Made available in DSpace on 2014-06-11T19:23:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-25Bitstream added on 2014-06-13T18:09:13Z : No. of bitstreams: 1 nobre_mdp_me_sjc.pdf: 1018659 bytes, checksum: dbe488e3a217fc107f7384423ac8711f (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Este trabalho analisou a ação local do alendronato sódico no processo de reparação óssea em fêmures de ratos espontaneamente hipertensos (SHR). Foram utilizados quarenta ratos machos e quarenta fêmeas, para a confecção de um defeito ósseo de 2,5mm de diâmetro. De acordo com o material utilizado, criaram-se quatro grupos: controle (C), amido (Am), alendronato 1mol (A1) e alendronato 2mol (A2). Os animais do grupo C não tiveram seus defeitos ósseos preenchidos. Após o período de sete e 21 dias, os animais foram sacrificados. Foi realizada a análise histológica e histomorfométrica e os dados submetidos à análise estatística ANOVA. Aos sete dias, encontrava-se tecido conjuntivo com hemorragia e infiltrado inflamatório ocupando a área do defeito em todos os grupos experimentais e, em alguns grupos, focos de matriz osteóide. Os animais dos grupos A1 e A2 apresentavam uma rede de fibrina no tecido conjuntivo. Aos 21 dias, as trabéculas ósseas fechavam praticamente toda a extensão do defeito nos grupos C e Am. No grupo A1 de animais machos, observavam-se trabéculas que se irradiavam do interior da medula óssea até a área do defeito. Nos demais grupos A1 e A2 constatava-se apenas a presença de tecido conjuntivo, com deposição de fibras colágenas e mínima deposição de matriz osteóide. Um achado histológico marcante foi a formação de tecido ósseo extra-cortical subperiosteal nos animais dos grupos A1 e A2. O estudo concluiu que, neste modelo experimental, a administração local do alendronato sódico não contribuiu para o processo de reparação óssea nas concentrações molares utilizadas. / This study evaluated the local action of alendronate sodium on bone repair in spontaneously hypertensive rats (SHR). A bone defect of diameter 2,5mm was created in forty males and forty females. Four groups were created according to the treatment received: control (C), amido (Am), alendronate 1mol (A1) and alendronate 2mol (A2). The C group did not have their defect filled in with any material. The animals were sacrificed seven and 21 days after the surgical procedure. Histological and histomorfometric analyses were performed and the results submitted to ANOVA statistical analysis. On the seventh day, all groups presented a connective tissue with hemorrhage and inflammatory cells in the bone defect. In some groups osteoid matrix was observed. In A1 and A2 groups, the animals also presented a fibrin deposition. After 21 days, a formation of bone trabeculae was observed closing the superficial extension of the bone defect in C and Am groups. On male rats of group A1, the trabeculae formation projected from inside the bone medulla to the defect site, without completely closing it. In the others animals of groups A1 and A2, bone trabeculae were not observed in the defect site. It was only observed a deposition of dense collagen fibers and minimal osteoid matrix. An important histological feature found in this study was the formation of extra-cortical subperiosteal bone in the animals of A1 and A2 groups. The study concluded that the local administration of alendronate sodium did not contribute for the bone repair, in this experimental model.

