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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

Evaluation of the impact of cardiovascular safety concerns of thiazolidinediones on the utilization of oral antidiabetic drugs

Bui, Cat Nguyen 17 June 2011 (has links)
The overall objective of this study was to evaluate the impact of cardiovascular safety concerns on the utilization of the thiazolidinediones (TZDs), pioglitazone and rosiglitazone, and other oral antidiabetic drugs. In May 2007, a meta-analysis was published that found a potential increased risk of myocardial infarction (MI) associated with TZDs, particularly with rosiglitazone. A two-year retrospective study of patients diagnosed with type 2 diabetes (ICD9 250.xx) using prescription and medical databases from the Scott & White Health System (SWHS) was conducted. Patients aged 18 or older who were continuously enrolled with SWHS from 2006 to 2008 and had high adherence (Medication Adherence Ratio ≥80%) for either pioglitazone or rosiglitazone during the pre-safety warning period (May 2006- April 2007) were included. Patients were followed through the post-safety warning period (May 2007 - October 2008) or occurrence of event (discontinuation of index TZD drug). Patients who discontinued their index TZD drug by April 2008 were identified if they had a prescription filled for a new oral antidiabetic drugs (OADs), and followed until October 2008 or occurrence of event (discontinuation of new OAD). Cox proportional hazards models were used to assess the rate of and time to discontinuation of index TZD and new OAD with adjustment of age, gender and Charlson Comorbidity Index (CCI). A total of 531 patients (58 percent male; mean age [SD] = 61 [9.1] years) were included in the final analysis, 255 and 276 patients in the rosiglitazone and pioglitazone groups, respectively. The rate of discontinuation for the pioglitazone and rosiglitazone groups began to separate within 90 days of the index event (meta-analysis published in May 2007). In the pioglitazone group, the rate of discontinuation was significantly lower than in the rosiglitazone group ( HR = 0.56; 95% CI = 0.47, 0.67). A total of 21 patients did not experience discontinuation of their index medication. Among patients receiving a new OAD after discontinuing their index TZD (N = 95 rosiglitazone and N = 33 pioglitazone patients), there was no statistical significant in the rate of discontinuing their new OAD between the rosiglitazone and pioglitazone groups (HR = 0.98; 95% CI = 0.61, 1.59). However, patients who received metformin/sulfonylurea combinations had a lower rate of discontinuation compared to patients who received sulfonylureas (HR = 0.38; 94% CI = 0.21, 0.66). The analysis showed the cardiovascular safety concern of TZDs had a significant impact on the utilization of oral antidiabetic drug utilization. / text
2

Effect of hyperglycemia and thiazolidinediones on cardiac angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) in db/db diabetic mice.

Fadnavis, Rucha 30 August 2017 (has links)
No description available.
3

Atividade de novos derivados de tiazolidinodionas sobre a diferenciação de pré-osteoblastos e pré-adipócitos / Activity of new derivatives of thiazolidinediones on differentiation of preosteoblasts and preadipocytes

