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• W115979857 abstract "The research presented in this thesis has centred on chemical and pharmacological investigations of the phenazine antibiotic clofazimine and certain substituted phenazine analogues.A simple extraction system was developed with dichloromethane and sodium hydroxide which quantitatively extracted all of the agents tested from tissue, faecal and blood samples. The extracted drugs could then be quantified using a reversed phase HPLC method with a mobile phase of tetrahydrofuran/acetic acid/hexane sulphonic acid and U.V. detection at 285 nm. Purity and chemical structure o f the agents studied was confirmed using NMR, TLC, PDA-HPLC, silica column chromatography and elemental analysis.The tissue distribution of clofazimine (B663) and phenazines B749, B3954, B4090 and B4100 was investigated by oral gavaging these agents into mice for 3 weeks and measuring drug levels using the HPLC method described. B4100 and especially B4090 gave superior tissue levels to clofazimine in all tissues tested except fat. A simpler method of administering phenazines in food was developed for dosing rats. B663, B4090, B4100, B4103 and B4154 were incorporated into rat food which was given to rats in specially made metabolism cages which allowed the measurement of food and water intake and collection of uncontaminated faeces.The absorption of these agents was estimated by giving groups of rats a single dose of drugged food containing the non-adsorbable dietary marker chromic oxide, with subsequent collection and analysis of faecal drug and chromium levels using HPLC and spectrophotometric assays respectively. Absorption levels were found to be different for all the agents B4090 giving the poorest absorption at 50.5% and B4103 giving the most absorption at 92%. The bio-distribution of these compounds was measured after 4 weeks of administration. Again B4090 gave the highest levels in all tissues excluding fat. During this study potential toxicity of these agents was investigated using blood enzyme markers, blood cell counts, measurement of food and water intake, behavioural observation, urinary markers and post mortem tissue weights. A newly developed method of analysing animal urine by proton-NMR spectroscopy was also used to investigate toxicity. None of these tests provided evidence that any of the compounds tested were more toxic than clofazimine.The absorption and distribution of complexes of clofazimine with P-cyclodextrin (P-CD) and hydroxypropyl-p-cyclodextrin (H-p-CD) were tested. The H-P-CD formulation gave a greater absorption of clofazimine and increased blood and tissue drug levels.Phenazine conjugates to the proteins bovine serum albumin, thyroglobulin and keyhole limpet haemocyanin (KLH) were produced using phenazine derivatives with amino acid substituents. These conjugates were characterised using TLC, PDA-HPLC and spectrophotometric assays. The thyroglobulin and KLH conjugates were used to immunise rabbits to produce specific anti-phenazine antibodies which were purified and characterised." @default.
• W115979857 created "2016-06-24" @default.
• W115979857 creator A5080035538 @default.
• W115979857 date "1995-01-01" @default.
• W115979857 modified "2023-09-24" @default.
• W115979857 title "An investigation of the pharmacology of selected anti-mycobacterial phenazines" @default.
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