Diss. (sammanfattning) Linköping : Univ., 2001. / Härtill 5 uppsatser.

Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 131-142). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2008. / Härtill 5 uppsatser.

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Pharmaceutical Science." Includes bibliographical references (p. 98-107).

Erythromycin, a macrolide antibiotic used mainly against gram-positive bacteria has been in clinical use since 1952 (1). Previous pharmacokinetic data published on this antibiotic have been derived predominantly from microbiological assay techniques. However, these techniques are relatively imprecise as well as being non-specific and extremely tedious to perform. A novel high performance liquid chromatographic analysis of erythromycin in human serum and urine using U.V. detection at 200 nm and/or electrochemical detection using both an amperometric and a coulometric electrochemical detector is presented. The method involves a solid phase extraction procedure followed by a simple phase separation step and chromatography on a reverse phase column. In order to select the optimum U.V. detector for this analysis, five "state of the art" detectors were compared in terms of their signal-to-noise ratios at U.V. wavelengths between 200 and 210 nm. A known metabolite des-N-methylerythromycin is readily detectable using U.V. detection, whilst another metabolite/degradation product anhydroerythromycin is not seen using U.V. detection but is readily observable using an electrochemical detector. The method has a limit of sensitivity of 0.25 μg/mL and 1.00 μg/mL in serum and urine respectively (U.V. detection) and is sufficiently sensitive to monitor serum and urine concentrations of erythromycin in man after administration of a single 500 mg erythromycin stearate tablet. / KMBT_363 / Adobe Acrobat 9.53 Paper Capture Plug-in

The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.

Objetivos: Simular um ajuste de dose em pacientes com sobrepeso e com obesidade que utilizam a doxorrubicina (DOX), que proporcione curvas de concentração plasmática e concentrações máximas (Cmáx) semelhantes às de pacientes com peso normal. Metodologia: Determinou-se as concentrações plasmáticas de DOX em pacientes com câncer de mama após a administração i.v. de 60 mg/m2, com ajuste de dose pelo BSA e com tempo de infusão de 40 minutos (0,66 h). As pacientes foram divididas em três grupos: a) pacientes com peso normal (IMC até 24,9) (n = 3); b) pacientes com sobrepeso (IMC 25,0 – 29,9) (n = 5); c) pacientes com obesidade (IMC acima 30,0) (n = 2). Os tempos de coleta utilizados foram: 0,66, 1,66, 8,66, e 24,66 h. Os perfis farmacocinéticos da DOX foram avaliados após quantificação da DOX através de metodologia por CLAE desenvolvida e validada. Resultados e Discussão: Os parâmetros farmacocinéticos ASC e Cmáx foram analisados por abordagem não-compartimental e compartimental. Em ambas as análises encontraram-se diferenças significativas (α = 0,05) entre os grupos com sobrepeso e com obesidade comparados com o grupo com peso normal para ASC e diferenças significativas entre o grupo com sobrepeso comparado ao grupo de pacientes com peso normal para o Cmáx. Após simulação de ajuste de dose pelo peso e pelo IMC, para as pacientes com sobrepeso e obesas, obtivemos novos valores de ASC e Cmáx. Houve diferenças significativas (α = 0,05) para o grupo de pacientes com sobrepeso comparado ao grupo com peso normal para a ASC e nenhuma diferença significativa entre os grupos estudados para Cmáx. Os percentuais de diferença da ASC e Cmáx do grupo das pacientes com sobrepeso e obesas comparados com o grupo de pacientes com peso normal foram diminuindo quando a dose era ajustada pelo peso e IMC. Conclusões: O ajuste de dose pelo índice BSA, comumente usado na prática clínica, não produz concentrações plasmáticas iguais em grupos de pacientes com peso normal e com sobrepeso, indicando que outros índices devem ser considerados, como peso e IMC. / Objectives: to simulate a dose adjustment in patients with overweight and obesity using doxorrubicin (DOX), providing plasma concentrations similar to those of patients with normal weight. Methodology: plasma concentrations of DOX were determined in patients with breast cancer after the iv. administration of 60 mg/m2 of DOX, adjusted by the BSA and with an infusion time of 40 minutes (0.66 h). The patients were divided into three groups: (a) patients with normal weight (BMI < 24.9) (n = 3); b) patients with overweight (BMI 25.0 – 29,9) (n = 5); c) patients obese (BMI > 30.0) (n = 2). Samples were collected at 0.66, 1.66, 8.66, and 24,66 h. DOX's pharmacokinetic profiles were evaluated after quantification of DOX using a new HPLC method developed and validated. Results and discussion: pharmacokinetic parameters (AUC and Cmax) were analyzed by non-compartmental and compartmental approaches. Significant differences (α = 0.05) between overweight and obese groups when compared with the normal weight group were found with respect to AUC and significant difference between the group with overweight compared to the patients with normal weight was found for Cmax. After simulating the dose adjustment by weight and by BMI for overweight and obese patients, new values for Cmax ASC were calculated. The new values obtained using both weight and BMI were closer to the normal group than those obtained with the BSA. The percentage of difference of ASC and Cmax of the overweight and obese group compared with the Group of patients with normal weight were lower when the dose was adjusted by weight and IMC. Conclusions: dose adjustment index BSA, commonly used in clinical practice, produced different plasma concentrations in groups of patients with normal weight, overweight, and obese, indicating that other indexes must be considered, such as weight and BMI.

