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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Effective use of TNF antagonists

Yocum, David January 2004 (has links)
Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined with the availability of the anti-TNF agents, has contributed to a shift in treatment paradigms favoring the early and timely use of DMARDs with biologic therapies. Improvement in symptom control does not always equate to a reduction in disease progression or disability. With the emergence of structure-related outcome measures as the primary means for assessing the effectiveness of antirheumatic agents, the regular use of X-rays is recommended for the continued monitoring and evaluation of patients. In addition to the control of symptoms and improvement in physical function, a reduction in erosions and joint-space narrowing should be considered among the goals of therapy, leading to a better quality of life. Adherence to therapy is an important element in optimizing outcomes. Durability of therapy with anti-TNF agents as reported from clinical trials can also be achieved in the clinical setting. Concomitant methotrexate therapy might be important in maintaining TNF antagonist therapy in the long term. Overall, the TNF antagonists have led to improvements in clinical and radiographic outcomes in patients with RA, especially those who have failed to show a complete response to methotrexate.
2

A Retrospective Study Determining the Efficacy of Etanercept Treatment in Juvenile Rheumatoid Arthritis Patients in a Small Clinic Setting

Cox, Rosalie January 2006 (has links)
Class of 2006 Abstract / Objectives: To determine the effectiveness of etanercept therapy on C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), height, weight and body mass index (BMI) of patients with juvenile rheumatoid arthritis in an ambulatory pediatric clinic. Methods: This project used a pretest-posttest design that assessed patients before treatment with etanercept and then 6 months after the treatment was begun. Pre-treatment and post-treatment data were obtained through a retrospective chart review. A chart review was performed to collect each patient’s ESR, CRP, height, weight, BMI, and demographic data using a standardized data collection instrument. A paired t-test was performed to compare the pre-treatment and post-treatment data for the ESR, CRP, height, weight and BMI measurements. Results: Nine patients were identified that met the study inclusion. The mean age (SD) of the patients was 13.1 (4.4) years. Increases in weight and height parameters were seen after 6 months of etanercept treatment (p= 0.05, 0.002, respectively). There were no differences found in BMI, CRP and ESR parameters (p= 0.133, 0.753, 0.188, respectively) between the pre and post measurements. Conclusions: This pre-post analysis of 9 patients with juvenile rheumatoid arthritis found that etanercept therapy was associated with a significant gain in weight and height. However, this study found no differences in CRP or ESR after etanercept treatment. Additional research in larger populations is needed to more fully describe the changes in monitoring parameters following etanercept therapy.
3

Hur effektiv och säker är en kombination av metotrexat och etanercept, jämfört med monoterapi vid behandling av Reumatoid Artrit? / How effective and safe is a combination of methotrexate and etanercept, compared to monotherapy in the treatment of rheumatoid arthritis?

Johannesson, Frida January 2018 (has links)
Reumatoid artrit (RA) är en kronisk sjukdom som drabbar kroppens leder. Sjukdomen karakteriseras av inflammerade, smärtande, svullna och stela leder. I Sverige är ungefär 0,5 % av befolkningen drabbad. Mer än hälften av de som drabbas är kvinnor och insjuknandefrekvensen är högst i 50-årsåldern. Det finns ingen behandling som botar sjukdomen. Behandlingen är istället inriktad på att förhindra eller mildra symptomen som uppstår vid RA. Patienter med RA har ett flertal behandlingsalternativ, bland annat ASA, NSAID, kortison, biologiska läkemedel och DMARDs. Biologiska läkemedel har inneburit en revolution för behandling av RA. Många patienter kan med hjälp av dessa läkemedel återfå den livskvalitet de hade innan sjukdomen bröt ut. Syftet med arbetet var att undersöka hur effektiv och säker är en kombination av metotrexat och etanercept är, jämfört med monoterapi vid behandling av reumatoid artrit. Arbetet är ett litteraturarbete där sökningar gjordes i sökbasen PubMed med sökorden ”Methotrexate rheumatoid arthritis”, ”Etanercept methotrexate”, ”Etanercept rheumatoid arthritis”. Fem studier valdes ut och utvärderades. Resultatet av studierna visar på att en kombination av läkemedlen ger en något effektivare behandling med likvärdiga biverkningar. Men med tanke på de ekonomiska aspekterna bör kombinationsbehandling endast användas vid mycket hög sjukdomsaktivitet och vid otillräcklig effekt av andra läkemedel. I framtiden bör fler studier göras för att bedöma den långsiktiga effekten av en kombination av läkemedlen. / Rheumatoid arthritis, RA, is a chronic disease affecting joints in the body. The disease is characterized by periodic inflammation causing pain, swelling and damage of joints. The patient loses quality of life. In Sweden, approximately 0.5% of the population has the diagnosis RA. More than half of those affected are women and the incidence rate is highest in the 50s. RA cannot be cured by any treatment. The symptoms of the disease are treated symptomatically with for example NSAID and ASA. Patients can also be treated by immunomodulation therapy to decrease the inflammatory activity in the body. This helps to slow down the course of illness. Methotrexate belongs to the class of cytotoxic agents and is a folic acid antagonist. The drug acts by inhibiting the enzyme dihydrofolate reductase that converts folic acid to tetrahydrofolic acid. Tetrahydrofolic acid is an important building block for the cell's inheritance. In RA a low dose MTX is used and the drug inhibits the immune system and inhibits disease progression. Etanercept is a fusion protein that is genetically produced. It consists of two identical TNFR2 extracellular regions fused to an Fc domain of human IgG1. The drug blocks / neutralizes TNFα from interacting with receptors and has enabled the development of breakthrough therapies to treat a variety of autoimmune inflammatory diseases. In RA, the proinflammatory cytokine TNF stimulates the inflammation and thereby plays a central role in the process. TNF inhibitors slow down the effect of the substance and the inflammation of the joints in the body decreases. The aim of this study was to examine how effective and safe a combination of methotrexate and etanercept is, compared to monotherapy in the treatment of RA. The searches were made in PubMed and the keywords used were “Methotrexate rheumatoid arthritis”, ”Etanercept methotrexate”, ”Etanercept rheumatoid arthritis”. Five studies were chosen. The results of the studies indicate that a combination of drugs provides a slightly more effective treatment with equivalent side effects. However, given the economic aspects, combination therapy should only be used in very high disease activity and in intolerance to other drugs. In the future, more studies should be done to assess the long-term effect of a combination of drugs.
4

