Ce travail de thèse reposait sur l’hypothèse que la variabilité génétique des protéines « cibles » des médicaments immunosuppresseurs de la famille des inhibiteurs de la calcineurine (ICN ; ciclosporine et tacrolimus) pourrait expliquer une partie de la variabilité observée dans leur efficacité et toxicité. Une revue de la littérature nous a permis de lister un panel de variants génétiques au sein de la voie de la calcineurine, considérés comme étant de bons candidats pour des études en transplantation. Ces variants n’ont pas été associés au risque de rejet aigu ou d’infection grave dans une étude incluant 381 patients transplantés rénaux suivis durant un an après la transplantation. La variabilité pharmacodynamique des ICN a ensuite été explorée au travers des régulations épigénétiques. Une analyse de la méthylation de l’ADN après exposition médicamenteuse a été menée sur deux modèles. Premièrement, la lignée cellulaire JURKAT a été utilisée pour développer la méthode d’immunoprécipitation de l’ADN méthylé (MeDIP). Chez des souris traitées par ciclosporine et tacrolimus durant 3 mois, nous avons ensuite isolé les cellules cibles des médicaments, les lymphocytes T CD4 puis, après immunoprécipitation de l’ADN méthylé et analyse par séquençage pangénomique haut débit (MeDIP-seq, séquençeur Ion Proton), nous avons recherché les régions du génome présentant des différences de méthylation induites par le traitement. L’analyse différentielle bio-informatique a été menée à l’aide des outils SAMtools (Li et col., 2009), BEDtools (Quinlan and Hall, 2010), MACS2 (Zhang et col., 2008) et Diffbind (Stark and Brown, 2011 - Bioconductor). Sur l’ensemble du génome, nous n’avons identifié que 24 régions présentant un niveau de méthylation modifié par l’exposition au tacrolimus. Le promoteur du gène Calm2, codant pour l’isoforme 2 de la calmoduline, semble être davantage méthylé chez les souris traitées. Ces résultats préliminaires semblent prometteurs pour la découverte de biomarqueurs épigénétiques de la réponse thérapeutique aux immunosuppresseurs. / Inter-individual genetic variation might account for diverse efficacy and toxicity of calcineurin inhibitors (cyclosporin and tacrolimus). In particular, some variants located within genes coding for proteins of the calcineurin pathway can explain part of this variability. In this manuscript, a panel of candidate genes was selected based on bibliographic review and tested in a pharmacogenetics study encompassing 381 renal transplants followed for one year after surgery. None of these candidates was associated with the acute rejection or serious infection risks. Furthermore, the pharmacodynamic variability of these drugs was also investigated, exploring the use of epigenomics profiling as proximal readout of the calcineurin inhibition treatment. In particular, we investigated the impact of drug exposure on DNA methylation in two experimental models. Methylated DNA immunoprecipitation followed by high-throughput sequencing (MeDIP-seq, Ion Proton technology) was deployed in JURKAT cell line, used as in vitro model, and in CD4 T lymphocytes isolated from mice treated with either cyclosporin or tacrolimus for three months. After sequencing, the differentiated methylated regions caused by drug exposure were analyzed. Bioinformatics analyses were performed using SAMtools (Li et al., 2009), BEDtools (Quinlan and Hall, 2010), MACS2 (Zhang et al., 2008) and Diffbind (Stark and Brown, 2011 - Bioconductor). Overall, the genome-wide analysis revealed only 24 regions with a differentiated enrichment in DNA methylation after three month-tacrolimus treatment, indicating a targeted effect of these treatments on a subset of key genes. Of note, CALM2 promoter, coding for the calmodulin isoform 2 protein, showed significant hypermethylation in tacrolimus-treated mice. These preliminary results corroborate the interest in using DNA methylation as promising approach to identify candidate biomarkers for therapeutic drug monitoring in calcineurin inhibitor treatments.

