Drug repositioning can save considerable time and resources and significantly speed up the drug development process. The increasing availability of drug action and disease-associated transcriptome data makes it an attractive source for repositioning studies. Here, we have developed a transcriptome-guided approach for drug/biologics repositioning based on multi-layer self-organizing maps (ml-SOM). It allows for analyzing multiple transcriptome datasets by segmenting them into layers of drug action- and disease-associated transcriptome data. A comparison of expression changes in clusters of functionally related genes across the layers identifies “drug target” spots in disease layers and evaluates the repositioning possibility of a drug. The repositioning potential for two approved biologics drugs (infliximab and brodalumab) confirmed the drugs’ action for approved diseases (ulcerative colitis and Crohn’s disease for infliximab and psoriasis for brodalumab). We showed the potential efficacy of infliximab for the treatment of sarcoidosis, but not chronic obstructive pulmonary disease (COPD). Brodalumab failed to affect dysregulated functional gene clusters in Crohn’s disease (CD) and systemic juvenile idiopathic arthritis (SJIA), clearly indicating that it may not be effective in the treatment of these diseases. In conclusion, ml-SOM offers a novel approach for transcriptome-guided drug repositioning that could be particularly useful for biologics drugs.

No description available.

[pt] O Brasil ao longo dos últimos anos passou por uma transformação econômica que possibilitou milhões de pessoas de menor renda a elevarem seu patamar de consumo. Diante de tal fenômeno, empresas tiveram que repensar seus modelos de negócio tradicionais e se reposicionar, pois já não bastava produzir algo a um preço mais acessível; era necessário investir em qualidade e inovação para conquistar esse consumidor emergente. A marca, portanto, passa a ser um bem de significativo valor para empresas interessadas em vender a esse mercado, visto que consumidores de baixa renda a usam como um elemento de pertencimento e distinção social. No entanto, poucas empresas efetivamente realizam reposicionamentos com esse objetivo. O presente estudo apresenta um estudo de caso de reposicionamento de uma marca centenária líder em seu segmento de origem para o mercado de lentes oftálmicas cujo propósito era conquistar o consumidor de baixa renda no Brasil. Para isso, foram realizadas entrevistas em profundidade com funcionários da empresa diretamente envolvidos nesse processo. Na análise, foi possível entender as principais adaptações de marketing que a empresa adotou para vender ao mercado em questão. Conclui-se, então, que empresas que pretendem inserir-se com sucesso nesse mercado devem, em primeiro lugar, entender a heterogeneidade desse grupo de consumidores e planejar de maneira cuidadosa suas estratégias mercadológicas, alterando um ou vários componentes do composto de marketing. É fundamental, sobretudo, que tais mudanças sigam além do discurso e que na prática toda a organização possa estar comprometida com as modificações nos processos da empresa. / [en] Brazil has undergone an economic transformation that has enabled millions of low income people to raise their level of consumption over the past few years. Faced with this phenomenon, companies have had to rethink their traditional business models and reposition themselves because it was not enough to produce something at a more affordable price; it was necessary to invest on quality and innovation to conquer this consumer. Thus, the brand becomes a significant value business asset for companies interested in selling to this new market, as low-income consumers use it as an element of belonging and social distinction. Nevertheless, few companies actually do repositioning for this purpose. This paper presents a study of a repositioning case concerning a century-old brand, leader in its source segment, of ophthalmic lenses market whose purpose was to conquer the low-income consumers in Brazil. For this, in-depth interviews were conducted with employees directly involved in this process. In the analysis, it was possible to understand the main marketing adaptations that the company has taken to sell to the market in question. It follows, then, that companies seeking to insert themselves successfully in this market must first understand the heterogeneity of this group of consumers and plan carefully your marketing strategies by changing one or more components of the marketing mix. It is essential, in particular, that such changes follow beyond discourse and in practice throughout the organization compromise with the changes in business processes.