Objetivo: Avaliar a farmacocinética da vildagliptina em animais sadios e diabéticos, através da análise dos níveis plasmáticos totais e livres teciduais, empregando-se a técnica de microdiálise. Metodologia: A doença foi induzida nos animais através da administração de 42mg/kg de aloxano através da via intravenosa (i.v.). A vildagliptina foi administrada nas doses de 50 mg/kg (n = 6) e 75 mg/kg (n = 6) via i.v. nos animais diabéticos e na dose de 50 mg/kg (n = 6) nos animais sadios. As concentrações plasmáticas foram quantificadas por CLAE-EM-EM em método desenvolvido e validado. A ligação às proteínas plasmáticas foi determinada por microdiálise, assim como a avaliação tecidual. As sondas de microdiálise foram calibradas in vitro através de diálise e retrodiálise e in vivo utilizando retrodiálise. Para determinação das concentrações teciduais, uma segunda metodologia foi desenvolvida e validada em CLAE-EM-EM. Avaliações compartimentais (software Scientist ®) e não compartimentais (software Excel ®) foram realizadas. Resultados e Discussão: A ligação as proteínas plasmáticas apresentou um valor médio de 9,44 % ± 3,23, condizente com valores encontrados na literatura. Os valores de Ke, clearance, tempo de meia vida, MRT e VDss não apresentaram diferença estatística significativa entre as diferentes doses administradas nos animais diabéticos e entre os animais sadios. As calibrações in vitro por diálise e retrodiálise apresentaram uma recuperação média de 30%, sem diferença estatística entre as duas metodologias empregadas (α = 0,05). A recuperação in vivo também apresentou o mesmo valor médio de recuperação. A penetração tecidual do fármaco em animais diabéticos para as diferentes doses estudadas apresentou mesmo valor nos tecidos estudados, uma média de 0,20. A penetração tecidual semelhante no animal diabético pode ser devido ao dano similar entre os órgãos sofrido durante a indução da doença. Já os animais sadios apresentaram penetração tecidual similar no músculo sem diferença estatística significativa em relação aos diabéticos, entretanto no fígado foi observada uma penetração quarenta e quatro vezes inferior a observada no músculo. Essa disparidade pode ser atribuída a diferença de expressão de proteínas transportadoras no fígado do animal diabetico quando comparado ao sadio. O perfil farmacocinético plasmático foi semelhante entre os dois grupos avaliados, sendo que os parâmetros não diferiram estatisticamente (α = 0,05). Foi empregado o modelo de dois compartimentos para prever as concentrações teciduais. A previsão supõe concentrações superiores as encontradas experimentalmente, contradizendo dados de literatura. Esses dados são inéditos na literatura e demostram a importância da determinação do fármaco em tecidos alvo, uma vez que nem sempre modelos matemáticos conseguem prever a realidade fisiológica. Conclusões: As metodologias analíticas para quantificação da vildagliptina em microdialisado e plasma foram desenvolvidas e validadas, seguindo os requisitos do FDA. O perfil farmacocinético plasmático foi adequadamente descrito pelo modelo de 2 compartimentos. Os perfis teciduais obtidos nesse trabalho podem contribuir para o melhor entendimento dos mecanismos farmacológicos envolvidos e contribuir para futura otimização de terapias. / Objective: To evaluate the pharmacokinetics of vildagliptin in healthy and diabetic animals using a microdialysis technique. Methodology: Diabetes was induced in animals by administration of 42 mg/kg of alloxan intravenously (iv). Vildagliptin was administered intravenously as 50 mg/kg (n = 6) and 75 mg/kg doses (n = 6) in the diabetic animals and as a 50 mg/kg dose (n = 6) in healthy animals. Plasma concentrations were quantified by a HPLC-MS-MS method developed and validated. The plasma protein binding was determined by microdialysis and tissue evaluation. Microdialysis probes were calibrated in vitro using dialysis and retrodialysis and in vivo using retrodialysis. A second method was developed and validated using HPLC-MS-MS to determine tissue concentrations. Results and Discussion: Mean plasma protein was 9.44% ± 3.23, consistent with values reported in the literature. The values of Ke, clearance, half-life, MRT and Vdss showed no statistical difference between the evaluated doses in diabetic animals and between healthy animals (α = 0.05). Calibrations in vitro by dialysis and retrodialysis showed mean recovery of 30%, with no statistical difference between the two methodologies. Mean recovery in vivo also showed the same value. The tissue penetration of the drug in diabetic animals for the different doses studied showed the same value in both tissues studied, an mean of 0.20. The tissue penetration similar in diabetic animals could be due to the similar damage suffered between organs during induction of the disease. The healthy animals showed similar muscle penetration, compared with diabetics animals, although the liver showed a penetration forty four times lower than muscle. This discrepancy can be attributed to differential expression of transporter proteins in the liver of diabetic animals, when compared to the healthy group. The plasma pharmacokinetic profile was similar between the investigated groups, and the parameters did not differ. The two-compartment model was employed to describe the data and used to predict the concentration in the tissues. This is the first study to present these tissue profiles, which presented concentrations below the estimated by the model. These data demonstrate the importance of determining the drug inside the target tissue, as the mathematical models sometimes cannot predict physiology. Conclusions: The analytical methods for the quantification of vildagliptin in microdialysate and plasma were developed and validated by following the requirements of the FDA. The plasma pharmacokinetic profile was correctly described by the model of two compartmental models. The novel tissue profiles obtained in this study may contribute to a better understanding of the pharmacological mechanisms involved and contribute to optimization of future therapies.

