published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Access to abstract permanently restricted to Ball State community only. / Access to thesis permanently restricted to Ball State community only. / Department of Physiology and Health Science

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 263-321) Also available in print.

A farmacocinética dos enantiômeros da ciclofosfamida (CPA) foi avaliada em pacientes portadores de nefrite lúpica distribuídos em dois grupos de acordo com o clearance da creatinina: Grupo 1 90,6-144,6mL/min/1,73m2 e Grupo 2 42,8-76,4mL/min/1,73m2. Os pacientes foram tratados com doses de 0,75 a 1,3g de ciclofosfamida racêmica sob forma de infusão com duração de 2h e com 1mg de midazolam (MDZ) administrado via endovenosa para a avaliação da atividade in vivo do CYP3A. As concentrações plasmáticas dos enantiômeros da CPA e do MDZ foram avaliadas por LC-MS/MS. Os enantiômeros da CPA foram resolvidos na coluna Chiralcel OD-R, com fase móvel constituída por mistura de acetonitrila e água (75:25, v/v) adicionada de 0,2% de ácido fórmico. Os enantiômeros da CPA foram extraídos do plasma com recuperações maiores que 95% e o limite de quantificação obtido foi de 2,5ng de cada enantiômero da CPA/mL plasma. As seguintes diferenças (teste de Wilcoxon, p<0,05) foram observadas nos parâmetros farmacocinéticos entre os enantiômeros (S)-(-)-CPA e (R)-(+)-CPA para os pacientes do Grupo 1: AUC do tempo 0 ao infinito 152,41 vs 129,25g.h/mL; Cl 3,28 vs 3,89L/h; Vd 31,38 vs 29,74L e t1/2 6,79 vs 5,56h e para os pacientes do Grupo 2: AUC do tempo 0 ao infinito 167,20 vs 139,08g.h/mL; Cl 2,99 vs 3,59L/h e t1/2 6,15 vs 4,99h. Não foi observada diferença (teste de Mann-Whitney, p<0,05) nos parâmetros farmacocinéticos de ambos os enantiômeros entre os grupos 1 e 2. Não foi observada corrrelação entre o clearance do MDZ (2,92-16,40ml/min.kg) e o clearance de cada enantiômero da CPA. Concluindo, a farmacocinética da CPA é enantiosseletiva em pacientes portadores de nefrite lúpica com acúmulo plasmático do enantiômero (S)-(-)-CPA e a farmacocinética de ambos os enantiômeros da CPA não é alterada pela agravamento da função renal. / The pharmacokinetics of cyclophosphamide (CYC) enantiomers was evaluated in patients with lupus nephritis distributed in two groups according to creatinine clearance; Group 1 - 90.6-144.6mL/min/1.73m2 and Group 2 - 42.8- 76.4mL/min/1.73m2. All patients were treated with 0.75 to 1.3g of racemic CYC as a 2-hour infusion and with 1mg intravenous midazolam as a drug marker. CYC enantiomers and midazolam concentrations in plasma were measured by LC-MS/MS. CYC enantiomers were separated on a Chiralcel OD-R column, with the mobile phase consisting of a mixture of acetonitrile and water (75:25, v/v) plus 0.2% formic acid. Recovery rates were higher than 95% and the quantification limit was 2.5ng/ml plasma for both enantiomers. The coefficients of variation and the relative errors obtained for the validation of intra- and interassay precision and accuracy were less than 10%. The following differences in the pharmacokinetic parameters (Wilcoxon test, p<0.05) were observed between the (S)-(-) and (R)-(+) enantiomers for Group 1 AUC from time 0 to infinity 152.41 vs 129.25g.h/mL, Cl 3.28 vs 3.89L/h, Vd 31.38 vs 29.74L and t1/2 6.79 vs 5.56h and for Group 2 AUC from time 0 to infinity 167.20 vs 139.08g.h/mL, Cl 2.99 vs 3.59 L/h and t1/2 6.15 vs 4.99 h. No differences (Mann-Whitney test, p<0.05) were observed between Groups 1 and 2 in the pharmacokinetics parameters of both enantiomers. No significant relationship was observed between midazolam clearance (2.92-16.40 ml/min.kg) and clearance of each CYC enantiomer. In conclusion, CYC kinetic disposition is enantioselective resulting in higher exposure of (S)-(-)-CYC in lupus nephritis patients and the pharmacokinetic parameters of both enantiomers are not altered by the worsening of renal condition.