La réparation nerveuse périphérique constitue un véritable défi pour le chirurgien. En effet, les lésions nerveuses sont fréquentes et graves, avec une récupération fonctionnelle incomplète et un coût induit au niveau professionnel. Malgré des progrès dans le délai de prise en charge et dans la qualité du geste technique chirurgical, les résultats ne se sont pas améliorés depuis une vingtaine d’années. Devant ces limites du traitement chirurgical, une approche biologique s’est progressivement imposée avec la recherche de molécules neurotrophiques capables d’améliorer la croissance axonale et de limiter la perte neuronale.Initialement, nous nous sommes intéressés au FK506 (Tacrolimus), qui est un immunosuppresseur dont les propriétés neurotrophiques ont été décrites au niveau du système nerveux périphérique, avec l’objectif de réaliser un essai clinique. Cependant cette molécule présente de nombreux effets secondaires dont la balance bénéfice/risque est discutable dans cette indication. Par conséquent notre intérêt s’est porté sur la vitamine D dont les propriétés neuroprotectrices ont largement été étudiées au niveau du système nerveux central.Au cours de cette thèse, nous avons eu pour objectifs: 1. d’évaluer le potentiel thérapeutique de la Vitamine D dans la repousse nerveuse périphérique au travers d’une étude comparative avec le FK506 ;2. de déterminer la molécule de calciférol la plus efficace - ergocalciférol (vitamine D2) versus cholécalciférol (vitamine D3) - et la posologie optimale ;3. d’analyser les mécanismes moléculaires d’action de la vitamine D au niveau des cellules de Schwann et des motoneurones.Dans notre première étude (Chabas et al, 2008), nous avons confirmé que le FK506 favorisait une récupération fonctionnelle précoce et améliorait la récupération de la métabosensibilité. Par ailleurs, dans notre deuxième étude (Chabas et al, 2009), nous avons montré, pour la première fois, les effets neurotrophiques de la vitamine D2 dans la repousse nerveuse périphérique. De même, au travers d’une étude pharmacologique, nous avons mis en évidence que la vitamine D3 à la posologie de 500 UI/Kg/jour constituait la molécule et la posologie les plus efficaces dans la régénération nerveuse périphérique. Enfin, l’étude transcriptionnelle des mécanismes moléculaires retrouve une régulation des gènes intervenant dans l’axogénèse et la myélinisation.Tous ces résultats nous confortent dans notre volonté de réaliser un essai clinique randomisé, en double aveugle, avec bénéfice individuel direct, utilisant la vitamine D3 (Uvedose®) dans les plaies nerveuses du membre supérieur. / Nerve repair remains a challenge for surgeons who have to face unpredictable and very often disappointing outcomes. These suboptimal results have prompted researches on molecules that support cell survival and stimulate axonal outgrowth.For this research project, we chose to compare two AFSSAPS-approved compounds which display a have well documented immunomodulatory role and are suspected to act, within the nervous system, as neuroprotective and neuroregenerative molecules. On the one hand, we elected FK506 (Tacrolimus) that promotes nerve regeneration in addition to its immunosuppressant properties. However this molecule may induce critical side effects. On the other hand, we opted for vitamin D whose neuroprotective and neurotrophic actions are increasingly recognized.The aims of the research project were to:1. assess the potential therapeutic benefit of vitamin D on peripheral nerve regeneration and compare its efficiency to FK506;2. compare the efficiency of two doses (100 and 500 IU/kg/d) of the two main forms of vitamin D: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol);3. get an insight on the molecular mechanisms underlying the role of vitamin D3.In a first study (Chabas et al, 2009), we observed that FK506 significantly increased the diameter of regenerated axons in the distal portion of the graft and potentiates metabosensitive nerve fiber regeneration.In a second study (Chabas et al, 2008), we observed that vitamin D2 potentiates axon regeneration in the peripheral nervous system.In a third study, we observed that vitamin D3 is more efficient than vitamin D2 and, when delivered at high dose (500 IU/kg/day), cholecalciferol induces a dramatic locomotor and electrophysiological recovery and increases the number of preserved or newly formed axons in the proximal end and neurite myelination in both the distal and proximal ends. Using cDNA microarrays, we also performed an in vitro study on vitamin D-treated Schwann cells or dorsal root ganglia and observed that vitamin D3 triggers the expression of several genes involved in axogenesis and myelination.Altogether, these data indicate that vitamin D3 is a potent neurotrophic and myelinating agent that can be tested in phase I clinical trials for nerve repair.

