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 IKr. 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.Fil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Mayer, Marcos Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentin

Applicability of reverse microdialysis in pharmacological and toxicological studies

A recent application of microdialysis is the introduction of a substance into the extracellular space via the microdialysis probe. The inclusion of a higher amount of a drug in the perfusate allows the drug to diffuse through the microdialysis membrane to the tissue. This technique, actually called as reverse microdialysis, not only allows the local administration of a substance but also permits the simultaneous sampling of the extracellular levels of endogenous compounds. Local effects of exogenous compounds have been studied in the central nervous system, hepatic tissue, dermis, heart and corpora luteae of experimental animals by means of reverse microdialysis. In central nervous studies, reverse microdialysis has been extensively used for the study of the effects on neurotransmission at different central nuclei of diverse pharmacological and toxicological agents, such as antidepressants, antipsychotics, antiparkinsonians, hallucinogens, drugs of abuse and experimental drugs. In the clinical setting, reverse microdialysis has been used for the study of local effects of drugs in the adipose tissue, skeletal muscle and dermis. The aim of this review is to describe the principles of the reverse microdialysis, to compare the technique with other available methods and finally to describe the applicability of reverse microdialysis in the study of drugs properties both in basic and clinical research.Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentin

Effect of α-methyldopa on striatal doparninergic neurotransmision

Se estudió el efecto del inhibidor de la decarboxilasa de aminoácidos aromáticos α-metildopa sobre la neurotransmisión dopaminérgica en el cuerpo estriado de ratas mediante la técnica de perfusión por microdiálisis. La α-metildopa, que a la dosis de 100 mg/kg (i.p.) sólo muestra una acción cardíaca, induce la acumulación de la l-dopa en el cuerpo estriado de ratas, sugiriendo una inhibición de la síntesis de dopamina, pero al mismo tiempo provoca también un incremento de la concentración de dopamina en las muestras de perfusato. Este último efecto podría deberse a alguna accibn de la droga sobre la liberación del neurotransmisor.The effect of α-methyIDOPA, an inhibitor of aromatic aminoacid decarboxilase on dopaminergic neurotransmision, was studied in rat striatum by using the technique of microdialysis perfusion. At a dose (100 mg/kg, i.p.) with only cardiac action, α-Methyldopa induces striatal accumulation of l- dopa, suggesting an inhibition of doparnine synthesis in rat striatum. However, an increase of dopamine level was also seen which could be due by an action of α-methyIDOPA on the neurotransmitter release.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Anterior hypothalamic β-adrenergic activity in the maintenance of hypertension in aortic coarctated rats

The aim of this work was to demonstrate an alteration of the anterior hypothalamic catecholaminergic system in aortic coarctated (ACo) rats by the perfusion of β-adrenergic antagonist and the microinfusion of β-adrenergic agonist. Wistar urethane-chloralose anesthetized rats were used. The carotid artery was cannulated for blood pressure recording and changes in blood pressure were measured. A concentric microdialysis probe was inserted in the anterior hypothalamus. Metoprolol (a β1- adrenoceptor antagonist) perfusion (6μgml-1) reduced the mean arterial pressure (MAP) in the ACo rats but not in sham operated (SO) animals. The anterior hypothalamic infusion of non-specific β-adrenergic agonist isoproterenol induced a dose-dependent decrease of blood pressure in both experimental groups, but the depressor response was significantly lower in ACo rats. The pretreatment with atenolol, a selective β1- adrenoceptor antagonist, increased the depressor effect of isoproterenol in ACo rats, but not in SO rats. On the other hand, the hypotensive action of isoproterenol was significantly diminished after the administration of non-specific β-adrenoceptor antagonist propranolol in SO and ACo rats. The anterior hypothalamic infusion of clenbuterol, a selective β 2-adrenergic agonist, induced a dose-dependent decrease of blood pressure in both experimental groups. The depressor response to clenbuterol (1nmol) was significantly lower in ACo rats than in SO rats. In summary, this study provides the evidence that there is a β1-adrenergic compromise in anaesthetized ACo rats and this compromise may be involved in the maintenance of hypertension. On the other hand, this study also suggests the existence of pressor β1-adrenoceptors in the anterior hypothalamic area of ACo rats but not in SO rats. We also found a diminished depressor β2-adrenergic activity in ACo rats.Fil: Höcht, Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Effect of α-methyldopa on striatal doparninergic neurotransmision

Se estudió el efecto del inhibidor de la decarboxilasa de aminoácidos aromáticos α-metildopa sobre la neurotransmisión dopaminérgica en el cuerpo estriado de ratas mediante la técnica de perfusión por microdiálisis. La α-metildopa, que a la dosis de 100 mg/kg (i.p.) sólo muestra una acción cardíaca, induce la acumulación de la l-dopa en el cuerpo estriado de ratas, sugiriendo una inhibición de la síntesis de dopamina, pero al mismo tiempo provoca también un incremento de la concentración de dopamina en las muestras de perfusato. Este último efecto podría deberse a alguna accibn de la droga sobre la liberación del neurotransmisor.The effect of α-methyIDOPA, an inhibitor of aromatic aminoacid decarboxilase on dopaminergic neurotransmision, was studied in rat striatum by using the technique of microdialysis perfusion. At a dose (100 mg/kg, i.p.) with only cardiac action, α-Methyldopa induces striatal accumulation of l- dopa, suggesting an inhibition of doparnine synthesis in rat striatum. However, an increase of dopamine level was also seen which could be due by an action of α-methyIDOPA on the neurotransmitter release.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Intranasal administration of antiretroviral-loaded micelles for anatomical targeting to the brain in HIV