Orientador: Elcio Marcantonio Junior / Coorientador: Luis Carlos Spolidorio / Banca: Paulo Sérgio da Silva Santos / Banca: Juliana Rico Pires / Banca: Helder Antonio Rebelo Pontes / Banca: Cleverton Roberto de andrade / Resumo: O objetivo deste projeto foi desenvolver, em ratos, modelos experimentais de osteonecrose induzida pelos bisfosfonatos por meio da combinação de uma série de fatores de risco para esta doença, como o uso prolongado de altas doses de alendronato por via parenteral, procedimentos cirúrgicos operatórios e o estresse crônico. Os parâmetros foram estabelecidos por meio de análise histológica descritiva e por escores, análise radiográfica de alvéolos dentais, estereometria de alvéolos dentais e implantes, torque de remoção dos implantes e avaliação de marcadores do metabolismo ósseo e do estresse. No primeiro e segundo estudos foram administradas altas doses diárias ou semanais de alendronato, respectivamente, associado a exodontias dos primeiros molares inferiores. No terceiro e quarto estudos foram administradas altas doses semanais de alendronato, associado à indução de estresse crônico e instalação de implantes osseointegráveis na maxila e/ou na metáfise tibial. De um modo geral, os resultados dos estudos demonstraram que a terapia com alendronato foi associada à supressão significativa do metabolismo ósseo. Nos estudos 1 e 2, após as extrações dentais, observou-se o desenvolvimento de áreas de exposição e necrose óssea, associadas à presença de infecção significativa, especialmente na região de septo inter-dental. No estudo 3 observou-se que a indução de estresse crônico apresentou efeitos negativos sobre o metabolismo e volume do tecido ósseo neoformado nas espiras dos implantes tibiais, os quais não foram observados nos animais tratados com alendronato. Ao contrário, nestes animais, observou-se uma melhora significativa nos parâmetros de osseointegração. Já o estudo 4 demonstrou que a administração de alendronato resultou no desenvolvimento expressivo de áreas... (Resumo completo, clicar aesso eletrônico abaixo) / Abstract: This study aimed to develop, in rodents, experimental models of bisphosphonatesinduced osteonecrosis through the association of several risk factors to this disease, including the long-term therapy with high dosages of alendronate by parenteral route, surgical procedures and chronic stress. The parameters were established by descriptive and scored histological analysis, radiographic evaluation of alveolar sockets, stereometry of alveolar sockets and implants, torque removal of implants and biomarkers of bone metabolism and stress. In the first and second studies, it was administered daily or weekly high doses of alendronate, respectively, associated to the lower first molar extractions. In the third and fourth studies it was administered weekly high doses of alendronate plus chronic stress induction and osseointegrated implants in the maxillae and/or tibia. In general, the outcomes of this study demonstrated that alendronate therapy was associated to a markedly bone turnover suppression. In the first and second studies, after tooth extraction, it was observed the development of exposed and necrotic bone associated to a significant infectious process, especially at the inter-radicular area. In the study three the chronic stress was related to deleterious effects on the bone metabolism and volume among tibial implants threads, which weren't presented in animals treated with alendronate. On the contrary, in these animals, it was observed a markedly increase in the osseointegration parameters. On the other hand, the fourth study showed that the alendronate treatment resulted in the substantial development of osteonecrosis regions associated to infection at lateral areas of maxillary bone implant cavity, even with absence of exposed bone areas. In this way, we conclude that the alendronate therapy suppress significantly the bone... (Complete abstract click electronic access below) / Doutor

