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.

The role of pioglitazone in antioxidant, anti-inflammatory, and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance

We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.

Vertebral fractures in adult women with type 2 diabetes mellitus / Fracturas vertebrales en mujeres adultas con diabetes mellitus tipo 2

Introduction. Diabetes is a chronic disease associated with important comorbidities. Type 2 diabetes (T2DM) is associated with a three times increased risk of hip fracture but reports describing potential associations with vertebral fractures (VF) are contradictory. Our objective was to evaluate the factors involved in the prevalent VF in women with and without T2DM. Materials and methods. A cross-sectional design was used and the relationship between morphometric VF and T2DM in adult women was evaluated. The cases were adult women with morphometric VF and the controls were adult women without VF. Thoracic and spinal radiographs in lateral and antero-posterior projections were obtained. Bone mineral density (BMD) values of the lumbar spine (L-BMD) were measured by DXA. Results. A greater number of women with T2DM were found in the VF group (61% vs 31.5%). Non-T2DM women with VF were significantly older and with lower L-BMD than non-T2DM without VF. We observed a negative correlation between age and L-BMD (r=-0.463) in non-T2DM women, but not in the T2DM with FV group. T2DM was a risk factor for prevalent VF with OR of 3.540 (IC95% 1.750-7.160). Conclusion. Our study showed a higher prevalence of T2DM in the VF group. T2DM women with VF were younger and had higher L-BMD than non-T2DM women, L-BMD did not correlate with age and VF were not distributed according to BMD-L and age. (AU)

Introducción. La diabetes es una enfermedad crónica asociada con comorbilidades importantes. La diabetes tipo 2 (DM2) se asocia con un riesgo tres veces mayor de fractura de cadera pero la asociación con fracturas vertebrales (FV) es contradictoria. Nuestro objetivo fue evaluar los factores involucrados en las FV prevalentes en mujeres adultas con y sin DM2. Materiales y métodos. Se realizó un diseño transversal y se evaluó la relación entre FV morfométrica y DM2 en mujeres adultas. Los casos fueron mujeres adultas con FV morfométricas y los controles fueron mujeres adultas sin FV. Se obtuvieron radiografías torácicas y espinales en proyecciones lateral y anteroposterior. Los valores de densidad mineral ósea (DMO) de la columna lumbar (DMO-L) se midieron por DXA. Resultados. Se observó un mayor número de mujeres con DM2 en el grupo de FV (61% frente a 31.5%). Las mujeres sin DM2 con FV eran significativamente mayores y con una DMO-L más baja que las mujeres sin DM2 sin FV. Observamos una correlación negativa entre la edad y la DMO-L (r= -0.463) en mujeres sin DM2 y FV, pero no en DM2 con FV. La DM2 fue un factor de riesgo para FV prevalente con un OR 3.540 (IC95% 1.750-7.160). Conclusión. Nuestro estudio demostró una mayor prevalencia de DM2 en el grupo de FV. Las mujeres con DM2 y FV eran más jóvenes y tenían mayor DMO-L que las mujeres sin DM2, la DMO-L no correlacionó con la edad y las FV no se distribuyeron de acuerdo a la DMO-L y edad. (AU)

Salud sexual y reproductiva de los pacientes con esquizofrenia y trastorno afectivo bipolar / Sexual and Reproductive Health in Patients with Schizophrenia and Bipolar Disorder