This research attempts to evaluate temporary urban regeneration potential by integrating two systems that make up an interim intervention which addresses an observed problem. The research proposes a systematic approach for a multi-system life cycle assessment model which lays out the process of working with two separate systems to provide a pathway for temporary urban development strategies. To achieve this, the research starts with identifying parameters of temporary urban regeneration through a systematic review of the literature. Key parameters are categorized based on objectives, indicators, as well as, physical characteristics of the literature explored case studies. Then, the findings are utilized to guide the proposed model of connecting two given systems to assess their joint impacts on a temporary urban regeneration system. The proposed MSLCA framework utilizes a holistic modeling structure with a process to integrate and analyze separate systems and quantify results for overall sustainability performance. Finally, the model is used to evaluate a case study involving two systems that address observed problems and provide urban services. The results explore the environmental impacts of the proposed intervention and highlight the effects of individual components on both systems. Through the implementation of the model, decisions on temporary urban intervention are guided by hotspots in the results. The findings reveal an opportunity for future research to expand the model's application to other processes and further its scope beyond environmental indicators. Subsequent studies can investigate opportunities for a holistic approach that includes economic and social aspects. / Doctor of Philosophy / The way we live in cities is heavily influenced by how they are planned. Improvident city planning could deny residents opportunities to enjoy some basic urban amenities. These problems could be self-induced as they are often a result of planning, policies, or personal habits and choice. Planners, urban designers, and regulators are constantly experimenting with different tools of urban regeneration to rediscover genuine urban experiences. This research sets out to investigate opportunities for temporary urban interventions on vacant lands in the city of Riyadh through repurposing idle shipping containers as a tool. This is to address the issues of a lack of urban services within residential subdivisions in the city, the high prevalence of vacant lands, and a wide availability of decommissioned shipping containers. The use of shipping containers for non-cargo purposes has seen an increased interest among architects and designers for their versatility and accessibility. Empty container accumulation is often a result of an unbalanced trading system which is mainly an issue of import-based countries. Therefore, the upcycling potential of intermodal containers can extend their life cycles and take advantage of their structure. It also maximizes the environmental returns of their raw materials. Through such processes of circular economy, potential waste objects can be repurposed as resources into usable structures and thus avoids the use and extraction of new raw materials. It is generally thought that the repurposing of shipping containers into building structures introduces environmental advantages when compared to traditional construction. Similarly, vacant lands are a valuable and well-established resource that can provide the setting for temporary urban interventions. Finding a joint productive use of these systems is at the center of this research as it attempts to assess the urban regeneration value of their merged utility during their idle stage. This helps address a key challenge that most urban area suffers from which is the lack of easily accessible and timely deployable temporary urban intervention to serve a particular use. This research aims to create a model that evaluates the lifecycles of temporary uses based on the joint intersection of contributing systems. The proposed Multi-System Life Cycle Assessment (MSLCA) model is to be applied to assess temporary urban regeneration interventions and help make decisions regarding appropriate approaches. The goal of the model is to propose a value-based approach based on characteristics from two systems. The resulting MSLCA model answers questions on how to apply LCA processes to a transitional intervention with new processes. In doing so, it highlights parameters for systems integration and processes for planning appropriate scenarios for urban interventions. It also highlights the need for unique system boundaries and specifies approaches for system assessment and interpretation. Finally, it provides broader impact categories beyond environmental impacts to consider specific economic and social indicators.