Well know therapies for the treatment of osteoporosis, syndrome characterized by increased bone fragility and fracture consist primarily of drugs which prevent bone losses, such as bisphosphonates. Among them, alendronate (PO3)-(OH)-C-((CH2)3 NH3)-(PO3) is one of the chosen treatments in the clinic, IC50 = 50 nM. In this work a study of the molecular alendronate and three of its crystals (sodium alendronate trihydrate and anhydrous and calcium alendronate ) is performed in the scope of Density Functional Theory (DFT). In the first case, the focus is the lowest energy conformations of the molecular alendronate in vacuum, in an aqueous medium in accordance with the model of polarization continuum (PCM), and interacting with three molecules of water of a sodium atom based on the characteristics structural relevadas diffraction X-ray crystal alendrontao sodium trihydrate; their vibrational infrared and Raman spectra are calculated to explain in detail the abundant signatures of the phosphate group in the frequency range 400-1400 cm −1 with the assignments of the most important vibrational modes. In the case of crystals, their structural, electronic and optical properties are obtained in the generalized gradient approximation taking into account the description of the term correlation and exchange Tchatschenko (GGA+TS ); Hirshfeld population analysis in which verified is presented alendronate is that the three crystals is in zwitterionic state. From the calculation of the band structure was obtained GAPs with very close values for the three crystals, however, with the density of states and characteristic for each crystal. The effective masses, dielectric function and theoretical optical absorptions for all crystals are presented. / Terapias estabelecidas para o tratamento da osteosporose, sÃndrome caracterizada por aumento na fragilidade Ãssea e fraturas, consistem primariamente de drogas que previnem a perda Ãssea, como os bisfosfonatos. Entre eles, o alendronato (PO3)-(OH)-C-((CH2)3 NH3)-(PO3) à um dos tratamentos escolhidos na clÃnica, pois possui o IC50=50 nM. Neste trabalho à realizado um estudo do alendronato molecular e de trÃs de seus cristais (alendronato de sÃdio trihidratado e anidro, e alendronato de cÃlcio) utilizando da Teoria do Funcional da Densidade (DFT). No primeiro caso, o foco sÃo os confÃrmeros de menor energia do alendronato molecular no vÃcuo, em meio aquoso de acordo com o modelo contÃnuo polarizÃvel (PCM), e interagindo com trÃs molÃculas de Ãgua e um Ãtomo de sÃdio de acordo com as caracterÃsticas estruturais reveladas por difraÃÃo de raios-X do cristal do alendrontao de sÃdio trihidratado; seus espectros vibracionais no infravermelho e Raman sÃo calculados para explicar com detalhes as abundantes assinaturas do grupo fosfato no intervalo de frequÃncia 400-1400 cm−1, com as atribuiÃÃes dos modos vibracionais mais importantes. No caso dos cristais, sÃo obtidas suas propriedades estruturais, eletrÃnicas e Ãpticas na aproximaÃÃo da gradiente generalizado levando-se em conta a descriÃÃo do termo de correlaÃÃo e troca de Tchatschenko (GGA+TS); à apresentada a anÃlise populacional de Hirshfeld na qual verificou-se que o alendronato nos trÃs cristais encontra-se no estado zwitterionico. A partir do cÃlculo de estrutura de banda, foi obtido GAPs com valores muito prÃximos para os trÃs cristais, porÃm, com densidade de estados bem caracterÃstica para cada cristal. SÃo apresentadas as massas efetivas, funÃÃo dielÃtrica e absorÃÃes Ãpticas teÃricas para todos os cristais.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A periodontite, a principal causa de perda de dentes em adultos, à uma doenÃa inflamatÃria onde ocorre perda do osso alveolar e destruiÃÃo das fibras do ligamento periodontal. Tanto as bactÃrias periodontopatogÃnicas como os fatores provenientes do hospedeiro sÃo necessÃrios para o desenvolvimento e progressÃo desta patologia. Os bisfosfonatos constituem uma nova classe de drogas, os quais inibem a reabsorÃÃo do osso causando alteraÃÃes morfolÃgicas ou apoptose nos osteoclastos. O objetivo do presente estudo foi investigar os mecanismos envolvidos no efeito de um bisfosfonato Alendronato DissÃdico (AD) na doenÃa periodontal experimental (DPE), comparando