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Biomedical subjects

M I Saunders

Publications and source records attributed to M I Saunders.

At least 109 records · Page 6Linked to original sources
PubMed1986

A comparison of the tumour concentrations obtainable with misonidazole and Ro 03-8799.

Both Ro 03-8799 and misonidazole were administered to six patients before tumour sampling. Using similar doses, tumour concentrations of Ro 03-8799 were approximately double those of misonidazole. Examination of the data with regard to the relative sensitising efficiencies of these two compounds gives us, as a conservative estimate, a factor of 1.6 in favour of Ro 03-8799. From these observations it is predicted that, when given with radiotherapy in a 25-fraction course Ro 03-8799, is likely to be at least five times more effective as a hypoxic cell sensitiser than misonidazole.

Adult↗
PubMed1986

A comparative study of Ro 03-8799: racemic mixture and enantiomers.

The maximum single dose of the 2-nitroimidazole hypoxic cell radiosensitiser Ro 03-8799 is limited to 1 g/m2 by the occurrence of a well characterised acute syndrome of sweating, nausea and mental changes. In an attempt to increase the tolerable dose, the clinical toxicity of the racemic mixture was compared with that of the R- and S-enantiomers of Ro 03-8799. Twelve patients received escalating alternate doses of racemic mixture and R- or S-enantiomer, the dose levels being 0.25 g/m2, 0.5 g/m2, 0.75 g/m2 and 1.0 g/m2. Careful monitoring of the acute syndrome failed to demonstrate any consistent differences between racemic mixture and either enantiomer. This would suggest that the toxicity is not mediated via any specific central nervous system receptor. It is concluded that separation of Ro 03-8799 into its enantiomers will not enable a clinically useful increase in dosage.

Dose-Response Relationship, Drug↗
PubMed1984

The pharmacokinetics of a new radiosensitiser, Ro 03-8799 in humans.

A new hypoxic cell radiosensitiser, Ro 03-8799 has been administered intravenously to human volunteers and its kinetic parameters derived from plasma and urine data. Good penetration of drug into tumour tissue is found, consistent with its large volume of distribution. The plasma clearance of this compound is rapid due to high metabolic and renal clearances. These parameters combine to produce an elimination half-life of 5.6 h, approximately half that of misonidazole, a well studied radiosensitiser. It is hoped that this decrease in total body exposure will also reduce the cumulative toxicity seen when misonidazole is administered repeatedly.

Adult↗
PubMed1984

Primary tumor control after radiotherapy for carcinoma of the bronchus.

The primary tumor control and the appearance of distant metastasis was observed closely in 62 patients entered into a randomized controlled trial of the radiosensitizing drug, misonidazole, in carcinoma of the bronchus. Sixty-one of the 62 patients are now dead; an autopsy examination was carried out in 42 (69%). Although survival was comparable to that observed in similar studies, tumor persisted or recurred at the primary site in 95% (58/61) while 39% (24/61) showed no evidence for distant metastasis. In these patients, improvement in the primary tumor control would be important in extending survival.

Bronchial Neoplasms↗
PubMed1984

The relationship between tumor response and survival following radiotherapy for carcinoma of the bronchus.

Tumor response was closely observed in a randomized controlled trial of a radiosensitizing drug in the radiotherapy of carcinoma of the bronchus. The persistence of tumor cells in the sputum after treatment and the degree of regression measured radiologically at two months did not correlate with the subsequent course. However, total regression of tumor and time to regrowth both assessed radiologically showed a highly significant correlation with survival (P less than 0.0005).

Bronchial Neoplasms↗
PubMed1984

The clinical testing of Ro 03-8799--pharmacokinetics, toxicology, tissue and tumor concentrations.

Ro 03-8799, a lipophilic nitroimidazole with a basic side chain, has now been administered intravenously to 69 patients. The elimination half-life in plasma was 5.1 hr and the plasma concentration at 30 min was 14.8 micrograms/ml standardized to a dose of 1 g per square meter of surface area. Immediate symptoms of malaise, heat, sweating and disorientation limit the amount of the drug which may be given on any one occasion. However, a dose of 750 mg per square meter of surface area may be given combined with daily radiotherapy. Our data suggest that when given with a 20 fraction course of radiotherapy, sensitization of hypoxic cells may be achieved equal to a 10-fold increase in the dose of misonidazole above that presently permitted.