Objetivos: Simular um ajuste de dose em pacientes com sobrepeso e com obesidade que utilizam a doxorrubicina (DOX), que proporcione curvas de concentração plasmática e concentrações máximas (Cmáx) semelhantes às de pacientes com peso normal. Metodologia: Determinou-se as concentrações plasmáticas de DOX em pacientes com câncer de mama após a administração i.v. de 60 mg/m2, com ajuste de dose pelo BSA e com tempo de infusão de 40 minutos (0,66 h). As pacientes foram divididas em três grupos: a) pacientes com peso normal (IMC até 24,9) (n = 3); b) pacientes com sobrepeso (IMC 25,0 – 29,9) (n = 5); c) pacientes com obesidade (IMC acima 30,0) (n = 2). Os tempos de coleta utilizados foram: 0,66, 1,66, 8,66, e 24,66 h. Os perfis farmacocinéticos da DOX foram avaliados após quantificação da DOX através de metodologia por CLAE desenvolvida e validada. Resultados e Discussão: Os parâmetros farmacocinéticos ASC e Cmáx foram analisados por abordagem não-compartimental e compartimental. Em ambas as análises encontraram-se diferenças significativas (α = 0,05) entre os grupos com sobrepeso e com obesidade comparados com o grupo com peso normal para ASC e diferenças significativas entre o grupo com sobrepeso comparado ao grupo de pacientes com peso normal para o Cmáx. Após simulação de ajuste de dose pelo peso e pelo IMC, para as pacientes com sobrepeso e obesas, obtivemos novos valores de ASC e Cmáx. Houve diferenças significativas (α = 0,05) para o grupo de pacientes com sobrepeso comparado ao grupo com peso normal para a ASC e nenhuma diferença significativa entre os grupos estudados para Cmáx. Os percentuais de diferença da ASC e Cmáx do grupo das pacientes com sobrepeso e obesas comparados com o grupo de pacientes com peso normal foram diminuindo quando a dose era ajustada pelo peso e IMC. Conclusões: O ajuste de dose pelo índice BSA, comumente usado na prática clínica, não produz concentrações plasmáticas iguais em grupos de pacientes com peso normal e com sobrepeso, indicando que outros índices devem ser considerados, como peso e IMC. / Objectives: to simulate a dose adjustment in patients with overweight and obesity using doxorrubicin (DOX), providing plasma concentrations similar to those of patients with normal weight. Methodology: plasma concentrations of DOX were determined in patients with breast cancer after the iv. administration of 60 mg/m2 of DOX, adjusted by the BSA and with an infusion time of 40 minutes (0.66 h). The patients were divided into three groups: (a) patients with normal weight (BMI < 24.9) (n = 3); b) patients with overweight (BMI 25.0 – 29,9) (n = 5); c) patients obese (BMI > 30.0) (n = 2). Samples were collected at 0.66, 1.66, 8.66, and 24,66 h. DOX's pharmacokinetic profiles were evaluated after quantification of DOX using a new HPLC method developed and validated. Results and discussion: pharmacokinetic parameters (AUC and Cmax) were analyzed by non-compartmental and compartmental approaches. Significant differences (α = 0.05) between overweight and obese groups when compared with the normal weight group were found with respect to AUC and significant difference between the group with overweight compared to the patients with normal weight was found for Cmax. After simulating the dose adjustment by weight and by BMI for overweight and obese patients, new values for Cmax ASC were calculated. The new values obtained using both weight and BMI were closer to the normal group than those obtained with the BSA. The percentage of difference of ASC and Cmax of the overweight and obese group compared with the Group of patients with normal weight were lower when the dose was adjusted by weight and IMC. Conclusions: dose adjustment index BSA, commonly used in clinical practice, produced different plasma concentrations in groups of patients with normal weight, overweight, and obese, indicating that other indexes must be considered, such as weight and BMI.

