Orientador: Chung Man Chin / Banca: Leoberto Costa Tavares / Banca: Agnaldo Bruno Chies / Banca: Maria do Carmo Longo / Banca: Veni Maria Andres Felli / Resumo: A inflamação é uma reação de defesa e reparo fisiológico, importante em resposta a agressões físicas, químicas ou biológicas ao organismo, que geram o aparecimento dos quatro sinais cardinais dor, edema, calor, rubor, incluindo, muitas vezes a perda de função do tecido ou órgão. O processo inflamatório agudo é imediato e inespecífico contra o agente agressor, podendo evoluir para crônico, caso haja a permanência do agente agressivo e é caracterizado pelo aumento de celularidade e outros elementos teciduais. Várias substâncias estão envolvidas no processo inflamatório, como a prostaglandinas, histamina, serotonina e citocinas pró-inflamatórias como IL-1b, 1L-6, IL-8, TNF-a, NF-kB. Estima-se que exista na terapêutica, mais de 50 antiinflamatórios não esteróides (AINEs) diferentes, mas nenhum deles totalmente destituído de efeitos tóxicos, como a gastrotoxicidade, mesmo os compostos mais novos, seletivos para receptores COX2, como o celecoxibe. Por este motivo nenhum AINEs é recomendado para utilização em processos inflamatórios crônicos. Neste sentido, Vizioli (2006) e Castro (2008), planejaram pró-fármacos taurínicos e híbridos ftalimídicos, respectivamente, obtendo resultados promissores como antiinflamatórios potenciais destituídos de gastrotoxicidade. O presente trabalho visa realizar os testes pré-clinicos de atividade antiinflamatória aguda e crônica. Os resultados demostraram que que todos os derivados testados não apresentam gastrotoxicidade em relação ao padrão AINE testado, sem alteração significativa da resposta inflamatória aguda, com exceção do derivado de ibuprofeno N-(1,3-dioxo-1,3-diidro-2H-isoindol-2-il)-2-(4-isobutilfenil) propanamida, que demonstrou atividade inferior. Em estudo de atividade inflamatória crônica... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Inflammation is a defense and repair physiologic reaction important in response to an physical, chemical or biological aggression of the body, providing the appearance of the four cardinal signs of pain, swelling, heat, redness, including often the loss of function of the tissue or organs. The acute inflammatory process is immediate and nonspecific against the aggressive agent and it is characterized by increased cellular and other tissue elements. Series of substances are involved in the inflammatory process such as prostaglandins, histamine, serotonin and pro-inflammatory cytokines such as 1L-6, IL-8, a-TNF, NF- kB. It is estimated that exists more than 50 different non steroidal anti-inflammatory drugs (NSAIDs) drugs in the market, but none of them are wholly without side effects such as gastro toxicity, even the newer compounds, selective to COX2 receptors, as the celecoxib. For this reason none of NSAIDs is recommended for use in chronic inflammatory diseases. In this sense, Vizioli (2006) and Castro (2008), planned new taurine prodrugs and phtalimide hybride NSAIDs, respectively, showing promising results as anti-inflammatory without toxicity. This work aims to accomplish pre-clinical assay by acute and chronic models of inflammation. The results showed that all derivatives tested have no gastro toxicity when compared with the NSAIDs standard. No significant inflammatory response was observed with the exception toibuprofen derivative N-(1,3-dioxo-1,3-diidro-2H-isoindol-2-il)-2-(4-isobutilfenil) propanamide, which showed less activity. In the chronic inflammatory study activity all compounds phthalimide and taurine showed increase of activity compared to standard NSAIDs with decrease of the mortality and exclusion of the clinical signals such as bleeding, weight loss, and increased defecation rate... (Complete abstract click electronic access below) / Doutor