Orientadores: Simone Appenzeller, Lilian Tereza Lavras Costallat, Roberto Marini / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T13:05:21Z (GMT). No. of bitstreams: 1 Pelicari_KarinadeOliveira_M.pdf: 707715 bytes, checksum: 41d920f7671a64c2ce3b93fd4dbcdf3f (MD5) Previous issue date: 2013 / Resumo: Lúpus Eritematoso Sistêmico (LES) e uma doença autoimune, crônica e mutissistemica, caracterizada por períodos de atividade e remissão. Anormalidades hematológicas e imunológicas são comumente encontrados. A avaliação laboratorial, incluindo o perfil de citosinas, auxilia no diagnostico e na determinacao da atividade da doença. O presente estudo, de característica transversal, teve como objetivo avaliar os níveis de IL- 17 em pacientes com LESj (inicio da doença ?16 anos), familiares de primeiro grau e controles sadios e ainda elucidar sua associação com a atividade da doença, dados laboratoriais e de tratamento. Foram selecionados pacientes consecutivos com LESj acompanhados na Unidade de Reumatologia Pediátrica da UNICAMP entre 2009/2011. Manifestações clinicas, laboratoriais, atividade da doença [SLE Disease Activity Index (SLEDAI)], dano cumulativo [Lúpus International Collaborating Clinics / American College of Rheumatology Damage Index (SDI)] e medicação em uso foram avaliados. Os transtornos de humor foram determinados através dos inventários de Depressão (BDI) e Ansiedade (BAI) de Beck. A dosagem da citosina foi realizada por ELISA. Níveis séricos de IL-17 estavam aumentados no LESj (p?0,05) quando comparado controles sadios. Observamos uma associação entre os níveis séricos de IL-17 e migranea (p = 0,03) e nefrite (p = 0,01). Níveis de IL-17 não foram associados com atividade da doença (p = 0,32), dano cumulativo (p = 0,34), medicação (p = 0,63), ansiedade (p = 0,42) e depressão (p = 0,42). Estudos longitudinais sao necessários para determinar se a dosagem de IL-17 pode ser utilizado como um biomarcador em LESj / Abstract: Systemic lupus erythematosus (SLE) is a chronic, multisistemic autoimmune disease, , characterized by periods of activity and remission. Haematological and immunological abnormalities are commonly observed. Laboratory evaluation, including the cytokine profile, aids in the diagnosis and determination of disease activity. The present transverse study, we aimed to evaluate levels of IL-17 in patients with childhood-onset SLE (cSLE) (disease onset ? 16 years), first-degree relatives and healthy controls and to determine the association between IL-17 levels and disease activity, laboratory data and treatment. We selected consecutive patients with cSLE followed at the Pediatric Rheumatology Unit at UNICAMP between 2009/2011. Clinical, laboratory, disease activity [SLE Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index (SDI)] and medication use were assessed. Mood disorders were measured using the Beck's Depression Inventory (BDI) and Anxiety Inventory (BAI). Determination of cytokine levels was carried out by ELISA. Serum levels of IL-17 were increased in SLE (p ? 0.05) when compared to healthy controls. An association was observed between serum IL-17 levels and migraine (p = 0.03) and nephritis (p = 0.01). IL-17 levels were not associated with disease activity (p = 0.32), cumulative damage (p = 0.34), medication (p = 0.63), anxiety (p = 0.42) and depression (p = 0.42). Longitudinal studies are needed to determine if serum IL-17 levels can be used as a biomarker in SLE / Mestrado / Clinica Medica / Mestra em Ciências

