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1. Bahmed, Amina. The design and synthesis of novel pro-drugs for the treatment of nephropathic cystinosis.

Degree: PhD, 2015, Robert Gordon University

Cystinosis is a metabolic disorder characterised by the abnormal accumulation of the amino acid cystine in cells leading to a slow destruction of all major organs. If patients diagnosed with cystinosis are untreated, death due to kidney failure ensues in the second decade of life. A number of studies have shown the ability of the drug cysteamine (Cystagon®) to lower cystine accumulation within cells resulting in reduced organ and tissue damage. Cysteamine therapy however, is associated with a number of side effects involving the gastrointestinal tract and the central nervous system. Most of these arise due to the large amount of cysteamine present in the stomach and gut following administration. In addition, cysteamine possesses an unpleasant taste and smell, resulting in poor patient compliance. In an attempt to overcome these problems, a number of pro-drug derivatives of cysteamine and cystamine, the disulfide analogue of cysteamine, have been synthesised and evaluated. Pro-drugs were synthesised using a route established in our laboratories. Briefly, cystamine dihydrochloride was basified and allowed to react with a number of cyclic anhydrides under basic conditions. The resulting di-acids were reacted with carbonyldiimidazole and monoBoc-cystamine to yield the desired pro-drugs. Removal of the tBoc-protecting group was achieved in a facile manner by use of trifluoroacetic acid to yield product. The efficacy of the synthesised pro-drugs was determined by incubation of 50μM compound in a suspension of cultured cystinotic fibroblasts, with 50μM cysteamine as control. Cell growth was measured at 72 h and the level of thiol determined. All except one of the pro-drugs tested were significantly more effective than the control at lowering the cystine burden of the cells. Further work will concentrate on repeating these studies and evaluating a more robust Structure Activity Relationship for these compounds. The overall aim of all this work remains the production of an odourless, tasteless and orally active treatment for cystinosis and, if possible, improve on the current dosing regimen of every 6h. By using pro-drugs, cysteamine will be chemically camouflaged and hence, the side effects associated with its administration will be minimised or even entirely abolished.

Subjects/Keywords: 610; Cystagon; Cysteamine; Cystamine; Pro-drugs; Multicomponent crystals; Nephropathic Cystinosis; Peptide synthesis

…CHAPTER 1 Introduction 15 1.1. Nephropathic cystinosis 16 1.1.1. Background and Historical… …Nephropathic Cystinosis 1.1.1. Background and Historical Aspects Cystinosis is a rare inherited… …of France is 1 case per 326,440 population.7,48,49 In particular, nephropathic cystinosis… …Figure 6) Figure 6.: Patients with Nephropathic Cystinosis. 22 8 Sex A ratio of 1:4… …been categorised into 2 general phenotypes, nephropathic and non-nephropathic cystinosis… 

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APA (6th Edition):

Bahmed, A. (2015). The design and synthesis of novel pro-drugs for the treatment of nephropathic cystinosis. (Doctoral Dissertation). Robert Gordon University. Retrieved from http://hdl.handle.net/10059/1227

Chicago Manual of Style (16th Edition):

Bahmed, Amina. “The design and synthesis of novel pro-drugs for the treatment of nephropathic cystinosis.” 2015. Doctoral Dissertation, Robert Gordon University. Accessed December 04, 2020. http://hdl.handle.net/10059/1227.

MLA Handbook (7th Edition):

Bahmed, Amina. “The design and synthesis of novel pro-drugs for the treatment of nephropathic cystinosis.” 2015. Web. 04 Dec 2020.

Vancouver:

Bahmed A. The design and synthesis of novel pro-drugs for the treatment of nephropathic cystinosis. [Internet] [Doctoral dissertation]. Robert Gordon University; 2015. [cited 2020 Dec 04]. Available from: http://hdl.handle.net/10059/1227.

Council of Science Editors:

Bahmed A. The design and synthesis of novel pro-drugs for the treatment of nephropathic cystinosis. [Doctoral Dissertation]. Robert Gordon University; 2015. Available from: http://hdl.handle.net/10059/1227

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