Saito, Cristiane Akemi Iamamoto 06 February 2015 (has links)
As tiazolidinodionas (TZDs) são sensibilizadores de insulina utilizados no tratamento do diabetes mellitus tipo 2. Contudo, apesar dos efeitos benéficos sobre a glicemia, importantes efeitos adversos incluindo perda óssea e aumento de adiposidade são relatados com o uso clínico das TZDs. Assim, é necessário o desenvolvimento de novos derivados de TZDs com potenciais efeitos benéficos sobre a hiperglicemia e menos efeitos adversos. Neste estudo, investigamos os efeitos de 5 novos derivados de TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) sobre a diferenciação celular de pré-osteoblastos murinos MC3T3-E1, pré-adipócitos murinos 3T3-L1 e pré-adipócitos SGBS de linhagem humana. Seus potenciais efeitos sobre a utilização de glicose, a produção de adipocinas e mediadores pró-inflamatórios também foram avaliados, utilizando linhagens murinas e humanas de adipócitos, e macrófagos THP-1 de linhagem humana. O principal achado de nosso estudo foi que os novos derivados de TZDs estimulam a utilização celular de glicose, porém não alteram o processo de diferenciação celular de pré-osteoblastos e pré-adipócitos, quando comparados com a TZD clássica Rosiglitazona. Conforme esperado, o tratamento com Rosiglitazona na concentração de 5 μM inibiu a osteogênese de pré-osteoblastos murinos MC3T3-E1. No entanto, o tratamento com 2 novos derivados de TZDs (GQ-89 e GQ-177) na mesma concentração não afetou a diferenciação celular, sendo possível observar níveis de mineralização de matriz extracelular similares aos do grupo controle. Além disso, enquanto a GQ-89 estimulou a atividade da fosfatase alcalina, a GQ-177 não modulou sua atividade enzimática e induziu a expressão gênica de osteocalcina. Contudo, ambos inibiram a expressão de Runx2 e colágeno. Por sua vez, quando os efeitos foram avaliados sobre a diferenciação de adipócitos, foi possível observar que ao contrário do efeito pró-adipogênico constatado com a Rosiglitazona na concentração de 1 μM, as TZDs GQ-150, GQ-177, LYSO-7 e SF-3 foram incapazes de induzir o acúmulo lipídico em pré-adipócitos murinos e humanos. Além disso, a GQ-150 inibiu a expressão gênica de C/EBPα, assim como a expressão gênica e os níveis protéicos de CD36, enquanto que a SF-3 estimulou a expressão gênica de C/EBPα e de FABP4 e diminuiu a expressão gênica e os níveis protéicos de CD36, os quais não foram modificados pela LYSO-7 em pré-adipócitos murinos 3T3-L1. No entanto, em pré-adipócitos SGBS de linhagem humana, nenhum efeito sobre os marcadores de fenótipo adipogênico C/EBPα e FABP4 foi observado com os novos derivados de TZDs. Ademais, os novos derivados de TZDs não interferiram na via de sinalização de Wnt, não apresentaram qualquer efeito sobre a expressão de adipocinas (adiponectina, resistina e leptina) e mediadores pró-inflamatórios (IL-6, CCL2/MCP-1, TNF-α e JNK), bem como não ativaram o fator de transcrição PPARγ no ensaio de gene repórter. Por sua vez, a LYSO-7, GQ-150 e SF-3 aumentaram o consumo de glicose em presença de insulina em adipócitos 3T3-L1 e modificaram a atividade de enzimas mitocondriais em adipócitos SGBS e macrófagos THP-1. Entretanto, o efeito sensibilizador de insulina foi confirmado somente com a GQ-177 pelo aumento da captação de glicose e somente a LYSO-7 e a SF-3 foram capazes de inibir o consumo de oxigênio e modificar a taxa de glicólise em macrófagos, sugerindo que também poderiam alterar os níveis de ATP/ADP. Considerando que baixos níveis de ATP estimulam a via de sinalização de AMPK, essa via também foi investigada em nosso estudo. Entretanto, os resultados sobre a ativação de AMPK foram inconclusivos. Desse modo, nossos resultados apontam que os novos derivados de TZDs não atuam como ligantes de PPARγ, apresentam atividade sensibilizadora de insulina in vitro, e que exercem menores efeitos antiosteoblásticos e adipogênicos quando comparados com a Rosiglitazona. Mais estudos são necessários para elucidar os mecanismos responsáveis por