Drug Evaluation↗
PubMed1982

The radiosensitizer Ro 03-8799 and the concentrations which may be achieved in human tumours: a preliminary study.

A new hypoxic cell radiosensitizer, Ro 03-8799, has been administered i.v. to 2 normal and 6 patient volunteers. Generally in non-necrotic tumours the concentrations obtained were 3 times greater than in plasma sampled at the same time. These observations added to the reports concerning toxicology in monkeys and rats and radiosensitizing efficiency in the laboratory, suggest that Ro 03-8799 may prove to be much more effective sensitizer than misonidazole in man.

Adult↗
PubMed1981

The concentration of desmethylmisonidazole in human tumours and in cerebrospinal fluid.

The concentration of desmethylmisonidazole (DESMISO) was determined in 60 biopsy samples taken from 13 human tumours and in cerebrospinal fluid (CSF) from 8 patients after oral administration. In comparison with misonidazole (MISO), peak concentrations in plasma were reached at earlier times and half-lives were shorter, so that the area under the curve of plasma concentration with time (AUC) was reduced by 45%; the AUC of CSF concentration with time was reduced by 67%. Between 1 and 2 h after administration of DESMISO, concentrations in tumours were generally 85-90% of those of MISO estimated approximately 4 h after it was given. The two drugs when tested in equimolar concentrations have been found in laboratory experiment to be equally potent as hypoxic cell radiosensitizers. Recognizing the lower mol. wt of DESMISO and the trend to higher concentrations in the more necrotic areas of the tumours studied equal doses by weight of the two drugs given orally may give equal radiosensitization of hypoxic cells in human tumours.

Breast Neoplasms↗
PubMed1980

Tumour regression as a guide to prognosis: a clinical study.

The response seen at the end of a course of radiotherapy in 116 patients with advanced carcinoma of the cervix included in hyperbaric oxygen trials was assessed by reduction in bulk and by histological examination. These patients have now been carefully followed for a minimum of three and a maximum of 13 years. The degree of regression, three and a maximum of 13 years. The degree of regression, as measured by reduction in bulk at the primary site, was as measured by reduction in bulk at the primary site, was found to predict closely the subsequent local tumour failure, survival and freedom from metastasis. The histological assessment also could be associated with the subsequent course, but the correlation was much weaker. In a trial of hyperbaric oxygen, where radiotherapy was given in 27 fractions to both groups, the immediate response was significantly better in the patients treated in oxygen, so predicting the result of the trial seen in long-term follow up. In the radiotherapy of carcinoma of cervix, reduction in bulk of the primary tumour at the end of treatment is a valuable prognostic index.

Female↗
PubMed1980

Tumour regression and prognosis: a clinical study.

In advanced carcinoma of the uterine cervix reduction in the size of the tumour at the end of external beam radiotherapy closely correlated with subsequent local tumour control, freedom from metastasis and survival. A histological assessment of response showed a weaker correlation with subsequent events. In carcinoma of the bronchus the reduction in bulk of tumour assessed radiologically and the disappearance of tumour cells from the sputum did not correlate with the duration of survival. In the observation of tumour response the considerable differences which must be expected when comparing different tumours should not detract from the current and potential value of such studies.

Bronchial Neoplasms↗
PubMed1978

Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the cervix.

In a randomized controlled clinical trial of hyperbaric oxygen in the radiotherapy of advanced carcinoma of the uterine cervix a total of 320 cases were contributed by four radiotherapy centres in the United Kingdom. The use of hyperbaric oxygen resulted in improved local control and survival. The benefit was greatest in patients under the age of 55 who presented with stage III disease. There was a slight increase in radiation morbidity but it seemed that the benefit of hyperbaric oxygen outweighed this increase in morbidity and that there was a true improvement in the therapeutic ratio.

Adult↗
PubMed1978

The optimum regime for the administration of misonidazole and the establishment of multi-centre clinical trials.

The amount of misonidazole which may be given to one patient is limited because of the risk of neurotoxicity. The drug may be given with every treatment of a multi-fraction course of radiotherapy or only with some of the treatments. The number of radiotherapy treatments can be reduced or multiple treatments given after each dose of the drug. Experience in 19 patients given daily doses of misonidazole is reported. This is practical regime to be considered for clinical trials of this hypoxic cell sensitizer.

Drug Administration Schedule↗