Tiempos de reperfusión de un programa guiado por telemedicina para la atención del infarto agudo de miocardio con elevación del ST en la Provincia de La Pampa / Reperfusion Times in a Telemedicine-guided Program for the Management of ST-segment Elevation Myocardial Infarction in the Province of La Pampa

RESUMEN Introducción: Los tiempos de atención médica son un factor relevante para la mortalidad por infarto agudo de miocardio con elevación del segmento ST (IAMCEST). Objetivos: Evaluar los tiempos de reperfusión en pacientes con IAMCEST participantes de un programa de atención médica cardiológica basada en telemedicina en la provincia de La Pampa durante el período transcurrido entre agosto de 2018 y diciembre de 2021. Material y Métodos: Este programa consiste en la protocolización de la atención de los pacientes que cursan un síndrome coronario agudo (SCA) en las diferentes localidades de la provincia, con asistencia cardiológica remota las 24 horas del día, que incluye tanto la asistencia diagnóstica como la coordinación de las medidas terapéuticas, incluyendo la posibilidad de administrar trombolíticos a nivel local, con asistencia remota. Resultados: De un total de 72 IAMCEST evaluados, 44 recibieron como terapia de reperfusión trombolisis, 25 angioplastia primaria, y 3 trombolisis seguida de angioplastia de rescate. De los 47 sujetos que recibieron trombolisis, sólo 5 requirieron de traslado al centro de referencia para realizar este procedimiento. La mediana de tiempo puerta-aguja fue de 24 minutos y el tiempo puerta-balón fue de 105 minutos. El 28% de los sujetos con angioplastia primaria tuvieron un tiempo puerta-balón inferior a los 90 minutos y el 53,2% de los tratados con trombolíticos cumplieron con un tiempo puerta-aguja menor a 30 minutos. Conclusiones: La implementación de un programa de atención descentralizada guiada por telemedicina se asoció a un elevado porcentaje de cumplimento de las metas de implementación de la terapia de reperfusión basada en fibrinolíticos.

ABSTRACT Background: Timing of medical care is a relevant factor for ST-segment elevation myocardial infarction (STEMI) mortality. Objectives: The aim of the present study is to evaluate reperfusion times in STEMI patients participating in a telemedicinebased cardiology care program in the province of La Pampa during the period between August 2018 and December 2021. Methods: This program consists of a protocol for the management of patients with acute coronary syndrome (ACS) in the different locations of the province, with 24-hour remote assistance provided by cardiologists including both diagnostic support and coordination of on-site thrombolysis. Results: Of a total of 72 STEMI patients evaluated, 44 received thrombolysis as reperfusion therapy, 25 received primary percutaneous coronary intervention, and 3 received thrombolysis followed by rescue percutaneous coronary intervention. Of the 47 subjects who received thrombolysis, only 5 required to be transferred to the referral center for this procedure. Median door-to-needle time was 24 minutes and door-to balloon-time was 105 minutes. Twenty-five percent of the subjects had a door-to-balloon time <90 minutes and 53.2% fulfilled a door-to-needle time <30 minutes. Conclusions: The implementation of a telemedicine-guided program for decentralized management of STEMI patients was associated with a high percentage of compliance with the goals of implementing fibrinolytic-based reperfusion therapy.

Inhibitory control and obesity in adolescents: A prospective cohort study.

INTRODUCTION: Inhibitory control (IC) is an executive function that plays a central role in the capability to control one's attention and behavior. Growing evidence suggests that deficits in IC are related to calorie consumption and obesity development. However, there are only a few studies that have addressed this issue prospectively. The aim of the present study was to evaluate the influence of IC on anthropometric changes at one year follow up in a cohort of Argentinian adolescents. METHODS: A prospective cohort study of 569 students (264 boys and 305 girls) aged 13.18 ± 0.36 years at initial evaluation and 14.22 ± 0.29 years at follow up was performed. IC was assessed at baseline and at follow up by means of a computerized Go/No-Go task, and anthropometric measures were performed following standardized procedures. At follow up an abbreviated Three Factor Eating Questionnaire (TFEQ-R21C) was performed. RESULTS: Cross sectional analysis performed at the age of 14 revealed an association between IC and obesity, meanwhile at the age of 13 IC was associated with the degree of obesity. Prospective analysis showed that a lower IC at baseline predicted a higher increase in body mass index (BMI) and waist circumference at one year of follow up. Subjects with lower IC at follow up rated higher in the uncontrolled eating domain of TFEQ-R21C and presented higher snacking frequency. CONCLUSIONS: A higher IC capacity at baseline might be associated with a more favorable evolution in BMI and waist circumference. A low IC at follow up is associated with obesity and higher uncontrolled eating. This suggests that the identification of subjects with low IC might be useful in order to detect adolescents at risk of obesity at earlier stages.