RESUMEN Introducción: Las personas con esquizofrenia y trastorno afectivo bipolar (TAB) tienen alto riesgo de embarazos no deseados y abortos, debido a su condición de vulnerabilidad o comportamientos hipersexuales (frecuentes en este último trastorno); a esto se asocia dificultad en la planeación de sus actos y escasez de educación sexual y consejos del personal médico, lo cual lleva a resultados obstétricos negativos e incapacidad para cuidar adecuadamente a sus hijos. Objetivo: Describir las características de una muestra de pacientes con trastorno bipolar y esquizofrenia en Medellín, Colombia, sobre salud sexual y reproductiva, el uso de anticoncepción y el asesoramiento al respecto en las consultas de psiquiatría. Métodos: Se realizó un estudio observacional de corte transversal. Se incluyó a los 160 participantes del ensayo clínico «Los Efectos de un Programa de Intervención Multimodal en Pacientes con Trastorno Afectivo Bipolar y Esquizofrenia¼, captados de la consulta del grupo de trastornos del ánimo y psicosis del Hospital Universitario San Vicente Fundación de Medellín. Un residente de tercer año de Psiquiatría contactó con ellos vía telefónica y les aplicó una encuesta acerca de las características de su vida sexual y reproductiva y la anticoncepción. Resultados: Casi todos los pacientes con esquizofrenia estaban solteros, no tenían estudios de pregrado y se encontraban desempleados. No se encontraron diferencias significativas en cuanto a la edad de inicio de las relaciones sexuales al comparar por diagnóstico y por sexo. Casi todos los pacientes con esquizofrenia y casi la mitad de los pacientes con TAB reportaron no tener vida sexual activa. Casi todos los que reconocieron tenerla afirmaron que usaban siempre algún método anticonceptivo; del grupo de TAB, solo el 48,8% de las mujeres solteras reconocieron estar planificando y poco más de la mitad de los varones afirmaron que se servían del condón en sus relaciones sexuales. Una cuarta parte de los embarazos fueron no planeados. El 57,4% de los pacientes con TAB y el 78,8% de los que tenían esquizofrenia se consideraban bien informados sobre planificación familiar, a pesar de que la mayoría afirmaba que nunca habían recibido información sobre este tema durante las consultas con su psiquiatra. Conclusiones: Los pacientes con enfermedad mental tienen alteraciones cognitivas y conductuales que afectan a su vida sexual y reproductiva, por lo cual los psiquiatras deben abordar este tema para garantizar la educación en cuanto a anticoncepción, planeación de la natalidad y riesgo de enfermedades de transmisión sexual, entre otras, y así velar por la seguridad y la calidad de vida de sus pacientes.

ABSTRACT Introduction: People with schizophrenia and bipolar disorder (BD) have a high risk of unwanted pregnancies and abortions, due to their condition of vulnerability or hypersexuality (common in BD). This is associated with difficulty in planning their actions and lack of sex education and counselling by medical personnel, and can lead to adverse obstetric outcomes and inability to care adequately for their children. Objective: To describe the characteristics in terms of sexual and reproductive health, and the use of contraception and counselling in psychiatric consultations, in a sample of patients with BD and schizophrenia in Medellin, Colombia. Methods: Observational cross-sectional study. We included the 160 participants from the clinical trial, "The effects of a multimodal intervention programme in patients with bipolar disorder and schizophrenia", who were recruited from the mood and psychosis disorders group clinic at Hospital Universitario de San Vicente Fundación in Medellin. They were contacted by phone by a third-year psychiatry resident, who applied a survey about the characteristics of their sex life, contraception and reproduction. Results: Almost all of the patients with schizophrenia were single, had no undergraduate studies and were unemployed. No significant differences were found regarding the age of starting sexual relations when comparing by diagnosis and gender. Almost all patients with schizophrenia and almost half of the patients with BD reported not having an active sexual life. Almost all of those who admitted to having an active sexual life claimed to always use contraception; in the BD group, only 48.8% of single women admitted to using contraception and a little over half of men stated that they used a condom when having sex. A quarter of the pregnancies were unplanned. Although the majority of the patients stated that they had never received information about family planning in the consultations with their psychiatrist, 57.4% of the patients with BD and 78.8% of those who had schizophrenia, considered themselves to be well informed on the subject. Conclusions: Patients with mental illness have cognitive and behavioural alterations that affect their sexual and reproductive lives. Psychiatrists should therefore address this issue, to ensure education in areas such as contraception, family planning and sexually transmitted diseases and help safeguard the safety and quality of life of their patients.

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway / Pioglitazona Induz Apoptose e Inibe Hipertrofia de Cardiomiócitos pela Via de Sinalização do VEGFR-2

Abstract Background: Pioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial. Objectives: In this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway. Methods: Cardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups. Results: Pioglitazone and VEGFR-2-selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy. Conclusions: These findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway.

