Javier Opezzo
Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Department Member
Research Interests:
Research Interests:
Research Interests: Cardiology, Complementary and Alternative Medicine, Medicine, Humans, Female, and 15 moreMale, HERG, Long QT syndrome, Risk factors, Clinical Sciences, Hypokalemia, Sex Factors, Fisiología, Risk Factors, QT interval, Amiodarone, Torsades de pointes, Severity of Illness Index, Pharmacology and pharmaceutical sciences, and Genetic predisposition to disease
Research Interests: Pharmacology, Pharmacokinetics, Medicine, Blood Pressure, Blood sampling, and 13 moreHeart rate, Central Nervous System, Clinical Sciences, Pharmacodynamics, Veterinary Sciences, Angiotensin II, Carotid Artery, Protein Binding, Aortic Coarctation, Area Under the Curve, Irbesartan, Experimental Group, and Pharmacology and pharmaceutical sciences
Research Interests:
Research Interests:
Research Interests: Complementary and Alternative Medicine, Medicine, Humans, Female, Male, and 12 moreLong QT syndrome, Risk factors, Clinical Sciences, Hypokalemia, Sex Factors, Fisiología, Risk Factors, QT interval, Amiodarone, Torsades de pointes, Severity of Illness Index, and Pharmacology and pharmaceutical sciences
Research Interests:
Research Interests:
The aim of the present study was to investigate the effects of the alpha2-adrenoceptor antagonist yohimbine on blood pressure and heart rate (HR) regulation, as well as on adrenergic and serotoninergic neurotransmission, in fructose... more
The aim of the present study was to investigate the effects of the alpha2-adrenoceptor antagonist yohimbine on blood pressure and heart rate (HR) regulation, as well as on adrenergic and serotoninergic neurotransmission, in fructose hypertensive (F) rats. The anterior hypothalamic area of control (C) and F rats was perfused with Ringer's solution containing 10 and 100 microg/mL yohimbine through a microdialysis concentric probe. The effects of yohimbine on mean arterial pressure (MAP) and HR, as well as on hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) levels, were measured according to perfusion time. Although intrahypothalamic perfusion of yohimbine increased blood pressure in C rats (DeltaMAP 9 +/- 1 and 11 +/- 2 mmHg for 10 and 100 microg/mL yohimbine, respectively; P < 0.05 vs Ringer's perfusion), the alpha-adrenoceptor antagonist did not modify MAP in F. Intrahypothalamic yohimbine had no effect on HR at either concentration tested. Intrahypothalamic perfusion of 10 and 100 microg/mL yohimbine increased DOPAC levels in C rats (135 +/- 6 and 130 +/- 5% of basal levels, respectively; both n = 6; P < 0.05 vs Ringer's perfusion), but not in F animals (115 +/- 6 and 102 +/- 6% of basal levels, respectively; both n = 6). In both C and F rats, yohimbine administration induced an increase in 5-HIAA dialysate levels. The results of the present study support the notion that alpha2-adrenoceptor tone of the anterior hypothalamus of normotensive rats, which contributes to normal blood pressure regulation, is not involved in the control of HR in either normotensive C or hypertensive F rats. The absence of changes in MAP after yohimbine perfusion in F rats suggests that the alpha2-adrenoceptor tone could be decreased in this group of rats and that this may be responsible for the maintenance of hypertension in this model. Intrahypothalamic perfusion of yohimbine increased DOPAC in the dialysate only in C rats, suggesting changes in presynaptic alpha2-adrenoceptor activity in fructose-overloaded rats. Conversely, increased 5-HIAA levels did not differ between C and F groups.
Research Interests:
The pharmacokinetics of methyldopa (12.5, 25 and 50 mg kg−1, i.p.) was studied in anesthetized sham-operated (SO) and abdominal aorta-coarctated (ACo) rats using a microdialysis technique. A non-linear relationship between the area under... more
The pharmacokinetics of methyldopa (12.5, 25 and 50 mg kg−1, i.p.) was studied in anesthetized sham-operated (SO) and abdominal aorta-coarctated (ACo) rats using a microdialysis technique. A non-linear relationship between the area under the curve (AUC) and dose was observed in SO rats. However, in ACo rats the AUC showed a proportional increase with dose. Abdominal aortic coarctation produced significant
Research Interests:
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... more
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.
