La présence de la glycoprotéine P (P-gp) dans la barrière hémato-encéphalique (BHE) conduit à l’échec de nombreuses thérapies ciblant le système nerveux central (SNC). Cependant la P-gp protège aussi le cerveau contre des composés nocifs, essentiellement lipophiles, endogènes et exogènes susceptibles de passer la BHE par diffusion simple. Par conséquent, toute inhibition de la P-gp qui vise à améliorer la distribution des agents pharmacologiques dans le cerveau doit prendre en compte la neurotoxicité potentielle de cette inhibition. Les premiers travaux ont montré que l’elacridar et le tariquidar, deux modulateurs de la P-gp de troisième génération, augmentaient la distribution dans le cerveau de plusieurs de ses substrats. Malheureusement, d’autres études plus récentes, suggèrent l’utilisation de doses élevées de l’elacridar et du tariquidar pour moduler efficacement l’activité de la P-gp dans la BHE. Néanmoins, ces doses élevées en co-administration avec des substrats de la P-gp peuvent être associées à des interactions pharmacocinétiques et à des profils toxiques, limitant ainsi l'utilisation de ces inhibiteurs.Dans ce contexte, l’objectif principal de cette thèse est d’obtenir une modulation transitoire mais efficace de la P-gp dans la BHE par administration intraveineuse de doses faibles mais thérapeutiques de l’elacridar et du tariquidar sous leur forme libre ou co-encapsulé dans les liposomes. Le lopéramide, substrat de la P-gp, a été également administré sous sa forme libre comme une preuve in vivo d’une inhibition efficace de la P-gp dans la BHE.L'administration simultanée de ces deux modulateurs de la P-gp n’a pas modifié leurs concentrations plasmatiques ou celles du lopéramide, mais a entraîné une importante distribution du lopéramide dans le cerveau en raison de leur activité inhibitrice non- compétitive. De plus, la co-encapsulation de l’elacridar et du tariquidar dans des immunoliposomes stabilisées stériquement a amélioré la demi-vie et la distribution dans le cerveau des ceux deux composés. Par conséquent, la distribution dans le cerveau du lopéramide a été considérablement augmentée, sans aucune modification de sa pharmacocinétique ou distribution tissulaire. Par ailleurs, la diminution partielle de l'activité inhibitrice du tariquidar par des liposomes vides suggère l’utilisation de ce nanovecteur comme une approche de bio-détoxification pour le traitement des surdoses de tariquidar. En résumé, cette thèse propose différentes approches pour exploiter pleinement l’elacridar et le tariquidar. Les résultats décrits dans ce manuscrit devraient ouvrir des pistes intéressantes pour atteindre une inhibition efficace de la P-gp dans la BHE et pour réussir des thérapies ciblant le système nerveux central / Although the P-glycoprotein (P-gp) represents an obstacle in several central nervous system (CNS) pharmacotherapies, the P-gp also protects the brain from intoxication by endogenous and exogenous harmful lipophilic compounds that otherwise could penetrate the blood-brain barrier (BBB) by simple diffusion. Therefore, any modulation of the efflux transporter has to consider the potential neurotoxicity of such modulation. Early studies showed that elacridar and tariquidar, two third-generation P-gp modulators, increase the distribution of several P-gp substrates in the brain. Unfortunately, recent studies suggest the use of high doses of elacridar and tariquidar to efficiently modulate the P-gp at the BBB. Nevertheless, when co-administered with P-gp substrates, these high doses may be associated with pharmacokinetic interactions and toxic profiles, thus limiting the use of these compounds.Hence, this thesis aimed to attain a transient but efficient modulation of the P-gp at the BBB using elacridar and tariquidar but avoiding the use of large doses of these compounds. For this purpose we took advantage of the possible in vivo intravenous co-administration of low but therapeutic doses of elacridar and tariquidar, under their free form or co-encapsulated in liposomes. The brain distribution of free loperamide was determined as an in vivo probe of full inhibition of the P-gp activity at the BBB.The concurrent administration of both free P-gp modulators does not modify their plasma concentrations or those of the P-gp substrate but significantly increased the brain uptake of loperamide as a result of their non-competitive modulatory activity. Moreover, the co-encapsulation of elacridar and tariquidar in targeted sterically stabilized immunoliposomes improved the half-lives and brain distribution of both compounds. Consequently, the brain uptake of free loperamide was significantly enhanced without any modification of its pharmacokinetics or tissue distribution. Moreover, the partial impairment of the modulatory activity of tariquidar by empty liposomes, supports the use of this nanocarrier as a bio-detoxifying approach for the treatment of tariquidar overdoses.In summary, this thesis proposes different approaches for full exploitation of elacridar and tariquidar. The findings described in this manuscript should open interesting avenues to achieve an efficient overcoming of the P-gp at the BBB and succeed CNS pharmacotherapies.

