Thèse de doctorat : Biologie médicale : Strasbourg 1 : 2006. / Titre provenant de l'écran-titre. Bibliogr. p. 142-163.

In the intensive care units, hyperglycaemia among the critically ill is associated with poor outcomes. Many studies have been done on managing hyperglycaemia in the critically ill. Patients in the ICU continue to benefit from the outcome of extensive studies including several randomized clinical trials on glycaemic control with intensive insulin therapy. Tight glycaemic control has now emerged as a major research focus in critical care due to its potential to simultaneously reduce both mortality and cost. Although the debate on tight glycaemic control is on going, managing glycaemic level in ICUs is gaining widespread acceptance as the adverse effects are well known. However, in the less acute wards, to date there have only been a single randomized, controlled study to examine the benefit of glycaemic control. Patients in the less acute wards do not receive the same level of care, as glycaemic control is not regarded as important and not a priority. Glycaemic goals in the less acute wards are often judged based on clinical experience rather than adhering to a standard protocol or a treatment guideline. It is important that patients in the less acute wards received the level of care as practised in the ICU. If hyperglycaemia worsens outcome in the ICU, a similar effect is seen within less acute wards. Hence, tight glycaemic control needs to be extended in the less critical setting as well. To support the establishment of a control protocol for patients in less acute wards, a method that has been successful in the critical care and can be adapted to the less acute wards, is the model based or model-derived control protocol. Model-based protocol can deliver a safe and effective patient-specific control, which means the glycaemic control protocol can be devised to each individual patient. Hence, a physiological model that represents the glucose-insulin regulatory system is presented in this thesis. The developed model, Intensive Control Insulin-Nutrition-Glucose (ICING) is based on the best aspects of two previous clinically-validated glucose-insulin models.

Gestational diabetes, a common medical complication in pregnancy, may lead to severe fetal consequences if left untreated. A major concern with the use of antidiabetic drugs in pregnancy is the potential for placental transfer and fetal toxicity. The presence of endocytic pathways and several ABC transporter proteins has been demonstrated in the human placenta and are believed to play an important role in determining fetal exposure to drugs used in pregnancy. The objective of this thesis is to investigate the safety and transfer of the oral hypoglycemic agent, glyburide, and the new long acting insulin analog, insulin glargine, across the human placenta. The oral antidiabetic, glyburide, has been shown to be actively effluxed across the placenta in the fetal to maternal direction. The transport of glyburide in the presence of a breast cancer resistance protein (BCRP) inhibitor was investigated in the dually perfused human placenta model. The results of the perfusion studies indicate that BCRP plays a role in protecting the fetus from the accumulation of glyburide. Subsequently, cellular studies were carried out to determine the effect of the naturally occurring single nucleotide polymorphism within the coding region of BCRP (C421A/Q141K) on glyburide transport. Results suggest that glyburide transport may be reduced in the presence of the Q141K polymorphism. While insulin remains as the gold standard, the potential for maternal hypoglycemia with insulin injection has resulted in the development of insulin analogs. Insulin glargine, a human insulin analog, has a long half life with no pronounced peak when compared to currently used NPH insulin. Human placental perfusion experiments examining the extent and rate of transfer of insulin glargine across the placenta demonstrated that, at therapeutic concentrations, insulin glargine does not cross the placenta to a measurable extent. To further determine the fetal safety of insulin glargine therapy compared with NPH insulin, a systematic review and meta-analysis were performed. No evidence was identified for increased adverse fetal outcomes with the use of insulin glargine during pregnancy. Overall, the results of this research serve to provide improved treatment options for women with diabetes in pregnancy.

Gestational diabetes, a common medical complication in pregnancy, may lead to severe fetal consequences if left untreated. A major concern with the use of antidiabetic drugs in pregnancy is the potential for placental transfer and fetal toxicity. The presence of endocytic pathways and several ABC transporter proteins has been demonstrated in the human placenta and are believed to play an important role in determining fetal exposure to drugs used in pregnancy. The objective of this thesis is to investigate the safety and transfer of the oral hypoglycemic agent, glyburide, and the new long acting insulin analog, insulin glargine, across the human placenta. The oral antidiabetic, glyburide, has been shown to be actively effluxed across the placenta in the fetal to maternal direction. The transport of glyburide in the presence of a breast cancer resistance protein (BCRP) inhibitor was investigated in the dually perfused human placenta model. The results of the perfusion studies indicate that BCRP plays a role in protecting the fetus from the accumulation of glyburide. Subsequently, cellular studies were carried out to determine the effect of the naturally occurring single nucleotide polymorphism within the coding region of BCRP (C421A/Q141K) on glyburide transport. Results suggest that glyburide transport may be reduced in the presence of the Q141K polymorphism. While insulin remains as the gold standard, the potential for maternal hypoglycemia with insulin injection has resulted in the development of insulin analogs. Insulin glargine, a human insulin analog, has a long half life with no pronounced peak when compared to currently used NPH insulin. Human placental perfusion experiments examining the extent and rate of transfer of insulin glargine across the placenta demonstrated that, at therapeutic concentrations, insulin glargine does not cross the placenta to a measurable extent. To further determine the fetal safety of insulin glargine therapy compared with NPH insulin, a systematic review and meta-analysis were performed. No evidence was identified for increased adverse fetal outcomes with the use of insulin glargine during pregnancy. Overall, the results of this research serve to provide improved treatment options for women with diabetes in pregnancy.