esses efeitos, bem como para estabelecer se os novos derivados de TZDs são mais seguros in vivo, com relação ao risco de fraturas ósseas e ganho de massa adiposa. / Thiazolidinediones (TZDs) are insulin sensitizers used in the treatment of type 2 diabetes mellitus. However, despite the beneficial effects on blood glucose, significant adverse effects including bone loss and increased adiposity are reported with the clinical use of TZDs. Thus, it is necessary to develop new derivatives of TZDs with potential beneficial effects on hyperglycemia and fewer adverse effects. In this study, we investigated the effects of 5 new derivatives of TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) on cellular differentiation in murine MC3T3-E1 preosteoblasts, murine 3T3-L1 preadipocytes, and SGBS preadipocytes from human lineage. Potential effects on glucose consumption, adipokines, and pro-inflammatory mediators were also assessed using murine and human strains of adipocytes, and macrophages from human THP-1 lineage. The main finding of this study was that new derivatives of TZDs stimulate glucose consumption, but do not change the cell differentiation process of preosteoblasts and preadipocytes compared to classical TZD Rosiglitazone. As expected, the treatmet with Rosiglitazone, at 5μM, inhibited the osteogenesis in murine MC3T3-E1 preosteoblasts. However, the treatment with 2 new derivatives of TZDs (GQ-89 and GQ-177) at the same concentration did not affect cell differentiation, and levels of mineralization of the extracellular matrix similar to the control group were observed. In addition, whereas the GQ-89 stimulated the activity of alkaline phosphatase, GQ-177 does not modulate its enzymatic activity and induced gene expression of osteocalcin. However, both of them inhibit the expression of Runx2 and collagen. In turn, when the effects were assessed on the adipocyte differentiation, unlike the proadipogenic effect observed with Rosiglitazone at a concentration of 1 μM, the new TZDs GQ-150, GQ-177, LYSO-7 and SF-3 were unable to induce lipid accumulation in human and murine preadipocytes. In addition, GQ-150 inhibited the gene expression of C/EBPα , as well as the gene expression and protein levels of CD36, whereas SF-3 stimulated the gene expression of C/EBPα and FABP4 and decreased gene expression and protein levels of CD36, which was not modified by LYSO-7 on murine 3T3- L1 preadipocytes. However, no effect on markers of adipogenic phenotype C/EBPα and FABP4 has been observed with the novel derivatives of TZDs in human SGBS preadipocytes. Furthermore, the new derivatives of TZDs do not interfere with the Wnt signaling pathway, showed no effect on the adipokines expression (adiponectin, resistin and leptin) and proinflammatory mediators (IL-6, CCL2 / MCP-1, TNF α and JNK) and did not activate the transcription factor PPARγ in the gene reporter assay. In turn, LYSO-7, GQ-150, and SF-3 increased glucose consumption in the presence of insulin in 3T3-L1 adipocytes and modified the activity of mitochondrial enzymes in SGBS adipocytes and THP-1 macrophages. However, the effect on insulin sensitization was confirmed only to GQ-177 that increased glucose uptake and just LYSO-7 and SF-3 were able to inhibit oxygen consumption and modify the rate of glycolysis in macrophages, suggesting that they could also alter the levels of ATP/ADP. Since low levels of ATP could stimulate AMPK pathway, this signaling pathway was also investigated in our study. However, the results on the AMPK activation were inconclusive. Thus, our results demonstrate that the new derivatives of TZDs do not act as PPARγ ligands, present insulin sensitizing activity in vitro, and display minor antiosteoblastic and adipogenic effects when compared to Rosiglitazone. More studies are needed to elucidate the exact mechanisms responsible for these effects, as well as to establish whether the safety of the new TZDs with respect to the risk of bone fractures and body mass gain using in vivo models.
4

Pharmacological intervention in type 2 diabetes observational studies and bias related issues /

Lévesque, Linda Estelle. January 1900 (has links)
Thesis (Ph.D.). / Written for the Dept. of Epidemiology and Biostatistics. Title from title page of PDF (viewed 2008/05/09). Includes bibliographical references.
5

Avaliação da atividade imunomoduladora de novos derivados tiazolidínicos em células do sangue periférico de pacientes portadores de Psoríase

CARDOSO, Pablo Ramon Gualberto 15 April 2014 (has links)
Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-06-29T13:21:09Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Pablo Cardoso 2014.pdf: 3350391 bytes, checksum: 407ec26dd181ec31e5ed50bee8e4f25a (MD5) / Made available in DSpace on 2016-06-29T13:21:09Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Pablo Cardoso 2014.pdf: 3350391 bytes, checksum: 407ec26dd181ec31e5ed50bee8e4f25a (MD5) Previous issue date: 2014-04-15 / FACEPE / Introdução: A psoríase afeta cerca de 2-3% da população. Esta doença é uma dermatite crônica, recorrente e tem envolvimento inflamatório mediado por células T. A apresentação mais comum da psoríase é o envolvimento da pele com placas eritematosas bem definidas, escamosas, de posição e tamanhos variados. Na placa psoriásica há uma disfunção imunológica que envolve vários tipos celulares e mediadores inflamatórios, como citocinas, tal qual IL -17A. Estuda-se uma atividade imunomoduladora dos derivados tiazolidinadionas (TZD). Esta classe de medicamentos tem uma possível ação anti-inflamatória, e pode ser capaz de reduzir as lesões de psoriásicas. Materiais e Métodos: Portanto, decidiu-se estudar três novos derivados TZD em células mononucleadas do sangue periférico (PBMC) de pacientes com psoríase. Depois da confirmação da estrutura química, os compostos LPSF-SF-33, LPSF-SF-34 e LPSF-SF-35 foram adicionados em cultura de PBMC estimuladas ou não com PMA/Iono. Após 48h os sobrenadantes destas culturas foram utilizados para a avaliação da IL-17A, IL-22 e IL-6. Resultados: O LPSF-SF-33 mostrou uma boa atividade imunomoduladora, reduzindo os níveis de IL - 17A e IL - 22 no sobrenadante de cultura em comparação com a estimulação por PMA/Iono. O LPSF-SF-34 mostrou bons resultados de inibição de IL-17A e IL-22 e ainda em todas as doses foi mais eficaz do que a metilprednisolona, droga padrão, na redução da IL-22. O composto do LPSF-SF-35 diminuiu a produção de IL-17A e IL-22 e também foi capaz de diminuir a produção de IL-6 quando comparado com PMA/Iono. Conclusão: Estes novos derivados tiazolidínicos LPSF-SF-33, LPSF-SF-34 and LPSF-SF-3 são capazes de inibir a produção de IL-17A, IL-22 e IL-6 em doses diferentes e o efeito pode indicar melhoria da inflamação. / Introduction: Psoriasis affects about 2-3% of the population. This is a chronic dermatitis, recurrent and inflammatory disease mediated by T cells. The most common presentation of psoriasis is skin involvement with well-defined and demarcated erythematous plaque, scaly, and random position in the patient's body. In psoriatic plaque, there is an immune dysfunction involving many cell types and inflammatory mediators such as cytokines like IL-17A. There is an immunomodulatory activity of thiazolidinedione derivatives. This class of drugs has a possible anti-inflammatory action, may be able to mitigate the psoriatic lesions. Objectives and Methods: Therefore, we decided to study three new TZD derivatives in PBMC of patients with Pso. After chemical structure confirmation, the thiazolidinedione derivatives LPSF-33, LPSF-34 and LPSF-35 were prepared in culture of PBMC, stimulated or not with PMA / Iono. After that, the supernatant of these cultures were used for IL-17A, IL-22 and IL-6 evaluation. Discussion: The three new TZDs tested were able to reduce the expression of IL-17A and IL-22 at different doses compared to PMA/Iono, but only LPSF-SF-35 was able to reduce a significant IL-6 levels. The compounds differ in their molecular structure that is added by the radical and perhaps the LPSF-SF-35 has been better because in its final structure it features a pyridine. Conclusion: The new thiazolidinedione derivatives LPSF-SF-33, LPSF-SF-34 and LPSF-SF-35 are capable of inhibiting the production of IL-17A, IL-22 and IL-6 at different doses and the effect may indicate improvement in inflammation.
6

Atividade de novos derivados de tiazolidinodionas sobre a diferenciação de pré-osteoblastos e pré-adipócitos / Activity of new derivatives of thiazolidinediones on differentiation of preosteoblasts and preadipocytes

