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Biomedical subjects

I R Flockhart

Publications and source records attributed to I R Flockhart.

At least 19 recordsLinked to original sources
PubMed1985

Assessment of an in situ rat intestine preparation with perfused vascular bed for studying the absorption and first-pass metabolism of drugs.

The perfused in situ rat jejunum preparation originally described by Hanson and Parsons (1976) was adapted for use in absorption and metabolism studies with drugs. The preparation allows simultaneous perfusion of the gut lumen and associated vasculature and is viable for one hour. The viability of the preparation was assessed, and the application of the method is illustrated by experiments with the opiate analgesic, buprenorphine.

Animals↗
PubMed1984

Effects of idazoxan on catecholamine systems in rat brain.

Experiments have been performed to assess the potency of idazoxan (RX 781094) at alpha and beta-adrenoceptors and dopamine receptors and on catecholamine uptake processes in rat brain. The effects of idazoxan on the turnover rates of noradrenaline and dopamine have been determined. Radioligand binding studies with cerebral cortex membranes have demonstrated that idazoxan exhibits 46-fold selectivity for alpha 2-adrenoceptors labelled by (3H)-idazoxan (Mean Ki +/- S.E.M. = 3.1 +/- 0.4 nM) compared with alpha 1-adrenoceptors labelled by (3H)-prazosin (Mean Ki +/- S.E.M. = 142 +/- 27 nM). Under the same conditions, yohimbine showed 6-fold selectivity for alpha 2-adrenoceptors. Idazoxan had low affinity for beta-adrenoceptors labelled by (3H)-dihydroalprenolol (IC50 value greater than 10 microM), for dopamine receptors labelled by (3H)-domperidone (IC50 value greater than 20 microM), for the (3H)-noradrenaline uptake site in rat hypothalamus (IC50 = 31 microM) and for the (3H)-dopamine uptake site in rat striatum (IC50 value approximately 800 microM). In rats treated with alpha-methyl-p-tyrosine, idazoxan (10-80 mg/kg, po) produced a marked increase (63% at 10, 217% at 20 mg/kg, po) in the apparent rate of turnover of noradrenaline in rat cortex/striatum, without affecting the rate of turnover of dopamine. This was in contrast to yohimbine (5-20 mg/kg, po) which increased the turnover rates of both catecholamines. In the absence of alpha-methyl-p-tyrosine, idazoxan (5-40 mg/kg, po) produced a dose related increase in the MHPG concentration and a small (20-30%) reduction in the steady state concentration of NA; the duration of the reduction was dose-related. DA steady state concentrations were unaffected. Idazoxan is a new selective alpha 2-adrenoceptor antagonist which should prove a valuable investigative tool in neurochemical studies and which may be a useful clinical agent in the management of the affective disorders.

Adrenergic alpha-Antagonists↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. I. Sensitization efficiency.

The efficiency of 35 nitroaromatic and nitroheterocyclic compounds in radiosensitizing hypoxic Chinese Hamster cells in vitro was determined. The concentration C of the compound required to achieve an enhancement ratio of 1.6 was measured, and the redox and partition properties were quantified as the one-electron reduction potential at pH 7, E, and the octanol: water partition coefficient, P, respectively. Most of the compounds studied were 2-nitroimidazoles, but some 4- and 5-nitromidazoles, 5-nitrofurans and nitrobenzenes were investigated for comparison. Together with data for nine nitroimidazoles previously reported, the results were fitted to a structure-activity relationship of the form -log C = b0 + b1E + b2 log P + b3 (log P)2 using multiple linear regression analysis. Statistical tests showed that the coefficients b2 and b3 were not significantly different from zero and the simpler equation, obtained by omitting the terms in log P, explained 85 per cent of the variance in log C. Earlier reports that the radiosensitization efficiency of nitro compounds in vitro largely depends on the reduction potential were confirmed. The conclusive demonstration that P is unimportant in vitro is valuable in interpreting the results of experiments in vivo, where P is expected to have a much greater influence on biological response.