BARROS, Allen Lopes de. Estudos de degradação de fármacos em meio aquoso por processos oxidativos avançados. 2014. 99 f. Tese (doutorado em química)- Universidade Federal do Ceará, Fortaleza-CE, 2014. / Submitted by Elineudson Ribeiro (elineudsonr@gmail.com) on 2016-04-05T17:40:48Z No. of bitstreams: 1 2016_dis_albarros.pdf: 3063549 bytes, checksum: a95b83f685ed44a7833c464cf5e4a41c (MD5) / Approved for entry into archive by José Jairo Viana de Sousa (jairo@ufc.br) on 2016-05-20T18:30:12Z (GMT) No. of bitstreams: 1 2016_dis_albarros.pdf: 3063549 bytes, checksum: a95b83f685ed44a7833c464cf5e4a41c (MD5) / Made available in DSpace on 2016-05-20T18:30:12Z (GMT). No. of bitstreams: 1 2016_dis_albarros.pdf: 3063549 bytes, checksum: a95b83f685ed44a7833c464cf5e4a41c (MD5) Previous issue date: 2014 / The use of PET as a support material for TiO2 films in advanced oxidation processes (AOPs) for water treatment was investigated. A green, low-cost immobilization procedure was developed and the amount of deposited photocatalyst ranged from 0.036 to 0.202 mg per cm2 PET. Photocatalytic activity of the films was evidenced by degrading paracetamol solutions under UV radiation. The highest kinetic constants were observed for at least 0.09 mg TiO2 per cm2 PET. Scan Electron Microscopy (SEM) and Energy-Dispersive X-ray (EDX) analyses indicated 0.15 mg TiO2 per cm2 PET as enough to provide complete covering of the PET support. Characterization analyses were performed with a film after 30 h of use in a UV/TiO2/O3 reactor. According to SEM analyses, the photocatalyst was not detached from the PET support, while EDX and gravimetric data indicated the possibility of the TiO2 to have been contaminated by compounds present in the solution during the treatment. Further experiments were performed, concerning the study of the degradation of the pharmaceuticals paracetamol, ibuprofen, ketoprofen, and naproxen. Degradation studies were carried out in a pilot-scale reactor, by using several AOP’s, namely direct photolysis, heterogeneous photocatalysis, and ozonation, either individually or simultaneously. Special attention was given to the identification of significant factors considered, in order to contribute to the optimization of systems in which such AOPs or their combination can be used. Also, the detection and indication of degradation products is presented. / O uso de PET (politereftalato de etileno) como material de suporte para filmes de TiO2 foi estudado. Um procedimento de baixo custo e ambientalmente correto foi desenvolvido para a obtenção dos filmes e a quantidade de fotocatalisador depositada variou de 0,036 a 0,202 mg por cm2 de PET. A atividade fotocatalítica dos filmes obtidos foi evidenciada por ensaios de degradação de paracetamol sob radiação UV. As maiores constantes cinéticas foram observadas quando 0.09 mg de TiO2 ou mais foram depositados por cm2 PET. Análises por microscopia eletrônica de varredura (MEV) e energia dispersive de raios-X (EDX) indicaram que 0,15 mg de TiO2 por cm2 de PET foram suficientes para completa cobertura do suporte. Análises de caracterização também foram realizadas em filmes com mais de 30 h de uso em sistema UV/TiO2/O3. De acordo com as análises de MEV, o fotocatalisador não foi removido do suporte de PET, enquanto dados de EDX e de análise gravimétrica indicaram a probabilidade de contaminação dos filmes por compostos presentes na solução durante o tratamento. Outros experimentos foram realizados, relacionados ao estudo da degradação dos fármacos paracetamol, ibuprofeno, cetoprofeno e naproxeno. Os estudos de degradação foram realizados em reator em escala piloto, utilizando-se diversos POAs (fotólise direta, fotocatálise heterogênea, ozonização) de forma individual ou simultaneamente. Atenção especial foi dada à identificação dos fatores significativos, dentre aqueles considerados nos ensaios, de modo a contribuir para a otimização de sistemas em que estes POAs venham a ser utilizados. A detecção e indicação de prováveis produtos de degradação também é apresentada.