Cristiane Akemi Iamamoto Saito 06 February 2015 (has links)
As tiazolidinodionas (TZDs) são sensibilizadores de insulina utilizados no tratamento do diabetes mellitus tipo 2. Contudo, apesar dos efeitos benéficos sobre a glicemia, importantes efeitos adversos incluindo perda óssea e aumento de adiposidade são relatados com o uso clínico das TZDs. Assim, é necessário o desenvolvimento de novos derivados de TZDs com potenciais efeitos benéficos sobre a hiperglicemia e menos efeitos adversos. Neste estudo, investigamos os efeitos de 5 novos derivados de TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) sobre a diferenciação celular de pré-osteoblastos murinos MC3T3-E1, pré-adipócitos murinos 3T3-L1 e pré-adipócitos SGBS de linhagem humana. Seus potenciais efeitos sobre a utilização de glicose, a produção de adipocinas e mediadores pró-inflamatórios também foram avaliados, utilizando linhagens murinas e humanas de adipócitos, e macrófagos THP-1 de linhagem humana. O principal achado de nosso estudo foi que os novos derivados de TZDs estimulam a utilização celular de glicose, porém não alteram o processo de diferenciação celular de pré-osteoblastos e pré-adipócitos, quando comparados com a TZD clássica Rosiglitazona. Conforme esperado, o tratamento com Rosiglitazona na concentração de 5 μM inibiu a osteogênese de pré-osteoblastos murinos MC3T3-E1. No entanto, o tratamento com 2 novos derivados de TZDs (GQ-89 e GQ-177) na mesma concentração não afetou a diferenciação celular, sendo possível observar níveis de mineralização de matriz extracelular similares aos do grupo controle. Além disso, enquanto a GQ-89 estimulou a atividade da fosfatase alcalina, a GQ-177 não modulou sua atividade enzimática e induziu a expressão gênica de osteocalcina. Contudo, ambos inibiram a expressão de Runx2 e colágeno. Por sua vez, quando os efeitos foram avaliados sobre a diferenciação de adipócitos, foi possível observar que ao contrário do efeito pró-adipogênico constatado com a Rosiglitazona na concentração de 1 μM, as TZDs GQ-150, GQ-177, LYSO-7 e SF-3 foram incapazes de induzir o acúmulo lipídico em pré-adipócitos murinos e humanos. Além disso, a GQ-150 inibiu a expressão gênica de C/EBPα, assim como a expressão gênica e os níveis protéicos de CD36, enquanto que a SF-3 estimulou a expressão gênica de C/EBPα e de FABP4 e diminuiu a expressão gênica e os níveis protéicos de CD36, os quais não foram modificados pela LYSO-7 em pré-adipócitos murinos 3T3-L1. No entanto, em pré-adipócitos SGBS de linhagem humana, nenhum efeito sobre os marcadores de fenótipo adipogênico C/EBPα e FABP4 foi observado com os novos derivados de TZDs. Ademais, os novos derivados de TZDs não interferiram na via de sinalização de Wnt, não apresentaram qualquer efeito sobre a expressão de adipocinas (adiponectina, resistina e leptina) e mediadores pró-inflamatórios (IL-6, CCL2/MCP-1, TNF-α e JNK), bem como não ativaram o fator de transcrição PPARγ no ensaio de gene repórter. Por sua vez, a LYSO-7, GQ-150 e SF-3 aumentaram o consumo de glicose em presença de insulina em adipócitos 3T3-L1 e modificaram a atividade de enzimas mitocondriais em adipócitos SGBS e macrófagos THP-1. Entretanto, o efeito sensibilizador de insulina foi confirmado somente com a GQ-177 pelo aumento da captação de glicose e somente a LYSO-7 e a SF-3 foram capazes de inibir o consumo de oxigênio e modificar a taxa de glicólise em macrófagos, sugerindo que também poderiam alterar os níveis de ATP/ADP. Considerando que baixos níveis de ATP estimulam a via de sinalização de AMPK, essa via também foi investigada em nosso estudo. Entretanto, os resultados sobre a ativação de AMPK foram inconclusivos. Desse modo, nossos resultados apontam que os novos derivados de TZDs não atuam como ligantes de PPARγ, apresentam atividade sensibilizadora de insulina in vitro, e que exercem menores efeitos antiosteoblásticos e adipogênicos quando comparados com a Rosiglitazona. Mais estudos são necessários para elucidar os mecanismos responsáveis por