose...
In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed a initial peripheral neuropathy rate of 55%, despite a dose limitation of 12g/m2 of misonidazole. Tumor response at 9 months was most encouraging. We are now able to examine tumor response and persistence of neuropathy in these patients 2 1/2 years after radical radiotherapy. The results are comparable with those obtained with hyperbaric oxygen in a clinical trial at this center during the 1970's. Neuropathy was a serious side effect but the drug phenytoin has been shown to shorten the half-life of misonidazole. We have examined the effect of phenytoin on the pharmacokinetics of misonidazole in 13 patients who received radical radiotherapy for advanced head and neck tumors or oesophageal tumors. Misonidazole was given in multiple doses, i.e. daily or weekly as it would be used in conventional therapy. Phenytoin was given either daily throughout treatment, or it was withdrawn during treatment. There were dramatic changes in the half-life of misonidazole, but the concentration at the time of irradiation was little affected. The significant changes in the half-life of misonidazole and the increased concentration of the metabolite desmethylmisonidazole are discussed.
Topics: Drug Interactions; Half-Life; Head and Neck Neoplasms; Humans; Kinetics; Misonidazole; Nervous System Diseases; Nitroimidazoles; Phenytoin
PubMed: 7107352
DOI: 10.1016/0360-3016(82)90640-x -
International Journal of Molecular... Sep 2019We study the reactivity of misonidazole with low-energy electrons in a water environment combining experiment and theoretical modelling. The environment is modelled by...
We study the reactivity of misonidazole with low-energy electrons in a water environment combining experiment and theoretical modelling. The environment is modelled by sequential hydration of misonidazole clusters in vacuum. The well-defined experimental conditions enable computational modeling of the observed reactions. While the NO 2 - dissociative electron attachment channel is suppressed, as also observed previously for other molecules, the OH - channel remains open. Such behavior is enabled by the high hydration energy of OH - and ring formation in the neutral radical co-fragment. These observations help to understand the mechanism of bio-reductive drug action. Electron-induced formation of covalent bonds is then important not only for biological processes but may find applications also in technology.
Topics: Electrons; Misonidazole; Models, Molecular; Models, Theoretical; Molecular Structure; Solvents; Spectrum Analysis; Water
PubMed: 31489947
DOI: 10.3390/ijms20184383 -
International Journal of Radiation... May 1988The potential therapeutic benefit of misonidazole was tested in radiotherapy with 1, 2, 5, and 10 equal fractions, using as endpoints local tumor control (TCD50) of...
The potential therapeutic benefit of misonidazole was tested in radiotherapy with 1, 2, 5, and 10 equal fractions, using as endpoints local tumor control (TCD50) of murine mammary carcinoma MDAH-MCa-4 and leg contracture at the TCD50, measured 120 days after irradiation. In controls and misonidazole-treated mice, the TCD50 increased with the number of fractions, from 66.7 to 114.6 Gy in controls, and from 43.3 to 75.7 Gy with misonidazole. At doses of greater than or equal to 0.1 mg/g body weight, misonidazole reduced the TCD50 in all fractionation schedules; however, because of toxicity, 1.0 and 0.6 mg/g could be given with only 1 or 2 fractions. Leg contracture at the TCD50 was greatest (14.5 mm) in control mice treated with a single dose of radiation, and was least (7.2 to 7.4 mm) in those treated with a single dose of radiation preceded by 1.0 or 0.6 mg misonidazole/g body weight. With 0.1 mg misonidazole/g, the leg contracture at the TCD50 was less (9.8 to 12.2 mm with the various schedules) than in controls (12.0 to 14.5 mm) for 1, 5, or 10 fractions. Therefore, a therapeutic gain could be obtained by using misonidazole with 1, 2, 5, or 10 fractions, but the greatest gain occurred with 1 fraction, with high doses of misonidazole, that is, 0.6 to 1.0 mg/g.
Topics: Animals; Female; Mammary Neoplasms, Experimental; Mice; Misonidazole; Muscle Contraction; Radiotherapy Dosage
PubMed: 3360661
DOI: 10.1016/0360-3016(88)90018-1 -
International Journal of Molecular... Jul 2019Misonidazole (MISO) was considered as radiosensitizer for the treatment of hypoxic tumors. A prerequisite for entering a hypoxic cell is reduction of the drug, which may...