Resumo Fundamento: A pioglitazona tem sido amplamente utilizada como droga sensibilizadora da insulina para melhorar o controle glicêmico em pacientes com diabetes mellitus tipo 2. No entanto, o risco cardiovascular bem como os efeitos protetores da pioglitazona ainda são controversos. Objetivos: Neste estudo, investigamos se os efeitos da pioglitazona sobre a apoptose e a hipertrofia de cardiomiócitos ocorrem via regulação da via de sinalização do VEGFR-2. Métodos: os cardiomiócitos foram isolados enzimaticamente dos ventrículos de ratos Sprague-Dawley de 1-3 anos de vida. Os efeitos da pioglitazona e do inibidor seletivo de VEGFR-2 apatinib sobre a taxa de apoptose dos cardiomiócitos foram avaliados por citometria de fluxo, e a hipertrofia avaliada por incorporação de leucina-[3H]. As expressões de VEGFR-2, Akt, P53, e mTOR fosforiladas e não fosforiladas foram determinadas por Western Blotting. Análise de variância (ANOVA) foi usada para avaliar diferenças entre os grupos. Resultados: a pioglitazona e o apatinib reduziram a viabilidade e a hipertrofia de cardiomiócitos induzida por angiotensina II in vitro. Além disso, no mesmo modelo in vitro, a pioglitazona e o apatinib aumentaram significativamente a expressão de Bax e P53 fosforilada, e diminuiu a expressão de VEGFR-2, Akt, e mTOR, que promove hipertrofia de cardiomiócitos. Conclusões: Esses resultados indicam que a pioglitazona induz a apoptose e inibe a hipertrofia de cardiomiócitos pela modulação da via de sinalização de VEGFR-2.

[RETRACTED ARTICLE] Therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis

Caspase recruitment domain-containing protein 9 (Card9) is located upstream of the nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) inflammatory pathways. This study investigated the therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis (SAP). SAP was induced by a retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct of Sprague Dawley rats (n=54), which were then treated with pioglitazone. Blood and pancreatic tissues were harvested at 3, 6, and 12 h after SAP induction. Pancreatic pathological damage was evaluated by hematoxylin and eosin staining. Serum amylase, serum pro-inflammatory cytokines, and pancreatic myeloperoxidase (MPO) activities were determined by enzyme-linked immunosorbent assay. The expression of Card9 mRNA and protein in pancreatic tissues was detected by real-time polymerase chain reaction and western blotting. Pioglitazone had a therapeutic effect in treating rats with SAP by decreasing the level of amylase activity, ameliorating pancreatic histological damage, decreasing serum pro-inflammatory cytokine levels and tissue MPO activity, and downregulating the expression of NF-κB, p38MAPK, and Card9 mRNAs and proteins (P<0.05). The present study demonstrated that the inhibition of Card9 expression could reduce the severity of SAP. Card9 has a role in the pathogenic mechanism of SAP.

Seguridad cardiovascular de los antidiabéticos orales / Cardiovascular safety of oral antidiabetics

Resumen La Diabetes Mellitus tipo 2 (DM-2) es un equivalente de riesgo cardiovascular. Existe una gran variedad de fármacos para el control de la glicemia en los pacientes con DM-2, los cuales tienen diferencias en su perfil cardiovascular, unos han demostrado un beneficio en la reducción de riesgo de eventos cardiovasculares, otros tienen un efecto neutro, y en el caso de otros fármacos como las sulfonilureas y las tiazolinedionas existe dudas sobre su seguridad cardiovascular. Sien do DM-2 un equivalente de riesgo coronario, es fundamental tomar en cuenta el perfil de riesgo cardiovascular de estos medicamentos a la hora de iniciar alguna de estas drogas y no solo su eficacia para controlar los niveles de glicemia. El objetivo de esta revisión es comentar sobre los estudios más recientes que evalúan el riesgo cardiovascular con el uso de los distintos antidiabéticos orales.

Abstract Cardiovascular Safety of Oral Antidiabetics Diabetes Mellitus type 2 (DM-2) is an equivalent of cardiovascular risk. There is a wide variety of drugs for the glycemic control in patients with DM-2, which have differences in their cardiovascular profile, some have shown a benefit in reducing the risk of cardiovascular events, others have a neutral effect, and in the case of other drugs such as sulfonylurea and thiazolidinedione, there are doubts about their cardiovascular safety. Being DM-2 an equivalent of coronary risk, it is essential to consider the cardiovascular risk profile of these medicines when starting any of these drugs and not only their effectiveness in controlling glycaemia levels. The objective of this review is to comment on the most recent studies evaluating cardiovascular risk with the use of different oral antidiabetics.

