The in vivo susceptibility of Leishmania donovani to sodium stibogluconate is drug specific and can be reversed by inhibiting glutathione biosynthesis

Resistance to pentavallent antimonial (Sb-v) agents such as sodium stibogluconate (SSG) is creating a major problem in the treatment of visceral leishmaniasis. In the present study the in vivo susceptibilities of Leishmania donovani strains, typed as SSG resistant (strain 200011) or SSG sensitive (strain 200016) on the basis of their responses to a single SSG dose of 300 mg of Sb-v/kg of body weight, to other antileishmanial drugs were determined. In addition, the role of glutathione in SSG resistance was investigated by determining the influence on SSG treatment of concomitant treatment with a nonionic surfactant vesicle formulation of buthionine sulfoximine (BSO), a specific inhibitor of the enzyme gamma-glutamylcysteine synthetase which is involved in glutathione biosynthesis, and SSG, on the efficacy of SSG treatment. L. donovani strains that were SSG resistant (strain 200011) and SSG sensitive (strain 200016) were equally susceptible to in vivo treatment with miltefosine, paromomycin and amphotericin B (Fungizone and AmBisome) formulations. Combined treatment with SSG and vesicular BSO significantly increased the in vivo efficacy of SSG against both the 200011 and the 200016 L. donovani strains. However, joint treatment that included high SSG doses was unexpectedly associated with toxicity. Measurement of glutathione levels in the spleens and livers of treated mice showed that the ability of the combined therapy to inhibit glutathione levels was also dependent on the SSG dose used and that the combined treatment exhibited organ-dependent effects. The SSG resistance exhibited by the L. donovani strains was not associated with cross-resistance to other classes of compounds and could be reversed by treatment with an inhibitor of glutathione biosynthesis, indicating that clinical resistance to antimonial drugs should not affect the antileishmanial efficacies of alternative drugs. In addition, it should be possible to identify a treatment regimen that could reverse antimony resistance.

Semantic and organization considerations in database conceptual modelling : the Semantic Conceptual Organizational Model (SECOM)

This thesis presents a new approach to designing large organizational databases. The approach emphasizes the need for a holistic approach to the design process. The development of the proposed approach was based on a comprehensive examination of the issues of relevance to the design and utilization of databases. Such issues include conceptual modelling, organization theory, and semantic theory. The conceptual modelling approach presented in this thesis is developed over three design stages, or model perspectives. In the semantic perspective, concept definitions were developed based on established semantic principles. Such definitions rely on meaning - provided by intension and extension - to determine intrinsic conceptual definitions. A tool, called meaning-based classification (MBC), is devised to classify concepts based on meaning. Concept classes are then integrated using concept definitions and a set of semantic relations which rely on concept content and form. In the application perspective, relationships are semantically defined according to the application environment. Relationship definitions include explicit relationship properties and constraints. The organization perspective introduces a new set of relations specifically developed to maintain conformity of conceptual abstractions with the nature of information abstractions implied by user requirements throughout the organization. Such relations are based on the stratification of work hierarchies, defined elsewhere in the thesis. Finally, an example of an application of the proposed approach is presented to illustrate the applicability and practicality of the modelling approach.