Misonidazole (MISO) was considered as radiosensitizer for the treatment of hypoxic tumors. A prerequisite for entering a hypoxic cell is reduction of the drug, which may occur in the early physical-chemical stage of radiation damage. Here we study electron attachment to MISO and find that it very effectively captures low energy electrons to form the non-decomposed molecular anion. This associative attachment (AA) process is exclusively operative within a very narrow resonance right at threshold (zero electron energy). In addition, a variety of negatively charged fragments are observed in the electron energy range 0-10 eV arising from dissociative electron attachment (DEA) processes. The observed DEA reactions include single bond cleavages (formation of NO), multiple bond cleavages (excision of CN) as well as complex reactions associated with rearrangement in the transitory anion and formation of new molecules (loss of a neutral HO unit). While any of these AA and DEA processes represent a reduction of the MISO molecule, the radicals formed in the course of the DEA reactions may play an important role in the action of MISO as radiosensitizer inside the hypoxic cell. The present results may thus reveal details of the molecular description of the action of MISO in hypoxic cells.
Topics: Electrons; Misonidazole; Radiation-Sensitizing Agents
PubMed: 31315268
DOI: 10.3390/ijms20143496 -
International Journal of Radiation... Aug 1984Misonidazole, after reduction to the hydroxylamine derivative, reacts with glutathione (GSH) under physiological conditions. The reaction product has been identified as...
Misonidazole, after reduction to the hydroxylamine derivative, reacts with glutathione (GSH) under physiological conditions. The reaction product has been identified as a mixture of two isomeric conjugates. When water soluble extracts of CHO cells exposed to misonidazole under hypoxic conditions are subjected to HPLC analysis, misonidazole derivatives, having the same chromatographic properties as the GSH-MISO conjugates, were detected. The identity of the synthetic and cellular products was further confirmed by identification of the amine derivative of misonidazole after desulfurization with Raney Nickel. When CHO cells were incubated with misonidazole in the presence of added GSH, a substantial increase in the amount of the conjugate was detected. When extracts of CHO cells exposed to misonidazole under hypoxia were subsequently exposed to GSH, an increased formation of the conjugate was observed. A rearrangement product of the hydroxylamine derivative of misonidazole is postulated as the reactive intermediate responsible for the formation of the conjugate.
Topics: Animals; Carbon Radioisotopes; Cell Line; Cricetinae; Cricetulus; Female; Glutathione; Liver; Mice; Mice, Inbred C3H; Misonidazole; Nitroimidazoles; Ovary; Oxygen
PubMed: 6540764
DOI: 10.1016/0360-3016(84)90345-6 -
International Journal of Radiation... 1982A detailed investigation was undertaken of reported modifiers of the toxicity towards hypoxic cells of misonidazole. The modifiers tested were medium type, cell type,...
A detailed investigation was undertaken of reported modifiers of the toxicity towards hypoxic cells of misonidazole. The modifiers tested were medium type, cell type, cell density, concentration of misonidazole, addition of serum, addition of sulfhydryl, addition of oxygen and pH. The latter 5 modifiers were found to be most important and were studied in many of the possible combinations. Serum has its greatest protective effect at low concentration (e.g. 0.5 mM) of misonidazole. In the absence of serum, the (log10) survival curve for misonidazole toxicity can be described mathematically as a function of time by a shoulder (DQ) inversely related to misonidazole concentration, and a slope (1/D0) related directly to log10 misonidazole concentration. Sulfhydryl's (cysteamine) protective effect dominates at high concentrations of misonidazole. The protective action of SH can change to potentiative in the absence of serum or at high pH. Addition of oxygen results in overall protection but no relative changes in the effect of the other modifiers. Drugs like ascorbate and disulfide may only potentiate toxicity to the level found in the absence of serum.
Topics: Animals; Cell Survival; Cells, Cultured; Cricetinae; Cricetulus; Hydrogen-Ion Concentration; Misonidazole; Nitroimidazoles; Oxygen Consumption; Sulfhydryl Compounds; Time Factors
PubMed: 7107400
DOI: 10.1016/0360-3016(82)90714-3 -
International Journal of Radiation... Jun 1979
Clinical Trial
Topics: Anorexia; Clinical Trials as Topic; Drug Eruptions; Female; Humans; Male; Misonidazole; Nausea; Neoplasms; Nitroimidazoles; Peripheral Nervous System Diseases; Seizures
PubMed: 227822
DOI: 10.1016/0360-3016(79)90070-1