We investigated the intranasal administration of poly(ethylene oxide)–poly(propylene oxide) polymeric micelles loaded with high payloads of the first-line antiretroviral drug efavirenz for targeting to the CNS. The effect of micellar size and composition and drug payload was assessed, employing simple micelles made of a highly hydrophilic copolymer, poloxamer F127, loaded with 20 mg/ml drug and mixed micelles containing 75% of a medium hydrophobic poloxamine, T904, and 25% F127 loaded with 20 and 30 mg/ml drug, respectively. F127 confers high physical stability, while T904 substantially improves the encapsulation capacity of the micelles. The bioavailability of the drug in the CNS was increased fourfold and the relative exposure index (ratio between the area-under-the-curve in the CNS and plasma) was increased fivefold with respect to the same system administered intravenously. These findings demonstrate the potential of this scalable and cost-viable strategy to attack the HIV sanctuary in the CNS.Fil: Chiappetta, Diego Andrés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina;Fil: Hocht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina;Fil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina;Fil: Sosnik, Alejandro Dario. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina

Applicability of microdialysis as a technique for pharmacokinetic- pharmacodynamic (PK-PD) modeling of antihypertensive beta-blockers

Introduction: The aim of the present work was to examine microdialysis as a technique for the study of pharmacokinetic-pharmacodynamic modeling of antihypertensive drugs. For this purpose, we studied the antihypertensive and the chronotropic effect of metoprolol and its plasma concentrations in sham operated (SO) and aortic coarctated (ACo) rats at an early hypertensive stage. Methods: Plasma metoprolol concentrations were obtained by means of a "shunt" vascular microdialysis probe. Changes in mean arterial pressure and heart rate were also measured in the same experiment. Results: A rapid decay of metoprolol levels was observed in both experimental groups. For the chronotropic effect, a good association between plasma levels and the chronotropic effect was observed in SO and ACo rats. ACo rats had a greater sensitivity to the chronotropic effect (Emax:-38±2%, n=5, p<0.05) than SO animals (Emax:-27±1%, n=5). A delay in the blood pressure reduction induced by metoprolol was observed in both experimental groups. A good association was observed between concentrations of metoprolol in the effect compartment and the corresponding hypotensive effect in both experimental groups. The calculated PK-PD parameters were not different between SO and ACo groups. Discussion: A good correlation was found between metoprolol concentration and its chronotropic and antihypertensive effects in normotensive and ACo hypertensive rats, allowing the employment of PK-PD models. The microdialysis technique allows simultaneous determination of plasma levels of antihypertensive drugs and their cardiovascular effects, and is therefore a powerful tool for PK-PD modeling.Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: DiVerniero, Carla. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Pharmacokinetic-pharmacodynamic (PK-PD) modeling of cardiovascular effects of metoprolol in spontaneously hypertensive rats: a microdialysis study

The present work addressed possible alterations inthe pharmacokinetics and the in vivo pharmacodynamic ofmetoprolol (MET) in spontaneously hypertensive (SH) ratsand Wistar Kyoto (WKY) animals by means of the microdialysistechnique. The correlation between MET unboundplasma concentrations and its pharmacological effects, such asheart rate and blood pressure change,was also examined in SHand WKY rats by the application of a PK-PD model. METdialysate concentrations and its chronotropic and bloodpressure effect were determined during 3 h after theadministration of 3 and 10 mg.kg−1 of the drug. A PK-PDmodel with a separate effect compartment was used toanalyse the data. A good correlation between plasma METconcentrations and its hypotensive and chronotropic effectwas found in all experimental groups. Although a greatermaximal effect (Emax) for the antihypertensive effect of METwas observed in SH rats (WKY: Emax: −17±1 mmHg; SH:Emax: −28±4 mmHg; P<0.05 versus WKY rats), no differenceswere found in the concentration yielding half-maximalresponse (IC50) comparing SH (IC50: 583±146 ng.ml−1) andWKY animals (IC50: 639±187 ng.ml−1). The bradycardiceffect of MET was greater in SH rats (Emax: −29±1%, P<0.05versus WKY rats) than in WK animals (Emax: −22±2%), butno differences were observed in the IC50 comparing bothexperimental groups (WKY: IC50: 187±53 ng.ml−1; SH: IC50:216±62 ng.ml−1). Pharmacokinetic analysis shows that thevolume of distribution of MET was greater in SH rats (Vd:3.4±0.5 l, P<0.05 versus WKY rats) with regard to WistarKyoto (WKY) animals (Vd: 1.9±0.2 l). The results suggestthat the pharmacokinetic behaviour of metoprolol aremodified in SH rats, resulting in an increased volume ofdistribution. A greater maximal efficacy to the hypotensiveeffect of metoprolol was observed in SH rats, suggestingparticipation of â-adrenoceptors in the maintenance of thehypertension. Also, a greater chronotropic response tometoprolol was found in the hypertensive group comparedwith WKY animals, suggesting that, at least in part, thegreater cardiac effect of metoprolol explained the enhancedhypotensive response of the beta blocker in the SH animals.Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Di Verniero, Carla. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Opezzo, Javier A.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentin

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 Emax 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 Emax model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified Emax 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 Emax model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified Emax model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified Emax pharmacodynamic model is the most suitable for verapamil PK-PD modeling.Fil: Bertera, Facundo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Mayer, Marcos Alejandro. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; ArgentinaFil: Höcht, Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentin