New nitric oxide donor drugs
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Nitric oxide is a recognised dilator of vascular smooth muscle and therefore is central in the control of blood flow. A lack of blood flow in humans can have very important implications in a number of disorders of both cutaneous tissue and internal circulation. In this thesis we look at the synthesis of new nitric oxide donors, their stabilities and their possible medicinal usage. These donors have been based on the S-nitrosothiol group, connected to sugar moieties, simple amino acids or linked glycoaminoacids. The donors prepared have been used to investigate the skin blood flow and localised responses to nitric oxide, proving that NO has an important role in the maintenance of healthy skin. These will be further investigated as possible treatments for disorders involving a lack of cutaneous blood flow, such as connective tissue disorders and the repeated ulceration often seen in diabetic patients. A set of clinical trials have been carried out comparing the responses of healthy patients and sufferers of Raynaud's Phenomenon to exogenous nitric oxide. In this we have highlighted a number of differences and have helped to determine a possible cause of the disorder. We have prepared a number of slow release NO donors which have been shown to produce a sustained vasodilatory response in blood vessels with removed or damaged endothelial cells. These show promise for use in the treatment of patients with circulatory disorders, especially for subjects following treatment for atherosclerosis. Basic studies investigating the stabilities of these compounds have been carried out, in order to aid our understanding of their mode of breakdown.
Thesis, PhD Doctor of Philosophy