Orientadores: Simone Appenzeller, Lilian Teresa Lavras Costallat / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T20:43:38Z (GMT). No. of bitstreams: 1 Postal_Mariana_M.pdf: 2371381 bytes, checksum: f17ddfd3643881ea1b2d3482a2de1cb8 (MD5) Previous issue date: 2012 / Resumo: Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune, crônica e mutissistêmica, caracterizada por períodos de atividade e remissão. O interesse em identificar biomarcadores que se correlacionem com a atividade sistêmica do LES e que possam predizer um envolvimento orgânico futuro é crescente. O presente estudo, de característica transversal, teve como objetivo avaliar os níveis de interferon alfa (INF-?) e fator de necrose tumoral alfa (TNF-?) em pacientes com LES juvenil (LESj) (início da doença?16 anos), familiares de primeiro grau e indivíduos sadios não aparentados e elucidar sua associação com a atividade da doença, dados laboratoriais e de tratamento. Foram selecionados pacientes consecutivos com LESj acompanhados na Unidade de Reumatologia Pediátrica da UNICAMP entre 2009/2010. Manifestações clínicas, laboratoriais e medicação em uso foram avaliadas. A atividade da doença [SLE Disease Activity Index (SLEDAI)], dano cumulativo [Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)] foi determinado para cada paciente no dia da coleta de sangue. Os transtornos de humor foram determinados através dos inventários de Depressão (BDI) e Ansiedade (BAI) de Beck. A dosagem das citocinas foi realizada por ELISA (Enzyme Linked Immuno Sorbent Assay). Níveis séricos de INF-? e TNF-? estavam aumentados no LESj quando comparado a familiares de primeiro grau e indivíduos sadios não aparentados. Níveis séricos de INF-? e de TNF-? foram significativamente maiores em pacientes com doença ativa (p=0,031; p=0,014, respectivamente). INF-? (r=0,33; p=0,012) e TNF-? (r=0,39; p=0,002) correlacionaram-se com SLEDAI. INF-? foi significativamente maior em pacientes com anti-dsDNA positivo (p=0,011), pacientes com vasculite cutânea (p=0,001), pacientes com rash malar (p=0,032) e em pacientes sem medicação (p=0,035). Níveis séricos de INF-? correlacionaram-se com níveis de C3 (r=0,34; p=0,032) e idade (r=-0,17; p=0,025). Níveis séricos de TNF-? foram significativamente maiores em pacientes com nefrite (p=0,009) e em pacientes com depressão (p=0,001). De acordo com nossos resultados, INF-? e TNF-? estiveram associados com a atividade da doença e poderiam ser considerados biomarcadores para avaliar atividade, porém estudos longitudidinais são necessários para determinar se o aumento dessas citocinas pode prever períodos de atividade em pacientes com LESj / Abstract: Systemic lupus erythematosus (SLE) is a chronic, multisystemic, relapsing and remitting autoimmune disease. The interest in identifying biomarkers that correlate with the SLE systemic activity and that can predict a future organ involvement is growing. The present cross-sectional study aimed to assess the levels of interferon alpha (IFN-?) and tumor necrosis factor alpha (TNF-?) in pediatric SLE patients (disease onset ?16 years), first-degree relatives and healthy unrelated controls and to elucidate its association with the activity disease, laboratory data and treatment. We selected consecutive pediatric SLE patients followed at the Pediatric Rheumatology Unit of UNICAMP between 2009/2010. Clinical, laboratory, disease activity [SLE Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index (SDI)] and current drug exposure were evaluated. Mood disorders were determined through the Depression (BDI) and Anxiety (BAI) Becks Inventory. The measurement of cytokines was performed by ELISA (Enzyme Linked Immuno Sorbent Assay). Serum levels of INF-? and TNF-? were increased in pediatric SLE patients (p?0.05) when compared to first-degree relatives and unrelated healthy controls. Serum levels of INF-? and TNF-? were significantly higher in patients with active disease (p=0.031; p=0,014, respectively). INF-? (r=0.33; p=0.012) and TNF-? (r=0.39; p=0.002) correlated with SLEDAI. INF-? was significantly higher in patients with positive anti-dsDNA (p=0.011), patients with cutaneous vasculitis (p=0.001), patients with malar rash (p=0.032) and patients without medication (p=0.035). Serum levels of IFN-? correlated with C3 levels (r=0.34; p=0.032) and age (r=-0.17; p=0.025). Serum levels of TNF-? were significantly higher in patients with nephritis (p=0.009) and in patients with depression (p=0.001). According to our results, IFN-? and TNF-? were associated with disease activity and could be considered biomarkers to assess disease activity in pediatric SLE patients, however longitudinal studies are needed to determine if increase of these cytokines may predict flares in pediatric SLE patients / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

Background. Lupus nephritis (LN) can be complicated with requirement for kidney replacement therapy and death. Efficacy of induction therapies using mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVCYC) has been reported from studies, but there is limited data in Africans comparing both treatments in patients with proliferative LN. Methods. This was a retrospective study of patients with biopsy-proven proliferative LN diagnosed and treated with either MMF or IVCYC in a single centre in Cape Town, South Africa, over a 5-year period. *e primary outcome was attaining complete remission after completion of induction therapy. Results. Of the 84 patients included, mean age was 29.6 ± 10.4 years and there was a female preponderance (88.1%). At baseline, there were significant differences in estimated glomerular filtration rate (eGFR) and presence of glomerular crescents between both groups (p ≤ 0.05). After completion of induction therapy, there was no significant difference in remission status (76.0% versus 87.5%; p = 0.33) or relapse status (8.1% versus 10.3%; p = 0.22) for the IVCYC and MMF groups, respectively. Mortality rate for the IVCYC group was 5.5 per 10,000 person-days of follow-up compared to 1.5 per 10,000 person-days of follow-up for the MMF group (p = 0.11), and there was no significant difference in infection-related adverse events between both groups. Estimated GFR at baseline was the only predictor of death (OR: 1.0 [0.9–1.0]; p = 0.001). Conclusion. This study shows similar outcomes following induction treatment with MMF or IVCYC in patients with biopsy-proven proliferative LN in South Africa. However, a prospective and randomized study is needed to adequately assess these outcomes.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20270号 / 医博第4229号 / 新制||医||1021(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 亮, 教授 福原 俊一, 教授 小川 修 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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