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Title: Pharmacological characterisation of novel furoxans and furoxan-aspirin hybrid drugs in blood vessels and platelets
Author: Turnbull, C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Abstract:
A novel range of hybrid drugs in which a furoxan nitric oxide (NO)-donating moiety is joined by ester linkage to the aspirin molecule were developed in the hope that the cytoprotective actions of drug-derived NO would overcome the gastric side-effects of aspirin. In addition, the presence of the NO group instils the potential for them to have additional cardiovascular benefit over the parent compound. These effects are investigated in this thesis and compared to that of an established nitroxy-ester derivative of aspirin (NCX4016). The NO-mediated effects in the vasculature were investigated via their capability to cause relaxation of phenylephrine-constricted isolated rat aortic rings. The furoxan hybrids were found to be powerful vasodilators and the effect was shown to be NO-mediated on account of the lack of effect with their NO-free equivalents and a susceptibility to the guanylate cyclise inhibitor, ODQ. Myography also revealed the phenomenal potency of the stand-alone furoxan compound B13, which was demonstrated to cause vasorelaxation in the picomolar range – approximate 300-fold more potent than an established powerful NO donor, DEA/NO. Antiplatelet studies in both platelet rich plasma (PRP) and washed platelets (WP) revealed the furoxan-aspirin hybrids to inhibit platelet aggregation in both WP and PRP. The effects were attenuated in PRP, likely due to the acetyl instability in plasma. Electrochemical detection of NO release revealed the compounds to be stable in solution and to only release significant amounts of NO in response to intracellular concentrations of antioxidant elements glutathione and ascorbate, raising a potential for primarily intracellular delivery of NO. Finally, the capability of the compounds to inhibit release of pro-inflammatory cytokines from monocytes and monocyte-derived macrophages was investigated. Following LPS stimulation, cells treated with furoxan-aspirin hybrid, B8, displayed reduced TNFα release.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.663095  DOI: Not available
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