Background: Arterial allografts are used as vascular conduits in the treatment of prosthetic graft infection. Immunosuppression decreases their rupture risk rate. However, immunosuppression can be unprofitable in florid infection. Previously, we confirmed inhibition of cell-mediated destruction of rat aortic grafts by delayed use of tacrolimus. In this work, we studied the influence of this protocol on the antibody-mediated rejection.

La prédiction du devenir du greffon et de sa survie permettrait d’optimiser la prise en charge des patients transplantés. Le suivi des patients transplantés rénaux inclue des mesures répétées de marqueurs longitudinaux tels que la créatinine sérique et l’exposition aux médicaments immunosuppresseurs. L’approche statistique récemment proposée des modèles conjoints permet d’analyser la relation entre un processus longitudinal et la survenue d’un événement clinique. Dans la première partie de ce travail de thèse, nous avons utilisé les modèles conjoints à classes latentes pour étudier l’impact du profil de créatinine sérique au cours des 18 premiers mois post-greffe sur la survie du greffon à long terme. Dans la cohorte étudiée, trois groupes homogènes caractérisés par une trajectoire spécifique de l’évolution de la créatinine sérique en fonction du temps et un risque d’échec de greffe spécifique ont été identifiés. Les probabilités individuelles de l’échec de greffe pendant les 10 premières années post-transplantation ont été calculées sur la base du modèle conjoint développé. Chez les patients qui n’avaient pas développé d’anticorps anti-HLA spécifiques du donneur, le risque d’échec de greffe en fonction du temps était prédit avec un niveau de performance satisfaisant en termes de spécificité, sensibilité et précision.L’utilité clinique de cet outil devra être évaluée avec une approche dynamique. Dans une seconde partie, les modèles non linéaires à effets mixtes combinés avec l’approche des modèles de mélange a été utilisée pour analyser (i) l’association entre la variabilité de l’exposition au tacrolimus au cours du temps et l’adhésion au traitement rapportée par le patient et (ii) l’impact de cette variabilité d’exposition sur le risque de rejet aigu. Ce modèle a montré un effet significatif de la variabilité de l’exposition au cours du temps du tacrolimus sur la survenu de rejet aigu au-delà de 3 mois post-transplantation. Au contraire, aucune association entre l’adhésion et la variabilité de l’exposition au tacrolimus d’une part, et le risque de rejet aigu d’autre part n’a été observée dans cette étude qui n’incluait que des patients modérément non-adhérents. Ce résultat pose la question de l’impact d’une non adhésion modérée sur le devenir du greffon. / Prediction of graft outcome would be useful to optimize patient care. Follow-up of kidneytransplant patients include repeated measurements of longitudinal markers, such as serum creatinine and immunosuppressive drug exposure. Recently proposed joint models areappropriate to analyze relationship between longitudinal processes and time-to-event data. In the first part of present work, we used the approach of joint latent class mixed models tostudy the impact of time-profiles of serum creatinine collected within the first 18 months after kidney transplantation on long-term graft survival. The studied cohort was parted into three homogenous classes with a specific time-evolution of serum creatinine and a specific risk of graft failure. The individual predicted probabilities of graft failure up to 10 years posttransplantation, calculated from this joint model were satisfying in terms of sensitivity, specificity and overall accuracy, for patients who had not developed de novo donor specificanti-HLA antibodies. The clinical usefulness of developed predictive tooI needs to beevaluated with a dynamic approach. In the second part, non-linear mixed effects models witha mixture of distribution for random effects were used to investigate (i) the associationbetween variability over time of tacrolimus exposure and self-reported drug adherence and(ii) the impact of this variability on the acute rejection risk. This model found a significantimpact of tacrolimus time-exposure variability on acute rejection onset beyond 3 months posttransplantation. On the contrary, no association between adherence and (i) variability oftacrolimus time-exposure and (ii) acute rejection was observed in our study which included moderate non-adherent patients only. This result questions the impact of moderate nonadherence on graft outcome.