Research Interests: Pharmacology, Biology, Neurotransmission, Pharmacokinetics, Medicine, and 15 moreAdipose tissue, Humans, Clinical research, Animals, Lipolysis, Anesthesia, Muscles, Central Nervous System, Drug Delivery Systems, Perfusion, Microdialysis, Basic Research, Drugs of Abuse, Clinical Application, and Pharmacology and pharmaceutical sciences
Research Interests: Pharmacology, Chemistry, Pharmacokinetics, Medicine, Hypertension, and 15 moreCardiovascular Pharmacology, Animals, Male, Fructose, Microdialysis, In Vivo, Rats, Pharmacodynamics, Propranolol, Potency, Area Under Curve, Metoprolol, Antihypertensive agents, Cardiovascular medicine and haematology, and Pharmacology and pharmaceutical sciences
The bioequivalence of two 600-mg oxcarbazepine oral formulations (Aurene, Ivax Argentina, [test]; and Trileptal, Novartis Laboratories, [reference]) were assessed through the simultaneous determination of oxcarbazepine and the active... more
The bioequivalence of two 600-mg oxcarbazepine oral formulations (Aurene, Ivax Argentina, [test]; and Trileptal, Novartis Laboratories, [reference]) were assessed through the simultaneous determination of oxcarbazepine and the active metabolite 10,11-dyhydro-10-hydroxy-carbamazepine derivative (MHD). 12 healthy male volunteers received a single oral dose of 600 mg of each formulation, in a balanced, randomized, paired, crossover design, with a 7-day wash out period. Oxcarbazepine and MHD concentrations were established at 0.5,1, 1.5, 2, 3, 4, 6, 8, 24 and 48 h post dose by high performance liquid chromatography (HPLC). The regression coefficient determined for oxcarbazepine calibration curves was 0.9933 +/- 0.0236; and for MHD, was 0.9897 +/- 0.0017. The working range for both oxcarbazepine and its metabolite was from 0.1 to 10.0 microg/ml. The quantification limit was 0.1 microg/ml. The 90% confidence interval (CI) geometric mean for oxcarbazepine C(max), AUC(0-48 h) and AUC(0-infinity) ratios (test : reference) were 74.1-146.2%, 85.6-171.5% and 89.6-169.8%, respectively, and the 90% CI geometric mean for MHD C(max), AUC(0-48 h) and AUC(0-infinity) ratios (test : reference) were 84.0-122.3, 93.2-117.9 and 96.5-116.7, respectively. These results established the bioequivalence of two oxcarbazepine formulations from MHD kinetic data used in 12 healthy volunteers, while it was not possible to establish bioequivalence with oxcarbazepine. MHD quantification is preferred to that of the oxcarbazepine in order to assess bioequivalence, as the metabolite is responsible for the antiepileptic activity, presents linear kinetics in the therapeutic range, has lower intra-individual variability and higher plasma levels and half life than the parent drug.
Research Interests: Pharmacokinetics, Pharmaceutical Chemistry, Medicine, Linear models, Humans, and 15 moreCalibration, Male, High Pressure Liquid Chromatography, Bioequivalence, Adult, Carbamazepine, MHD, Biotransformation, Metabolite, Area Under Curve, Confidence Interval, Oxcarbazepine, Geometric mean, Pharmacology and pharmaceutical sciences, and crossover study
1. The present study addressed possible changes in the dissociation constant of metoprolol and its inverse agonist activity in spontaneously hypertensive rats (SHR). In addition, a possible correlation between cardiac hypertrophy and the... more
1. The present study addressed possible changes in the dissociation constant of metoprolol and its inverse agonist activity in spontaneously hypertensive rats (SHR). In addition, a possible correlation between cardiac hypertrophy and the inverse agonist activity of metoprolol was explored. 2. In order to determine the dissociation constant (expressed as the pKb) of metoprolol, a cumulative concentration-response curve to noradrenaline was constructed in the absence or presence of metoprolol (0.1, 1 or 10 micromol/L). In a second experiment, a cumulative concentration-response curve to metoprolol was constructed to determine its inverse agonist activity. 