Made available in DSpace on 2014-06-11T19:28:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-02-23Bitstream added on 2014-06-13T20:17:47Z : No. of bitstreams: 1 campos_ml_me_arafcf.pdf: 1120091 bytes, checksum: 64c3422147bb240179227727fd56175b (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Universidade Estadual Paulista (UNESP) / O pró-fármaco de diclofenaco, 1-(2,6-diclorofenil)indolin-2-ona (DICCIC), apresenta atividade anti-inflamatória comparável ao diclofenaco sem efeitos gastroulcerativos. Essa vantagem torna-o uma possível alternativa terapêutica em quadros de inflamação onde há a indicação de anti-inflamatórios não esteroidais. Assim neste trabalho, foi investigado o perfil farmacocinético do DICCIC e seu potencial para conversão no diclofenaco. O DICCIC e o diclofenaco foram administrados em dose única a ratos Wistar (n=20) intravenosamente. Foram colhidas amostras seriadas de sangue. As amostras de plasma foram processadas e o extrato final do processamento foi analisado por CLAE. O sistema cromatográfico consistiu de uma bomba 600E Waters®, com detector UV-vis operando a 276 e 250 nm. A separação foi feita em coluna Symmetry C18 (4,6 x 250 mm, 5µm) sob eluição da fase móvel metanol:acetonitrila: ácido metanoico 0,1%, na proporção de 5:55:40, em modo isocrático e fluxo de 1 mL/min. O método bioanalítico foi validado e seus limites de confiança foram apropriados para sua aplicação. As médias dos parâmetros farmacocinéticos foram calculadas pelas curvas de concentração plasmática versus tempo e comparadas pelo teste de Mann-Whitney (p<0,05). A meia-vida do diclofenaco a partir de DICCIC (49,7 ± 10,9 min) foi significativamente menor que a meia-vida do diclofenaco após administração de diclofenaco (188,3 ± 78 min). O mesmo foi observado para a área sob a curva, cujo resultado para diclofenaco de DICCIC (48,8 ± 4,2 µg.min/mL) foi mais de dez vezes menor que a do diclofenaco após administração... / The diclofenac prodrug, 1-(2,6-dichlorophenyl)indolin-2-one (DICCIC), has anti-inflammatory effects comparable to diclofenac, but without gastroulcerative effect. This advantage makes it a potential therapeutic approach in inflammation frames where there is an indication of nonsteroidal anti-inflammatory drugs. Thus, in this study, we investigated the pharmacokinetic profile of DICCIC and its potential for conversion to diclofenac. The DICCIC and diclofenac were administered in single dose to Wistar rats (n = 20) intravenously. Blood samples were collected serially. The plasma samples were processed and thereafter analyzed by HPLC. The HPLC system consisted of a Waters® 600E pump with a UV-Vis detector (Waters® 2487), and a reverse phase C18 column (5µm, 250mm x 4.6 mm I.D, Symmetry®, Waters). The mobile phase was 0.1% methanoic acid:methanol:acetonitrile (40:5:55) at a flow rate 1 mL/min. The UV-Vis detector was set to 276 nm for detection of diclofenac and naproxen (Internal Standard), and 250 nm for DICCIC. The HPLC method for simultaneous determination of diclofenac and DICCIC was validated to perform the profile evaluation. The confidence limits were appropriate for its application. The mean pharmacokinetic parameters were then calculated (using) the curves of plasma concentration versus time and compared using the Mann-Whitney test (p <0.05). The half-life of diclofenac from DICCIC (49.7 ± 10.9 min) was significantly lower than the half-life of diclofenac after administration of diclofenac (188.3 ± 78 min). The area under the curve for diclofenac from DICCIC (48.8 ± 4.2 μg.min/mL) was more than ten-fold lower than that of diclofenac originated from diclofenac ... (Complete abstract click electronic access below)

Resumo: O pró-fármaco de diclofenaco, 1-(2,6-diclorofenil)indolin-2-ona (DICCIC), apresenta atividade anti-inflamatória comparável ao diclofenaco sem efeitos gastroulcerativos. Essa vantagem torna-o uma possível alternativa terapêutica em quadros de inflamação onde há a indicação de anti-inflamatórios não esteroidais. Assim neste trabalho, foi investigado o perfil farmacocinético do DICCIC e seu potencial para conversão no diclofenaco. O DICCIC e o diclofenaco foram administrados em dose única a ratos Wistar (n=20) intravenosamente. Foram colhidas amostras seriadas de sangue. As amostras de plasma foram processadas e o extrato final do processamento foi analisado por CLAE. O sistema cromatográfico consistiu de uma bomba 600E Waters®, com detector UV-vis operando a 276 e 250 nm. A separação foi feita em coluna Symmetry C18 (4,6 x 250 mm, 5µm) sob eluição da fase móvel