Dysfonction endothéliale et polyarthrite rhumatoïde : cinétique, mécanismes et traitements. Etude chez le rat / Endothelial dysfunction and rheumatoïd arthritis : time-course, mechanisms and treatment. Study in adjuvant-induced arthritis rat model

Totoson, Perle 30 November 2015 (has links)
La polyarthrite rhumatoïde (PR) représente le plus fréquent des rhumatismes inflammatoires chroniques. En plus d’une atteinte ostéo-articulaire responsable de l’invalidité fonctionnelle, la PR est associée à une surmortalité d’origine cardiovasculaire (CV). Les données récentes de la littérature identifient la dysfonction endothéliale (DE) comme la pierre angulaire du processus athéromateux et des complications CV au cours de la PR. Cependant, la physiopathologie et les possibilités thérapeutiques de cette DE sont mal connues. L’objectif de mon travail a été d’étudier la cinétique de la DE au cours de la PR, la différence de sa survenue entre les lits macrovasculaire et microvasculaire, le lien entre la DE et des marqueurs circulants d’inflammation ou d’activation endothéliale, et l’impact de l’Etanercept, un anti-TNFα utilisé comme traitement de fond de la PR, sur la DE. Les expériences ont été réalisées sur le modèle d’Arthrite Induite à l’Adjuvant (AIA) chez le rat Lewis, la fonction endothéliale étant étudiée sur des anneaux aortiques isolés (macrocirculation) ou des artères mésentériques isolées (microcirculation).Dans la première étude, nous avons montré que la DE microvasculaire est d’apparition plus précoce que la DE macrovasculaire (premiers symptômes d’arthrite versus inflammation maximale), et plus durable. Les taux circulants de CRP, ICAM-1 et VCAM-1 ne peuvent pas être utilisés comme marqueurs de DE dans l’arthrite.Dans la deuxième étude, nos résultats ont montré que, malgré l’absence de DE aortique au stade précoce de l’arthrite (premiers symptômes d’arthrite), les anomalies endothéliales sont déjà présentes mais initialement compensées par une augmentation de l’activité de la NOS. Nous avons identifié l’IL-1β, le TNF-α et le MIP-1α plasmatiques comme des marqueurs circulants potentiels de la DE macrovasculaire dans la PR.Notre troisième étude a démontré la capacité d’un traitement curatif par Etanercept : un anti TNF-α, à améliorer la fonction endothéliale dans le modèle AIA, indépendamment de son impact sur les facteurs traditionnels de risque CV et sur la sévérité de la maladie.En conclusion, nos travaux ont permis de mieux comprendre la DE en cas d’arthrite, et ont apporté des éléments qui ouvrent des perspectives diagnostiques et thérapeutiques pour une meilleure prise en charge du risque CV du patient PR / Rheumatoid arthritis (RA) is the most common systemic autoimmune disease which is associated with excessive cardiovascular (CV) mortality and morbidity. Endothelial dysfunction (ED) has been identified as a key element in the development of atherosclerosis and CV complications in RA. However, both pathophysiology and therapeutic options of ED are still ill-defined. In this work we aimed to determine the time-course of ED in RA, the differences of ED between macro- and microvasculature, the link between ED and circulating markers of inflammation or endothelial activation, and the effect of an anti-TNFα agent, Etanercept, for reversing ED. Experiments have been conducted on the model of adjuvant-induced arthritis (AIA) in Lewis rats. Endothelial function was assessed in isolated aortic rings (macrovasculature) and in isolated mesenteric arteries (microvasculature). In a first study, we showed that ED occurred earlier in microvascular bed (first symptoms of arthritis) than in macrovascular bed (at maximal inflammation), and is more sustainable. Circulating levels of CRP, ICAM-1 and VCAM-1 cannot be used as markers of ED in arthritis.In a second study, we characterized the mechanisms involved in ED in AIA rats. Our results showed that despite the absence of aortic ED in the early stage of arthritis (first symptoms of arthritis), endothelial abnormalities are already present but initially compensated by an increase in NOS activity. We identified plasma levels of IL-1β, TNF-α and MIP-1α as potential circulating markers of macrovascular ED in RA.Our third study demonstrated the ability of a curative treatment with Etanercept, an anti-TNFα, to improve endothelial function in the AIA model, regardless its impact on traditional CV risk factors and on the severity of the diseaseIn conclusion, our results led to improve the understanding of ED in case of arthritis. They provide diagnostic and therapeutic perspectives to enhance the management of CV risk in RA patients
5