La présence de la glycoprotéine P (P-gp) dans la barrière hémato-encéphalique (BHE) conduit à l’échec de nombreuses thérapies ciblant le système nerveux central (SNC). Cependant la P-gp protège aussi le cerveau contre des composés nocifs, essentiellement lipophiles, endogènes et exogènes susceptibles de passer la BHE par diffusion simple. Par conséquent, toute inhibition de la P-gp qui vise à améliorer la distribution des agents pharmacologiques dans le cerveau doit prendre en compte la neurotoxicité potentielle de cette inhibition. Les premiers travaux ont montré que l’elacridar et le tariquidar, deux modulateurs de la P-gp de troisième génération, augmentaient la distribution dans le cerveau de plusieurs de ses substrats. Malheureusement, d’autres études plus récentes, suggèrent l’utilisation de doses élevées de l’elacridar et du tariquidar pour moduler efficacement l’activité de la P-gp dans la BHE. Néanmoins, ces doses élevées en co-administration avec des substrats de la P-gp peuvent être associées à des interactions pharmacocinétiques et à des profils toxiques, limitant ainsi l'utilisation de ces inhibiteurs.Dans ce contexte, l’objectif principal de cette thèse est d’obtenir une modulation transitoire mais efficace de la P-gp dans la BHE par administration intraveineuse de doses faibles mais thérapeutiques de l’elacridar et du tariquidar sous leur forme libre ou co-encapsulé dans les liposomes. Le lopéramide, substrat de la P-gp, a été également administré sous sa forme libre comme une preuve in vivo d’une inhibition efficace de la P-gp dans la BHE.L'administration simultanée de ces deux modulateurs de la P-gp n’a pas modifié leurs concentrations plasmatiques ou celles du lopéramide, mais a entraîné une importante distribution du lopéramide dans le cerveau en raison de leur activité inhibitrice non- compétitive. De plus, la co-encapsulation de l’elacridar et du tariquidar dans des immunoliposomes stabilisées stériquement a amélioré la demi-vie et la distribution dans le cerveau des ceux deux composés. Par conséquent, la distribution dans le cerveau du lopéramide a été considérablement augmentée, sans aucune modification de sa pharmacocinétique ou distribution tissulaire. Par ailleurs, la diminution partielle de l'activité inhibitrice du tariquidar par des liposomes vides suggère l’utilisation de ce nanovecteur comme une approche de bio-détoxification pour le traitement des surdoses de tariquidar. En résumé, cette thèse propose différentes approches pour exploiter pleinement l’elacridar et le tariquidar. Les résultats décrits dans ce manuscrit devraient ouvrir des pistes intéressantes pour atteindre une inhibition efficace de la P-gp dans la BHE et pour réussir des thérapies ciblant le système nerveux central / Although the P-glycoprotein (P-gp) represents an obstacle in several central nervous system (CNS) pharmacotherapies, the P-gp also protects the brain from intoxication by endogenous and exogenous harmful lipophilic compounds that otherwise could penetrate the blood-brain barrier (BBB) by simple diffusion. Therefore, any modulation of the efflux transporter has to consider the potential neurotoxicity of such modulation. Early studies showed that elacridar and tariquidar, two third-generation P-gp modulators, increase the distribution of several P-gp substrates in the brain. Unfortunately, recent studies suggest the use of high doses of elacridar and tariquidar to efficiently modulate the P-gp at the BBB. Nevertheless, when co-administered with P-gp substrates, these high doses may be associated with pharmacokinetic interactions and toxic profiles, thus limiting the use of these compounds.Hence, this thesis aimed to attain a transient but efficient modulation of the P-gp at the BBB using elacridar and tariquidar but avoiding the use of large doses of these compounds. For this purpose we took advantage of the possible in vivo intravenous co-administration of low but therapeutic doses of elacridar and tariquidar, under their free form or co-encapsulated in liposomes. The brain distribution of free loperamide was determined as an in vivo probe of full inhibition of the P-gp activity at the BBB.The concurrent administration of both free P-gp modulators does not modify their plasma concentrations or those of the