3. The ventricular weight of SHR was significantly greater compared with Wistar-Kyoto (WKY) rats. A rightward shift of the concentration-response curve to noradrenaline was observed in SHR compared with WKY rats. The pKb of metoprolol was smaller in SHR compared with WKY rats (6.35 +/- 0.14 vs 6.99 +/- 0.12, respectively; P < 0.05). No difference was observed in the maximal response (Emax) of the concentration-time effect of metoprolol in WKY rats and SHR (-29.1 +/- 7.1 vs-28.2 +/- 8.5%, respectively; n = 6 for both). However, the concentration of metoprolol eliciting a half-maximal effect (expressed as the pEC50) was significantly smaller in SHR compared with WKY rats (4.82 +/- 0.07 vs 5.29 +/- 0.13, respectively; n = 6; P < 0.05). Although a significant correlation (r = -0.876) between the ventricular weight/bodyweight (VW/BW) ratio and the pEC50 of the chronotropic effect of metoprolol was found, no relationship (r = -0.257) was found between the VW/BW ratio and Emax. 4. In summary, the present study provides the first evidence of a change in the in vitro pharmacodynamic properties of metoprolol in SHR. The sympathetic overactivity present in SHR not only reduces the positive chronotropic effect of noradrenaline, but also diminishes the constant dissociation of metoprolol from atrial beta1-adrenoceptors and its inverse agonist activity. A significant correlation between the VW/BW ratio and the inverse agonist potency of metoprolol was found, suggesting a possible link between cardiac hypertrophy and the reduction of the inverse agonist activity of metoprolol.
Research Interests:
SUMMARY1. The aim of the present study was to investigate the activity of anterior hypothalamic β‐adrenoceptors and angiotensin (Ang) II receptors on blood pressure in normotensive rats and aortic‐coarctated (ACo) animals at a chronic... more
SUMMARY1. The aim of the present study was to investigate the activity of anterior hypothalamic β‐adrenoceptors and angiotensin (Ang) II receptors on blood pressure in normotensive rats and aortic‐coarctated (ACo) animals at a chronic stage of hypertension. A possible interaction between β‐adrenoceptors and AngII pressor activity was also investigated.2. Injection of isoproterenol (0.1–10 nmol) in the anterior hypothalamic area induced a dose‐dependent decrease in mean arterial pressure (MAP) in sham‐operated (SO), but not in ACo, animals. Isoproterenol (1 nmol) reduced blood pressure in SO rats (ΔMAP −10.1 ± 1.4 mmHg; n = 10) but not in ACo animals (ΔMAP −0.9 ± 1.6 mmHg; n = 10; P < 0.05 vs SO rats). Whereas previous administration of atenolol (40 nmol) enhanced the cardiovascular effect of isoproterenol (1 nmol) in ACo rats but not in SO animals, propranolol (40 nmol) prevented the hypotensive action of isoproterenol in both experimental groups. Intrahypothalamic administration...
Research Interests: Endocrinology, Physiology, Medicine, Internal Medicine, Hypertension, and 15 moreBlood Pressure, Chronic Disease, Female, Animals, Clinical, Heart rate, Clenbuterol, Medical Physiology, Propranolol, Angiotensin II, Aortic Coarctation, Isoproterenol, Atenolol, Mean Arterial Pressure, and Pharmacology and pharmaceutical sciences
Microdialysis has been developed during the last 25 years by several authors primarily to study brain function and changes in levels of endogenous compounds such as neurotransmitters or metabolites. The development of microdialysis for... more
Microdialysis has been developed during the last 25 years by several authors primarily to study brain function and changes in levels of endogenous compounds such as neurotransmitters or metabolites. The development of microdialysis for the purpose of measuring drugs was initiated during the late eighties. This technique provides a means of continuous plasma sampling without repeated blood sampling and the applicability to the study of drug metabolism and pharmacokinetics in experimental animals and human. Also, the microdialysis technique allows the study of plasma protein binding and the saturation of protein binding. The implantation of the microdialysis probe in other tissues and organs, like central nervous system, adipose tissue and heart, allows the study of drug distribution. On the other hand, the measurement of endogenous substances using the microdialysis technique permits the study of the effect of drugs on neurotransmission and metabolism. Moreover, as this technique allows the simultaneous determination of different physiological parameters such as blood pressure, locomotor and convulsive activity, it is a suitable tool for pharmacokinetic-pharmacodynamic studies of drugs and pharmacokinetic-pharmacodynamic (PK-PD) modeling. Lastly, the reverse microdialysis is a powerful technique for the study of local actions of drugs in different tissues such as specific brain nuclei, myocardium, liver or skeletal muscle. So, this article reviewed the vast applications of the microdialysis technique for the study of pharmacokinetic and pharmacodynamic properties of drugs.