Introduction : Plusieurs effets secondaires sont associés au traitement de l’apnée obstructive du sommeil (AOS) par appareil d’avancement mandibulaire (AAM). Pour minimiser leur occurrence, plusieurs professionnels préconisent l’utilisation d’une attelle de repositionnement matinal (ARM) malgré le manque d’évidences valides soutenant cette approche. Objectifs : L’objectif principal de cette étude pilote randomisée contrôlée est d’évaluer l’utilisation d’une ARM comme moyen d’atténuer les effets secondaires à court terme associés au traitement par AAM. Méthode : 9 sujets souffrant d’AOS nécessitant un traitement par AAM ont été inclus et assignés aléatoirement au groupe témoin (n=5) et au groupe traitement (n=4). Tous les participants ont été traités avec un AAM fabriqué sur mesure et ajustable (SomnoDent Flex, SomnoMed, USA). Les sujets du groupe traitement ont également reçu une qu’ils devaient porter 1 heure le matin suivant le retrait de leur AAM. La participation comprenait 6 visites échelonnées sur une période approximative de 8 mois durant lesquelles plusieurs variables ont été évaluées, notamment les changements occlusaux, les effets secondaires et l’adhérence au traitement. Résultats : Des tendances de réduction des surplombs horizontaux et verticaux, de la distance intermolaire maxillaire et de la longueur d’arcade totale supérieure ont été observées uniquement au sein du groupe témoin (p=0,063). Six mois suivant la fin de la période de titration, les problèmes masticatoires étaient plus fréquemment rapportés dans le groupe témoin. 60% des sujets traités uniquement avec un AAM en rapportaient sur une base hebdomadaire comparativement à ceux recevant conjointement une ARM, où la survenue était rare, voire absente. Conclusion : Nos résultats suggèrent que l’ajout d’une ARM pourrait être bénéfique au traitement de l’AOS par AAM en réduisant la survenue de certains effets secondaires à court terme. D’autres études bien construites sont nécessaires pour confirmer nos observations. / Introduction: There are several side-effects associated with mandibular advancement devices (MAD) used to treat obstructive sleep apnea (OSA). Despite the lack of evidence supporting their use, some providers advocate the use of morning repositioning splints (MRS) to minimize these side effects. Objectives: The main objective of this randomized controlled pilot study is to evaluate MRS-use as a means of mitigating MAD-associated short-term side-effects. Methods: 9 subjects with OSA requiring MAD-use were included in this study and were randomized into a control group (n=5) and a treatment group (n=4). All participants were treated with a customized adjustable MAD (SomnoDent Flex, SomnoMed, USA). Subjects in the treatment group also received an MRS that was to be used every morning for 1 hour after removal of their MAD. Follow-up consisted of 6 appointments over approximately 8 months. During this time, variables including occlusal changes, side effects and treatment adherence were evaluated. Results: A tendency for overjet and overbite reduction as well as maxillary intermolar distance reduction and superior arch length shortening were observed in the control group only (P=0.063). Six months after completion of MAD titration, masticatory problems were more frequently reported by subjects in the control group. 60% of these subjects reported masticatory problems on a weekly basis whereas subjects in the treatment group never or rarely reported these issues. Conclusion: Our results suggest that MRS-use can minimize short-term side effects associated with MADs used to treat OSA. Additional, well-constructed, studies are needed to confirm these findings.

A artrite reumatoide (AR) é uma doença autoimune, inflamatória, crônica, sistêmica e de etiologia desconhecida que pode ser induzida experimentalmente em animais por administração de colágeno e adjuvante (CIA). Os medicamentos biológicos contra o fator de necrose tumoral (TNF)-α são indicações terapêuticas atualmente consolidadas para os casos mais severos de AR. As limitações ao uso dessa classe de medicamentos têm sido o alto custo e a dificuldade em fabricar genéricos ou similares com composição, qualidade e desempenho equivalentes na mesma dose e via de administração. O presente estudo avaliou a hipótese de que drogas sintéticas que inibam a produção de TNF-α e / ou fatores relacionados teriam potencial para tornarem-se terapias complementares ou alternativas eficientes para esta doença. Para isso, foram utilizados ratos submetidos ao modelo CIA e tratados cronicamente com pentoxifilina (PTX), rolipram (ROL), talidomida (TAL) e rupatadina (RUP). Um tratamento com prednisolona (PRED) foi também efetuado para avaliar sua influência na eventual ação antiartrítica de PTX, ROL, TAL e RUP, de modo a mimetizar seu efeito imunossupressor, quando administrada agudamente (AG) antes de medicamentos biológicos, bem como pelo seu conhecido efeito anti-inflamatório, quando administrada cronicamente (CR) no tratamento da AR. O desenvolvimento da AR e a efetividade dessas drogas sobre a AR foram avaliadas, de forma seletiva e sequencial, por meio da detecção de eritema e cianose, bem como medidas de edema, massa corporal, hemograma, TNF-α no plasma, fator reumatoide (FR) e anticorpo antinuclear (ANA) no soro, interleucina (IL)-1β e IL-6 no soro e líquido sinovial, atividade de aminopeptidase básica (APB) na fração solúvel (FS) do tecido sinovial (TS) e de células mononucleares do sangue periférico (PBMCs), densitometria óssea e análise histológica. A hepatotoxicidade dessas drogas foi avaliada pelas medidas de alanina-transaminase (ALT) e aspartato-transaminase (AST) no plasma. A AR caracterizou-se pelo aumento de TNF-α plasmático e de IL-1β e IL-6 no líquido sinovial, alterações histológicas na articulação tíbio-tarsal, bem como edema, cianose, eritema, diminuição de linfócitos e atividade APB de FS aumentada no TS e diminuída em PBMCs. A AR aumentou ALT e AST. O tratamento com PRED crônico promoveu um efeito antiedematogênico. O coquetel (MIX de PTX+ROL+RUP+TAL) também apresentou efeito antiedematogênico. A administração concomitante de PRED AG ou PRED CR com MIX não produziu sinergismo ou potenciação do efeito antiedematogênico da administração isolada do MIX ou da PRED crônica. Além do MIX, ROL e TAL diminuíram o edema. MIX, ROL e TAL melhoraram TNF-α no plasma e APB na FS do TS e não causaram hepatotoxicidade, tal como refletido nos níveis de ALT e AST. TAL recuperou ALT e AST, sem alteração do hemograma. Uma vez que PTX e RUP não apresentaram efeito antiedematogênico, ROL e TAL foram hipotetizados como os prováveis responsáveis pela atividade antiartrítica do MIX. Então, os tratamentos com ROL, TAL e ROL+TAL foram selecionados para avaliação da histologia óssea e medidas de parâmetros diferenciais entre animais controles sadios e artríticos. Esta avaliação mostrou que o tratamento isolado da AR com ROL ou TAL não alterou IL-6, mas recuperou IL-1β no líquido sinovial, efeitos esses que não se diferenciaram do tratamento combinado de ROL+TAL, exceto pelo fato de que essa combinação também diminuiu a massa corporal. TAL se destacou por seu efeito hepatoprotetor nos animais AR. Considerando os efeitos conhecidos de RUP, PTX, TAL e ROL é possível hipotetizar que a ação antiartrítica de TAL e ROL deve-se à inibição da síntese de TNF-α decorrente da inibição de PDE4 em suas principais fontes celulares. Os dados deste estudo prospectivo fornecem subsídios adicionais que estimulam a realização de novos ensaios clínicos, mais amplos e sistematizados, sobre os efeitos antiartríticos de ROL e TAL. Conclui-se que o uso isolado de TAL emerge como uma alternativa terapêutica econômica, simples e eficaz para a AR, enquanto a combinação de ROL+TAL pode ser uma opção viável para portadores de AR com sobrepeso ou obesidade / Rheumatoid arthritis (RA) is an autoimmune, inflammatory, chronic and systemic disease with unknown etiology that can be experimentally induced in animals by administration of collagen and adjuvant (CIA). Biological drugs against tumor necrosis factor (TNF)- α are therapeutic indications currently consolidated for the most severe cases of RA. The limitations for the use of this class of drugs have been the high cost and the difficulty to manufacture a generic or similar ones with equivalent composition, quality and performance under the same dosage and route of administration. The present study evaluated the hypothesis that synthetic drugs that inhibit the production of TNF-α and/or related factors would have potential to become efficient complementary or alternative therapies for this disease. For this purpose, male rats submitted to the CIA model were chronically treated with pentoxifylline (PTX), rolipram (ROL), thalidomide (TAL) and rupatadine (RUP). The treatment with prednisolone (PRED) was also performed to evaluate its influence on the possible antiarthritic action of PTX, ROL, TAL and RUP, in order to mimic its immunosuppressive effect when acutely (AG) administered prior to biological drugs, as well as due to its known anti-inflammatory effect when administered chronically (CR) to treat RA. The development of RA and the efficacy of these drugs on RA were evaluated, by selective and sequential ways, through the detection of erythema and cyanosis, as well as measurements of edema, body mass, hemogram, plasma TNF-α, rheumatoid factor (FR) and anti-nuclear antibody (ANA) in serum, interleukin (IL)-1β and IL-6 in serum and synovial fluid, basic aminopeptidase activity (APB) in soluble fraction (FS) from synovial tissue (TS) and from peripheral blood mononuclear cells (PBMCs), bone densitometry and histological analysis. The hepatotoxicity of these drugs was evaluated by measurements of alanine-transaminase (ALT) and aspartate-transaminase (AST). RA was characterized by increased TNF-α in plasma and IL-1β and IL-6 in synovial fluid, histological alterations in the tibio-tarsal joint, as well as edema, cyanosis, erythema, decreased lymphocyte number and increased APB activity in TS and decreased APB activity in PBMCs. RA produced increased ALT and AST. As expected, the chronic treatment with PRED promoted an antiedematogenic effect. The cocktail (MIX of PTX+ROL+RUP+TAL) also presented antiedematogenic effect. Concomitant administration of acute or chronic PRED with MIX did not produce synergism or potentiation of the antiedematogenic effect due to the single administration of MIX or chronic PRED. In addition to MIX, ROL and TAL were also antiedematogenic. MIX, ROL and TAL ameliorated plasma TNF-α and APB in FS from TS without hepatotoxicity, as reflected by ALT and AST levels. TAL recovered ALT and AST, but it did not affect the hemogram. Since PTX and RUP did not present antiedematogenic effects, ROL and TAL were hypothesized as probable responsible for the antiarthritic activity of MIX. Thus, the treatments with ROL, TAL and ROL+TAL were selected for evaluation of bone histology and measurements of differential parameters between healthy control and arthritic animals. This evaluation showed that the treatment of RA with ROL or TAL alone did not alter IL-6 levels, but recovered IL-1β in the synovial fluid. Both these effects were not different from those of the concomitant treatment with ROL+TAL, except that this combination also decreases the body mass. TAL stands out for its hepatoprotective effect in RA animals. Considering the known effects of RUP, PTX, TAL and ROL it can be hypothesized that antiarthritic action of TAL and ROL is due to the inhibition of TNF-α synthesis as consequence of its inhibition in its main cellular sources by PDE4. Data from this prospective study provide additional subsidies that stimulate further and more comprehensive clinical trials on the antiarthritic effects of ROL and TAL. In conclusion, the treatment with TAL alone emerges as an economical, simple and effective therapeutical alternative for RA, while the combination of ROL+TAL can be a viable option for RA sufferers with overweight or obesity

Cette thèse de doctorat étudie trois questions de recherche en matière de marchés publics et de politique de la concurrence. Le premier chapitre se concentre sur une analyse microéconométrique des relations stratégiques entre d’une part l’entreprise choisie pour l’attribution d’un marché public et d’autre part l’autorité publique chargée de la régulation d’un service public. Il exploite des données sur le transport public urbain en France pour étudier les déterminants de choix réglementaires qui impactent à leur tour la rentabilité des opérateurs de transport. Le deuxième chapitre explore une évaluation ex-post d’une fusion qui a eu lieu entre deux grands groupes de transport en France (Veolia Transport et Transdev), en se concentrant sur l’existence éventuelle de gains d’efficacité dans les fusions. Enfin, le troisième chapitre donne un aperçu de l’impact d’une fusion lorsque les entreprises se font concurrence pour la qualité et repositionnent leurs services en analysant l’industrie hospitalière française. / This PhD dissertation studies three research questions in public procurement and competition policy presented in the respective chapters and preceded by a general introduction. The first chapter focuses on a microeconometric analysis of the strategic relationships between a firm awarded a public contract and the public authority responsible for regulating a public service. It exploits data on the French urban public transport industry to study the determinants of regulatory contract choices which in turn impact the cost efficiency of transport operators. The second chapter explores an ex-post assessment of a merger which took place between two major transport groups in France (Veolia Transport and Transdev), focusing on the possible existence of merger efficiency gains. Finally, the third chapter provides insight on the impact of merger when firms compete in quality and reposition their services by analyzing the French hospital industry.