Desenvolvimento de nanocápsulas de núcleo lipídico com funcionalização de superfície versátil com potencial aplicação para o tratamento da artrite reumatoide e do câncer de mama

Oliveira, Catiúscia Padilha de January 2014 (has links)
A área das Ciências Farmacêuticas busca constantemente por tratamentos mais eficientes, direcionados para alvos específicos, com diminuição da dose necessária e com a minimização dos efeitos adversos. Neste contexto, a área de Nanotecnologia Farmacêutica apresenta grande potencial de aplicabilidade, com resultados bastante promissores para o tratamento de diversas doenças. Os sistemas nanoestruturados têm sido avaliados para a incorporação de fármacos já utilizados em tratamentos administrados formas farmacêuticas convencionais que apresentam problemas farmacocinéticos ou farmacodinâmicos quando administrados. E, também, para a incorporação de novas moléculas com potencial para o tratamento de determinada doença. Neste trabalho de tese, nanocápsulas de núcleo lipídico versáteis contendo metotrexato na forma ácida e éster, bromelina, etanercept e infliximab foram desenvolvidas buscando contornar as limitações e aumentar a eficácia terapêutica desses fármacos. Inicialmente, as propriedades anti-inflamatórias de nanocápsulas de núcleo lipídico revestidas por micelas de polissorbato 80 contendo metotrexato encapsulado foram avaliadas em experimentos in vitro e in vivo, em células mononucleares obtidas a partir do líquido sinovial de pacientes com artrite reumatoide e em ratos Lewis com artrite induzida por adjuvante completo de Freund, respectivamente. As nanocápsulas de núcleo lipídico demonstraram serem altamente eficazes no controle da inflamação, sendo que os efeitos anti-inflamatórios in vivo foram alcançados em doses 75% menores que o metotrexato em solução. Na sequência, o tratamento in vitro da linhagem de células de carcinoma de mama humano, MCF-7, com nanocápsulas de núcleo lipídico multiparede funcionalizadas com bromelina demonstrou uma redução de 160 vezes na concentração necessária para obter o mesmo efeito quando comparada a uma solução de bromelina. A influência das pseudofases aniônicas e catiônicas no mecanismo de distribuição da indometacina, tacrolimus, aciclovir, metotrexato e éster etílico de metotrexato, foram avaliadas aplicando um algoritmo desenvolvido para nanocápsulas de núcleo lipídico. Verificou-se que somente a indometacina sofreu influência da presença de cargas, aumentando a afinidade pela fase dispersa das formulações. Formulações de nanocápsulas de núcleo lipídico multiparede contendo metotrexato na forma ácida e éster encapsulados e/ou funcionalizando a superfície das nanocápsulas foram desenvolvidas e testadas in vitro em linhagens de células tumorais (MCF-7) e em linhagens de células sadias (HaCaT). Essas formulações demonstraram atividade antiproliferativa maior para as MCF-7 (com redução em mais de 50% na viabilidade celular) em comparação com as soluções de metotrexato e éster etílico de metotrexato e esta atividade foi maior para as formulações em que as moléculas foram funcionalizadas na superfície das nanopartículas. A captação das nanopartículas pelas células também foi maior para as formulações funcionalizadas com metotrexato ou éster etílico de metotrexato em comparação com a formulação em que o éster de metotrexato está encapsulado. As três formulações contendo metotrexato na forma ácida ou éster não demonstraram ação antiproliferativa em linhagens de células sadias (HaCaT). Devido à baixa expressão de receptores de folato nessas células, não houve aumento da captação celular em comparação à formulação sem fármaco. Por último, foram desenvolvidas satisfatoriamente formulações de nanocápsulas de núcleo lipídico multiparede funcionalizadas com os anticorpos monoclonais infliximab e etanercept, e contendo éster etílico de metotrexato encapsulado, demonstrando que são adequadas para futuros estudos visando o tratamento da artrite reumatoide. Esse conjunto de resultados demonstra que as nanocápsulas de núcleo lipídico com funcionalização de superfície versátil, sejam revestidas com polissorbato 80 ou multiparede funcionalizadas são um sistema bastante promissor para a administração de fármacos de modo a aumentar sua especificidade e eficácia. / The Pharmaceutical Sciences field is constantly searching for more effective treatments, aiming specific targets, with dose reduction and minimization of side effects. In this context, the Pharmaceutical Nanotechnology field presents great applicability potential, with highly promising results for the treatment of several diseases. Nanostructured systems have been evaluated for the encapsulation of drugs approved for use in conventional pharmaceutical dosage forms that, however, exhibit pharmacokinetic or pharmacodynamics problems when administered, and for the encapsulation of novel molecules with potential to treat a determined disease. In the present thesis, versatile lipid-core nanocapsules containing methotrexate in the acid and ester forms, bromelain, etanercept and infliximab were developed, seeking to circumvent the limitations and increase the therapeutic efficacy of these drugs. Initially, the anti-inflammatory properties of methotrexate-loaded lipid-core nanocapsules coated with polysorbate 80 micelles were evaluated in in vitro and in vivo experiments, using mononuclear cells obtained from the synovial fluid of rheumatoid arthritis patients and Lewis rats with Freund complete adjuvant-induced arthritis. Lipid-core nanocapsules demonstrated to be highly effective in the control of inflammation, and the in vivo anti-inflammatory effects were reached in a dose 75% lower than the methotrexate in solution. In the sequence, the in vitro treatment of a human breast cancer cell line, MCF-7, with bromelina-functionalized multiple-wall lipid-core nanocapsules demonstrated a 160-fold reduction of the concentration required to obtain the same effect when compared with a bromelain solution. The influence of the anionic and cationic pseudo-phases in the distribution mechanism of indomethacin, tacrolimus, acyclovir, methotrexate and methotrexate ethyl ester was evaluated through an algorithm developed for lipid-core nanocapsules. It was verified that only indomethacin underwent influence in the presence of charge, increasing the affinity by the disperse phase of the formulations. Multiple-wall lipid-core nanocapsules formulations containing methotrexate in the acid and ester forms encapsulated and/or functionalizing the surface of the nanoparticles were developed and tested in vitro in tumour MCF-7 cells and in a healthy cell line (HaCaT). These formulations demonstrated higher anti-proliferative activity for the MCF-7 cells (reduction of over 50 % in cellular viability) in comparison with the methotrexate and methotrexate ethyl ester solutions and this activity was higher for the formulations in which the molecules were functionalized in the surface of the nanoparticles. A higher cellular uptake was observed for the formulations functionalized with methotrexate or methotrexate ethyl ester in comparison with the formulations in which the methotrexate ester is encapsulated. The three formulations containing methotrexate in the acid or ester form did not demonstrate anti-proliferative activity in non-tumour cell lines (HaCaT). Since these cells have a small expression of folate receptors, the uptake was not increased in comparison with the formulation without drug. Lastly, formulations of methotrexate ethyl ester-loaded multiwall lipid core nanocapsules functionalized with monoclonal antibodies infliximab and etanercept were successfully developed demonstrating suitability for future studies aiming the treatment of rheumatoid arthritis. These groups of results demonstrate that versatile lipid core nanocapsules, either coated with polysorbate 80 or multiwalled functionalized are a very promising system for the administration of drugs aiming their specificity and efficacy.
6