esses efeitos, bem como para estabelecer se os novos derivados de TZDs são mais seguros in vivo, com relação ao risco de fraturas ósseas e ganho de massa adiposa. / Thiazolidinediones (TZDs) are insulin sensitizers used in the treatment of type 2 diabetes mellitus. However, despite the beneficial effects on blood glucose, significant adverse effects including bone loss and increased adiposity are reported with the clinical use of TZDs. Thus, it is necessary to develop new derivatives of TZDs with potential beneficial effects on hyperglycemia and fewer adverse effects. In this study, we investigated the effects of 5 new derivatives of TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) on cellular differentiation in murine MC3T3-E1 preosteoblasts, murine 3T3-L1 preadipocytes, and SGBS preadipocytes from human lineage. Potential effects on glucose consumption, adipokines, and pro-inflammatory mediators were also assessed using murine and human strains of adipocytes, and macrophages from human THP-1 lineage. The main finding of this study was that new derivatives of TZDs stimulate glucose consumption, but do not change the cell differentiation process of preosteoblasts and preadipocytes compared to classical TZD Rosiglitazone. As expected, the treatmet with Rosiglitazone, at 5μM, inhibited the osteogenesis in murine MC3T3-E1 preosteoblasts. However, the treatment with 2 new derivatives of TZDs (GQ-89 and GQ-177) at the same concentration did not affect cell differentiation, and levels of mineralization of the extracellular matrix similar to the control group were observed. In addition, whereas the GQ-89 stimulated the activity of alkaline phosphatase, GQ-177 does not modulate its enzymatic activity and induced gene expression of osteocalcin. However, both of them inhibit the expression of Runx2 and collagen. In turn, when the effects were assessed on the adipocyte differentiation, unlike the proadipogenic effect observed with Rosiglitazone at a concentration of 1 μM, the new TZDs GQ-150, GQ-177, LYSO-7 and SF-3 were unable to induce lipid accumulation in human and murine preadipocytes. In addition, GQ-150 inhibited the gene expression of C/EBPα , as well as the gene expression and protein levels of CD36, whereas SF-3 stimulated the gene expression of C/EBPα and FABP4 and decreased gene expression and protein levels of CD36, which was not modified by LYSO-7 on murine 3T3- L1 preadipocytes. However, no effect on markers of adipogenic phenotype C/EBPα and FABP4 has been observed with the novel derivatives of TZDs in human SGBS preadipocytes. Furthermore, the new derivatives of TZDs do not interfere with the Wnt signaling pathway, showed no effect on the adipokines expression (adiponectin, resistin and leptin) and proinflammatory mediators (IL-6, CCL2 / MCP-1, TNF α and JNK) and did not activate the transcription factor PPARγ in the gene reporter assay. In turn, LYSO-7, GQ-150, and SF-3 increased glucose consumption in the presence of insulin in 3T3-L1 adipocytes and modified the activity of mitochondrial enzymes in SGBS adipocytes and THP-1 macrophages. However, the effect on insulin sensitization was confirmed only to GQ-177 that increased glucose uptake and just LYSO-7 and SF-3 were able to inhibit oxygen consumption and modify the rate of glycolysis in macrophages, suggesting that they could also alter the levels of ATP/ADP. Since low levels of ATP could stimulate AMPK pathway, this signaling pathway was also investigated in our study. However, the results on the AMPK activation were inconclusive. Thus, our results demonstrate that the new derivatives of TZDs do not act as PPARγ ligands, present insulin sensitizing activity in vitro, and display minor antiosteoblastic and adipogenic effects when compared to Rosiglitazone. More studies are needed to elucidate the exact mechanisms responsible for these effects, as well as to establish whether the safety of the new TZDs with respect to the risk of bone fractures and body mass gain using in vivo models.
7