metanol:acetonitrila: ácido metanoico 0,1%, na proporção de 5:55:40, em modo isocrático e fluxo de 1 mL/min. O método bioanalítico foi validado e seus limites de confiança foram apropriados para sua aplicação. As médias dos parâmetros farmacocinéticos foram calculadas pelas curvas de concentração plasmática versus tempo e comparadas pelo teste de Mann-Whitney (p<0,05). A meia-vida do diclofenaco a partir de DICCIC (49,7 ± 10,9 min) foi significativamente menor que a meia-vida do diclofenaco após administração de diclofenaco (188,3 ± 78 min). O mesmo foi observado para a área sob a curva, cujo resultado para diclofenaco de DICCIC (48,8 ± 4,2 µg.min/mL) foi mais de dez vezes menor que a do diclofenaco após administração... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The diclofenac prodrug, 1-(2,6-dichlorophenyl)indolin-2-one (DICCIC), has anti-inflammatory effects comparable to diclofenac, but without gastroulcerative effect. This advantage makes it a potential therapeutic approach in inflammation frames where there is an indication of nonsteroidal anti-inflammatory drugs. Thus, in this study, we investigated the pharmacokinetic profile of DICCIC and its potential for conversion to diclofenac. The DICCIC and diclofenac were administered in single dose to Wistar rats (n = 20) intravenously. Blood samples were collected serially. The plasma samples were processed and thereafter analyzed by HPLC. The HPLC system consisted of a Waters® 600E pump with a UV-Vis detector (Waters® 2487), and a reverse phase C18 column (5µm, 250mm x 4.6 mm I.D, Symmetry®, Waters). The mobile phase was 0.1% methanoic acid:methanol:acetonitrile (40:5:55) at a flow rate 1 mL/min. The UV-Vis detector was set to 276 nm for detection of diclofenac and naproxen (Internal Standard), and 250 nm for DICCIC. The HPLC method for simultaneous determination of diclofenac and DICCIC was validated to perform the profile evaluation. The confidence limits were appropriate for its application. The mean pharmacokinetic parameters were then calculated (using) the curves of plasma concentration versus time and compared using the Mann-Whitney test (p <0.05). The half-life of diclofenac from DICCIC (49.7 ± 10.9 min) was significantly lower than the half-life of diclofenac after administration of diclofenac (188.3 ± 78 min). The area under the curve for diclofenac from DICCIC (48.8 ± 4.2 μg.min/mL) was more than ten-fold lower than that of diclofenac originated from diclofenac ... (Complete abstract click electronic access below) / Orientador: Rosângela Gonçalves Peccinini / Coorientador: Jean Leandro dos Santos / Banca: Chug Man Chin / Banca: Regina Helena Costa Queiroz / Mestre

Philosophiae Doctor - PhD / The skin is the largest and most readily accessible organ of the body. The stratum corneum forms the outermost layer of the skin, which functions as a barrier to the external environment and regulates the passage of molecules across the skin. Drug delivery across the skin offers advantages over other routes of administration, bypassing the hepatic first pass metabolism, maintaining therapeutically effective drug levels, and improved patient compliance. Currently, there is a strong trend in the use of plant materials and extracts for medicinal purposes. Devil’s Claw (Harpagophytum procumbens) is a medicinal plant located in many regions throughout Southern and South Africa. It is used for its anti-inflammatory and analgesic properties with the harpagoside and harpagide components present reported to be responsible for these properties. Its activity has been reported to be as a result of the direct and indirect inhibition of Cyclooxygenase- 2 enzyme (COX-2). Efforts to improve the permeation of synthetic conventional compounds are constantly investigated, and great improvements of these formulations have led to very effective formulation of transdermal dosage forms such as anti-inflammatory drugs. The same should be possible for medicinal plants. Optimal permeation across the skin requires a drug to possess lipophilic as well as hydrophilic properties. Research suggests that a drug should have an aqueous solubility of more than 1 mg/ml and an octanol-water partition coefficient (log P) between 1 and 2 to optimally penetrate the skin (higher values indicating increased lipophilicity). Compounds not possessing these characteristics may be facilitated across the skin by the introduction of permeation enhancers in the formulation that include Azone® and sodium dodecyl sulphate xvi (SDS). The main aims of this study were to make an extract