Desenvolvimento de nanocápsulas de núcleo lipídico com funcionalização de superfície versátil com potencial aplicação para o tratamento da artrite reumatoide e do câncer de mama

Oliveira, Catiúscia Padilha de January 2014 (has links)
A área das Ciências Farmacêuticas busca constantemente por tratamentos mais eficientes, direcionados para alvos específicos, com diminuição da dose necessária e com a minimização dos efeitos adversos. Neste contexto, a área de Nanotecnologia Farmacêutica apresenta grande potencial de aplicabilidade, com resultados bastante promissores para o tratamento de diversas doenças. Os sistemas nanoestruturados têm sido avaliados para a incorporação de fármacos já utilizados em tratamentos administrados formas farmacêuticas convencionais que apresentam problemas farmacocinéticos ou farmacodinâmicos quando administrados. E, também, para a incorporação de novas moléculas com potencial para o tratamento de determinada doença. Neste trabalho de tese, nanocápsulas de núcleo lipídico versáteis contendo metotrexato na forma ácida e éster, bromelina, etanercept e infliximab foram desenvolvidas buscando contornar as limitações e aumentar a eficácia terapêutica desses fármacos. Inicialmente, as propriedades anti-inflamatórias de nanocápsulas de núcleo lipídico revestidas por micelas de polissorbato 80 contendo metotrexato encapsulado foram avaliadas em experimentos in vitro e in vivo, em células mononucleares obtidas a partir do líquido sinovial de pacientes com artrite reumatoide e em ratos Lewis com artrite induzida por adjuvante completo de Freund, respectivamente. As nanocápsulas de núcleo lipídico demonstraram serem altamente eficazes no controle da inflamação, sendo que os efeitos anti-inflamatórios in vivo foram alcançados em doses 75% menores que o metotrexato em solução. Na sequência, o tratamento in vitro da linhagem de células de carcinoma de mama humano, MCF-7, com nanocápsulas de núcleo lipídico multiparede funcionalizadas com bromelina demonstrou uma redução de 160 vezes na concentração necessária para obter o mesmo efeito quando comparada a uma solução de bromelina. A influência das pseudofases aniônicas e catiônicas no mecanismo de distribuição da indometacina, tacrolimus, aciclovir, metotrexato e éster etílico de metotrexato, foram avaliadas aplicando um algoritmo desenvolvido para nanocápsulas de núcleo lipídico. Verificou-se que somente a indometacina sofreu influência da presença de cargas, aumentando a afinidade pela fase dispersa das formulações. Formulações de nanocápsulas de núcleo lipídico multiparede contendo metotrexato na forma ácida e éster encapsulados e/ou funcionalizando a superfície das nanocápsulas foram desenvolvidas e testadas in vitro em linhagens de células tumorais (MCF-7) e em linhagens de células sadias (HaCaT). Essas formulações demonstraram atividade antiproliferativa maior para as MCF-7 (com redução em mais de 50% na viabilidade celular) em comparação com as soluções de metotrexato e éster etílico de metotrexato e esta atividade foi maior para as formulações em que as moléculas foram funcionalizadas na superfície das nanopartículas. A captação das nanopartículas pelas células também foi maior para as formulações funcionalizadas com metotrexato ou éster etílico de metotrexato em comparação com a formulação em que o éster de metotrexato está encapsulado. As três formulações contendo metotrexato na forma ácida ou éster não demonstraram ação antiproliferativa em linhagens de células sadias (HaCaT). Devido à baixa expressão de receptores de folato nessas células, não houve aumento da captação celular em comparação à formulação sem fármaco. Por último, foram desenvolvidas satisfatoriamente formulações de nanocápsulas de núcleo lipídico multiparede funcionalizadas com os anticorpos monoclonais infliximab e etanercept, e contendo éster etílico de metotrexato encapsulado, demonstrando que são adequadas para futuros estudos visando o tratamento da artrite reumatoide. Esse conjunto de resultados demonstra que as nanocápsulas de núcleo lipídico com funcionalização de superfície versátil, sejam