Animals↗
PubMed1978

Pharmacokinetic and metabolic studies of the hypoxic cell radiosensitizer misonidazole.

1. The metabolism of the radiosensitizing 2-nitroimidazole, misonidazole, has been investigated in mice, rats, baboons, human volunteers, and in patients receiving radiotherapy for advanced malignant disease. 2. Plasma levels of unchanged drug and its desmethylated metabolite have been measured, and in humans there is good correlation of peak plasma concn. with drug dose. All drug-related material in plasma was accounted for as unchanged misonidazole or its desmethylated metabolite, both compounds being radiosensitizers in vitro. 3. Extensive faecal excretion of material not containing any nitro group occurred in mice, rats, and baboons dosed with radiolabelled drug. 4. Renal excretion is the preferred route of elimination in man, baboon and mouse. Nitroimidazole metabolites accounting for over half the urinary excretion in all species were identified. 5. The compound penetrates solid murine tumours in concentrations sufficient to achieve radiosensitization.

Animals↗
PubMed1978

The neurotoxicity of misonidazole and its relationship to dose, half-life and concentration in the serum.

Misonidazole has been given to a total of 87 patients. Neurotoxicity has occurred--convulsions with the higher doses and peripheral neuropathy with the lowern ones. The data from 34 patients receiving 4--7 doses has been analysed. Peripheral neuropathy is related to the total tissue exposure. By monitoring serum levels and controlling the total dose given, convulsions are avoidable and peripheral neuropathy restricted to a low and acceptable level.

Drug Administration Schedule↗
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↗
PubMed1978

The rationale for the development of improved hypoxic cell radiosensitizers.

This paper outlines the chemical background to the selection of compounds likely to be clinically superior to the nitroimidazoles currently being evaluated in cancer therapy. The most important chemical properties to consider are electron affinity and lipophilicity, and the quantification and prediction of both these properties are considered. Examples are presented of the use of multiple regression analysis to evaluate the relative contribution of individual properties to the overall biological response.

Nitroimidazoles↗
PubMed1978

Some aspects of the metabolism of misonidazole.

The metabolism of the 2-nitroimidazole hypoxic cell radiosensitizer, misonidazole, has been studied in patients receiving radiotherapy. Results are presented which show that the compound reaches adequate levels in tumour tissue and that, in animal systems, reduction products of the nitro group may also be present. Ah h.p.l.c method is described which has been used to quantify unchanged misonidazole and its nitroimidazole metabolites.

Animals↗
PubMed1977

Clinical testing of the radiosensitizer Ro 07-0582: experience with multiple doses.

The hypoxic cell radiosensitizer, Ro 07-0582, has now been given in multiple doses to 16 patients. They have received a total of 15-51 g in 3-20 doses. Immediate tolerance was good, and satisfactory plasma levels of the drug were consistently obtained. Neurotoxicity was, however, troublesome: convulsions occurred in the patient given the highest dose, and there was peripheral neuropathy in 11 cases. Tumour concentrations similar to those in plasma were obtained in human tumours, in contrast to the findings in mouse tumours where concentrations are usually below 40% of plasma levels. In the treatment of human tumours, a lower dose of Ro 07-0582 should give useful hypoxic cell sensitization. Although the total dose of Ro 07-0582 must be limited, there is a real prospect that it will give benefit in clinical radiotherapy.

Adult↗
PubMed1976

Clinical testing of the radiosensitiser Ro-07-0582. I. Dose tolerance, serum and tumour concentrations.

Patients have been given single oral doses of the radiosensitiser Ro-07-0582 and serum concentrations have been attained in the range expected to be of value in radiosensitisation. Immediate gastrointestinal side effects appear to limit the dose to below 140 mg/kg but radiosensitising serum levels of approximately 200 mug/ml can be attained. Tolerance may be improved by giving anti-emetics and a more palatable preparation. Estimates of the concentration of Ro-07-0582 in tumour have ranged from 12 to 92% of the serum concentration at the time of determination.

Adult↗