of Harpagophytum procumbens and to determine the direct COX-2 inhibition activity of this extract and further to formulate this extract into a pharmaceutical gel, with permeation enhancers that maintains its COX-2 enzyme inhibition qualities after transdermal penetration. The analytical techniques verified the existence of a harpagide and harpagoside components in the crude Harpagophytum procumbens extract and they were quantified in the extract at 3% and 1% respectively. COX-2 inhibition by the Harpagophytum procumbens extract was determined by a direct enzyme inhibition study and quantified by means of measuring the production of the product formed by the enzyme over a time interval in the presence of excess enzyme substrate. Crude Harpagophytum procumbens extract demonstrated a greater COX-2 enzyme inhibition than pure harpagide and harpagoside individually and combined. This indicated the existence of compounds in the extract contributing to this synergistic effect. This was reflected in the IC50 values indicating that the Harpagophytum procumbens crude extract had the lowest IC50 values concentration when compared to the harpagide and harpagoside. Octanol-PBS partition coefficient (log D) experiments were performed with various permeation enhancers and gels with varying combinations in order to determine the changing partitioning properties of harpagide and harpagoside. The octanol-PBS partition coefficient (log D) experiments indicated that harpagoside had a higher log D value than harpagide. The addition of permeation enhancers resulted in changes in the partition co-efficient of the marker compounds. The permeation enhancer, Azone®, resulted in the smallest reduction of Log D for harpagoside and the largest increase in Log D compared to other permeation enhancers tested for harpagide. xvii When the 2 marker compounds were formulated into different gel formulations (hydroxypropyl cellulose, Carbopol Ultrez 21® and Pluronic®), harpagide had the largest increase in Log D with the Carbopol Ultrez 21® gel. Harpagoside had the largest increase in the hydroxypropyl cellulose gel.Combinations of gel formulations with permeation enhancers were tested. The 2 best performing permeation enhancers in hydroxypropyl cellulose gel were SDS and Azone®. These compounds resulted in the largest increase in lipophilic partitioning for harpagide and harpagoside compound and higher values were achieved with SDS. Following the partition co-efficient determination, permeation studies with synthetic membranes were performed with the selected enhancer/gel formulations using Franz diffusional cells. The permeation (flux) across the hydrophobic synthetic membrane (Sil-Tec®) indicated flux of 27.1μg.cm-2.h-1 for harpagoside and 156.0 μg.cm-2.h-1 for harpagide in the hydroxypropyl cellulose gel. Incorporation of Azone® in the hydroxypropyl cellulose formulation resulted in an enhancement ratio (ER) of 14 for harpagoside. The hydroxypropyl cellulose gel with the permeation enhancers (Azone® and SDS) did not result in enhancement of permeation of the harpagide. Permeation of harpagoside and harpagide across the hydrophilic synthetic membrane (Tuffyrn®) yielded flux values of 537.1 μg.cm-2.h-1 and 101.1μg.cm-2.h-1 respectively in the Gel formulations. The Gel formulation containing Azone® and SDS, resulted in similar flux across this membrane compared to the formulation consisting of the Gel only, with the Azone® containing formulation resulting in lower flux for harpagide. Transdermal permeation was measured through excised female human abdominal skin using Franz diffusion cells. xviii Flux values for harpagoside and harpagide were 18.4 μg.cm-2.h-1 and 5.0 μg.cm-2.h-1 respectively when the crude extract was in the hydroxypropyl cellulose gel tested on human skin. Formulation of the crude extract in hydroxypropyl cellulose gel including Azone® and SDS permeation enhancers resulted in enhancement of 8 and 7 respectively for harpagide. Azone® increased the flux of harpagoside 14 times in the same hydroxypropyl cellulose gel formulation. The SDS had very little effect. The enhancement ratios achieved with the human skin was higher than that of the synthetic membranes. Post transdermal COX-2 inhibition activity studies were performed with the Azone® Gel formulation after it permeated across the human skin membrane to determine to what extent inhibitory activity of the crude extract was maintained. The crude drug retained its direct COX-2 inhibitory activity after permeation across the human skin with 77% inhibitory activity.