revestidas com polissorbato 80 ou multiparede funcionalizadas são um sistema bastante promissor para a administração de fármacos de modo a aumentar sua especificidade e eficácia. / The Pharmaceutical Sciences field is constantly searching for more effective treatments, aiming specific targets, with dose reduction and minimization of side effects. In this context, the Pharmaceutical Nanotechnology field presents great applicability potential, with highly promising results for the treatment of several diseases. Nanostructured systems have been evaluated for the encapsulation of drugs approved for use in conventional pharmaceutical dosage forms that, however, exhibit pharmacokinetic or pharmacodynamics problems when administered, and for the encapsulation of novel molecules with potential to treat a determined disease. In the present thesis, versatile lipid-core nanocapsules containing methotrexate in the acid and ester forms, bromelain, etanercept and infliximab were developed, seeking to circumvent the limitations and increase the therapeutic efficacy of these drugs. Initially, the anti-inflammatory properties of methotrexate-loaded lipid-core nanocapsules coated with polysorbate 80 micelles were evaluated in in vitro and in vivo experiments, using mononuclear cells obtained from the synovial fluid of rheumatoid arthritis patients and Lewis rats with Freund complete adjuvant-induced arthritis. Lipid-core nanocapsules demonstrated to be highly effective in the control of inflammation, and the in vivo anti-inflammatory effects were reached in a dose 75% lower than the methotrexate in solution. In the sequence, the in vitro treatment of a human breast cancer cell line, MCF-7, with bromelina-functionalized multiple-wall lipid-core nanocapsules demonstrated a 160-fold reduction of the concentration required to obtain the same effect when compared with a bromelain solution. The influence of the anionic and cationic pseudo-phases in the distribution mechanism of indomethacin, tacrolimus, acyclovir, methotrexate and methotrexate ethyl ester was evaluated through an algorithm developed for lipid-core nanocapsules. It was verified that only indomethacin underwent influence in the presence of charge, increasing the affinity by the disperse phase of the formulations. Multiple-wall lipid-core nanocapsules formulations containing methotrexate in the acid and ester forms encapsulated and/or functionalizing the surface of the nanoparticles were developed and tested in vitro in tumour MCF-7 cells and in a healthy cell line (HaCaT). These formulations demonstrated higher anti-proliferative activity for the MCF-7 cells (reduction of over 50 % in cellular viability) in comparison with the methotrexate and methotrexate ethyl ester solutions and this activity was higher for the formulations in which the molecules were functionalized in the surface of the nanoparticles. A higher cellular uptake was observed for the formulations functionalized with methotrexate or methotrexate ethyl ester in comparison with the formulations in which the methotrexate ester is encapsulated. The three formulations containing methotrexate in the acid or ester form did not demonstrate anti-proliferative activity in non-tumour cell lines (HaCaT). Since these cells have a small expression of folate receptors, the uptake was not increased in comparison with the formulation without drug. Lastly, formulations of methotrexate ethyl ester-loaded multiwall lipid core nanocapsules functionalized with monoclonal antibodies infliximab and etanercept were successfully developed demonstrating suitability for future studies aiming the treatment of rheumatoid arthritis. These groups of results demonstrate that versatile lipid core nanocapsules, either coated with polysorbate 80 or multiwalled functionalized are a very promising system for the administration of drugs aiming their specificity and efficacy.
7

Desenvolvimento de nanocápsulas de núcleo lipídico com funcionalização de superfície versátil com potencial aplicação para o tratamento da artrite reumatoide e do câncer de mama

