Desirability Function in analytical method development for determination of glitazones and metabolites employing HF-LPME

Abstract Thiazolidinedione, often shortened to TZD or glitazone, helps lower insulin resistance, which is the underlying problem for many people with type 2 diabetes. The two most known glitazones are pioglitazone (PGZ), with the brand name medicine Actos®, and rosiglitazone (RSG), which is Avandia®. This study presented a multivariate optimization in the microextraction procedure employing Fractional Factorial Design (FFD) combined with Desirability Function (DF) to determine TZD and metabolites in biological samples. Microextraction requires several parameters to be optimized; however, most of them still use univariate optimization. Finding optimum conditions by simple response is relatively simple, but the problems, in case of microextractions, are often more complex when it has more responses. For example, changing one factor that promotes one response may suppress the effect of the others. Thus, this multivariate optimization was applied for two bioanalytical methods for determination of TZD and metabolites, one by HPLC and other by CE, both using Hollow Fiber Liquid-Phase Microextraction (HF-LPME). The results establish the optimal values and elucidate how the factors that affect HF-LPME procedure perform in extraction efficiency for TZDs. Additionally, this study demonstrates that DF can be an important tool to optimize microextraction procedures.

Effect of pioglitazone on lipid profile in type 2 diabetic patients

To determine the effect of pioglitazone on lipid profile in type 2 diabetic patients treated and followed up for three months after initiation of therapy. This hospital based quasi-experimental study was conducted in the medical B unit, Lady Reading Hospital Peshawar from July 2008 to June 2009. A total of 161 patients with type 2 diabetes mellitus were included in this study using convenient [non-probability] sampling. Clinical and laboratory evaluation of all the patients were done to note the change in lipid profile after the use of 30 mg pioglitazone. Continuous variables such as age and lipid profile [triglycerides; Low Density Lipoprotien [LDL]; High Density Lipoprotien [HDL]; cholesterol] at baseline and after 3 months time were expressed as mean +/- S.D. Paired sample t-test was used to analyze the mean difference in pre-post lab investigation by SPSS version15. Out of the 161 patients, 79 [49.1%] were males and 82 [50.9%] were females. The mean age of the sample was 51.2 +/- 11.33 years. Triglycerides decreased from 219.2 +/- 34.4 to 189.2 +/- 33.7 mg/dl with a mean difference of 29.9 mg/dl [p<0.001]. Total cholesterol changed from 201.4 +/- 29.8 to 203.2 +/- 28.9 mg/dl with a mean difference of 1.8mg/dl [p<0.001]. LDL changed from 153.7 +/- 21.1 to 154.7 +/- 20.7 mg/dl with a mean difference of 0.9 mg/dl [p<0.001]. HDL increased from 37.2 +/- 2.9 to 41.5 +/- 3.1 mg/dl with a mean difference of 4.3 mg/dl [p<0.001]. Pioglitazone was found to have beneficial effects on lipid profile. It significantly reduced the levels of triglycerides and increased levels of HDL cholesterol in patients with Type 2 diabetes

Severe HDL-c reduction during rosiglitazone therapy in an obese woman with type 2 diabetes / Redução severa de HDL-colesterol durante terapia com rosiglitazona em uma mulher obesa com diabetes tipo 2

Treatment with rosiglitazone has been associated with severe paradoxical HDL-c reductions. To our knowledge, there are very few reports of this reaction occurring when patients are treated without the combination of a fibrate. A case of severe HDL-c lowering in a patient treated with rosiglitazone without a fibrate is presented. The patient has been treated at a private practice clinic in southern Brazil. A 64-year-old woman with a 2-year history of type 2 diabetes mellitus was referred to her endocrinologist in June 2008. Rosiglitazone 4 mg q.d. was prescribed. Nine months later, the patient experienced a 90.90 percent decrease of her HDL-c levels. Rosiglitazone was withdrawn and the HDL-c returned to baseline. This paradoxical HDL-c reduction is a potentially severe adverse event. Patients prescribed rosiglitazone should have their HDL-c levels measured before and during therapy.