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Submitted by JÚLIO HEBER SILVA (julioheber@yahoo.com.br) on 2017-06-28T18:31:50Z No. of bitstreams: 2 Dissertação - Lígia Marquez Andrade - 2014.pdf: 2192489 bytes, checksum: 4e087a9c020f51aff171c3730746c30d (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Cláudia Bueno (claudiamoura18@gmail.com) on 2017-07-07T18:14:31Z (GMT) No. of bitstreams: 2 Dissertação - Lígia Marquez Andrade - 2014.pdf: 2192489 bytes, checksum: 4e087a9c020f51aff171c3730746c30d (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-07-07T18:14:31Z (GMT). No. of bitstreams: 2 Dissertação - Lígia Marquez Andrade - 2014.pdf: 2192489 bytes, checksum: 4e087a9c020f51aff171c3730746c30d (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2014-02-26 / The use of topical medications, such as clobetasol propionate (CLO) and tacrolimus (TAC) is the main treatment for inflammatory skin diseases including discoid lupus erythematosus (DLE). The DLE is a chronic disease that affects the skin and its treatment can be improved with the simultaneous use of these drugs. However, this condition is difficult to treat topically because of the thickening of the stratum corneum (SC). New formulations such as lipid nanoparticles and the use of permeation enhancers can improve drug penetration in the skin and improve the topical treatment of different pathologies. Therefore, the aim of this study was to develop and characterize nanostructured lipid carriers (NLC) containing TAC and CLO and NLC coated or not with chitosan oligosaccharide (CO), in order to increase the skin permeation and retention of drugs. NLCs were prepared by the dilution of the microemulsion and were subsequently coated with OQ. The carriers obtained contained both drugs or TAC or CLO separately. The formulations obtained were evaluated for average diameter and polydispersity index (PDI), zeta potential, drug recovery (DR), encapsulation efficiency (EE) and drug loading (DL). The drug penetration from the NLC was assessed in pig ear skin in Franz cells. Co-encapsulated NLCs showed an average diameter of 143.3 nm and PdI of 0.264. The particles showed negative zeta potential of about -40 mV. After coating with OQ, NLCs showed a significant increase in diameter (311.9 nm) (p <0.05) and positive zeta potential (24,4mV) due to the adsorption of CO on the surface of the NLC. Co-encapsulation of the drug was effective, EE was greater than 90% for both TAC and CLO. In studies of electron paramagnetic resonance (EPR) it was observed that the drugs slightly modified the dynamics of lipids in NLC on the surface of the matrix (5-DSA). There was a significant increase in the 2A// parameter, the TAC+CLO-NLC (47,1G) compared to NLCs with no drug (45,6G). When the samples were coated with CO, the lipid dynamic modified considerably. The 2A// values increased from 45.5 to 50.1 in the NLC and 46.5 to 50.7 in the TAC+CLO-NLC. The CO probably forms a frame around the nanocarriers which significantly reduces the lipids mobility. The encapsulation of the drugs increased penetration of both TAC and CLO to the skin layers when compared to non-encapsulated drugs. The NLC coated increased the amount of TAC retained in the deeper layers of the skin (approximately 1.8 times more drug). For the CLO, the coating favored retention in the EC (1.7 fold) and on the remaining skin (3 times more drug) as compared to uncoated particles. When co-encapsulated with TAC and CLO, TAC’s penetration was superior compared with the particle containing only TAC. Thus, this strategy has shown to be promising to increase TAC’s skin penetration , which is a drug that hardly passes through the SC and promote greater