Research Interests:
Resumen es: Objetivo Evaluar el papel del area hipotalamica anterior en la regulacion de la presion arterial en un modelo en ratas de hipertension arterial (HTA) e i...
Research Interests:
Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp,... more
Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P=0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma. Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962).
Research Interests:
Research Interests:
El sindrome QT largo adquirido es provocado principalmente por el uso de farmacos que prolongan la repolarizacion ventricular. Si bien es conocido que la mayoria de los antiarritmicos presentan esta propiedad, tambien es compartida por... more
El sindrome QT largo adquirido es provocado principalmente por el uso de farmacos que prolongan la repolarizacion ventricular. Si bien es conocido que la mayoria de los antiarritmicos presentan esta propiedad, tambien es compartida por alrededor de 100 drogas no antiarritmicas. Pese a que el riesgo de proarritmia con la mayoria de estos farmacos es bajo, la incidencia de esta reaccion adversa es importante debido a su amplio uso. Por otro lado, existen numerosos factores predisponentes que incrementan el riesgo de torsade de pointes, como la predisposicion genetica, el sexo femenino, la hipopotasemia y la disfuncion cardiaca. Ademas, la mayoria de los casos de torsade de pointes inducido por farmacos se han detectado en pacientes tratados con mas de un farmaco que presenta esta propiedad o bajo tratamiento con un inhibidor enzimatico. De acuerdo con esto, la mayoria de los casos de sindrome QT largo adquirido se podrian evitar mediante una seleccion correcta del paciente, asi como con un control adecuado de la terapia farmacologica. Por lo tanto, es de interes que los distintos profesionales de la salud esten actualizados en esta problematica y puedan aplicar medidas para evitar o reducir la incidencia de esta proarritmia. REV ARGENT CARDIOL 2004;72:474-480.
Con el proposito de determinar in vitro si la coartacion aortica en un estadio temprano de hipertension arterial modifica las propiedades farmacodinanicas de los betabloqueantes s-adrenergicos atenolol y propranolol, se estudiaron la... more
Con el proposito de determinar in vitro si la coartacion aortica en un estadio temprano de hipertension arterial modifica las propiedades farmacodinanicas de los betabloqueantes s-adrenergicos atenolol y propranolol, se estudiaron la constante de disociacion y la actividad de agonismo inverso de los betabloqueantes en auricula aislada de ratas con coartacion aortica (CoA) y de ratas con operacion simulada (OS). Para la determinacion de la constante de disociacion se midio el desplazamiento de la curva concentracion-efecto cronotropico de noradrenalina por agregado de distintas concentraciones de atenolol o de propranolol. El estudio del agonismo inverso de los betabloqueantes se realizo mediante la construccion de la curva concentracion-respuesta cronotropica del atenolol y del propranolol. Entre ambos grupos experimentales no se observaron diferencias en la constante de disociacion de atenolol (pKb ratas OS: 7,36 ± 0,23; ratas CoA: 7,17 ± 0,22) y de propranolol (pKb ratas OS: 8,06 ± 0,18; ratas CoA: 8,15 ± 0,19). Tampoco se hallaron diferencias en la actividad de agonismo inverso de atenolol (ratas OS: pCE50: 6,44 ± 0,17, n = 5; ratas CoA: pCE50: 6,13 ± 0,28, n = 5) y propranolol (ratas OS: pCE50: 5,35 ± 0,11, n = 5; ratas CoA: pCE50: 5,70 ± 0,19, n = 5) entre controles y ratas coartadas. En conclusion, la afinidad y la actividad de agonismo inverso de atenolol y propranolol no estarian alteradas en las ratas con coartacion aortica en un estadio hipertensivo temprano.