Submitted by Juliana da Silva Oliveira null (julianaoliveira_enf@yahoo.com.br) on 2016-09-11T21:03:04Z No. of bitstreams: 1 DISSERTACAO JULIANA OLIVEIRA pdf.pdf: 874937 bytes, checksum: e0c74af40cc92b0d03be09da8c3d52d1 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-09-12T17:21:46Z (GMT) No. of bitstreams: 1 oliveira_js_me_bot.pdf: 874937 bytes, checksum: e0c74af40cc92b0d03be09da8c3d52d1 (MD5) / Made available in DSpace on 2016-09-12T17:21:46Z (GMT). No. of bitstreams: 1 oliveira_js_me_bot.pdf: 874937 bytes, checksum: e0c74af40cc92b0d03be09da8c3d52d1 (MD5) Previous issue date: 2016-08-01 / Objetivos: Questionamentos têm sido lançados sobre a eficácia das formulações genéricas de vancomicina, empregadas com frequência nos países em desenvolvimento. No entanto, a grande disponibilidade de testes para monitorar a concentração de vancomicina no soro tornou possível ajustar as doses, a fim de melhorar os resultados. Nosso estudo teve como objetivo descrever os padrões de prescrição e monitorização de dose sérica de vancomicina genérica em um hospital brasileiro. Estávamos especialmente interessados no impacto desses parâmetros sobre o prognóstico de pacientes. Métodos: Uma coorte retrospectiva de 513 pacientes adultos que foram tratados com vancomicina em 2014 foi estudada. Desfechos de interesse foram: (a) atingir concentrações séricas mínimas sub-ótimas na primeira ocasião de monitoramento e (b) morte dentro de 30 dias da introdução vancomicina. A análise multivariada (regressão logística e de Cox) foi aplicada. Resultados: Menos de 25% dos indivíduos alcançaram concentração sérica mínima ótima (15-20 mg/L), mesmo depois de cinco testes e ajustes posológicos. No entanto, a soma dos indivíduos que apresentaram concentrações ideais e altas foi predominante em cada teste. Doença renal (OR = 4,86, IC95% = 2,05-11,53, P <0,001) e dose diária (OR para mg/kg = 1,04, IC95% = 1,01-1,07, P = 0,01) foram positivamente associada com níveis mais elevados de vancomicina. Além disso, indivíduos mais jovens eram menos propensos a apresentar baixa concentração sérica. Na análise de sobrevivência, as concentrações ideais foram associadas com melhores desfechos, mas apenas aqueles com níveis elevados apresentaram aumento significativo do risco (HR = 1,80, IC95% = 1,05-3,07, P = 0,03). Conclusão: Os resultados alertam para riscos de toxicidade com altas concentrações de vancomicina. O ajuste fino da posologia (por exemplo, com infusão contínua) pode contribuir para melhorar a segurança e eficácia. / Objectives: Concerns have been raised about generic formulations of vancomycin – especially in developing countries – but the wide availability of tests for monitoring serum vancomycin concentration made it possible to adjust doses in order to improve outcomes. We aimed at describing patterns of generic vancomycin prescription and monitoring in a Brazilian hospital and their impact on outcomes. Methods: A cohort of 513 adult patients who were treated with vancomycin in year 2014 was retrospectively studied. Outcomes of interest were achieving suboptimal serum trough concentrations in the first serum monitoring and death within 30 days of vancomycin introduction. Multivariable analysis (logistic and Cox regression was applied) Results: Less than 25% of subjects achieved optimal (15-20 mg/L) trough concentrations, even after five tests and dosing adjustments. However, the sum of subjects presenting optimal and high concentrations was predominant in each and every test. Renal disease (OR=4.86, 95%CI=2.05-11.53, P<0.001) and daily dosing (OR for mg/kg =1.04, IC95%=1.01-1.07, P=0.01) were positively associated with higher vancomycin levels. Additionally, younger subjects were less likely to present lower serum concentration. In survival analysis, optimal concentrations were associated with better outcomes, but only those with high levels presented significantly increased risk (HR=1.80, 95%CI=1.05-3.07, P=0.03). Conclusion: Our results warn about risks of toxicity with high concentrations of vancomycin. Fine adjustment of posology (e.g., with continuous infusion) may contribute to improve safety and efficacy.