retention of CLO in the upper layers of the skin. The results suggest that the co-encapsulated system is a potential formulation for skin drug delivery of the drugs. / O uso de medicamentos tópicos, como o propionato de clobetasol (CLO) e o tacrolimus (TAC), são o principal tratamento para doenças inflamatórias da pele incluindo o lúpus eritematoso discóide (LED). O LED é uma doença crônica que acomete a pele e pode ter seu tratamento melhorado com o uso simultâneo desses fármacos. Entretanto, essa condição é difícil de ser tratada topicamente devido ao espessamento do estrato córneo (EC). Novas formulações como nanopartículas lipídicas e a utilização de promotores da permeação, podem melhorar a penetração de fármacos na pele e aprimorar o tratamento de diferentes patologias tópicas. Sendo assim, o objetivo deste trabalho foi desenvolver e caracterizar carreadores lipídicos nanoestruturados (CLN) contendo TAC e CLO revestidos ou não com oligossacarídeo de quitosana (OQ), visando aumentar a permeação e retenção cutânea dos fármacos. Os CLN foram preparados pelo método de diluição da microemulsão e posteriormente foram revestidos com OQ. Foram obtidos carreadores contendo ambos os fármacos e carreadores contendo TAC ou CLO separadamente. As formulações obtidas foram avaliadas quanto ao diâmetro médio, índice de polidispersão (PdI), potencial zeta, recuperação do fármaco (REC%), eficiência de encapsulação (EE%) e carga de fármaco (CF%). A penetração dos fármacos a partir dos CLN foi avaliada em pele de orelha de porco em células de Franz. Os CLN com dupla encapsulação apresentaram diâmetro médio e PdI de 143,3 nm e 0,264, respectivamente. As partículas apresentaram potencial zeta negativo de aproximadamente -40 mV. Após o revestimento com OQ, os CLN apresentaram aumento significativo de diâmetro (311,9 nm) (p<0,05) e potencial zeta positivo (24,4mV), devido a adsorção de OQ na superfície dos CLN. A co-encapsulação dos fármacos mostrou-se eficiente, sendo que a EE% foi maior que 90% tanto para o TAC quanto para o CLO nas formulações obtidas. Nos estudos de Ressonância paramagnética eletrônica (RPE) foi possível observar que os fármacos modificaram um pouco a dinâmica dos lipídios do CLN na superfície da matriz (5-DSA). Observou-se um aumento significativo do parâmetro 2A//, das CLN-TAC+CLO (47,1G) em comparação com os CLN sem fármaco (45,6G). Quando as amostras foram revestidas com OQ a dinâmica dos lipídios modificou consideravelmente. Os valores de 2A// aumentaram de 45,5 para 50,1 nos CLN e de 46,5 para 50,7 nos CLN-TAC+CLO. Ou seja, o OQ provavelmente forma uma estrutura em torno dos nanocarreadores que reduz significativamente a mobilidade dos lipídios. A encapsulação dos fármacos nas partículas aumentou tanto a penetração do TAC quanto do CLO nas camadas da pele quando comparado com os fármacos não encapsulados. O revestimento do CLN com OQ aumentou a quantidade de TAC retido nas camadas mais profundas da pele (aproximadamente 1,8 vezes mais fármaco). Para o CLO, o revestimento dos CLN favoreceu tanto a retenção no EC (1,7 vezes mais) quanto na pele remanescente (3 vezes mais fármaco) em comparação com as partículas sem revestimento. Ainda, quando os dois fármacos estavam combinados nos CLN, a penetração do TAC foi superior quando comparado com a partícula contendo apenas TAC. Sendo assim, esta estratégia mostrou-se promissora para aumentar a penetração cutânea de TAC, que é um fármaco que dificilmente atravessa o EC e promover maior retenção de CLO nas camadas superficiais da pele. Os resultados sugerem que estes sistemas com dupla encapsulação podem apresentar potenciais benefícios para o tratamento de patologias cutâneas como o LED.

