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Co-trimoxazole, a combination of a 5-to-l ratio of Sulphamethoxazole (SMZ) and Trimethoprim (TMP) , is a highly effective, broad-spectrum antibacterial agent. Since its introduction in 1968, it has been extensively used in infections of the respiratory and urinary tracts. Co-trimoxazole was developed by the systematic investigation of a series of compounds whose mechanism of action was already known. As early as 1950 synergy between sulphonamides and 2,4-diaminopyrimidines was reported. This was to be expected as both groups of drugs exert their antibacterial activity by interfering with the same biochemical pathway in bacteria. TMP was chosen from among many 2,4-diaminopyrimidines tested because of its good antibacterial activity and low toxicity. SMZ was chosen from the sulphonamides available for combination with TMP because of similarity of their biological half-lives. The widespread use of the combination coupled with the fact that monitoring of the levels of all drugs in the body is becoming increasingly important has stimulated research into rapid and efficient methods for the analysis of TMP and SMZ in biological fluids. Another consequence of the immense popularity of the combination is the appearance on the market of several generic preparations of Co-trimoxazole. It is now generally recognized that drug products from different manufacturers which are chemically equivalent may not be therapeutically equivalent. This is due to the fact that the absorption rate and/or bioavailability (extent of absorption) of a poorly soluble drug may be markedly affected by its release rate from the product and by its subsequent dissolution rate in gastrointestinal fluids. Hence bioequivalence of these various products should be established

It has been demonstrated that by using 1H NMR spectroscopy in combination with multivariate statistical modelling (PLS) it is possible, using urine samples obtained from rats, to distinguish between different types of CNS lesions. Against this background this thesis will explore whether the combination of 1H NMR and PLS modelling on biofluids can be used q-1eientify biomarkers in .. - different neurological diseases and in clinically relevant animal models of neurologic disease. The results in this thesis demonstrate that it is possible to separate sets of animals at different stages of disease in models of multiple sclerosis and to identify the presence of early brain metastasis. The same methodology was also applied to human biofluids. In MS patient cohorts (RR- MS, PP-MS and SP-MS) it was also possible to differentiate between RR-MS and SP-MS as well between MS and healthy controls. Therapy for these two stages of MS are very different and therefore a rapid test to determine a patient's stage of MS would be hugely beneficial in the clinic. Further investigation revealed that it is possible to separate MS patients from individuals with Alzheimer's disease. Metabolomics was then combined with other eo- variants in a study of cerebrospinal fluid obtained from patients with HIV associated dementia (HAD) to discover whether disease progression could be followed in this manner. The results show that it is possible to detect neurocognitive changes in patients with HAD. Indeed, the results demonstrate. that metabolomics is a far more sensitive tool for the following progression than other non-PLS biomarker techniques and should provide a useful method for early diagnosis of CNS disease and the evaluation of therapy in prospective studies.

202 p. : ill. ; 28 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Physiology, 1967