Class of 2008 Abstract / Objectives: To determine the cost-effectiveness of adding a thiazolidinedione (TZD) versus insulin glargine (glargine) as a triple regimen for treatment of Type 2 diabetes mellitus for patients not controlled with metformin and a sulfonylurea. Methods: A decision analytic model was developed to compare the clinical outcomes and costs of triple therapy with either a TZD or glargine. Published literature was used to determine treatment efficacy and the frequency of clinically important adverse effects. Cost data were obtained from the 2007 Physician Fee Reference and North Carolina Industrial Commission website. The decision tree was built using TreeAge software. Clinical outcome measures included HgA1c (A1C) control, hypoglycemia frequency, and the development of edema associated with the use of these medications. A Monte Carlo probabilistic sensitivity analysis was conducted to determine the mean and 95% CIs for both treatment efficacy and costs. Results: There was no statistically significant difference in the efficacy of adding either a TZD or glargine in achieving a goal A1C ≤ 7%. However, glargine triple therapy was estimated to be significantly less costly than TZD triple therapy ($3,161/yr; 95% CI $3,116 to $3,356 versus $3,769/yr; 95% CI $3,667 to $3,902, respectively). Conclusions: Most patients requiring triple therapy for the management of T2DM should receive glargine rather than a TZD due to the significantly lower cost producing similar clinical efficacy.

Diabetes mellitus has reached epidemic proportions worldwide, eliciting extensive research on both the disease process and its treatment. Regardless of diabetes type, the progressive nature of the disease makes insulin the long-term mainstay of diabetes management. Recently, the insulin analog glargine was reported in several epidemiologic studies to be associated with an increased risk of cancer. Inconsistent study results and media attention have caused much angst and concern to health care professionals and the general population. A clear understanding of the current evidence is needed to adequately develop a patient-oriented risk:benefit assessment. Members of the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy evaluated available evidence to provide guidance and discussion on the risk of cancer with insulin glargine use. We believe the current link between insulin glargine and cancer is tenuous but merits further evaluation. An independent analysis of all available glargine clinical trial data should be performed, and a vigorous postmarketing safety study of glargine should be conducted. Until more substantial data are available, however, neither the choice of initial insulin therapy nor insulin maintenance regimens should be influenced by the current information linking insulin glargine to cancer.