Made available in DSpace on 2016-07-18T17:53:17Z (GMT). No. of bitstreams: 1 luis felipe zulim.pdf: 1410755 bytes, checksum: 10cd9caab094cc2991e4233b68367a1f (MD5) Previous issue date: 2016-05-05 / This study aimed to compare the efficacy of tacrolimus 0.03% eye drops diluted in two types of vehicle, flaxseed oil and olive oil in the treatment of keratoconjunctivitis sicca (CCS) in dogs. 60 dogs were used, twenty healthy dogs as a negative control group and 40 dogs diagnosed with bilateral CCS that were randomly divided into two groups, tacrolimus in olive oil (TO) and tacrolimus in flaxseed oil (TL). The dogs were evaluated monthly with ophthalmologic exams, Tear Test Schirmer (TLS), Break Test Tear Film (TRFL), Fluorescein test (TF), Test of Rose Bengal (TRB) and conjunctival cytology and at the beginning and end of the study with histopathological examination of the conjunctiva .In both groups, clinical signs, TLS, TRFL, TF and TRB showed significant improvement with one month of treatment. At study end in cytological and histopathologic evaluation, both groups showed a decrease of neutrophils, it is more significant in the TL group, and both groups showed an increase of goblet cells. Thus we can conclude that the drops of tacrolimus 0.03% diluted in olive oil and flaxseed oil was effective in the treatment of CCS and the TL group performed better as the decrease in neutrophils. Thus, the linseed oil may be a new alternative as the tacrolimus diluent. / O presente estudo teve como objetivo comparar a eficácia do colírio de tacrolimus 0,03% diluído em dois tipos de veículo, óleo de semente de linhaça e óleo de oliva, no tratamento de ceratoconjuntivite seca (CCS) em cães. Foram utilizados 60 cães, sendo vinte cães saudáveis como grupo controle negativo e 40 cães diagnosticados com CCS bilateral que foram alocados aleatoriamente em dois grupos, tacrolimus em óleo de oliva (TO) e tacrolimus em óleo de semente de linhaça (TL). Os cães foram avaliados mensalmente com exames oftálmicos, Teste Lacrimal de Schirmer (TLS), Teste de Ruptura do Filme Lacrimal (TRFL), Teste de Fluoresceína (TF), Teste de Rosa Bengala (TRB) e citologia conjuntival e no início e final do estudo com exame histopatológico de conjuntiva .Em ambos os grupos, os sinais clínicos, o TLS, TRFL, TF e TRB apresentaram melhora significativa com um mês de tratamento. Ao término do estudo na avaliação citológica e histopatológica, ambos os grupos apresentaram diminuição de neutrófilos, sendo ela mais significativa no grupo TL, e ambos grupos apresentaram aumento de células caliciformes. Desta forma podemos concluir que o colírio de tacrolimus 0,03% diluído em óleo de oliva e em óleo de semente de linhaça foi eficiente no tratamento de CCS e o grupo TL apresentou melhor desempenho quanto a diminuição de neutrófilos. Assim, o óleo de semente de linhaça pode ser uma nova alternativa como diluente do tacrolimus.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Este estudo teve como objetivos avaliar a ocorrência de crescimento gengival derivado da administração de duas drogas imunossupressoras ciclosporina-A (CsA) e tacrolimus, em indivíduos transplantados renais, e verificar as possíveis alterações dos parâmetros clínicos periodontais (IP, JEC-MG, PCS, NCI e SS) após o início da terapia imunossupressora. Foram avaliados dois grupos: grupo CsA que consistiu de 20 indivíduos que receberam o protocolo de imunossupressão composto por ciclosporina-A e o grupo tacrolimus que consistiu de 20 indivíduos que receberam tacrolimus. Ambos os grupos foram avaliados em três momentos: momento prétransplante , 30 dias após o transplante renal (momento 30 dias) e 90 dias após o transplante renal (momento 90 dias). Em todas as avaliações foram registrados os seguintes parâmetros clínicos: distância da junção esmalte-cemento à margem gengival (JEC-MG), profundidade clínica de sondagem (PCS), nível clínico de inserção (NCI), sangramento à sondagem (SS), índice de placa (IP) e índice de crescimento gengival (ICG). Foi observada redução significante do IP, em ambos os grupos, entre o momento pré-transplante e o momento 90 dias, mas não houve diferença significante entre os grupos nos três momentos avaliados. Com relação ao SS, foi observado no grupo tacrolimus uma redução significante entre o momento pré-transplante e o momento 30 