Oliveira, Catiúscia Padilha de January 2014 (has links)
A área das Ciências Farmacêuticas busca constantemente por tratamentos mais eficientes, direcionados para alvos específicos, com diminuição da dose necessária e com a minimização dos efeitos adversos. Neste contexto, a área de Nanotecnologia Farmacêutica apresenta grande potencial de aplicabilidade, com resultados bastante promissores para o tratamento de diversas doenças. Os sistemas nanoestruturados têm sido avaliados para a incorporação de fármacos já utilizados em tratamentos administrados formas farmacêuticas convencionais que apresentam problemas farmacocinéticos ou farmacodinâmicos quando administrados. E, também, para a incorporação de novas moléculas com potencial para o tratamento de determinada doença. Neste trabalho de tese, nanocápsulas de núcleo lipídico versáteis contendo metotrexato na forma ácida e éster, bromelina, etanercept e infliximab foram desenvolvidas buscando contornar as limitações e aumentar a eficácia terapêutica desses fármacos. Inicialmente, as propriedades anti-inflamatórias de nanocápsulas de núcleo lipídico revestidas por micelas de polissorbato 80 contendo metotrexato encapsulado foram avaliadas em experimentos in vitro e in vivo, em células mononucleares obtidas a partir do líquido sinovial de pacientes com artrite reumatoide e em ratos Lewis com artrite induzida por adjuvante completo de Freund, respectivamente. As nanocápsulas de núcleo lipídico demonstraram serem altamente eficazes no controle da inflamação, sendo que os efeitos anti-inflamatórios in vivo foram alcançados em doses 75% menores que o metotrexato em solução. Na sequência, o tratamento in vitro da linhagem de células de carcinoma de mama humano, MCF-7, com nanocápsulas de núcleo lipídico multiparede funcionalizadas com bromelina demonstrou uma redução de 160 vezes na concentração necessária para obter o mesmo efeito quando comparada a uma solução de bromelina. A influência das pseudofases aniônicas e catiônicas no mecanismo de distribuição da indometacina, tacrolimus, aciclovir, metotrexato e éster etílico de metotrexato, foram avaliadas aplicando um algoritmo desenvolvido para nanocápsulas de núcleo lipídico. Verificou-se que somente a indometacina sofreu influência da presença de cargas, aumentando a afinidade pela fase dispersa das formulações. Formulações de nanocápsulas de núcleo lipídico multiparede contendo metotrexato na forma ácida e éster encapsulados e/ou funcionalizando a superfície das nanocápsulas foram desenvolvidas e testadas in vitro em linhagens de células tumorais (MCF-7) e em linhagens de células sadias (HaCaT). Essas formulações demonstraram atividade antiproliferativa maior para as MCF-7 (com redução em mais de 50% na viabilidade celular) em comparação com as soluções de metotrexato e éster etílico de metotrexato e esta atividade foi maior para as formulações em que as moléculas foram funcionalizadas na superfície das nanopartículas. A captação das nanopartículas pelas células também foi maior para as formulações funcionalizadas com metotrexato ou éster etílico de metotrexato em comparação com a formulação em que o éster de metotrexato está encapsulado. As três formulações contendo metotrexato na forma ácida ou éster não demonstraram ação antiproliferativa em linhagens de células sadias (HaCaT). Devido à baixa expressão de receptores de folato nessas células, não houve aumento da captação celular em comparação à formulação sem fármaco. Por último, foram desenvolvidas satisfatoriamente formulações de nanocápsulas de núcleo lipídico multiparede funcionalizadas com os anticorpos monoclonais infliximab e etanercept, e contendo éster etílico de metotrexato encapsulado, demonstrando que são adequadas para futuros estudos visando o tratamento da artrite reumatoide. Esse conjunto de resultados demonstra que as nanocápsulas de núcleo lipídico com funcionalização de superfície versátil, sejam revestidas com polissorbato 80 ou multiparede funcionalizadas são um sistema bastante promissor para a administração de fármacos de modo a aumentar sua especificidade e eficácia. / The Pharmaceutical Sciences field is constantly searching for more effective treatments, aiming specific targets, with dose reduction and minimization of side effects. In this context, the Pharmaceutical Nanotechnology field presents great applicability potential, with highly promising results for the treatment of several diseases. Nanostructured systems have been evaluated for the encapsulation of drugs approved for use in conventional pharmaceutical dosage forms that, however, exhibit pharmacokinetic or pharmacodynamics problems when administered, and for the encapsulation of novel molecules with potential to treat a determined disease. In the present thesis, versatile lipid-core nanocapsules containing methotrexate in the acid and ester forms, bromelain, etanercept and infliximab were developed, seeking to circumvent the limitations and increase the therapeutic efficacy of these drugs. Initially, the anti-inflammatory properties of methotrexate-loaded lipid-core nanocapsules coated with polysorbate 80 micelles were evaluated in in vitro and in vivo experiments, using mononuclear cells obtained from the synovial fluid of rheumatoid arthritis patients and Lewis rats with Freund complete adjuvant-induced arthritis. Lipid-core nanocapsules demonstrated to be highly effective in the control of inflammation, and the in vivo anti-inflammatory effects were reached in a dose 75% lower than the methotrexate in solution. In the sequence, the in vitro treatment of a human breast cancer cell line, MCF-7, with bromelina-functionalized multiple-wall lipid-core nanocapsules demonstrated a 160-fold reduction of the concentration required to obtain the same effect when compared with a bromelain solution. The influence of the anionic and cationic pseudo-phases in the distribution mechanism of indomethacin, tacrolimus, acyclovir, methotrexate and methotrexate ethyl ester was evaluated through an algorithm developed for lipid-core nanocapsules. It was verified that only indomethacin underwent influence in the presence of charge, increasing the affinity by the disperse phase of the formulations. Multiple-wall lipid-core nanocapsules formulations containing methotrexate in the acid and ester forms encapsulated and/or functionalizing the surface of the nanoparticles were developed and tested in vitro in tumour MCF-7 cells and in a healthy cell line (HaCaT). These formulations demonstrated higher anti-proliferative activity for the MCF-7 cells (reduction of over 50 % in cellular viability) in comparison with the methotrexate and methotrexate ethyl ester solutions and this activity was higher for the formulations in which the molecules were functionalized in the surface of the nanoparticles. A higher cellular uptake was observed for the formulations functionalized with methotrexate or methotrexate ethyl ester in comparison with the formulations in which the methotrexate ester is encapsulated. The three formulations containing methotrexate in the acid or ester form did not demonstrate anti-proliferative activity in non-tumour cell lines (HaCaT). Since these cells have a small expression of folate receptors, the uptake was not increased in comparison with the formulation without drug. Lastly, formulations of methotrexate ethyl ester-loaded multiwall lipid core nanocapsules functionalized with monoclonal antibodies infliximab and etanercept were successfully developed demonstrating suitability for future studies aiming the treatment of rheumatoid arthritis. These groups of results demonstrate that versatile lipid core nanocapsules, either coated with polysorbate 80 or multiwalled functionalized are a very promising system for the administration of drugs aiming their specificity and efficacy.
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Remission of Severe Aphthous Stomatitis of Celiac Disease With Etanercept