The aim of this study is to explore and describe children’s experiences of the repositioning of their psychological birth order in a reconstituted family. The aim of this study is also to contribute to a better understanding of this phenomenon to aid the parents of these children as well as professionals working with such families. The systems theory was used as the meta-theory of this study. Gestalt field theory formed the connection between the systems theory and Adlerian theory, to portray the interaction between the individual and the different subsystems of which they are part, and formed the lens through which the study was done. Adlerian theory was used to explain the subsystems function in the micro system, with the focus on children’s experiences of the repositioning of their birth order in a reconstituted family. A qualitative research method with Interpretative Phenomenological Analysis was used as research design. Eight children took part in this study. The researcher used semi-structured interviews to explore their experiences of the repositioning of their psychological birth order and the data was analysed thematically. The researcher had a discussion with the participants’ parents to determine the children’s psychological birth order and to obtain background information regarding the original and reconstituted families. The findings indicated that children’s experiences in relation to their parents and siblings had the most profound effect on how they experienced the repositioning of their psychological birth order in a reconstituted family. It seemed that participants preferred their parents treating them congruent to their psychological birth order within the reconstituted family and they experienced incongruent treatment to their psychological birth order, as negative. Participants enjoyed being favoured by their parents. If the sibling who caused the repositioning was favoured, or his or her parents unfairly blamed the relevant participant, it contributed to tension in the sibling and child-parent relationships. Participants seemed to associate less time spent with parents as well as less attention from parents with step- and half-siblings in the reconstituted family. Participants expressed less responsibility in the reconstituted family as a favourable aspect and more responsibilities in the reconstituted family as a unfavourable aspect of being repositioned. In the participants’ experiences, which related to their siblings, the children seemed to defend their psychological positions in their renegotiation for new positions and roles in the reconstituted family often resulting in power struggles and sibling rivalry. Age and gender differences played a role in this process. When participants were ineffective in their negotiation of a new position within the new sibling subsystem, feelings of isolation were reported. Participants experienced frustration when they were unsuccessful in their negotiations regarding former roles associated with their psychological birth order in the new family system. Participants expressed companionship with a step- or half-sibling of the same gender as a favourable experience in their repositioning. The time elapsed since the reconstitution of the family, seemed to play an important role in how children experienced the repositioning of their psychological birth order. / Thesis (MA (Psychology))--North-West University, Potchefstroom Campus, 2013.

The aim of this study is to explore and describe children’s experiences of the repositioning of their psychological birth order in a reconstituted family. The aim of this study is also to contribute to a better understanding of this phenomenon to aid the parents of these children as well as professionals working with such families. The systems theory was used as the meta-theory of this study. Gestalt field theory formed the connection between the systems theory and Adlerian theory, to portray the interaction between the individual and the different subsystems of which they are part, and formed the lens through which the study was done. Adlerian theory was used to explain the subsystems function in the micro system, with the focus on children’s experiences of the repositioning of their birth order in a reconstituted family. A qualitative research method with Interpretative Phenomenological Analysis was used as research design. Eight children took part in this study. The researcher used semi-structured interviews to explore their experiences of the repositioning of their psychological birth order and the data was analysed thematically. The researcher had a discussion with the participants’ parents to determine the children’s psychological birth order and to obtain background information regarding the original and reconstituted families. The findings indicated that children’s experiences in relation to their parents and siblings had the most profound effect on how they experienced the repositioning of their psychological birth order in a reconstituted family. It seemed that participants preferred their parents treating them congruent to their psychological birth order within the reconstituted family and they experienced incongruent treatment to their psychological birth order, as negative. Participants enjoyed being favoured by their parents. If the sibling who caused the repositioning was favoured, or his or her parents unfairly blamed the relevant participant, it contributed to tension in the sibling and child-parent relationships. Participants seemed to associate less time spent with parents as well as less attention from parents with step- and half-siblings in the reconstituted family. Participants expressed less responsibility in the reconstituted family as a favourable aspect and more responsibilities in the reconstituted family as a unfavourable aspect of being repositioned. In the participants’ experiences, which related to their siblings, the children seemed to defend their psychological positions in their renegotiation for new positions and roles in the reconstituted family often resulting in power struggles and sibling rivalry. Age and gender differences played a role in this process. When participants were ineffective in their negotiation of a new position within the new sibling subsystem, feelings of isolation were reported. Participants experienced frustration when they were unsuccessful in their negotiations regarding former roles associated with their psychological birth order in the new family system. Participants expressed companionship with a step- or half-sibling of the same gender as a favourable experience in their repositioning. The time elapsed since the reconstitution of the family, seemed to play an important role in how children experienced the repositioning of their psychological birth order. / Thesis (MA (Psychology))--North-West University, Potchefstroom Campus, 2013.