Appropriateness of the use of Thiazolidinediones for the treatment of Type 2 Diabetes Mellitus at the Southern Arizona Veterans Affairs Hospital

Fletcher, Glory, Tincombe, Darcy January 2005 (has links)
Class of 2005 Abstract / Objectives: The purpose of the study was to evaluate if rosiglitazone was being used in full compliance with the SAVA consensus criteria for appropriate use of thiazolinediones. Methods: A retrospective chart review was performed on 50 SAVA patients selected at random from a list of patients that were on rosiglitazone treatment as of March 15, 2005. Results: The percent of patients who met all of the criteria set forth by the SAVA when initiating therapy was 44%. Rosiglitazone treatment should not have been started in 28 out of the 50 patients. Once initiated on rosiglitazone, patients’ follow-up ALT was only obtained in 16% of patients. Once rosiglitazone has been prescribed for 3 months, HbA1c should decrease. Twenty percent of the patients showed an increase in HbA1c from baseline and were continued on the medication despite the criteria. Implications: Once therapy was initiated, the majority of patients studied failed to meet the SAVA guidelines for the appropriate use of rosiglitazone. In addition, a majority failed to follow the aspects of the guideline regarding initiation of rosiglitazone therapy.
8

Thiazolidinediones: from peroxisome-proliferator-activated receptor γ(PPARγ) to anticancer agents

Shiau, Chung-Wai 08 November 2005 (has links)
No description available.
9

Etude du facteur de transcription précoce EGR1 dans l'effet antiprolifératif des ligands de PPAR[gamma] sur les cellules cancéreuses mammaires / Study of the early transcription factor EGR1 in the antiproliferative effect of PPAR[gamma] ligands in breast cancer cells

Chbicheb, Sarra 22 June 2011 (has links)
Les ligands des récepteurs nucléaires PPAR[gamma] (15-deoxy-[delta]12,14-Prostaglandine J2 (15d-PGJ2) et les thiazolidinediones (TZDs) : troglitazone (TGZ), ciglitazone (CGZ)) exercent un effet antiprolifératif sur les lignées cancéreuses mammaires. Plusieurs études suggèrent que les effets anticancéreux sont liés à des effets PPAR[gamma]-indépendants. Notre travail s?inscrit dans la compréhension de tels mécanismes d?action. Notre étude a montré une induction du facteur de transcription EGR1 (Early Growth Response gene 1) par certains ligands de PPAR[gamma] (TGZ, CGZ, 15d-PGJ2 et [delta]2-TGZ (agoniste inactif de PPAR[gamma])) dans les cellules cancéreuses mammaires hormono-dépendantes MCF7. Cet effet est précoce et PPAR[gamma]-indépendant. Il est lié à une libération quasi immédiate de calcium intracellulaire suivie de l?activation des ERK1/2. L?induction d?EGR1 a aussi lieu dans les cellules hormono-indépendantes MDA-MB-231 exposées à la [delta]2-TGZ. Cependant, l?induction d?EGR1 ne joue qu?un rôle partiel dans l?effet antiprolifératif. Les données d?une analyse par puce à ADN ont suggéré l?induction d?un stress du réticulum endoplasmique (RE) dans les cellules MCF7 exposées à la [delta]2-TGZ. Des analyses complémentaires ont confirmé que la [delta]2-TGZ induit un tel stress dans les cellules MCF7 et MDA-MB-231. Cependant, le rôle du stress du RE dans l?effet antiprolifératif de la [delta]2-TGZ reste à déterminer. Nous avons enfin testé l?hypothèse d?un lien entre EGR1 et stress du RE. En effet, EGR1 est aussi induit précocement par d?autres inducteurs de stress du RE. Les diverses situations où l?induction d?EGR1 est inhibée suggèrent une régulation possible de l?expression du facteur de transcription ATF3 par EGR1 / The ligands of PPAR[gamma] nuclear receptors (15-deoxy-[delta]12,14-Prostaglandin J2 (15d-PGJ2) and thiazolidinediones (TZDs) : troglitazone (TGZ), ciglitazone (CGZ)) show antiproliferative effects on breast cancer cell lines. Several studies suggest that the anti-cancer effects are PPAR[gamma]-independent. Our work is focused on the comprehension of such mechanisms of action. Our study has shown the induction of the transcription factor EGR1 (Early Growth Response gene 1) by some PPAR[gamma] ligands (TGZ, CGZ, 15d-PGJ2, and [delta]2-TGZ (PPAR[gamma] inactive agonist)) in the hormone-dependent breast cancer cells MCF7. This early effect is PPAR[gamma]-independent. It is associated with the almost immediate release of intracellular calcium followed by the activation of ERK1/2. EGR1 induction also occurs in the hormone-independent breast cancer cells MDA-MB-231 treated with [delta]2-TGZ. However, EGR1 induction plays only a partial role in the antiproliferative effect. Data analysis of DNA array has suggested the induction of an endoplasmic reticulum stress (ER) in MCF7 cells treated with [delta]2-TGZ. Complementary data have confirmed this result in MCF7 cells and in MDA-MB-231 cells. However, the role of ER stress in the antiproliferative effect is still to be determined. Finally, we have tested the hypothesis of a link between EGR1 and ER stress. Indeed, EGR1 is also early induced by other ER stress inductors. Diverse conditions where EGR1 is inhibited suggest a possible regulation of ATF3 expression by EGR1
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Métabolisme énergétique et traitements anticancéreux : caractérisation des effets de la Δ2-troglitazone et du 2-désoxyglucose sur les cellules d’adénocarcinomes mammaires / Energetic metabolism and anticancer treatments : study of Δ2-troglitazone and 2-deoxyglucose effects on breast cancer cells