P-gp substrate but significantly increased the brain uptake of loperamide as a result of their non-competitive modulatory activity. Moreover, the co-encapsulation of elacridar and tariquidar in targeted sterically stabilized immunoliposomes improved the half-lives and brain distribution of both compounds. Consequently, the brain uptake of free loperamide was significantly enhanced without any modification of its pharmacokinetics or tissue distribution. Moreover, the partial impairment of the modulatory activity of tariquidar by empty liposomes, supports the use of this nanocarrier as a bio-detoxifying approach for the treatment of tariquidar overdoses.In summary, this thesis proposes different approaches for full exploitation of elacridar and tariquidar. The findings described in this manuscript should open interesting avenues to achieve an efficient overcoming of the P-gp at the BBB and succeed CNS pharmacotherapies.

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No. of bitstreams: 1 Renato Almeida de Andrade.pdf: 2104371 bytes, checksum: 41c65c2aae76e3d84ab21c9e2210ca71 (MD5) Previous issue date: 2010-04-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The general objective of this thesis is to characterize the influence of the costing manners in the action of Private Executioner of Services Social Attendance, in the Metropolitan Region of Grande Vitória and the specific objectives are: a) to approach elements that characterize the economic values used in the costing of the expenses of Private Executioner of Services Social Attendance; b) to know there are changes in Private Executioner of Services Social Attendance caused after agreements and "partnerships"; c) to verify those changes means to redirect in some way the action type developed by Private Executioner of Services Social Attendance; d) to identify effects of the amplification of the process of co-administration of public actions in Private Executioner of Services Social Attendance. I affirm as research hypothesis that the access to the costing influences in the conception, in the operation and in Services Social Attendance reach in Private Executioner. I opted for studying the institutions in that Region for existing in her a great concentration of population, as well as the largest social disparities of Espírito Santo State. In virtue of those aspects, it can be observed that is in that Region, where she meets great part of the Services Social Attendance implemented on the part of the civil society in the Espírito Santo . These Executioner is not created, nor administered for the State, but there is not any difficulty with relationship to the greeting of resources of him, of any company, of individuals or of another Executioner. In this study I used a qualitative methodology, without opening hand of elements of the quantitative research, because the relationship enters to them it is not of opposition, but complementarity and of articulation. I accomplished in the collect of data of this thesis: 1) a bibliographical research on the theme; 2) a documental research in cadasters, reports and public budgets; and 3) interviews, using questionnaire, with the entities receivers leaders and payers defined in the sample and with the responsible technicians for the agreements and for their partnerships. These interviews were recorded and later on transcribed. One of the characteristics of the rendered service is to be continuous; another is the transparency search and the respect in the use of the public resources. Starting from the partnership/coadministration it was possible to enlarge: the number of attentions of Executioner, the recruitings and the professionals' qualification. In function of the agreements the political positioning of Executioner, in the public sphere, was not altered or affected for they be receiving public resources. One of the discussions always exposed by the interviewees it went to relationship between the financing and the autonomy of the institutions, because the financing cannot be a "shirt of force" that plasters the work and/or the political positioning of the institutions. These have been receiving strong impact starting from the moment in that they began to participate in those partnership/co-administration politics, but great