The impact of beef and soybean protein demand on carbon emissions in Argentina during the first two decades of the twenty-first century.

We quantified and analyzed the effect that the domestic and international demand for beef and soybean proteins had on carbon emissions in Argentina during the first two decades of the twenty-first century. We also analyzed the influence of both factors on the national deforestation rates. Principal component analysis and simple regression analyses were in turn used to detect components that maximize data variance, and to quantify relevant relationships. Our results show that not all activities considered carbon sources had the same impact on carbon emissions, and not all carbon emissions are equally affected by domestic and international demand of proteins throughout the period 2001-2018. We found a relevant association of both the domestic and international demand with carbon emissions during a first 2001-2009 period, and a less-significant one during a second 2010-2018 period. Deforestation (P <0.01), beef (P <0.05), and soybean production (P> 0.05) were the factors that decreasingly explained carbon emissions. Biased assumptions about the impact of protein demand on carbon emissions in Argentina should be cautiously taken unless they are supported by robust scientific evidence.

Short sleep and low milk intake are associated with obesity in a community of school aged children from Argentina.

OBJECTIVES: Understanding the factors related to obesity during childhood allows for improved preventive actions specifically adapted to particular communities. The purpose of this study was to identify individual and familiar factors related to obesity in children. METHODS: A cross-sectional study was conducted in an urban community in Argentina during the years 2015-2016. Weight and height were measured on a probabilistic sample of 1366 schoolchildren aged 6 to 12 years. BMI categories were established according to International Obesity Task Force (IOTF) cut-offs. Data were analyzed using multivariate and logistic regression models. Independent variables corresponded to four domains: anthropometric, socioeconomic and demographic, nutritional, and energy balance. RESULTS: Twenty percent of children were categorized as overweight (OW) and 12.2% were obese (OB). Parental IOTF grade was positively associated with childhood OW/OB (father B = 0.421 P = 0.000, OR = 1.52, 95% CI 1.24-1.88; mother B = 0.498 P = 0.000, OR = 1.65, 95% CI 1.37-1.97). The remaining variables were negatively associated with OW/OB: hours of sleep (B = -0.566 P = 0.001, OR = 0.57, 95% CI 0.41-0.79), physical activity (B = -0.362 P = 0.017, OR = 0.70, 95% CI 0-52-0.94), and daily milk intake (B = -0.178 P = 0.045, OR = 0.84, 95% CI 0.70-0.99). Parental IOTF predicted both OW and OB, while sleep hours predicted OW and physical activity predicted OB. CONCLUSIONS: Family should be considered the initial target for effective strategies to reduce obesity. Like physical activity, the promotion of milk and dairy intake, as well as sleep, may have a major role in obesity reduction because of their protective effects in this community.

Short-term effects of a green coffee extract-, Garcinia c ambogia- and L-carnitine-containing chewing gum on snack intake and appetite regulation.