Hasan, Adey, Patel, Hiren, Saleh, Hana, Youngberg, George, Litchfield, John, Krishnaswamy, Guha 24 December 2013 (has links)
Celiac disease is a common autoimmune disease triggered by gluten-containing foods (wheat, barley and rye) in genetically predisposed individuals. We present a patient with celiac disease complicated by severe aphthous stomatitis resulting in impairing swallowing, chewing and speaking. This led to weight loss, psychosocial problems as well as inability to perform her work. A variety of topical and systemic medications used resulted in either no improvement or only partial alleviation of the patient's symptoms. After informed consent, etanercept was initiated and resulted in complete remission of aphthous stomatitis, decrease in arthralgia and fatigue and considerable improvement in her quality of life. The use of newer biological agents for selected and severe manifestations of celiac disease may lead to improved morbidity in these patients, but more studies are needed to determine long-term efficacy as well as safety of these drugs in the mucosal and/or systemic complications of this disease.
9

Remission of Severe Aphthous Stomatitis of Celiac Disease With Etanercept

Hasan, Adey, Patel, Hiren, Saleh, Hana, Youngberg, George, Litchfield, John, Krishnaswamy, Guha 24 December 2013 (has links)
Celiac disease is a common autoimmune disease triggered by gluten-containing foods (wheat, barley and rye) in genetically predisposed individuals. We present a patient with celiac disease complicated by severe aphthous stomatitis resulting in impairing swallowing, chewing and speaking. This led to weight loss, psychosocial problems as well as inability to perform her work. A variety of topical and systemic medications used resulted in either no improvement or only partial alleviation of the patient's symptoms. After informed consent, etanercept was initiated and resulted in complete remission of aphthous stomatitis, decrease in arthralgia and fatigue and considerable improvement in her quality of life. The use of newer biological agents for selected and severe manifestations of celiac disease may lead to improved morbidity in these patients, but more studies are needed to determine long-term efficacy as well as safety of these drugs in the mucosal and/or systemic complications of this disease.
10

Efikasnost i bezbednost lečenja obolelih od reumatoidnog artritisa TNF-alfa inhibitorima / Efficacy and safety of the treatment with TNF-alpha inhibitors in rheumatoid arthritis patients