part of Private Executioner of Services Social Attendance sees in a positive way those changes and adaptations lived in the last years, because they got to increase and/or to qualify still more its actions. What doesn't want to move, starting from the partnership/co-administration, they are the values us which they believe. Any partnership type between State and Private Executioner of Services Social Attendance cannot release the first of its responsibilities in guaranteeing rights and social safety. The State needs to contribute so that the autonomy (beyond financial independence) and the critical attitude inherent of the own institutions they can be guaranteed / O objetivo geral desta tese é caracterizar a influência dos modos de custeio na ação dos Prestadores Privados de Serviços Socioassistenciais, na Região Metropolitana da Grande Vitória e os objetivos específicos são: a) aproximar elementos que caracterizem os valores econômicos utilizados no custeio dos gastos dos Prestadores Privados de Serviços Socioassistenciais; b) conhecer se há mudanças nos Prestadores Privados de Serviços Socioassistenciais ocasionadas após acordos e parcerias ; c) constatar se essas mudanças significam redirecionar de alguma forma o tipo de ação desenvolvida pelos Prestadores Privados de Serviços Socioassistenciais; d) identificar efeitos da ampliação do processo de co-gestão de ações públicas nos Prestadores Privados de Serviços Socioassistenciais. Afirmo como hipótese de pesquisa que o acesso ao custeio influi na concepção, no funcionamento e no alcance dos Serviços Socioassistenciais nos Prestadores Privados. Optei por estudar as instituições nessa Região por existir nela uma grande concentração populacional, bem como as maiores disparidades sociais do Estado do Espírito Santo. Em virtude desses aspectos, pode-se observar que é nessa Região, onde se encontra grande parte dos Serviços Socioassistenciais implementados por parte da sociedade civil no Espírito Santo. Estes Prestadores não são criados, nem geridos pelo Estado, mas não há qualquer empecilho quanto ao recebimento de recursos dele, de qualquer empresa, de pessoas físicas ou de outros Prestadores. Neste estudo utilizei a abordagem qualitativa, sem abrir mão de elementos da pesquisa quantitativa, visto que a relação entre a elas não é de oposição, mas de complementaridade e de articulação. Realizei na coleta de dados desta tese: 1) uma pesquisa bibliográfica sobre o tema; 2) uma pesquisa documental em cadastros, relatórios e orçamentos públicos; e 3) entrevistas, utilizando questionário, com os dirigentes das entidades recebedoras e financiadoras definidas na amostra e com os técnicos responsáveis pelos convênios e pelas parcerias delas. Estas entrevistas foram gravadas e posteriormente transcritas. Uma das características do serviço prestado é ser contínuo; outra é a busca de transparência e o respeito na utilização dos recursos públicos. A partir da parceria/co-gestão foi possível ampliar: o número de atendimentos dos Prestadores, as contratações e a qualificação dos profissionais. Em função dos convênios firmados o posicionamento político dos Prestadores, na esfera pública, não foi alterado ou abalado por estarem recebendo recursos públicos. Uma das discussões sempre exposta pelos entrevistados foi a relação entre o financiamento e a autonomia das instituições, pois o financiamento não pode ser uma camisa de força que engesse o trabalho e/ou o posicionamento político das instituições. Estas têm recebido forte impacto a partir do momento em que começaram a participar dessas políticas de parceria/co-gestão, mas grande parte dos Prestadores Privados de Serviços Socioassistenciais vê de forma positiva essas mudanças e adaptações vividas nos últimos anos, pois conseguiram aumentar e/ou qualificar ainda mais suas ações. O que não estão dispostos a mudar, a partir da parceria/co-gestão, são os valores nos quais acreditam. Qualquer tipo de parceria entre Estado e Prestadores Privados de Serviços Socioassistenciais não pode desobrigar o primeiro de suas responsabilidades em garantir direitos e segurança social. O Estado precisa contribuir para que a autonomia (que não significa apenas independência financeira) e a atitude crítica inerentes às próprias instituições sejam garantidas