Evaluación objetiva del procesamiento de las emociones. Estudio de un caso forense / Objective Assessment of Emotion Processing. Forensic Case Report

Introducción: El principal objetivo de las emociones consiste en garantizar la homeostasis, la supervivencia y el bienestar del organismo. Objetivo: Demostrar la utilidad de la aplicación de evaluaciones neurofisiológicas y neuropsicológicas a pacientes en quienes se pretenda demostrar el papel significativo de las emociones en la ejecución de determinadas conductas. Métodos: Se realizó entrevista psiquiátrica con fines forenses. Se registró la actividad eléctrica cerebral (EEG) en estado de vigilia y en condiciones basales, se calcularon los generadores de densidad de corriente en la banda theta y se realizó evaluación de reconocimiento de las emociones. Resultados: En la entrevista psiquiátrica se destaca que el miedo fue un elemento importante en el actuar impulsivo y poco previsor del acusado y se demostró una disminución sustancial de sus facultades para comprender el alcance de sus actos y dirigir su conducta en el periodo de tiempo de ocurrencia del delito que se le imputa. El EEG mostró alteraciones en regiones frontales y los generadores de densidad de corriente se localizaron en regiones frontotemporales y áreas asociativas occipitales. Conclusiones: Se recomienda asociar estos estudios con la evaluación psiquiátrica con fines forenses para acrecentar la objetividad de los diagnósticos formulados por peritos actuantes.

Introduction: The main objective of the emotions is to ensure the homeostasis, the survival and the well-being of the organism. Objective: To demonstrate the usefulness of performing neurophysiological and neuro-psychological assessments in patients, in order to demonstrate the significant role of the emotions in the execution of certain behaviours. Methods: A forensic psychiatric interview was conducted. EEG in vigil state was registered, the generators of current density to theta band were calculated, and the emotions recognition test was performed. Results: The results of the psychiatric interview demonstrated that fear was an important element in acting impulsively, and lack of foresight of the accused. A substantial decrease was demonstrated in the ability to understand the scope of the acts and the direction of the behaviour during the time the crime occurred. The EEG showed alterations in frontal regions, and the generators of current density were located in frontal-temporal regions and occipital associative areas. Conclusions: It is recommended to associate these studies with the forensic psychiatric assessment, in order to increase the objectivity of the diagnoses formulated by medical experts.

Pioglitazona para tratamiento de la esteatohepatopatia no alcohólica: revisión sistemática de la literatura / Pyoglitazone for the treatment of non-alcoholic fatty liver: a systematic review of the literature

Objetivo: Revisar sistemáticamente la evidencia acerca de la eficacia de administrar Pioglitazona para tratar la esteatohepatopatía no alcohólica en pacientes con intolerancia a la glucosaFuentes de datos: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, LILACS, ACP journal club, EBM, libros. Selección estudios: ensayos clínicos aleatorios que evaluarán la administración de Pioglitazona en pacientes con intolerancia a los carbohidratos comparados contra placebo u otro tratamiento que midiera la mejoría de la esteatohepatopatía noalcohólica Resultados: En esta revisión sistemática de la literatura se incluyeron sólo dos estudios que cumplieron los criterios de inclusión y se evaluaron los siguientes desenlaces: control glucémico y tolerancia a la glucosa, mostrando el aumento dela sensibilidad hepática a la insulina, el aumento en la depuración de glucosa y la disminución en la cantidad de ácidos grasos libres y de los niveles hepáticos de aspartato y alanino aminotranferasa; además se evidenció la mejoría histológica bajando el nivel en el contenido hepático de grasa mejorando así la esteatosis, la balonización y la inflamación...

Objective: To systematically asses the evidence about the effectiveness of prescribing pioglitazone to prevent non alcoholic esteatohepatitis in patient with glucose intolerance Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, LILACS, ACP journal club, EBM, books. Study Selection: Randomized clinical trials that evaluated the prescribing of pioglitazone to patient with carbohydrate intolerance compared against placebo or another treatment and the measured improvement of the non alcoholic esteatohepatistis picture.Main Results: A total of 2 studies were included in this systematic revision of the literature, and the following outcomes were evaluated: glicemic control and glucose tolerance, pioglitazone showed an increase in the hepatic sensibility to insulin, anincrease in the purification of glucose and a decrease in the quantity of free fatty acids, lowering of the hepatic levels of aspartate and alanin aminotransferase. Histologic improvement was also evidenced, diminishing the hepatic content of fat improving this way the steatosis, cytologic ballooning and the inflammation.