Research Interests:
Pharmacokinetics of methyldopa (MD) and the effect on the dopaminergic metabolism was studied in anesthetized sham-operated (SO) and sinoaortic-denervated (SAD) rats by using the microdialysis technique. A concentric microdialysis probe... more
Pharmacokinetics of methyldopa (MD) and the effect on the dopaminergic metabolism was studied in anesthetized sham-operated (SO) and sinoaortic-denervated (SAD) rats by using the microdialysis technique. A concentric microdialysis probe was placed in the striatum or in the posterior hypothalamus. Levels of MD, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by high pressure liquid chromatography coupled to electrochemical detection (HPLC-EC). Following the i.p. administration of MD (50 mg x kg(-1), i.p.), striatal dialysates showed that this drug rapidly reaches the brain. However, in SAD rats the MD levels of dialysates were lower and decreased more rapidly compared to SO rats. On the other hand, dialysates of posterior hypothalamus showed that in SAD animals the accumulation of MD was significantly greater than in SO rats.MD does not significantly reduce the striatal production of dopaminergic metabolite DOPAC in both groups of rats. The drug also...
Research Interests:
Immediate post-training intraperitoneal administration of alpha-D[+]-glucose (10-300 mg/kg) significantly enhanced retention of male Swiss mice tested 24 h after training in an inhibitory avoidance task. The dose-response curve was an... more
Immediate post-training intraperitoneal administration of alpha-D[+]-glucose (10-300 mg/kg) significantly enhanced retention of male Swiss mice tested 24 h after training in an inhibitory avoidance task. The dose-response curve was an inverted U in this range of dose. However, of the doses tested, only 30 mg/kg was effective. Glucose did not affect response latencies in mice not given the footshock on the training trial, suggesting that the actions of glucose on retention performance were not due to nonspecific effects on response latencies. The influence of glucose (30 mg/kg) was time-dependent, which suggests that glucose facilitated memory consolidation processes. Administration of glucose (30 mg/kg) 2 or 10 min prior to the retention test did not affect the retention performance of mice given post-training injections of either saline or glucose (30 mg/kg). These findings indicate that the memory-enhancing effects of post-training administration of glucose are not state-dependent...
Research Interests:
The present study was designed to explore the involvement of endogenous dopamine in furosemide excretion and in the actions of the diuretic on tubular sodium reabsorption. The dose-response relationship for the diuretic effect of... more
The present study was designed to explore the involvement of endogenous dopamine in furosemide excretion and in the actions of the diuretic on tubular sodium reabsorption. The dose-response relationship for the diuretic effect of furosemide given as i.v. bolus injections (0.2-7.5 mg.kg-1) was studied by clearance technique in pentobarbital-anesthetized rats treated with vehicle, benserazide (BZ) (25 mg.kg-1 i.v.) or SCH 23390 (50 micrograms.kg-1 + 10 micrograms.kg-1.min-1 i.v.). Furosemide induced the maximal diuresis 15 to 30 min after i.v. administration. The diuretic response was dose-dependent and was reduced in the animals treated with BZ and SCH 23390. Fractional sodium excretion was also increased by furosemide from 1.8 to 7.5% during the same period. This effect was reduced by both BZ or SCH 23390 by 35 to 50%. The effects of furosemide on proximal and distal renal tubules were dissected by measuring the renal lithium clearance (CLi+). Furosemide effective on proximal tubula...
Research Interests:
To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration. Systematic review of studies available at PubMed using the keywords... more
To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration. Systematic review of studies available at PubMed using the keywords retinoblastoma, topotecan, and camptothecins, including preclinical data such as cell lines and animal models, as well as clinical studies in patients with retinoblastoma. Forty-two available studies were reviewed. Evidence of antitumor activity against retinoblastoma as a single agent is based on data on cell lines and a limited number of affected patients with intraocular and extraocular disease when given in a protracted schedule. Evidence of additive or synergistic activity in combination with other agents such as carboplatin, melphalan, and vincristine was reported in preclinical and clinical models. In animal models, pharmacokinetic evaluation of topotecan administered by the periocular route shows that most of the drug reaches the vitreous through the systemic circulation. Topotecan administered by intravitreal injection shows high and sustained vitreal concentrations with limited systemic exposure and lack of retinal toxicity at a dose of up to 5 μg. Topotecan administered intraophthalmic artery shows higher passage to the vitreous compared with periocular administration in a swine model. Topotecan alone or in combination is active against retinoblastoma. It shows a favorable passage to the vitreous when given intravenously and intraarterially, and ocular toxicity is minimal by all routes of administration. However, its clinical role, optimal dose, and route of administration for the treatment of retinoblastoma are to be determined.