INTRODUCTION: Different studies have assessed the influence of chewing gum to aid control of appetite and reduce food intake. PURPOSE: The aims of the present study were to evaluate the effects of chewing gum on satiety, food hedonics and snack intake and to explore the potential effects of the combination of Garcinia c ambogia, green coffee extract and L-carnitine on satiety, when administered in a gum format. METHODS: This was a prospective study in which 57 subjects randomly received three kinds of treatments, in a crossover design: (1) active gum; (2) placebo gum; and (3) no gum. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preference Questionnaire and visual analog scales. RESULTS: There was a significant reduction in low-fat sweet snack intake with placebo gum and the active gum compared to no gum and a reduction in high-fat sweet snack intake with the active gum compared to placebo gum and no gum. Total caloric intake was only reduced in the active gum condition. Both the active and placebo gum conditions significantly reduced hunger and prospective food consumption and increased fullness compared to no gum and were associated with a reduced wanting for sweet food in the LFPQ, consistent in a reduction in the relative preference for sweet snacks versus savoury snacks. CONCLUSION: This study supports the notion that chewing gum containing nutraceutical products might aid in the control over snack intake and reduce hunger sensations.

Fructose increases corticosterone production in association with NADPH metabolism alterations in rat epididymal white adipose tissue.

Metabolic syndrome is an array of closely metabolic disorders that includes glucose intolerance/insulin resistance, central obesity, dyslipidemia, and hypertension. Fructose, a highly lipogenic sugar, has profound metabolic effects in adipose tissue, and has been associated with the etiopathology of many components of the metabolic syndrome. In adipocytes, the enzyme 11 ß-HSD1 amplifies local glucocorticoid production, being a key player in the pathogenesis of central obesity and metabolic syndrome. 11 ß-HSD1 reductase activity is dependent on NADPH, a cofactor generated by H6PD inside the endoplasmic reticulum. Our focus was to explore the effect of fructose overload on epididymal white adipose tissue (EWAT) machinery involved in glucocorticoid production and NADPH and oxidants metabolism. Male Sprague-Dawley rats fed with a fructose solution (10% (w/v) in tap water) during 9 weeks developed some characteristic features of metabolic syndrome, such as hypertriglyceridemia, and hypertension. In addition, high levels of plasma and EWAT corticosterone were detected. Activities and expressions of H6PD and 11 ß-HSD1, NAPDH content, superoxide anion production, expression of NADPH oxidase 2 subunits, and indicators of oxidative metabolism were measured. Fructose overloaded rats showed an increased potential in oxidant production respect to control rats. In parallel, in EWAT from fructose overloaded rats we found higher expression/activity of H6PD and 11 ß-HSD1, and NADPH/NADP+ ratio. Our in vivo results support that fructose overload installs in EWAT conditions favoring glucocorticoid production through higher H6PD expression/activity supplying NADPH for enhanced 11 ß-HSD1 expression/activity, becoming this tissue a potential extra-adrenal source of corticosterone under these experimental conditions.

Underweight, overweight and obesity prevalence among adolescent school children in the Province of La Pamp Argentina.

INTRODUCTION: While different epidemiological studies as part of their survey include data of adolescents of the province of La Pampa regarding overweight and obesity prevalence, their experimental designs have certain limitations as far as the description of the regional reality. OBJECTIVE: To obtain a diagnosis of the situation regarding the body composition profile among 13 year old adolescents in the Province of La Pampa. POPULATION AND METHODS: A cross-sectional study was conducted in a sample of male and female adolescents born in 2001. Weight, height, waist circumference, scapular and tricipital skinfolds were measured. RESULTS: Of the 711 adolescents assessed, 5 subjects (0.7%) had a weight below the third percentile for age and sex. In relation to overweight and obesity, the sample values were 26.4% and 14.1%, respectively (27.5% and 16.9% of male; 25.5% and 11.7% of female adolescents). Of the total sample, 15.8% (16.5% of male and 15.6% of female adolescents) had waist circumference values compatible with abdominal obesity. As far as body fat values, 36.8% (37.4% of male and 36% of female adolescents) had above normal values according to skinfold thickness measurements. CONCLUSIONS: In contrast with the small prevalence of low weight in the region, overweight and obesity are a significant problem among the studied population in La Pampa.