O tratamento com rosiglitazona tem sido associado a reduções paradoxais e severas no HDL-c. Há muito poucos relatos dessa reação ocorrendo em pacientes tratados com rosiglitazona sem a combinação com um fibrato. Apresentou-se um caso de diminuição severa no HDL-c em uma paciente tratada com rosiglitazona sem fibrato associado. A paciente foi tratada em uma clínica privada no Sul do Brasil. Uma mulher de 64 anos com história de diabetes melito tipo 2 há 2 anos foi encaminhada ao seu endocrinologista em junho de 2008. Prescreveu-se rosiglitazona 4 mg uma vez ao dia. Nove meses depois, a paciente teve redução de 90,90 por cento em seus níveis de HDL-c. A rosiglitazona foi retirada e o HDL-c retornou aos níveis prévios. Essa redução paradoxal do HDL-c é um evento adverso potencialmente severo. Pacientes aos quais se prescreve rosiglitazona devem ter seus níveis de HDL-c medidos antes e durante o tratamento.

Transparencia en la investigación biomédica: A propósito de los riesgos asociados al uso de Avandia / Transparency in biomedical research: About the risks associated with the use of Avandia

The question of how and when to communicate potential risks associated with new drugs has remained an important focus of tension between the pharmaceutical industry and regulatory entities, such as the American Food and Drug Administration. Recently there has been widespread concern related to the cardiovascular risks associated with the use of Avandia, a rosiglitazone produced by Glaxo Smith Kline. In fact, several metaanalyses involving rosiglitazone provided a relatively consistent message that rosiglitazone increases the risk of myocardial ischemic events. In the present article, we review the controversy regarding the way the pharmaceutical company handled this issue, and we describe examples of inappropriate conduct regarding an industry-sponsored clinical trial with this drug. We raise several important ethical questions related to the way researchers handle conflicts of interest when they are employees of the pharmaceutical industry. Finally, we discuss the requirements to conduct biomedical research funded by the pharmaceutical industry in Chile.

Diabetes melito, tiazolidinedionas e fraturas: uma história inacabada / Diabetes mellitus, thiazolidinediones and fractures: an unfinished story

A associação entre diabetes melito e risco aumentado de fraturas é bem estabelecida, sendo observada tanto no diabetes tipo 1 quanto tipo 2, com etiologia multifatorial. Evidências de modelos animais têm indicado que tiazolidinedionas (TZD), por meio da ativação do PPAR-gama, levam a aumento do conteúdo adiposo na medula óssea, em detrimento da osteoblastogênese, resultando em perda óssea. Estudos iniciais em humanos vêm evidenciando maior risco de fraturas na população em uso dessas medicações em relação a outros antidiabéticos orais. Sendo TZD drogas amplamente prescritas no tratamento do diabetes tipo 2, é necessário melhor entendimento dos seus mecanismos de ação e do seu impacto sobre a massa óssea e risco de fraturas, com o intuito de direcionar a abordagem desses pacientes quanto à profilaxia e ao tratamento adequados. Este artigo sumariza o conhecimento corrente sobre a relação entre diabetes, TZD e risco de fraturas, bem como, baseado nas evidências atuais, tenta propor formas de conduzir a população em uso dessas medicações.

The association of diabetes mellitus with increased fracture risk is well established, and is observed in both diabetes type 1 and type 2, due to multiple causes. Evidence from rodents suggests that thiazolidinediones (TZD), by activation of PPAR-gamma, cause increased bone marrow adiposity, with decreased osteoblastogenesis resulting in bone loss. Initial studies in humans evidence higher fracture risk in the population using these drugs, in comparison with other oral antidiabetic medications. TZD are largely prescribed for the treatment of type 2 diabetes, therefore, better understanding of their mechanisms of action and impact on bone mass and fracture risk is necessary, in order to guide the management of these patients in regards to prophylaxis and adequate treatment. This article summarizes current knowledge about the relationship between diabetes, TZD and fracture risk as well as, based on current evidence, tries to suggest ways to guide the population using these medications.

Comparison of metformin, gliclazide MR and rosiglitazone in monotherapy and in combination for type 2 diabetes / Comparação de metformina, gliclazida MR e rosiglitazona em monoterapia e em combinação para o diabetes tipo 2

OBJECTIVE: To compare the efficacy and tolerability of metformin, rosiglitazone and gliclazide MR as monotherapy and in combination in the treatment of type 2 diabetes. SUBJECTS AND METHODS: 250 patients treated with oral antidiabetic agents for at least 24 weeks in monotherapy or in combination therapy were included in this retrospective study. RESULTS: As monotherapy the reduction of fasting plasma glucose (FPG), postprandial glycemia (PPG) and HbA1c was similar with the three drugs after 24 weeks. Among patients on combination therapy, the reduction in HbA1c, FPG and PPG was significantly lower with rosiglitazone plus metformin, as compared to metformin plus gliclazide MR or gliclazide MR plus rosiglitazone. Patients treated with rosiglitazone achieved less favorable changes in lipid profile. CONCLUSION: In monotherapy all drugs were equally effective in improving glycemic control, whereas the combination of metformin plus gliclazide MR provided the best results concerning the improvement of both, glycemic control and lipid profile.