dias (p=0,001) e entre o momento pré-transplante e o momento 90 dias (p<0,001). Também não houve diferença significante entre os grupos nos momentos avaliados. Não foi encontrada diferença significante entre os grupos com relação à JEC-MG e PCS nos três momentos. Quanto ao NCI, houve diferença significante entre os momentos pré-transplante e 30 dias (p=0,015), e entre os momentos pré-transplante e 90 dias (p=0,03), independentemente do grupo. Com relação ao ICG, foi observado no grupo CsA diferença significante entre os momentos pré-transplante e 30 dias (p<0,001), pré-transplante e 90 dias (p<0,001) e entre 30 dias e 90 dias. No grupo tacrolimus, foi observada diferença significativa no ICG entre os momentos pré-transplante e 90 dias (p=0,007) e entre 30 dias e 90 dias (p=0,007). Ainda com relação ao ICG, o grupo ciclosporina-A sempre apresentou médias superiores ao grupo tacrolimus e essa diferença foi significativa nos momentos 30 dias (p=0,03) e 90 dias (p=0,014). Os autores concluíram que ambos os grupos apresentaram crescimento gengival após 90 dias de terapia imunossupressora. Entretanto, a média do índice de crescimento gengival do grupo CsA foi significantemente maior que a média do grupo tacrolimus após 30 dias e 90 dias. Além disso, os parâmetros clínicos periodontais IP, SS, JEC-MG, PCS e NCI não apresentaram diferenças significativas entre os grupos durante o estudo. / The purpose of this study was to evaluate the occurrence of gingival overgrowth induced by cyclosporin-A (CyA) and tacrolimus, in kidney transplant patients, and to verify the possible changes of the periodontal parameters (plaque index, bleeding on probing, distance of the enamel-cement junction to gingival margin, probing depth and clinical attachment level) after the beginning of the immunosuppressant therapy. Two groups were evaluated: group CyA that consisted of 20 individuals who received CyA and the group tacrolimus that consisted of 20 individuals who received tacrolimus. Both groups were evaluated at three moments: pre-transplant moment, 30 days after the kidney transplant (30 days moment) and 90 days after the kidney transplant (90 days moment). In all these evaluations we registered the following parameters: plaque index (PI), bleeding on probing (SS), distance of enamel-cement junction to gingival margin (JEC-MG), probing depth (PD), clinical attachment level (CAL) and gingival overgrowth index (GO). It was observed a significant reduction of the PI in both groups, between the pre-transplant moment and the 90 days moment, but it was not observed any significant difference between the groups in the three evaluated moments. A significant reduction was found in the SS between the pretransplant moment and the 30 days moment (p=0,001), and between the pretransplant moment and the 90 days moment (p<0,001) for the group tacrolimus. Again it was not found any significant difference between the groups in the evaluated moments. It was not found any significant difference between the groups in the three moments of the study when the JEC-MG and PD were compared. About the CAL, it was found a significant difference between the pre-transplant moment and the 30 days moment, and between the pre-transplant moment and the 90 days moment, independently of the group compared. When we evaluated the GO in the CyA group we found a significant difference between the pre-transplant moment and 30 days moment (p<0,001), the pre-transplant moment and the 90 days moment (p<0,001) and between the 30 days moment and the 90 days moment. In the group tacrolimus, it was observed a significant difference in the GO between the pre-transplant moment and the 90 days moment (p=0,007) and between the 30 days moment and the 90 days moment (p=0,007). The group CyA always presented superior GO mean scores when compared to the group tacrolimus and this difference was significant at the 30 days moment (p=0,03) and 90 days moment (p=0,014). The authors concluded that both groups presented gingival overgrowth after 90 days of immunosuppressant therapy. However, the mean GO scores of the group CyA was significantly higher than the mean of the group tacrolimus after 30 days and 90 days. Moreover, periodontal clinical parameters PI, SS, JEC-MG, PD and CAL did not present significant differences between the groups during the study.