OBJECTIVE: To determine the effect of anti-inflammatory drugs (4- methoxybenzophenone) and (kavain) on bone formation and bone resorption models using a three-dimensional (3D) live calvarial bone METHODS: Utilizing neonatal mouse calvarial bones on a grid system with media designed to cause bone formation or resorption. These models were used to study the effect of 4- methoxybenzophenone and kavain on bone remodeling. The spent media were evaluated by quantitative analysis of tartrate resistant acid phosphatase (TRAP), alkaline phosphatase (ALP) activity and calcium release. The calvaria were stained with neutral red and silver nitrate for histological analysis. RESULTS: Kavain and 4-methoxybenzophenone affected the calvarial bone remodeling by inhibiting resorption. Kavain stimulated bone formation as shown by ALP activity and prevented the transformation of macrophages into osteoclasts as shown by neutral red staining. Kavain prevented resorption as shown by silver nitrate staining. Histological examination of kavain treated bone showed new osteoid formation. The other factor, 4-methoxybenzophenone, had inconsistent effects on bone. Neutral red staining showed no osteoclast differentiation and silver nitrate staining showed no resorption. However calcium release increased in the resorption model and calcium uptake increased in the formation model. There was no effect on ALP or trap activities in either model.

No description available.

This study tested the hypothesis that administration of deracoxib, a cyclooxygenase-2 specific (COX-2) inhibitor, would result in lower gastric lesion scores than administration of buffered aspirin and gastric lesion scores similar to placebo when administered to healthy dogs for 28 days. Twenty-four, healthy, random source dogs were divided into three groups. Group I received buffered aspirin, 23.6 mg/kg PO q 8h, group II received deracoxib, 1.6 mg/kg PO q 24h and placebo twice daily PO q 8h after deracoxib administration, and group III received placebo PO q 8h. Gastroscopy was performed on days -7, 6, 14, and 28 of treatment. Four regions of the stomach (pylorus, incisura, cardia, and body) were evaluated separately and lesions scored on a scale of 1 (mucosal hemorrhage) to 12 (perforating ulcer) by an observer unaware of which treatments the dogs received. Dogs were observed every 8 hours for vomiting, diarrhea and anorexia. Feces were scored from 1-5 (scores <4 were considered diarrhea). Lesion scores for each group, at each location, and total scores, at each time period, were evaluated for the effects of time and treatment using a Kruskal-Wallis test. Total dog days of vomiting and dog days of diarrhea in each group were compared using a Wilcoxon rank sums test. Significance was determined at p<0.05. Significantly higher median total gastric lesion scores were found in the aspirin group compared to the deracoxib or placebo groups on days 6, 14, and 28. There were no significant differences in median total gastric lesion scores between the deracoxib or placebo groups at any time during the study. There was no location effect on gastric lesion scores and there was no significant change in gastric lesion scores over time in any of the groups during treatment. Significantly more dog-days of vomiting occurred in the aspirin group as compared to the deracoxib group. No significant differences were found between groups for dog-days of diarrhea. In this study, the administration of deracoxib to healthy dogs resulted in significantly lower gastric lesion scores compared to dogs receiving aspirin and lesion scores similar to those receiving placebo. / Master of Science