Thèse d'exercice : Médecine. Médecine générale : Paris 12 : 2006. / Titre provenant de l'écran-titre. Bibliogr. f. 53-58.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-07-17T15:08:05Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) CUSTO UTILIDADE DA INSULINA GLARGINA E NPH REV 4.pdf: 871032 bytes, checksum: 61243dd09cce2d9260cb9239a873d2ca (MD5) / Made available in DSpace on 2017-07-17T15:08:06Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) CUSTO UTILIDADE DA INSULINA GLARGINA E NPH REV 4.pdf: 871032 bytes, checksum: 61243dd09cce2d9260cb9239a873d2ca (MD5) Previous issue date: 2014-10-31 / INTRODUÇÃO: O Diabetes Mellitus é um transtorno metabólico, caracterizado por hiperglicemia. É considerada condição sensível à Atenção Primária, tendo impacto por reduzir ou retardar as complicações da doença. A reposição de insulina para o diabete mellitus tipo 2 é indicada quando somente mudanças no estilo de vida associados a hipoglicemiante oral forem insuficientes para obter controle glicêmico. OBJETIVOS: Determinar o custo-utilidade da insulina glargina e insulina NPH para o tratamento de pacientes com diabetes mellitus tipo 2 atendidos no Sistema Único de Saúde do Município de Recife – PE. MÉTODOS: Foi realizada comparação da categoria custos médicos diretos de duas intervenções terapêuticas indicadas para o tratamento do diabete mellitus tipo 2. A avaliação de custo-utilidade foi realizada a partir da perspectiva do Sistema Único de Saúde. Foi considerado um horizonte analítico de 10 anos. Os dados coletados foram de fontes secundárias, de sistema de informação em saúde, dados dos relatórios emitidos nos sistemas de informatização das Farmácias do Recife e da Farmácia do Estado de Pernambuco e fontes da literatura. Para a análise de decisão, foram consideradas as hipoglicemias noturnas e não noturnas graves e não graves. RESULTADOS: O indivíduo médio, representante de Pernambuco, apresenta 8,7 anos de diagnóstico do DM2, recebem aproximadamente 14,4 frascos de insulina NPH ou Glargina ao ano, dados estes, utilizados na probabilidade de transição. Para o cenário das complicações agudas, o custo do usuário foi calculado para 2013: sem complicação em uso da insulina NPH foi de R$ 1.237,95 e para insulina Glargina R$ 4.935,42. Foi considerado 12 episódios de hipoglicemia noturna grave ao ano. A redução de risco de hipoglicemia para pacientes em uso da insulina Glargina é de 50,9% apresentando cinco episódios ao ano. A razão de custo incremental (RCEI) do presente estudo, indica um valor agregado adicionado de R$ 12.987,4892 por AVAQ ganho a cada ano de tratamento com a insulina glargina em relação a NPH. CONCLUSÕES: Houve redução de episódio de hipoglicemia noturna grave da insulina glargina comparado com a insulina NPH. Os dados apresentados não permite afirmar qual da intervenção é mais efetiva, apenas mostra que a insulina glargina tem um maior custo-utilidade e um custo médico direto maior. Os custos incrementais e os benefícios alcançados em anos de vidas ganhos produziu uma Razão de R$ 12.987,4892 ao ano para a insulina glargina. Diante das incertezas acerca da efetividade das insulinas analisadas, faz-se necessário a realização de estudos aprofundados entre estas intervenções terapêuticas. / INTRODUCTION: Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. It is considered sensitive to Primary Health Care, considering its impacting to reduce or delay complications of the disease. Replacement of insulin for diabetes mellitus type 2 is indicated only when changes in lifestyle associated with oral hypoglycemic agents are insufficient to obtain glycemic control. OBJECTIVES: To determine the cost-utility of insulin glargine and NPH insulin for the treatment of patients with type 2 diabetes mellitus treated at the Unified Health System of the Municipality of Recife - Pernambuco. METHODS: We compared the direct medical costs of category two therapeutic interventions indicated for the treatment of diabetes mellitus type 2 was performed Assessment of cost-utility analysis was performed from the perspective of the Health System was considered an analytic horizon of 10 years.. The data were collected from secondary sources of health information system data reports issued in the computerization of Pharmacies and Pharmacy Recife Pernambuco State and literature sources systems. For decision analysis, were considered nocturnal hypoglycemia and nocturnal not serious and not serious. RESULTS AND DISCUSSION: The average individual, representative of Pernambuco, has 8.7 years of diagnosis of T2DM, receive approximately 14.4 vials of NPH or glargine per year, these data are used in the transition probability. For the setting of acute complications, the user cost was calculated for 2013: Uncomplicated in use NPH insulin was R$ 1,237.95 and R$ 4,935.42 insulin glargine. Was considered 12 episodes of severe nocturnal hypoglycemia per year. The reduced risk of hypoglycemia for patients on insulin glargine is 50.9% with five episodes per year. The ratio of incremental cost (ICER) of this study, indicates a value added of R$ 12,987.4892 per QALY gained every year of treatment with insulin glargine compared to NPH. CONCLUSION: There was a reduction of severe nocturnal hypoglycemia episode of insulin glargine compared with NPH insulin. The data presented allows not say which intervention is most effective, just shows that insulin glargine has a higher utility cost and a direct medical cost higher. Incremental costs and benefits achieved gains in years of life produced a ratio of R$ 12.987,4892 year to insulin glargine. Given the uncertainties about the effectiveness of insulin analyzed, it is necessary to conduct in-depth studies of these therapeutic interventions.