O crescimento gengival é um efeito colateral comum nos indivíduos que recebem transplante de órgão e estão sob terapia imunossupressora. O objetivo deste estudo foi avaliar prospectivamente a ocorrência e severidade do crescimento gengival induzido pelo tacrolimus ou ciclosporina-A, na ausência de bloqueadores de canais de cálcio em indivíduos transplantados renais. Participaram do estudo 64 indivíduos que passaram por cirurgia de transplante e receberam ciclosporina (n=33) ou tacrolimus (n=31) como droga imunossupressora principal. Eles foram avaliados em 5 momentos: pré-transplante, 1, 3, 6 e 12 meses após transplante. Em todas as avaliações foram coletados dados demográficos e parâmetros clínicos periodontais (distância da margem gengival à junção cemento-esmalte, profundidade clínica de sondagem, nível clínico de inserção, índice de placa, sangramento à sondagem, e crescimento gengival). O valor médio de crescimento gengival no grupo ciclosporina foi maior que no grupo tacrolimus após 1 (p=0,04), 3 (p=0,001), 6 (p=0,007) e 12 meses (p=0,001). O crescimento gengival clinicamente significante foi observado em 30,3% (10 sujeitos) no grupo ciclosporina e 12,9% (4 sujeitos) no grupo tacrolimus após o período de 12 meses. Porém, essa diferença não foi estatisticamente significante (p=0,56). Concluímos que apesar de não ter sido encontrada diferença significante na ocorrência de crescimento gengival clinicamente significante, a severidade no grupo ciclosporina foi maior que no grupo tacrolimus após 12 meses de terapia imunossupressora. / Gingival overgrowth (GO) is a common side effect in recipients of organ transplants that are under immunosuppressive therapy. The aim of this study was to assess prospectively the occurrence and severity of gingival overgrowth induced by tacrolimus (Tcr) or ciclosporin A (CiA), in the absence of calcium channel blockers, in renal transplant patients. Sixty-four individuals undergoing transplantation received as the main immunosuppressant CiA (n=33) or Tcr (n=31). They were assessed at five time intervals: pre-transplant, 1, 3, 6, and 12 months after transplant. Demographic data and periodontal clinical parameters (cement-enamel junction to the gingival margin, probing depth, clinical attachment level, plaque index, bleeding on probing, and GO) were measured at all time intervals. The mean GO scores in CiA group were higher than Tcr group after 1 (p=0.04), 3 (p=0.001), 6 (p=0.007) and 12 months (p=0.001). A clinically significant GO was observed in 30.3% (10 subjects) in CiA group, and 12.9% (4 subjects) in Tcr group after 12 months. However, this difference was not significant (p=0.56). Although there was no significant difference in the occurrence of clinically significant GO, the severity in CiA group was higher than in Tcr group after 12 months of immunosuppressive therapy.