OBJETIVO: Comparar a eficácia e a tolerabilidade da metformina, rosiglitazona e gliclazida MR em monoterapia ou em combinação no tratamento do diabetes tipo 2. SUJEITOS E MÉTODOS: 250 pacientes tratados com antidiabéticos orais por pelo menos 24 semanas, em monoterapia ou em terapia combinada, foram incluídos neste estudo retrospectivo. RESULTADOS: Como monoterapia, a redução da glicemia de jejum (GJ), glicemia pós-prandial (GPP) e HbA1c foi similar com as três drogas, após 24 semanas. Entre os pacientes em terapia combinada, a redução da HbA1c, GJ e GPP foi significativamente menor com rosiglitazona e metformina, em comparação com metformina e gliclazida MR ou gliclazida MR mais rosiglitazona. Os pacientes tratados com rosiglitazona obtiveram mudanças menos favoráveis no perfil lipídico. CONCLUSÃO: Em monoterapia todos os medicamentos foram igualmente eficazes na melhora do controle glicêmico, enquanto a combinação de metformina e gliclazida MR proporcionou os melhores resultados relativos à melhoria de ambos, controle glicêmico e perfil lipídico.

Three country comparison of selected safety information in the prescribing information for rosiglitazone [avandia]

A meta-analysis of 42 clinical trials published in 2007 found an increased risk of cardiac ischemia with the use of rosiglitazone [Avandia]. A communication from rosiglitazone's manufacturer indicated that safety revisions would be made the drug's prescribing information in Saudi Arabia. This prompted a comparison between selected safety information in the prescribing information for the drug available in the U.K., U.S. and Saudi Arabia. Three pharmacists conducted a comparison of selected safety information from the most recent prescribing information for rosiglitazone available in the U.K., U.S. and Saudi Arabia including the Arabic translation of the prescribing information available in The Kingdom. Differences in opinion or interpretation of the information contained in the prescribing information from the three countries were resolved by consensus. The prescribing information in Saudi Arabia for the drug was last revised in 2007. This information was amended in the U.K. and U.S. in March 2008 and July 2008 respectively. Compared to the U.K. and U.S. prescribing information the Saudi Arabian prescribing information there were differences in contraindications cardiac ischemia information, facture risk, and concomitant use with insulin. Saudi Arabian prescribers and patients should have access to the same safety information as their counterparts in the U.K. and U.S. In this three country comparison differences were found in the number and strength of selected categories of safety information for rosiglitazone. Information is provided on how to access the most current revisions of the prescribing information for drugs approved in Saudi Arabia that are also available in the U.K. or U.S. on the Internet at no charge

effect of peroxisome proliferator - activated gamma agonist on resistin in obese rats with type 2 diabetes

Adipocytes are highly differentiated cells and numerous genes are expressed significantly in fat cells, resistin is an adipocytokine highly expressed in murine adipose tissue. Peroxisome proliferator-activated gamma agonists [PPAR] down-regulate resistin gene expression in adipose tissue. The aim of the present work is to clarify the effect of peroxisome proliferator-activated gamma agonist [rosiglitazone] on resistin in obese rats and obese rats with type 2 diabetes. Forty eight white albino male rats of 150-250gm average weight were randomly divided into group 1: Control group [n=8], group 2: [n=8] rats received rosiglitazone, group 3s [n=32] obese rats, this group subdivided into group 3a: Obese rats recieved the drug [n=8]. Group 3b: Obese rats after induction of type 2 diabetes, Group 3c: Obese rats with diabetes and rosiglitazone [n=8]. At the time of scarification blood was collected and samples from central fat and peripheral fat was taken. The following parameters were assessed, serum glucose, triglycerides, cholesterol, insulin, serum resistin and resistin in fats. The results of the present work showed that serum glucose, insulin, triglycerides and cholesterol were significantly higher in [group 3, group 3b] compared to the control while their levels decreased after administration of the drug [Group 3c]. As regard resistin level in serum, central fat and peripheral fat were significantly higher in [group 3 and group 3b] compared to the control however its level significantly decrease after rosiglitazone administration. Also significant correlation were found between serum resistin and serum glucose, serum triglycerides and body mass index in all studied groups. Conclusion resistin seems to play an important role in development of type 2 diabetes particularly on top of obesity and its response to [PPAR] agonist may be used to relive insulin resistance in type 2 diabetes