abstract / Dentistry / Doctoral / Doctor of Philosophy

Thesis (M.S.)--University of Iowa, 2009. / Thesis supervisor: Steven Vincent. Includes bibliographical references (leaves 155-174).

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2007. / Includes bibliographical references. Also available in electronic version.

The nitrogen-containing bisphosphonates (NBPs) are the most widely used treatment for diseases involving excessive osteoclastic bone resorption, such as osteoporosis. The clinical efficacy of NBPs is due in large part to their affinity for bone mineral, but it has been suggested that lowering affinity may have benefits due to altered distribution and duration of action possibly allowing direct anti-tumour effects. In addition, the phosphonocarboxylate (PC) analogues inhibit prenylation more selectively through a different enzyme target, Rab geranylgeranyl transferase (RGGT), which may offer additional benefits by reducing side-effects associated with farnesyl diphosphate synthase (FPPS) inhibition. Using fluorescent analogues of PCs and NBPs demonstrated that mineral affinity not only affects initial bone-binding, but also influences desorption, reattachment and penetration at the bone surface, suggesting that lower affinity compounds have lower retention and increased access to other cell types, such as tumour cells. The work presented aimed to investigate the potential of low affinity analogues by characterising their intracellular potency for inhibiting their target enzymes. The results showed that modification to the phosphonate groups to produce phosphonoalkylphosphinate analogues reduced potency for inhibiting FPPS. By contrast, removal of one of the phosphonate groups to give a monophosphonate changed the target enzyme to RGGT. Modifications to the R1 side-chain (substituting with hydrogen or a halogen) of both NBPs and PCs were studied and showed contrasting results, modifications to the R1 side-chain of NBPs affect their ability to inhibit FPPS whereas the same modification to PCs is insignificant for inhibiting RGGT. This showed the distinction between the structural requirements for inhibition of RGGT and FPPS and furthers the understanding of the structure-activity relationships of both NBPs and PCs which could guide future drug design. Within this thesis the most potent inhibitor of RGGT to date, 3-IPEHPC, was characterised which in addition to having therapeutic potential may be used as tool to investigate the importance of Rab prenylation for cellular function.

Thesis (M.Med.Sc.)-- University of Adelaide, Dept. of Medicine, 2002. / Bibliography: leaves 86-103.

Thesis (MSc.(Chemistry))--University of Pretoria, 2008. / Includes bibliographical references.

Thesis (M.S.)--California Polytechnic State University, 2008. / Major professor: Scott Hazelwood, Ph.D. "Presented to the faculty of California Polytechnic State University, San Luis Obispo." "In partial fulfillment of the requirements for the degree [of] Master of Science in Engineering with a specialization in Biomedical Engineering." "June 2008." Includes bibliographical references (leaves 46-49). Also available online. Also available on microfiche (2 sheets).

Thesis (M.S.)--California Polytechnic State University, 2009. / Title from PDF title page; viewed on September 25, 2009. Major professor: Scott Hazelwood, Ph.D. "Presented to the faculty of California Polytechnic State University, San Luis Obispo." "In partial fulfillment of the requirements for the degree [of] Master of Science in Engineering with a specialization in Biomedical Engineering." "September 2009." Includes bibliographical references (p. 72-74). Also available on microfiche.

Thesis (M.S.)--University of Florida, 2003. / Title from title page of source document. Includes vita. Includes bibliographical references.

Orientador: Eduardo Hochuli Vieira / Banca: Leonardo Perez Faverani / Banca: Francisley Ávila Souza / Banca: Nicolas Homsi / Banca: Hernando Valentim da Rocha Junior / Resumo: Objetivo: Avaliar a prevenção da OMIM em ratos em risco de desenvolvimento de osteonecrose na região em que foi realizada a exodontia utilizando apenas coágulo, enxerto de osso xenógeno, e enxerto de β- trifosfato de cálcio (β-TCP). Métodos: Foram utilizados 20 Ratos Wistar machos com 3 meses de idade, pesando 350 - 450g, submetidos a indução da Osteonecrose por uso de ácido zoledrônico (0,04mg/kg) durante 05 semanas. Na 7a semana foi realizado a cirurgia de exodontia dos molares superiores direito e preenchimento do alvéolo com coágulo (controle), enxerto xenógeno (Grupo 2), e β- trifosfato de cálcio (β-TCP) (Grupo 3). A eutanásia foi realizada na 15a semana. Foram realizadas análises morfométrica, estereológica, e imunohistoquímica, onde aplicou-se os testes estatísticos ANOVA e Tukey, considerando-se um nível de significância de 5%. Resultados: Durante a análise macroscópica não houve manifestação clínica da OMIM nos grupos experimentais. A análise quantitativa demonstrou que o Grupo 3 (BTCP) apresentou menor formação de lacunas ósseas e maior formação de tecido ósseo sadio quando comparado com os grupos 1 e 2 (p<0,05). Não houve diferença estatística entre os grupos durante análise de formação de tecido epitelial. Na análise imunohistoquimica, o grupo experimental apresentou maior atividade de remodelação óssea. Conclusão: Os resultados deste trabalho demonstraram que os grupos experimentais apresentaram maior atividade de remodelação óssea, e ausência de manifestação clí... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objective: To evaluate the bone formation in rats with osteonecrosis in the region where the extraction was performed using only clot, xenogen bone graft, and calcium β-triphosphate (β-TCP) graft. METHODS: Twenty male Wistar rats weighing 350-450 g were submitted to osteonecrosis induction for the use of zoledronic acid (0.2 mg / kg) for 5 weeks. In the 7th week, the maxillary right molar extraction and filling of the alveolus with clot (control), xenogene graft (Group 2) and calcium β-triphosphate (β-TCP) were performed (Group 3). Euthanasia was performed in the 15th week. Morphometric and stereological analyzes were performed. The ANOVA and Tukey statistical tests were used, considering a level of significance of 5%. Results: During the macroscopic analysis there was no clinical manifestation of the OMIM in the experimental groups. Quantitative analysis showed that Group 3 (BTCP) presented less bone formation and greater formation of healthy bone tissue when compared to groups 1 and 2 (p <0.05). There was no statistical difference between groups during analysis of epithelial tissue formation. In the immunohistochemical analysis no difference was found in the bone remodeling process between the groups. Conclusion: The results of this work were favorable for the use of BTCP for guided bone regeneration and prevention of the clinical manifestation of OMIM in rats. However, more studies need to be performed until the development of a protocol to prevent this complication / Doutor