De nos jours, de nombreuses maladies chroniques telles que le cancer ou l’arthrose nécessitent encore de nouvelles modalités de traitement. Des biomatériaux naturels capables de véhiculer des substances actives font partie des solutions à cette problématique. Récemment, des travaux ont été menés sur un nouveau type de biomatériau, les Complexes de Polyélectrolytes Compacts (CoPEC). Dans le cadre de cette thèse, des CoPEC à base de polyélectrolytes biosourcés, le chitosan et l’alginate, fonctionnalisés avec la β-cyclodextrine (βCD) ont été formulés. Le CoPEC βCD-chitosan/alginate, non-cytotoxique, a présenté des propriétés anti-inflammatoires intrinsèques dans le cadre d’un modèle in vitro d’inflammation. De plus, ce CoPEC a présenté une capacité à contenir et relarguer deux substances actives hydrophobes modèles, le piroxicam et la prednisolone. Enfin, une stratégie d’inclusion de substances actives hydrophiles au sein du matériau a été mise en œuvre. Le nouveau CoPEC est prometteur car il peut exposer un effet anti-inflammatoire intrinsèque et d’autres effets thérapeutiques via l’inclusion de substances actives au sein des cyclodextrines. / Nowadays, many chronic diseases, such as cancer or osteoarthritis, still need new modalities of treatment. Natural biomaterials able to convey active substances represent a solution to this problematic. Lately, several research works have been conducted on a new type of biomaterial named Compact Polyelectrolyte Complexes (CoPEC). As part of this thesis, CoPEC have been prepared from two biosourced polyelectrolytes, chitosan and alginate, functionalized with β-cyclodextrin (βCD). Through an in vitro inflammation model, the non-cytotoxic βCD-chitosan/alginate CoPEC has displayed intrinsic anti-inflammatory properties. Moreover, this CoPEC has demonstrated a capacity to host and release piroxicam and prednisolone, two model hydrophobic active substances. Finally, a strategy to include hydrophilic active substances into the material has been implemented.Thus, the newly CoPEC is promising because it can exhibit an intrinsic anti-inflammatory effect as well as other therapeutic effects through the inclusion of active substances into the cyclodextrins.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications globally. There are generally two types: selective (COX-2) and traditional NSAIDs (COX-1). They are primarily used for the treatment of pain. They gained attention after a study about their basic mechanisms highlighted their toxicity. Several studies have reported an association between NSAIDs and risk of myocardial infarction (MI). However, the direction of the relationship is not conclusive. Further studies are needed to ascertain the direction of this relationship and evaluate the present situation with available drugs. Due to the seriousness of cardiovascular diseases as one of the leading cause of death, continuous monitoring of the NSAIDs-MI association is needed. The purpose of this dissertation was to investigate the association between NSAIDs and MI in a younger (30-64 years) Kentucky Medicaid population with a 12 year window of data. The three specific aims were: (1) to understand the characteristics of the Kentucky Medicaid population with respect to NSAID use: (2) to evaluate the NSAID-MI relationship with a 12 year follow-up in a young heavily-burdened population for cardiovascular diseases: and (3) to investigate the MI risk of meloxicam, celecoxib and naproxen compared to no exposure. A retrospective study was conducted employing data from January 1st 2000 and December 31st 2012. The data comprised demographic, prescription and medical files. Within this cohort, a nested case control study was conducted. Cases of MI were matched to four controls on race and gender. The results suggested that exposure to COX 2 presented an increased adjusted risk for MI (1.138(0.983, 1.318)). However, this risk was significantly increased for COX-2 only users compared to COX-1 only users (1.221 (1.03, 1.485)) and 30-40 year olds (1.600 (1.082, 2.367)). Meloxicam, celecoxib and naproxen compared to no exposure showed meloxicam presented a non-significant different risk for MI (1.26 (0.98, 1.63)) and celecoxib presented a significantly increased risk for MI (1.52 (1.26, 1.82)). This study considered pattern of use in determining continuous usage by looking at both continuous and sporadic users of NSAIDs and also considered patient switching patterns between classes of NSAIDs.