A artrite reumatoide (AR) é uma doença autoimune, inflamatória, crônica, sistêmica e de etiologia desconhecida que pode ser induzida experimentalmente em animais por administração de colágeno e adjuvante (CIA). Os medicamentos biológicos contra o fator de necrose tumoral (TNF)-α são indicações terapêuticas atualmente consolidadas para os casos mais severos de AR. As limitações ao uso dessa classe de medicamentos têm sido o alto custo e a dificuldade em fabricar genéricos ou similares com composição, qualidade e desempenho equivalentes na mesma dose e via de administração. O presente estudo avaliou a hipótese de que drogas sintéticas que inibam a produção de TNF-α e / ou fatores relacionados teriam potencial para tornarem-se terapias complementares ou alternativas eficientes para esta doença. Para isso, foram utilizados ratos submetidos ao modelo CIA e tratados cronicamente com pentoxifilina (PTX), rolipram (ROL), talidomida (TAL) e rupatadina (RUP). Um tratamento com prednisolona (PRED) foi também efetuado para avaliar sua influência na eventual ação antiartrítica de PTX, ROL, TAL e RUP, de modo a mimetizar seu efeito imunossupressor, quando administrada agudamente (AG) antes de medicamentos biológicos, bem como pelo seu conhecido efeito anti-inflamatório, quando administrada cronicamente (CR) no tratamento da AR. O desenvolvimento da AR e a efetividade dessas drogas sobre a AR foram avaliadas, de forma seletiva e sequencial, por meio da detecção de eritema e cianose, bem como medidas de edema, massa corporal, hemograma, TNF-α no plasma, fator reumatoide (FR) e anticorpo antinuclear (ANA) no soro, interleucina (IL)-1β e IL-6 no soro e líquido sinovial, atividade de aminopeptidase básica (APB) na fração solúvel (FS) do tecido sinovial (TS) e de células mononucleares do sangue periférico (PBMCs), densitometria óssea e análise histológica. A hepatotoxicidade dessas drogas foi avaliada pelas medidas de alanina-transaminase (ALT) e aspartato-transaminase (AST) no plasma. A AR caracterizou-se pelo aumento de TNF-α plasmático e de IL-1β e IL-6 no líquido sinovial, alterações histológicas na articulação tíbio-tarsal, bem como edema, cianose, eritema, diminuição de linfócitos e atividade APB de FS aumentada no TS e diminuída em PBMCs. A AR aumentou ALT e AST. O tratamento com PRED crônico promoveu um efeito antiedematogênico. O coquetel (MIX de PTX+ROL+RUP+TAL) também apresentou efeito antiedematogênico. A administração concomitante de PRED AG ou PRED CR com MIX não produziu sinergismo ou potenciação do efeito antiedematogênico da administração isolada do MIX ou da PRED crônica. Além do MIX, ROL e TAL diminuíram o edema. MIX, ROL e TAL melhoraram TNF-α no plasma e APB na FS do TS e não causaram hepatotoxicidade, tal como refletido nos níveis de ALT e AST. TAL recuperou ALT e AST, sem alteração do hemograma. Uma vez que PTX e RUP não apresentaram efeito antiedematogênico, ROL e TAL foram hipotetizados como os prováveis responsáveis pela atividade antiartrítica do MIX. Então, os tratamentos com ROL, TAL e ROL+TAL foram selecionados para avaliação da histologia óssea e medidas de parâmetros diferenciais entre animais controles sadios e artríticos. Esta avaliação mostrou que o tratamento isolado da AR com ROL ou TAL não alterou IL-6, mas recuperou IL-1β no líquido sinovial, efeitos esses que não se diferenciaram do tratamento combinado de ROL+TAL, exceto pelo fato de que essa combinação também diminuiu a massa corporal. TAL se destacou por seu efeito hepatoprotetor nos animais AR. Considerando os efeitos conhecidos de RUP, PTX, TAL e ROL é possível hipotetizar que a ação antiartrítica de TAL e ROL deve-se à inibição da síntese de TNF-α decorrente da inibição de PDE4 em suas principais fontes celulares. Os dados deste estudo prospectivo fornecem subsídios adicionais que estimulam a realização de novos ensaios clínicos, mais amplos e sistematizados, sobre os efeitos antiartríticos de ROL e TAL. Conclui-se que o uso isolado de TAL emerge como uma alternativa terapêutica econômica, simples e eficaz para a AR, enquanto a combinação de ROL+TAL pode ser uma opção viável para portadores de AR com sobrepeso ou obesidade / Rheumatoid arthritis (RA) is an autoimmune, inflammatory, chronic and systemic disease with unknown etiology that can be experimentally induced in animals by administration of collagen and adjuvant (CIA). Biological drugs against tumor necrosis factor (TNF)- α are therapeutic indications currently consolidated for the most severe cases of RA. The limitations for the use of this class of drugs have been the high cost and the difficulty to manufacture a generic or similar ones with equivalent composition, quality and performance under the same dosage and route of administration. The present study evaluated the hypothesis that synthetic drugs that inhibit the production of TNF-α and/or related factors would have potential to become efficient complementary or alternative therapies for this disease. For this purpose, male rats submitted to the CIA model were chronically treated with pentoxifylline (PTX), rolipram (ROL), thalidomide (TAL) and rupatadine (RUP). The treatment with prednisolone (PRED) was also performed to evaluate its influence on the possible antiarthritic action of PTX, ROL, TAL and RUP, in order to mimic its immunosuppressive effect when acutely (AG) administered prior to biological drugs, as well as due to its known anti-inflammatory effect when administered chronically (CR) to treat RA. The development of RA and the efficacy of these drugs on RA were evaluated, by selective and sequential ways, through the detection of erythema and cyanosis, as well as measurements of edema, body mass, hemogram, plasma TNF-α, rheumatoid factor (FR) and anti-nuclear antibody (ANA) in serum, interleukin (IL)-1β and IL-6 in serum and synovial fluid, basic aminopeptidase activity (APB) in soluble fraction (FS) from synovial tissue (TS) and from peripheral blood mononuclear cells (PBMCs), bone densitometry and histological analysis. The hepatotoxicity of these drugs was evaluated by measurements of alanine-transaminase (ALT) and aspartate-transaminase (AST). RA was characterized by increased TNF-α in plasma and IL-1β and IL-6 in synovial fluid, histological alterations in the tibio-tarsal joint, as well as edema, cyanosis, erythema, decreased lymphocyte number and increased APB activity in TS and decreased APB activity in PBMCs. RA produced increased ALT and AST. As expected, the chronic treatment with PRED promoted an antiedematogenic effect. The cocktail (MIX of PTX+ROL+RUP+TAL) also presented antiedematogenic effect. Concomitant administration of acute or chronic PRED with MIX did not produce synergism or potentiation of the antiedematogenic effect due to the single administration of MIX or chronic PRED. In addition to MIX, ROL and TAL were also antiedematogenic. MIX, ROL and TAL ameliorated plasma TNF-α and APB in FS from TS without hepatotoxicity, as reflected by ALT and AST levels. TAL recovered ALT and AST, but it did not affect the hemogram. Since PTX and RUP did not present antiedematogenic effects, ROL and TAL were hypothesized as probable responsible for the antiarthritic activity of MIX. Thus, the treatments with ROL, TAL and ROL+TAL were selected for evaluation of bone histology and measurements of differential parameters between healthy control and arthritic animals. This evaluation showed that the treatment of RA with ROL or TAL alone did not alter IL-6 levels, but recovered IL-1β in the synovial fluid. Both these effects were not different from those of the concomitant treatment with ROL+TAL, except that this combination also decreases the body mass. TAL stands out for its hepatoprotective effect in RA animals. Considering the known effects of RUP, PTX, TAL and ROL it can be hypothesized that antiarthritic action of TAL and ROL is due to the inhibition of TNF-α synthesis as consequence of its inhibition in its main cellular sources by PDE4. Data from this prospective study provide additional subsidies that stimulate further and more comprehensive clinical trials on the antiarthritic effects of ROL and TAL. In conclusion, the treatment with TAL alone emerges as an economical, simple and effective therapeutical alternative for RA, while the combination of ROL+TAL can be a viable option for RA sufferers with overweight or obesity