seus efeitos com a doxiciclina, tratamento jà estabelecido. A DPE foi induzida passando-se fio de nÃilon 3.0 em torno do segundo molar superior esquerdo de ratos Wistar fÃmeas, permanecendo durante 11d. AD (0,25mg/kg, s.c.) foi administrado 30 minutos antes e diariamente (tratamento preventivo) ou AD (0,25mg/kg, s.c.), DX (5 ou 10 mg/kg) ou salina (0,2ml) foram injetados a partir do 5 dia da induÃÃo da DPE (tratamento curativo). Os parÃmetros avaliados foram: Ãndice de perda Ãssea (IPO), anÃlise histopatolÃgica e microbiolÃgica, imunohistoquÃmica, migraÃÃo de neutrÃfilos, mieloperoxidase (MPO), leucogramas realizados antes e apÃs a cirurgia (6h e 1, 7 e 11 dias) e variaÃÃo da massa corpÃrea. No IPO, AD reduziu consideravelmente a reabsorÃÃo Ãssea tanto de forma preventiva como curativa sendo comparÃvel à doxiciclina. Na anÃlise histopatolÃgica, o periodonto dos animais tratados com AD mostrou preservaÃÃo do osso alveolar, cemento e das fibras colÃgenas, alÃm de reduÃÃo do infiltrado neutrofÃlico gengival de 6h. Esta inibiÃÃo da migraÃÃo neutrofÃlica foi confirmada atravÃs da MPO e em modelo de peritonite abdominal e o leucograma mostrou uma reduÃÃo da neutrofilia. A imunohistoquÃmica mostrou que o AD diminuiu a marcaÃÃo para TNF em 6h e 11d. No microbiolÃgico, AD inibiu qualitativamente o crescimento de bactÃrias caracterÃsticas da DP, tais como pigmentados e Fusobacterium nucleatum. AD promoveu um aumento na massa corpÃrea em relaÃÃo ao grupo salina. Esses resultados mostram que o AD possui importante atividade na DPE, sugerindo a relevÃncia de testes clÃnicos dos bisfosfonatos no tratamento da doenÃa periodontal / Periodontitis, the major cause of teeth loss in adults, is an inflammatory disease in which occurs alveolar bone resorption and collagen fibers destruction. Bacteria and host factors are necessary to the development of this pathology. Bisphosphonates are a new class of drugs that inhibit bone resorbtion by causing morphological alterations or death of osteoclasts. The objetive of this study is to investigate the effect of the bisphosphonate Dissodic Alendronate (DA) in periodontitis, comparing it with the doxicicline (DX), treatment currently used. Periodontitis was induced by a nylon thread ligature surgically placed around the cervix of the second left maxillary molars of female Wistar rats. Animals were treated with DA (0.25 mg/kg, s.c.) 30 minutes before periodontits induction and daily until sacrifice on 11th day (preventive group). Additionally, saline, DA or DX (5 or 10 mg/kg) were injected s.c. from 5th day and daily up to the 11th day of periodontal disease (curative treatment). The parameters analysed were alveolar bone loss (ABL), histopathologic and microbiological analysis, immunohistochemistry, myeloperoxidase (MPO), neutrophil migration, leukogram measured before and after challenge (6h and 1, 7 and 11 days) and body mass variation. AD, as curative or preventive treatment, reduced this alveolar bone loss similar DX. Histopatologically, the periodontium of animals treated with DA showed preservation of alveolar bone, cementum and collagen fibers of periodontal ligament, and reduced neutrophilic and mononuclear cell infiltrate. This effect on neutrophilic infiltrate was confirmed by MPO and in model of peritonitis induced by carrageenan. In imunohistochemistry, there was marked reduction of immunostaining for TNF in the group treated with DA compared to the saline group. In microbiologic analysis, DA inhibited the growth of bacteria involved in periodontitis. DA increased body mass compared to saline group. These results support clinical testing of bisphosphonates in the treatment of periodontal disease