Two concentrated analog insulins, long-acting insulin glargine U-300 (Toujeo) and rapid-acting insulin lispro (Humalog U-200), were recently approved by the FDA. Providers must be aware of clinical differences in these new product formulations compared with their nonconcentrated formulations, so that they can select appropriate patients for these products and minimize drug errors.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / hans, and is secreted into the bloodstream. It plays and important role in regulating the metabolic activities of the body, particularly the homeostasis of the blood glucose. Insulin glargine is a recombinant human insulin analogue produced by DNA technology using a strain of Escherichia coli and the insulin glargine differ only by three amino acids from human insulin. Reversed-phase liquid chromatography (RP-LC) and size exclusion liquid chromatography (SE-LC) methods were developed and validated for the assessment of insulin glargine in biopharmaceutical formulations. A RP-LC method was carried out on a Jupiter C4 column (250 mm x 4.6 mm i.d.), maintained at 30 ºC. The mobile phase A consisted of 0.05 M sodium sulphate buffer, pH 2.5, and the mobile phase B was acetonitrile. The SE-LC method was carried out on a BioSep-SEC-S 2000 column (300 mm x 7.8 mm i.d.), maintained at 25 ºC. The mobile phase consisted of 0.03 M MES acid buffer, pH 2.5, run isocratically at a flow rate of 0.6 mL/min. Chromatographic separation was obtained with retention times of 7.5 min, and 9.9 min, and was linear over the concentration range of 0.05 - 200 μg/mL (R2 = 0.9998) and 0.02 - 180 μg/mL (R2 = 0.9999), respectively, for RP-LC and SE-LC, with photodiode array (PDA) detection at 214 nm and 200 nm for RP-LC and SE-LC methods, respectively. The limits of detection and quantitation were 0.018 and 0.054 μg/mL, respectively, for the RP-LC and 0.009 and 0.027 μg/mL, for the SE-LC. Specificity was established in degradation studies, which also showed that there was no interference of the excipients. Equally, the accuracy was 100.13% and 99.38%, with bias lower than 0.85% and than 0.86%. The validated methods were applied for the determination of insulin glargine and related proteins and high molecular mass, in biotechnology-derived products, giving lower mean differences of the estimated content/potencies of 0.21% and 0.16% for the RP-LC and SE-LC related, compared to the in vitro cell culture assay. It is concluded that represents a contribution to establish alternatives to monitor stability, quality control and thereby assure therapeutic efficacy of the biotechnology-derived medicine. / A insulina humana é um hormônio secretado pelas células β, das ilhotas de Langerhans, e regula os níveis sanguíneos de glicose. A insulina glargina é produzida pela tecnologia do DNA recombinante, expressa em Escherichia coli, e difere da insulina humana pela modificação da aspargina na posição 21 da cadeia A por uma glicina, além da adição de dois resíduos de arginina C-terminais na cadeia B. No presente trabalho foram desenvolvidos e validados métodos por cromatografia líquida em fase reversa (CL-FR) e por exclusão molecular (CL-EM) para a avaliação de insulina glargina em formulações biofarmacêuticas. No método por CL-FR, foi utilizada coluna Júpiter C4 (250 mm x 4,6 mm d.i.), mantida a 30 ºC. A fase móvel A foi constituída por tampão sulfato de sódio 0,05 M, pH 2,5, e a fase móvel B por acetonitrila, eluídas com fluxo constante de 0,5 mL/min. No método por CL-EM foi utilizada coluna BioSep-SEC-S 2000 (300 mm x 7.8 mm d.i.), mantida a 25 ºC. A fase móvel foi constituída de tampão MES 0,03 M, pH 2,5, eluída em vazão isocrática de 0,6 mL/min. Para ambos os métodos utilizou-se detector de arranjo de diodos (DAD) com detecções em 214 nm e 200 nm para CL-FR e CL-EM, respectivamente. A separação cromatográfica foi obtida nos tempos de 7,5 e 9,9 min, sendo linear na faixa de concentração de 0,05 - 200 μg/mL (R2 = 0,9998) e 0,02 - 180 μg/mL (R2 = 0,9999), respectivamente, para os métodos por CL-FR e CL-EM. Os limites de detecção e quantificação foram 0,018 e 0,054 μg/mL, respectivamente, para o método por CL-FR e 0,009 e 0,027 μg/mL por CL-EM. A especificidade foi avaliada em estudos de degradação, que também demonstraram que não houve interferência dos excipientes. A exatidão foi 100,13 e 99,38%, com bias inferior a 0,85 e 0,86%, respectivamente, para os métodos por CL-FR e CL-EM. Os métodos propostos foram aplicados para avaliação da potência de insulina glargina, de proteínas relacionadas agregados de alta massa molecular em formulações biofarmacêuticas, e os resultados foram comparados com o bioensaio por cultura de células in vitro, observando-se diferenças das médias de teor/potência 0,21% e 0,16% inferiores para os métodos por CL-FR e CL-EM. Concluí-se que representa contribuição para estabelecer procedimentos para monitorar a estabilidade, o controle da qualidade, garantindo a segurança e eficácia terapêutica do produto biotecnológico.