Maksimović Simović Marina 21 March 2018 (has links)
<p>Uvod: Reumatoidni artritis (RA) je bolest koja dovodi do ireverzibilnog o&scaron;tećenja zglobova usled čega je neophodno pri postavljanju dijagnoze započeti lečenje. TNF-alfa inhibitori predstavljaju revolucionarno otkriće u lečenju RA, pri čemu su najče&scaron;će kori&scaron;ćeni Etanercept i Adalimumab. Oni nisu efikasni kod svih pacijenata kod kojih se primene, a mehanizmi gubitka odgovora nisu jasni. Cilj rada je odrediti uticaj Etanercepta i Adalimumaba na aktivnost bolesti (merenjem DAS28 SE i DAS28 CRP skora) i funkcionalni status pacijenata (merenjem HAQ-DI upitnika), broj bolnih i otečnih zglobova pre i tokom godinu dana primene ovih lekova, kao i utvrditi povezanost koncentracije Etanercepta i Adalimumaba u krvi sa vrednostima DAS28 SE u momentu odreĎivanja koncentracije leka. Praćena je i učestalost neželjenih efekata kod pacijenata lečenih sa ova dva leka. Ispitan je i uticaj primene Metotreksata na nivoe lekova u krvi, kao i doza Metotreksata pre i 6 meseci nakon uvoĎenja Etanercepta ili Adalimumaba. Metode: Studija je sprovedena u Specijalnoj bolnici za reumatske bolesti i Klinici za nefrologiju i kliničku imunologiju, Kliničkog centra Vojvodine u Novom Sadu i obuhvatila je 88 pacijenata kod kojih je postavljena dijagnoza RA, od kojih je 49 bilo lečeno Etanerceptom, a 39 Adalimumabom. Analizirana je medicinska dokumentacija, a nakon početka primene TNF-alfa inhibitora svim ispitanicima je u toku godinu dana svaka tri meseca raĎena kontrola koja je podrazumevala anamnezu i fizički pregled, analizu biohemijskih nalaza krvi, merena je aktivnost bolesti merenjem indeksa aktivnosti bolesti DAS28 SE i DAS28 CRP i raĎena procena funkcionalnog statusa tako &scaron;to je pacijent popunjavao HAQ-DI upitnik. Rezultati: Aktivnost RA merena DAS28 SE i DAS28 CRP indeksima, funkcionalni status meren HAQ-DI upitnikom, broj bolnih i otečenih zglobova i vrednosti reaktanata akutne faze značajno su veći pre početka terapije Etanerceptom i Adalimumabom i smanjuje se tokom prvih 6 meseci lečenja ovim lekovima i potom se taj efekat terapije održava do kraja perioda praćenja. Nema statistički značajne razlike u poreĎenju Etanercepta i Adalimumaba u odnosu na učestalost neželjenih dejstava. Doza Metotreksata je statistički značajno manja 6 meseci nakon upotrebe biolo&scaron;kog leka Etanercept i Adalimumab. Pacijenti lečeni Metotreksatom uz Adalimumab imali su statistički značajno veće nivoe leka, nego oni koji ga nisu koristili. Zaključak: TNF-alfa inhibitori ne dovode do zaustavljanja bolesti kod svih pacijenata kod kojih se primene. Mehanizam gubitka odgovora na terapiju TNF-alfa inhibitorima nije jasan. Kako bi se donela najbolja odluka za pacijenta, neophodno je odrediti nivo leka u krvi, kao i nivo antitela na lek prilikom svake promene stanja pacijenta. Za sada nema dovoljno studija koje ukazuju da li postoji veza izmeĎu ekspresije TNF-alfa gena i nivoa TNF-alfa u krvi, te da li bi se merenjem TNF-alfa u krvi mogla korigovati terapija i doza TNF-alfa inhibitora &scaron;to će verovatno biti predmet budućih istraživanja.</p> / <p>Rheumatoid Arthritis (RA) is a disease that leads to irreversible joint damage, which makes necessary to start treatment when the diagnosis is set. TNF-alpha inhibitors represent a revolutionary discovery in the treatment of RA, and the most commonly used are Etanercept and Adalimumab. They are not effective in all patients, and the mechanisms of loss of response are not clear. The aim of this study is to determine the effect of Etanercept and Adalimumab on disease activity (by measuring DAS28 SE and DAS28 CRP score) and the functional status of patients (by measuring the HAQ-DI questionnaire), the number of painful and swollen joints before and during the first year of administration of these drugs. Also, it was determined a correlation between the concentration of Etanercept and Adalimumab in blood and the values of DAS28 SE at the moment of drug concentration measurement. The incidence of adverse effects in patients treated with these two drugs was also observed. It was examined the effect of Methotrexate on drug levels in the blood as well as the dose of Methotrexate before and 6 months after the introduction of Etanercept or Adalimumab. Methods: The study was conducted at the Special Hospital for Rheumatic Diseases and the Clinic of Nephrology and Clinical Immunology, Clinical Center of Vojvodina in Novi Sad. It included 88 patients with RA, 49 were treated with Etanercept and 39 with Adalimumab. Medical documentation was analyzed, and during the first year of TNF-alpha inhibitor administration, every three months were done anamnesis and physical examination, analysis of blood biochemical findings, measurements of the disease activity with DAS28 SE and DAS28 CRP score and a functional status assessment with the HAQ-DI questionnaire. Results: Disease activity measured by DAS28 SE and DAS28 CRP scores, functional status measured with HAQ-DI questionnaire, number of painful and swollen joints and acute phase reactant values are significantly higher before Etanercept and Adalimumab therapy and decreased during the first 6 months of treatment with these drugs and then this effect of therapy is maintained until the end of the monitoring period. There is no statistically significant difference in the comparison of Etanercept and Adalimumab with respect to the frequency of adverse events. The dose of Methotrexate was statistically significantly lower for 6 months after the use of Etanercept and Adalimumab. Patients treated with Methotrexate and Adalimumab had statistically significantly higher drug levels than those who did not use it. Conclusion: TNF-alpha inhibitors are not effective in all patients who used them. The mechanism of loss of response to TNF-alpha inhibitors is not clear. In order to make the best decision for the patient, it is necessary to determine the drug level in the blood as well as the level of antibodies to the drug in each change in the patient&#39;s condition. For now, there are not enough studies to indicate whether there is a link between expression of the TNF-alpha gene and the level of TNF-alpha in the blood, and whether the measurement of the TNF-alpha in blood could be used for therapy correction and change of dose of TNF-alpha inhibitor, which is likely to be the subject of the future research.</p>

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