Berthe, Audrey 10 July 2017 (has links)
L’absence de réponse et la résistance des cellules cancéreuses mammaires aux thérapies actuelles justifient de développer de nouveaux traitements. Une stratégie prometteuse consiste à cibler le métabolisme énergétique des cellules cancéreuses. Dans ce contexte, des thiazolidinediones (TZD) présentent des effets antiprolifératifs qui pourraient résulter d’une atteinte du métabolisme énergétique. Notre laboratoire étudie des TZD dérivées de la troglitazone (TGZ). Durant cette thèse, nous avons cherché à déterminer si la Δ2-Troglitazone (Δ2-TGZ) modifie le métabolisme énergétique des cellules cancéreuses mammaires. Jusqu’à présent, les expériences menées au laboratoire étaient réalisées dans un milieu de culture contenant 1% de sérum de veau fœtal (SVF) qui crée un stress peu propice à l’étude du métabolisme. Nous avons donc d’abord caractérisé les effets de la Δ2-TGZ dans un milieu de culture contenant 10% SVF. Dans ces conditions, la Δ2-TGZ diminue toujours la prolifération des cellules cancéreuses mammaires, mais les doses requises sont plus élevées. En outre, la Δ2-TGZ induit des effets cytostatiques plutôt que l’apoptose. Nous avons ensuite montré que la Δ2-TGZ induit une perturbation du métabolisme énergétique, consistant en un blocage de la respiration mitochondriale que les cellules semblent compenser en stimulant la glycolyse. En parallèle, nous avons caractérisé le mode d’action du 2-désoxyglucose dont l’action antiproliférative dans les cellules cancéreuses mammaires est due à l’inhibition de la glycolyse et à la perturbation de la N-glycosylation des protéines. Il reste à déterminer la part des altérations métaboliques dans l’action anti-cancéreuse de la Δ2-TGZ / The absence of response and the resistance of cancer cells to therapies are strong arguments for the development of new therapeutic strategies. Data from the literature suggest that it could be interesting to target energy metabolism of cancer cells. In this context, thiazolidinediones (TZDs) display antiproliferative effects that could be the result of energy metabolism alteration. During this PhD, we aimed at determining if Δ2-Troglitazone (Δ2-TGZ) could modify energy metabolism of breast cancer cells. The experiments performed previously used a culture medium containing 1% of fetal calf serum (FCS) that is rather a stress inducing condition that can disturb cell metabolism. Thus, we first characterized the effects of Δ2-TGZ in a 10% FCS containing medium. In this case, Δ2-TGZ still decreases cell proliferation of breast cancer cells, but it requires high doses. Besides, Δ2-TGZ induces cell cycle arrest instead of apoptosis. Then, we have shown that Δ2-TGZ induced modifications of energy metabolism, which are due to a decrease in oxidative phosphorylation. We also observed an increase in glycolytic activity that is probably a compensatory mechanism. During this part of our work, we have also characterized the mechanisms involved in the anticancer activity of 2-deoxyglucose. We have shown that in breast cancer cells, this compound acts not only by glycolysis inhibition but also by protein N-glycosylation alteration. We have now to determine the part of metabolic alterations that are involved in the anti-cancer effects of Δ2-TGZ

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