INTRODUCTION: Introducción. Mientras que diversos estudios epidemiológicos incluyen como parte de su relevamiento datos de jóvenes de la provincia de La Pampa en relación con la prevalencia de sobrepeso y obesidad, sus diseños experimentales presentan ciertas limitaciones en cuanto a la descripción de la realidad regional. OBJECTIVE: Obtener un diagnóstico de situación acerca del perfil de composición corporal de adolescentes de 13 años de edad de la provincia de La Pampa. POBLACIÓN Y MÉTODOS: Se realizó un estudio de corte transversal en una muestra de varones y niñas nacidos en el año 2001, a los que se les tomó peso, tall perímetro de cintur pliegue subescapular y tricipital. RESULTS: De los 711 varones y niñas evaluados, 5 sujetos (0,7%) presentaron un peso por debajo del percentilo 3 para sexo y edad. En lo que hace a sobrepeso y obesidad, los valores de la muestra fueron 26,4% y 14,1%, respectivamente (27,5% y 16,9% en varones; 25,5% y 11,7% en niñas). Un 15,8% del total de la muestra (16,5% de los varones y 15,6% de las niñas) presentó valores de perímetro de cintura compatibles con obesidad abdominal. Un 36,8% (37,4% de varones y 36% de mujeres) mostró valores de grasa por encima de lo normal de acuerdo con la evaluación realizada a partir de los pliegues cutáneos. CONCLUSIÓN: En contraposición a la pequeña prevalencia de bajo peso en la región, el sobrepeso y la obesidad constituyen una problemática de magnitudes elevadas en nuestra provincia en lapoblación estudiada.

Evaluation of the satiating properties of a nutraceutical product containing Garcinia cambogia and Ascophyllum nodosum extracts in healthy volunteers.

A nutraceutical product composed of a combination of Garcinia cambogia, l-carnitine and a seaweed extract of Ascophyllum nodosum has been recently developed. The aim of the present study was to characterize its effects on subjective satiety sensations and food preferences in healthy volunteers. In a crossover design, 28 subjects (21 females and 7 males, aged 31 ± 5, BMI 22.6 ± 1.7) were randomly assigned to receive the active treatment (LIS) or placebo (PL) over one week. At the end of each treatment period, subjects were instructed to consume ad libitum a test meal. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preferences Questionnaire and visual analog scales, before and after meal, over three hours. There were no differences in energy intake between study groups. LIS was associated with a reduction in subjective hunger sensations (p = 0.018) and to an increase in satiety (p = 0.02) and fullness (p = 0.01) ratings. The preference for high fat foods was reduced after consuming the test meal in both study groups. There was a significant effect of LIS treatment on food explicit liking and implicit wanting, as evidenced by an increase in preference for sweet foods (relative to savory foods; p = 0.03 and p = 0.004, respectively), but no differences were observed regarding the preference for low or high fat foods (NS). These results provide proof of principle for the satiating properties of a nutraceutical containing Garcinia cambogia, Ascophyllum nodosum extract and l-carnitine and suggest that it might be useful as an appetite modulator.

The Mas receptor mediates modulation of insulin signaling by angiotensin-(1-7).

Angiotensin (Ang)-(1-7) stimulates proteins belonging to the insulin signaling pathway and ameliorates the Ang II negative effects at this level. However, up to date, receptors involved and mechanisms behind these observations remain unknown. Accordingly, in the present study, we explored the in vivo effects of antagonism of the Ang-(1-7) specific Mas receptor on insulin signal transduction in rat insulin-target tissues. We evaluated the acute modulation of insulin-stimulated phosphorylation of Akt, GSK-3ß (Glycogen synthase kinase-3ß) and AS160 (Akt substrate of 160kDa) by Ang-(1-7) and/or Ang II in the presence and absence of the selective Mas receptor antagonist A-779 in insulin-target tissues of normal rats. Also using A-779, we determined whether the Mas receptor mediates the improvement of insulin sensitivity exerted by chronic Ang-(1-7) treatment in fructose-fed rats (FFR), a model of insulin resistance, dyslipidemia and mild hypertension. The two major findings of the present work are as follows; 1) Ang-(1-7) attenuates acute Ang II-mediated inhibition of insulin signaling components in normal rats via a Mas receptor-dependent mechanism; and 2). The Mas receptor appears to be involved in beneficial effects of Ang-(1-7) on the phosphorylation of crucial insulin signaling mediators (Akt, GSK-3ß and AS160), in liver, skeletal muscle and adipose tissue of FFR. These results shed light into the mechanism by which Ang-(1-7) exerts its positive physiological modulation of insulin actions in classical metabolic tissues and reinforces the central role of Akt in these effects.

Sodium tungstate and vanadyl sulfate effects on blood pressure and vascular prostanoids production in fructose-overloaded rats.

This study analyzes the effects of sodium tungstate and vanadyl sulphate in the fructose-overloaded rat, a model of metabolic syndrome. Fructose (9 weeks) increased blood pressure, triglycerydemia, glycemia, and reduced release of vasodilator prostaglandins (prostacyclin and prostaglandin E2 ) in the mesenteric vascular bed. Sodium tungstate prevented those alterations; meanwhile vanadyl sulfate only prevented the increase in glycemia. In conclusion, the present experiments showed that sodium tungstate is more effective than vanadyl sulfate for the treatment of experimental metabolic syndrome in rats.

Centrally administered insulin potentiates the pressor response to angiotensin II.

The aim of the present study was to determine if insulin can modulate the pressor response to angiotensin II at brain level in normotensive rats. Anaesthetized male rats were intracerebroventricularly infused with insulin (12 mU/h, n=15) or Ringer's solution as vehicle (n=15) for 2 h. Immediately, changes in mean arterial pressure (MAP) in response to an intracerebroventricular subpressor dose of angiotensin II (5 pmol, n=10) or vehicle (n=5) were measured for 10 min. Then, hypothalami were removed and Akt and ERK1/2 phosphorylation levels were determined. In other subset of animals, PD98059 (MAPK inhibitor) or vehicle were intracerebroventricularly administered previously to insulin perfusion for 2 h and changes in MAP in response to intracerebroventricular angiotensin II (5 pmol) injection were evaluated for 10 min (n=6 for each group). Angiotensin II did not modify MAP in vehicle pre-treated rats, but increased MAP in insulin pre-treated animals. Insulin significantly increased Akt phosphorylation, but no changes were observed after angiotensin II injection in vehicle-pretreated animals. Angiotensin II or insulin infusion increased in more than two fold phospho-ERK 1/2 hypothalamic levels. Animals that received insulin infusion followed by Ang II injection presented 4.5 higher values than those which received vehicle, and nearly twice than those who received Ang II without insulin pre-treatment. PD98059 administration abolished the blood pressure response exerted by angiotensin II in insulin pre-treated rats. In conclusion, centrally administered insulin potentiates the pressor effects to angiotensin II, suggesting a novel mechanism, possibly involving MAPK activation, by which insulin influences blood pressure control at central level.

Cardiovascular drugs inducing QT prolongation: facts and evidence.

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

Angiotensin-(1-7) improves cardiac remodeling and inhibits growth-promoting pathways in the heart of fructose-fed rats.

The present study examined whether chronic treatment with angiotensin (ANG)-(1-7) reduces cardiac remodeling and inhibits growth-promoting signaling pathways in the heart of fructose-fed rats (FFR), an animal model of insulin resistance. Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of the corresponding diet, control and FFR were implanted with osmotic pumps that delivered ANG-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We determined heart weight, myocyte diameter, interstitial fibrosis, and perivascular collagen type III deposition as well as the phosphorylation degree of ERK1/2, JNK1/2, and p38MAPK. FFR showed a mild hypertension that was significantly reduced after ANG-(1-7) treatment. Also, FFR displayed higher ANG II circulating and local levels in the heart that remained unaltered after chronic ANG-(1-7) infusion. An increased heart-to-body weight ratio, myocyte diameter, as well as left ventricular fibrosis and perivascular collagen type III deposition were detected in the heart of FFR. Interestingly, significant improvements in these cardiac alterations were obtained after ANG-(1-7) treatment. Finally, FFR that received ANG-(1-7) chronically displayed significantly lower phosphorylation levels of ERK1/2, JNK1/2, and p38MAPK. The beneficial effects obtained by ANG-(1-7) were associated with normal values of Src-homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity in the heart. In conclusion, chronic ANG-(1-7) treatment ameliorated cardiac hypertrophy and fibrosis and attenuated the growth-promoting pathways in the heart. These findings show an important protective role of ANG-(1-7) in the heart of insulin-resistant rats.

Differential hippocampal pharmacokinetics of phenobarbital and carbamazepine in repetitive seizures induced by 3-mercaptopropionic acid.

Previous evidence has shown that chronic 3-mercaptopropionic acid (MP) administration induced brain P-glycoprotein (P-gp) overexpression altering target site accumulation of phenytoin. The aim of the present work was to assess the involvement of P-glycoprotein in carbamazepine and phenobarbital hippocampal pharmacokinetics in an experimental model of epilepsy, induced by repetitive MP administration. Seizures were induced in Wistar rats by injection of MP (45 mg kg(-1), i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular brain antiepileptic levels, a concentric probe was inserted into the hippocampus. Animals were administered with carbamazepine (10 mg kg(-1), i.v.) or phenobarbital (20 mg kg(-1), i.v.) 30 min after intraperitoneal administration of vehicle or nimodipine (2 mg kg(-1)), a well known P-glycoprotein inhibitor. No differences were found in hippocampal concentrations of carbamazepine comparing all groups. In vehicle pre-treated rats, hippocampal phenobarbital concentrations were lower in MP (maximal concentration, C(max): 6.0+/-0.6 microg ml(-1), p<0.05) than in C animals (C(max): 9.4+/-0.9 microg ml(-1)). Control rats pre-treated with nimodipine showed similar results (C(max): 10.7+/-0.6 microg ml(-1)) than those pre-treated with vehicle. Nimodipine pre-treatment in MP rats enhanced hippocampal phenobarbital concentrations (C(max): 10.2+/-1.0 microg ml(-1), p<0.05) as compared with vehicle pre-treatment. Results of our work suggest that P-glycoprotein (P-gp) overexpression by repetitive seizures induced by MP administration does not modify brain bioavailability of carbamazepine. Conversely, hippocampal levels of phenobarbital are reduced in MP rats with regard to non-epileptic rats, suggesting a potential role of P-gp overexpression in pharmacoresistance to phenobarbital.

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance.

The I kappaB kinase-beta (IKK-beta)/nuclear factor-kappaB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3beta. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.

Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension.

OBJECTIVES: The aim of this work was to evaluate the pharmacokinetic-pharmacodynamic properties of diltiazem in an experimental model of high-renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this model to calcium channel blockers. METHODS: A 'shunt' microdialysis probe was inserted in a carotid artery of anaesthetized ACo and control sham-operated (SO) rats for simultaneous determination of diltiazem plasma concentrations and their effects on mean arterial pressure and heart rate after the intravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levels and cardiovascular effects was established by fitting the data to a modified Emax model. KEY FINDINGS: Volume of distribution was greater in ACo than in SO rats. Diltiazem plasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO rats after administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo but not in SO rats. No differences were observed in the maximal bradycardic effect comparing both experimental groups, and sensitivity (S0) to diltiazem chronotropic effect was similar comparing SO and ACo rats. Differences were not found in the maximal response of the hypotensive effect comparing SO and ACo rats, but the S0 to diltiazem hypotensive effect was greater in ACo rats than in SO rats. CONCLUSIONS: ACo induced profound changes in diltiazem pharmacokinetic behaviour. In addition, our results suggested an increased sensitivity to diltiazem blood pressure lowering effect in experimental renovascular hypertension with high-renin levels.

Recent advances in obesity pharmacotherapy.

Obesity is considered a worldwide epidemic. Weight reduction by means of lifestyle changes is difficult to achieve, and pharmacotherapy is frequently needed. Although all currently approved anti-obesity agents have proven to be effective to achieve some degree of weight reduction and improve cardiometabolic risk factors, different compounds differ in their mechanism of action and safety profile. However, it is still difficult to achieve and maintain therapeutic objectives along time. The aim of the present article is to summarize the main characteristics of available anti-obesity agents and to explore novel agents that may provide significant clinical benefits in the future.