Research Interests:
Pharmacokinetic-pharmacodynamic (PK-PD) modelling describes the relationship between the pharmacokinetics and pharmacodynamics of a drug allowing the prediction of clinically relevant parameters. PK-PD modelling has several advantages... more
Pharmacokinetic-pharmacodynamic (PK-PD) modelling describes the relationship between the pharmacokinetics and pharmacodynamics of a drug allowing the prediction of clinically relevant parameters. PK-PD modelling has several advantages over classical dose-response studies because it allows a better pharmacodynamic characterisation of drugs and screening of dosage-regimen. However, PK-PD studies are limited by the need for simultaneous measurement of drug tissue levels and corresponding pharmacological effects at multiple time points. The microdialysis technique is a unique research tool that allows the simultaneous determination of unbound concentrations of drugs at several tissues and its action on biochemical and clinical markers during several hours and days. Therefore, microdialysis sampling is an attractive methodology for PK-PD studies. The aim of this review is to describe the applicability of the microdialysis technique for PK-PD modelling of therapeutic agents, including a description of PK-PD modelling concepts, an overview of the microdialysis technique and an analysis of PK-PD studies using microdialysis sampling both in the preclinical and clinical setting.
Research Interests:
Research Interests: Medicine, Blood Pressure, Renin Angiotensin Aldosterone System, Hypothalamus, Animals, and 14 moreMale, Stainless Steel, Heart rate, Cardiovascular system, Rats, Rat, Biological activity, Angiotensin II, Carotid Artery, Spontaneously Hypertensive Rats, Spontaneously Hypertensive Rat, Mean Arterial Pressure, Antihypertensive agents, and Medical and Health Sciences
Research Interests: Interaction, Medicine, Metabolic syndrome, Insulin Resistance, Hypertension, and 15 moreBlood Pressure, Hypothalamus, Animals, Male, Animal Model, Fructose, Microdialysis, Rats, Blood Pressure Control, Sympathetic Nervous System, Tetrazoles, Metoprolol, Antihypertensive agents, Medical and Health Sciences, and Angiotensin
Phyllanthus sellowianus Muell. Arg. (Euphorbiaceae) is used widely as a hypoglycemic and diuretic agent in South American folk medicine. In order to assess the diuretic activity of this plant, test animals were treated with a single oral... more
Phyllanthus sellowianus Muell. Arg. (Euphorbiaceae) is used widely as a hypoglycemic and diuretic agent in South American folk medicine. In order to assess the diuretic activity of this plant, test animals were treated with a single oral administration of an aqueous extract (5% w/v) of the stem bark of P. sellowianus (400 mg/kg body weight), which produced after 8 h a significant increase in the urinary excretion. In the studies on acute toxicity in mice neither mortality nor neurobehavioral or autonomic profile changes could be observed.
Research Interests: Complementary and Alternative Medicine, Plant Biology, Medicinal Plants, Phytomedicine, Mice, and 14 moreDiuretics, Female, Animals, Male, South America, Hydrochlorothiazide, Plant extracts, Euphorbiaceae, Electrolytes, medicinal & Aromatic plants, Rats, Experimental Diabetes Mellitus Type 1 and 2, Plant Epidermis, and Pharmacology and pharmaceutical sciences
The aim of the present work was to study the central and plasma pharmacokinetics of irbesartan (IRB) and its possible hypothalamic antihypertensive effect in sham-operated (SO) and aortic-coarctated (ACo) rats at a chronic hypertensive... more
The aim of the present work was to study the central and plasma pharmacokinetics of irbesartan (IRB) and its possible hypothalamic antihypertensive effect in sham-operated (SO) and aortic-coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique. Anesthetized Wistar rats were used 42 days after ACo or SO. For the study of plasma pharmacokinetics, a vascular shunt probe was inserted into the carotid artery. In a separated experiment, a concentric probe was placed into the anterior hypothalamus for the study of IRB distribution in the central nervous system. Based on the hypothalamic concentrations of IRB reached in ACo rats, the anterior hypothalamus of SO and ACo animals was perfused with a Ringer solution containing approximately 6 microg x ml(-1) of the drug. IRB (10 mg x kg(-1) i.v.) induced a late decrease of heart rate (HR) in ACo animals (DeltaHR: -42 +/- 10 bpm, n = 5, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 vs. SO rats) but not in SO rats (DeltaHR: 11 +/- 13 bpm, n = 5). Systemic administration of the drug reduced the mean arterial pressure (MAP) of both experimental groups, but the hypotensive effect was greater in ACo (DeltaMAP: -39.9 +/- 5.0 mm Hg, n = 5, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 vs. SO rats) than in SO rats (DeltaMAP: -25.4 +/- 2.1 mm Hg, n = 5). A similar pharmacokinetic profile was observed in both experimental groups. Hypothalamic distribution of IRB was greater in ACo (AUC: 730 +/- 130 ng x ml(-1) h(-1), n = 5, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 vs. SO rats) than in SO animals (AUC: 283 +/- 87 ng x ml(-1) h(-1), n = 5). The IRB hypothalamic perfusion induced an antihypertensive effect in ACo (DeltaMAP: -15.1 +/- 1.0 mm Hg, n = 5, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 vs. Ringer perfusion) but not in SO rats. In conclusion, the chronic aortic coarctation did not modify the plasma pharmacokinetics of IRB, but it increased the distribution of the drug in the central nervous system. The greater hypotensive effect of IRB observed in ACo animals suggests the involvement of AT1 receptors in the maintenance of the hypertensive stage in chronic ACo rats. The hypotensive effect of IRB in ACo animals could be explained, at least in part, due an action on the anterior hypothalamic angiotensin system.