A periodontite é uma doença de natureza multifatorial e infecciosa, que resulta na inflamação e perda dos tecidos de suporte dos dentes. Essa inflamação é causada por bactérias associadas ao biofilme, causando a perda progressiva de inserção. Os bisfosfonatos são fármacos com capacidade de inibir a reabsorção óssea, atuando nas células clásticas. O presente estudo teve como objetivo investigar os efeitos do alendronato, um bisfosfonato nitrogenado com grande potência antireabsortiva, na evolução da doença periodontal induzida em ratos, bem como a possível presença de necrose óssea no processo alveolar. Foram utilizados 48 ratos Wistar albinos, do sexo masculino, com 3 meses de vida e peso médio de 250g. Os animais foram divididos aleatoriamente em dois grupos: Alendronato (ALN) e Controle (CON). A periodontite foi induzida com a inserção de um fio de seda 4.0 no sulco gengival do segundo molar superior. Os ratos do grupo ALN, receberam doses diárias de 2,5 mg/kg durante 7 dias antes e 7, 14, 21 e 30 dias após a indução da doença; o grupo CON recebeu solução salina estéril. Nos tempos citados as maxilas foram fixadas, descalcificadas e incluídas em parafina ou resina Spurr. Os cortes foram corados com HE, para análise morfológica, e histomorfométrica. Alguns cortes foram submetidos à imuno-histoquímica para detecção de RANKL e OPG. Foi utilizado o método TRAP, marcador de osteoclastos e microscopia eletrônica de transmissão para análise ultraestrutural. O ALN inibiu a reabsorção da crista alveolar de todos os grupos tratados. As células clásticas apresentaram-se em estado latente. No grupo controle a crista alveolar foi reabsorvida e o TRAP revelou clastos ativos, achados confirmados pela microscopia eletrônica de transmissão. A expressão de RANKL, molécula ativadora da célula clástica, não foi inibida pela droga. A expressão de OPG foi aumentada nos animais tratados. Os animais do grupo tratado durante 21 e 30 dias, apresentaram sinais de osteonecrose na crista alveolar, como lacunas de osteócitos vazias e regiões exposta de osso. Os resultados demonstraram que o uso de alendronato durante a doença periodontal inibe a reabsorção óssea e que durante tempos prolongados pode gerar osteonecrose na região da crista óssea. / Periodontitis is an infectious disease of multifactor nature that results in the inflammation of the tissues supporting the teeth. This inflammation is caused by accumulation of biofilm and causes progressive insertion and bone loss. The bisphosphonates are drugs with the capability to inhibit the activity of clastic cells. The aim of this study was to investigate the effects of alendronate, a nitrogenated bisphosphonate with high antiresorptive power on experimental periodontal disease, and to analyze the possible presence of osteonecrosis in the rat alveolar process. Forty-eight male Wistar rats, three months old, with 250g weight were used. The animals were randomly divided into two groups: Alendronate (ALN) and Control (CON). The periodontitis was induced with a 4.0 silk wire inserted into the gingival sulcus around the right upper second molar. The ALN rats, received daily doses of 2.5 mg/kg alendronate (ALN) for 7 days before the induction of periodontitis; the treatment continued for additional 7, 14, 21 or 30 days. The CON rats, received sterile saline solution. In the time points cited, the maxillae were fixed, decalcified and embedded in Spurr resin or paraffin. The specimens were morphologically analyzed in HE stained sections, after which histomorphometry was carried out. Some stained sections were used for immunolabeling for RANKL and OPG. The osteoclasts were marker by tartrate-resistant acid phosphatase (TRAP) histochemistry. The ultrathin sections were examined in a transmission electron microscope. ALN reduced the activity of osteoclasts and significantly decreased the resorption of the alveolar crest. In the control group the alveolar crest appeared resorbed, while TRAP showed active osteoclasts, findings confirmed by transmission electron microscopy. The expression of RANKL, an osteoclast-activating molecule, was not inhibited by the drug. The expression of OPG was increased in the treated animals. The animals of the group treated for 21 and 30 days showed signs of osteonecrosis of the alveolar crest, as empty osteocyte lacunae in the exposed bone regions. The results showed that the use of ALN for periodontal disease inhibited bone resorption; when it was administered for prolonged periods it can cause osteonecrosis in the bone crest area.

Background: Osteoporosis has become a major problem worldwide as the population ages. An osteoporotic fracture is associated with a high rate of morbidity and mortality. Data on the prevalence, risk factors and outcome of osteoporotic fractures in South Africa remains sparse. Method: A retrospective audit was undertaken in all patients attending the Endocrine Clinic at Groote Schuur Hospital between March 2019 and March 2020 for the treatment of osteoporosis. Patients folders were reviewed to obtain the following information: demographic data, risk factors, laboratory investigations, treatment, baseline and follow up DEXA scans. Results: 264 patients were evaluated, average age 65.7 ± 12.3 years, 92.8% (n=245) were female. Common risk factors included smoking (50.8%, n=134), vitamin D deficiency (29.2%, n=77), steroid use (21.6%, n=57) and primary hyperparathyroidism (15.2%, n=40). A fragility fracture was diagnosed in 68.6% (n=181) - vertebral only (54.7%, n=99), hip only (14.9%, n=27), vertebral and hip (10.5%, n=19), wrist (7.2%, n=13) and other (12.7%, n=23). Bisphosphonates were used by 75% (n=198) of patients at the time of enrolment. Of these, 80.8% (n=160) received intravenous zoledonic acid alone, 6.1% (n=12) received oral alendronate alone and 13.1% (n=26) initially received alendronate followed by intravenous zoledronic acid. Over 5.2 years there was an improvement in bone mineral density (BMD) of 4.4% at the lumbar spine, while there was slight worsening of BMD at the femoral neck (- 0.17%). A fracture whilst on treatment occurred in 10.6% (n=21) of patients. Conclusion: The majority of patients with osteoporosis at Groote Schuur Hospital had a fragility fracture at diagnosis with a vertebral fracture being most common. Bisphosphonate treatment showed a measurable improvement in BMD at the lumbar spine, however, there was no improvement at the femoral neck. Despite this, few patients had a symptomatic vertebral or hip fracture whilst on treatment.

The mevalonate pathway plays an important role in cancer biology and has been targeted with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. Statins and bisphosphonates inhibit the mevalonate pathway at different steps, thus having negative effects at various levels on cancer cells. A combination of these drugs may result in an amplified cytotoxic effect and allow for use of significantly lower doses of the drugs involved. Statins inhibit the mevalonate pathway at 3-hydroxy-3-methylglutaryl coenzyme A reductase and bisphosphonates at farnesyl pyrophosphate synthase. Our results show that low-dose combinations of simvastatin and alendronate have a synergistic cytotoxic effect on androgen-independent prostate cancer PC-3 cells, but not on androgen-dependent LNCaP or DU 145 prostate cancer cells. These two drugs cause a sequential blockade of the mevalonate pathway and significantly affect survival and apoptotic pathways by down-regulating phospho-AKT and activating c-JUN and ERK.

Indiana University-Purdue University Indianapolis (IUPUI) / Bisphosphonates, effective inhibitors of bone resorption, are used in the treatment of postmenopausal osteoporosis. At present, the effects of bisphosphonate therapy on the maxilla have not been quantitatively studied. As part of the masticatory system, dentate alveolar bone is exposed to a unique pattern of loading. As such, data obtained from bisphosphonate studies of other bones may not be applicable to the cortical bone of the dentate maxilla. The objective of this study is to histomorphometrically quantify the effects of alendronate and risedronate therapy on alveolar bone of the dog maxilla (MX) and to determine if this site is affected differently than the cortical bone in the rib (R) from these same animals. Twenty-two female dogs were divided into three treatment groups of 1 mg/kg/day alendronate, 0.5 mg/kg/day risedronate, and a saline vehicle control. Fluorochrome labels were used to mark sites of bone formation. Maxillary and rib specimens from each dog were prepared for analysis of static and dynamic histomorphometric parameters. MX cortical bone surrounding the third premolar was further analyzed by side (buccal vs. lingual) and region (coronal vs. apical). Mineralizing surface (MS/BS) and bone formation rate (BFR) in the coronal maxilla of the control group is significantly (p < 0.05) higher than that of the bisphosphonate groups. In bisphosphonate treated animals, MS/BS, BFR, and activation frequency (AcF) were significantly (p < 0.05) higher in the R than in the MX. In all treatment groups, very little osteoid was detected, and no significant difference in the mineral apposition rate (MAR) was noted. These results indicate that: (1) bisphosphonate dosages used in this study effectively inhibited remodeling within the dog maxilla; (2) alveolar bone remodeling was decreased more than remodeling in rib cortical bone; (3) within the dentate maxilla, alveolar bone remodeling was decreased more in the coronal than in the apical region, and (4) none of the groups appears to show inhibition of mineralization.

L'ostéoporose est la maladie métabolique la plus fréquente qui touche l'os. Plusieurs substances actives sont utilisées pour le traitement pharmacologique de cette maladie. Cependant, ce sont les bisphosphonates et surtout l'alendronate de sodium, qui sont prescrits en première intention. L'alendronate de sodium est, en effet, très efficace mais présente une faible absorption quand il est administré par la voie orale. Sa solubilité dans l'eau est de 20 mg/ml. Il présente en outre une faible biodisponibilité (de 0,6 à 0,7%). Cette substance active est aussi à l'origine d'effets indésirables d'irritation au niveau de l'oesophage, l'estomac et l'intestin. Ces effets sont dus à un contact local des cristaux de la substance active avec la muqueuse. L'approche d'encapsulation des substances actives dans des particules polymériques a permis d'obtenir plusieurs bénéfices thérapeutiques comme l'amélioration de la biodisponibilité et la diminution des effets indésirables. Dans la première partie de notre étude, on a réalisé l'encapsulation de l'alendronate dans des nanoparticules à base de poly-epsilon-caprolactone en utilisant la nanoprécipitation et l'émulsion double. Les nanoparticules obtenues ont une forme sphérique et une taille comprise entre 200 et 450 nm. Le meilleur pourcentage d'encapsulation a été de 34% et il a été obtenu avec la technique d'émulsion double. Ceci confirme que cette méthode est plus adaptée à l'encapsulation des molécules hydrophiles. Le profil de libération in vitro a montré deux phases : une première phase de libération relativement rapide et une deuxième phase beaucoup plus lente. L'analyse par modélisation mathématique a montré que la libération in vitro de l'alendronate se fait par diffusion et relâchement des chaines polymériques / Osteoporosis is the most frequent metabolic disease that affects bone. Many actives have been used as pharmacological treatment of this disease. However, bisphosphonates, especially, alendronate sodium, are indicated as first line regimen. Alendronate is highly efficient but presents low absorption after oral administration. Its solubility in water is 20 mg/ml. It has also poor bioavailability (0.6-0.7%). In addition, this active could lead to many side effects, which are mainly related to the esophagus, the stomach and the intestine. Such effects are linked to a local contact of drug crystals with the mucosa. Encapsulation of active molecules allowed the obtaining of many advantages over conventional pharmaceutical forms such as, bioavailability and tolerance enhancement. In the first part of our study, we managed to encapsulate alendronate sodium in poly-epsilon-caprolactone nanoparticles via two techniques: nanoprecipitation and double emulsion. Obtained nanoparticles presented a spherical form. Their size ranged between 200 and 450 nm. The highest encapsulation efficiency value was 34% and was obtained via double emulsion technique. This confirms that double emulsion is more suitable for hydrophilic drugs encapsulation. In vitro release profile showed two phases: first phase of burst release and a second more prolonged phase. Mathematical modeling showed that alendronate in vitro release occurs by drug diffusion and polymer chain relaxation. In the second experimental part, we managed to find a more interesting alternative. In fact, we opted for the use of chitosan which is a natural hydrophilic polymer. One of the obtained advantages is the avoidance of organic solvents use. In addition, this approach allowed the enhancement of encapsulation efficiency as this value increased to 70%. The used technique is ionic gelation. It is a simple encapsulation technique that is based on the transformation of a dissolved polymer to a gel-like state

Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.