Chronic infusion of angiotensin-(1-7) improves insulin resistance and hypertension induced by a high-fructose diet in rats.

The current study was undertaken to determine whether Ang-(1-7) is effective in improving metabolic parameters in fructose-fed rats (FFR), a model of metabolic syndrome. Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of either diet, control and FFR were implanted with subcutaneous osmotic pumps that delivered Ang-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We measured systolic blood pressure (SBP) together with plasma levels of insulin, triglycerides, and glucose. A glucose tolerance test (GTT) was performed, with plasma insulin levels determined before and 15 and 120 min after glucose administration. In addition, we evaluated insulin signaling through the IR/IRS-1/PI3K/Akt pathway as well as the phosphorylation levels of IRS-1 at inhibitory site Ser(307) in skeletal muscle and adipose tissue. FFR displayed hypertriglyceridemia, hyperinsulinemia, increased SBP, and an exaggerated release of insulin during a GTT, together with decreased activation of insulin signaling through the IR/IRS-1/PI3K/Akt pathway in skeletal muscle, liver, and adipose tissue, as well as increased levels of IRS-1 phospho-Ser(307) in skeletal muscle and adipose tissue, alterations that correlated with increased activation of the kinases mTOR and JNK. Chronic Ang-(1-7) treatment resulted in normalization of all alterations. These results show that Ang-(1-7) ameliorates insulin resistance in a model of metabolic syndrome via a mechanism that could involve the modulation of insulin signaling.

Modelado farmacocinético-farmacodinámico de fármacos antihipertensivos: su aplicación en la práctica clínica / Pharmacokinetic-Pharmacodynamic Modelling of Antihypertensive Drugs: Its Application to Clinical Practice

El conocimiento de las propiedades farmacocinéticas-farmacodinámicas (PK/PD) de los fármacos puede optimizar la terapia antihipertensiva. El modelado PK/PD en la investigación clínica podría contribuir en el desarrollo del fármaco y en la práctica clínica en varios aspectos, entre ellos la evaluación de eficacia y seguridad de los antihipertensivos, mayor información durante el proceso del desarrollo, identificación de factores de variabilidad de la respuesta farmacológica, y permitir además una identificación rápida de malos respondedores o no respondedores y ayudar a determinar requerimientos óptimos del fármaco y dosis en cada paciente hipertenso. Hay algunas limitaciones en el modelado PK/PD de los antihipertensivos en la práctica clínica, entre las que se incluyen el uso de modelos farmacodinámicos inadecuados y la incapacidad de estudiar dosis elevadas de antihipertensivos para determinar el rango farmacodinámico completo del efecto antihipertensivo. El propósito de esta revisión es describir el conocimiento actual del modelado PK/PD de los fármacos antihipertensivos en la investigación clínica y sus usos futuros.

Knowing the pharmacokinetic-pharmacodynamic properties (PK/PD) of drugs might optimize antihypertensive therapy. PK/PD modelling might not only contribute to develop the drug but might also help in clinical practice assessing the efficacy and safety of antihypertensive drugs, bringing more information during the developing process, identifying factors responsible for the variability in pharmacologic response, bad responders or non-responders, and determining the optimal requisites of the drug and doses in each patient with hypertension. There are some limitations in PK/ PD modelling of antihypertensive drugs in clinical practice, such as inadequate pharmacodynamic models and the inability to study high doses of antihypertensive drugs to determine the whole pharmacodynamic range of the antihypertensive effect. The aim of this review is to describe the current knowledge on PK/PD modelling of antihypertensive drugs in clinical research, and its further uses.

Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension.

INTRODUCTION: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. METHODS: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg(-1)). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified E(max) model. RESULTS: No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK-PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK-PD parameters, linear and E(max) model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified E(max) model allows both a precise and accurate estimation of PK-PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK-PD parameters estimated for the hypotensive response. DISCUSSION: Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK-PD parameters estimation by using the linear and classical E(max) model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified E(max) model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified E(max) pharmacodynamic model is the most suitable for verapamil PK-PD modeling.