Research Interests: Pharmacology, Hypothalamus, Chronic Disease, Female, Animals, and 13 moreHeart rate, Central Nervous System, Microdialysis, Rats, Wistar Rats, Carotid Artery, Protein Binding, Aortic Coarctation, Tetrazoles, Experimental Group, Mean Arterial Pressure, Antihypertensive agents, and Pharmacology and pharmaceutical sciences
ABSTRACT
Research Interests:
Research Interests: Chemistry, Medicine, Hypertension, Blood Pressure, Female, and 15 moreAnimals, Regression Analysis, Heart rate, Norepinephrine, Rats, Pharmacodynamics, Time Factors, Pharmacological, Aortic Coarctation, Dissociation Constant, Metoprolol, Experimental Group, Arterial pressure, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
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 beta-adrenergic antagonist and the microinfusion of beta-adrenergic agonist.... more
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 beta-adrenergic antagonist and the microinfusion of beta-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 beta(1)-adrenoceptor antagonist) perfusion (6 microg ml(-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 beta-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 beta(1)-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 beta-adrenoceptor antagonist propranolol in SO and ACo rats. The anterior hypothalamic infusion of clenbuterol, a selective beta(2)-adrenergic agonist, induced a dose-dependent decrease of blood pressure in both experimental groups. The depressor response to clenbuterol (1 nmol) was significantly lower in ACo rats than in SO rats. In summary, this study provides the evidence that there is a beta(1)-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 beta(1)-adrenoceptors in the anterior hypothalamic area of ACo rats but not in SO rats. We also found a diminished depressor beta(2)-adrenergic activity in ACo rats.
Research Interests: Medicine, Hypertension, Blood Pressure, Animals, Male, and 15 moreClenbuterol, Rats, Wistar Rats, Hypotension, Pharmacological, Propranolol, Carotid Artery, Aortic Coarctation, Isoproterenol, Atenolol, Metoprolol, Experimental Group, Mean Arterial Pressure, Drug synergism, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, Electrochemistry, Kinetics, Medicine, Blood Pressure, and 15 moreAnimals, Male, Heart rate, Denervation, High Pressure Liquid Chromatography, Microdialysis, Rats, Methyldopa, Pharmacological, Carotid Artery, Normal Distribution, Anesthesia Intravenous, Urethane, Rate Constant, and Pharmacology and pharmaceutical sciences
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests: Algorithms, Pharmacy, Treatment Outcome, Medicine, Hypertension, and 13 morePharmacology and Clinical pharmacy, Blood Pressure, Animals, Male, Heart rate, High Pressure Liquid Chromatography, Microdialysis, Rats, Area Under Curve, Calcium Channel Blockers, Experimental Model, Antihypertensive agents, and Pharmacology and pharmaceutical sciences
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. A... more
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. A &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;shunt&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; 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. 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. 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.
Research Interests:
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... more
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. Plasma metoprolol concentrations were obtained by means of a &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;shunt&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; vascular microdialysis probe. Changes in mean arterial pressure and heart rate were also measured in the same experiment. 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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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. 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.