RESUMEN
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. CHEMICAL COMPOUNDS INCLUDED IN THIS MANUSCRIPT: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962).
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2-Piridinilmetilsulfinilbencimidazoles/farmacología , Barrera Hematorretinal/efectos de los fármacos , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Inhibidores de Topoisomerasa I/uso terapéutico , Topotecan/uso terapéutico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Barrera Hematorretinal/metabolismo , Humanos , Ratones Desnudos , Pantoprazol , Conejos , Neoplasias de la Retina/genética , Neoplasias de la Retina/metabolismo , Retinoblastoma/genética , Retinoblastoma/metabolismo , Inhibidores de Topoisomerasa I/farmacocinética , Topotecan/farmacocinética , Cuerpo Vítreo/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: To investigate 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. METHODS & MATERIALS: 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 poloxamine of intermediate hydrophobicity, T904, and 25% F127 loaded with 20 and 30 mg/ml drug. F127 confers high physical stability, while T904 substantially improves the encapsulation capacity of the micelles. RESULTS: 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. CONCLUSION: These findings demonstrate the potential of this scalable and cost-viable strategy to address the HIV sanctuary in the CNS.
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Benzoxazinas/administración & dosificación , Benzoxazinas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Micelas , Administración Intranasal , Alquinos , Animales , Ciclopropanos , Masculino , Polietilenos/química , Polipropilenos/química , Ratas , Ratas Wistar , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
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.
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Fármacos Cardiovasculares/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Torsades de Pointes/inducido químicamente , Antiarrítmicos/efectos adversos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Síndrome de QT Prolongado/genética , Masculino , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Torsades de Pointes/genéticaRESUMEN
Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.
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Antineoplásicos/administración & dosificación , Coroides/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Retina/efectos de los fármacos , Esclerótica , Topotecan/administración & dosificación , Animales , Antineoplásicos/farmacocinética , Coroides/metabolismo , Implantes de Medicamentos , Epinefrina/administración & dosificación , Poliésteres , Conejos , Retina/metabolismo , Distribución Tisular , Topotecan/farmacocinéticaRESUMEN
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.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Hipocampo/metabolismo , Fenobarbital/farmacocinética , Convulsiones/tratamiento farmacológico , Ácido 3-Mercaptopropiónico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Masculino , Microdiálisis , Nimodipina/farmacología , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , TiempoRESUMEN
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.
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Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Diltiazem/uso terapéutico , Hipertensión/tratamiento farmacológico , Algoritmos , Animales , Antihipertensivos/sangre , Antihipertensivos/farmacocinética , Área Bajo la Curva , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/uso terapéutico , Cromatografía Líquida de Alta Presión , Diltiazem/sangre , Diltiazem/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/sangre , Hipertensión/fisiopatología , Inyecciones Intravenosas , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Renina/sangre , Resultado del TratamientoRESUMEN
In the last decades new pharmacodynamic properties of beta-adrenoceptors have been discovered that could greatly impact in the use of beta-adrenergic agents in the clinical practice. Concepts such as multiple binding sites, constitutive activity, polymorphism and intracellular signaling of betaadrenoceptors may contribute in the discovery of more efficacious pharmacological agents for treatment of heart failure and asthma. beta-Adrenoceptors show a relative high constitutive activity in both cardiac and pulmonar tissues. Most beta-blockers exert an inverse agonist action that could contribute to their beneficial effects in the treatment of heart failure. Recently, the existence of multiple affinity sites has been described for beta1-adrenoceptor. It was proposed that beta-blockers that show agonist properties at the beta1L-adrenoceptors binding site may exert neutral or harmful effects when used for treatment of heart failure. Considering the cardiac effect of beta1L-adrenoceptors, activation of the low-affinity state of beta1-adrenoceptor could be deleterous in cardiovascular pharmacology. The ability of beta2-adrenoceptor to couple to Gs or Gi-protein gives the possibility that different agonists can activate different signaling cascades. Full beta2-adrenoceptor agonists would be highly useful for improvement bronchodilatation in the acute treatment of asthma. Polymorphic variants of beta-adrenoceptors have profound impact in the understanding of normal physiology and pathophysiology. Genotypic characterization of patients could improve selection of patients during beta-adrenergic pharmacotherapies. The aim of the present review is to describe new insights in pharmacological and biochemical properties of beta-adrenoceptors and their impact on the use of beta-adrenergic agents in the treatment of cardiovascular and respiratory diseases.
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Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Receptores Adrenérgicos beta/fisiología , Agonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Asma/tratamiento farmacológico , Asma/metabolismo , Agonismo Inverso de Drogas , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Polimorfismo Genético , Transducción de SeñalRESUMEN
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.
RESUMEN
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.
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Bloqueadores de los Canales de Calcio/farmacocinética , Hipertensión Renovascular/metabolismo , Modelos Biológicos , Verapamilo/farmacocinética , Animales , Aorta/cirugía , Coartación Aórtica/complicaciones , Coartación Aórtica/cirugía , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión Renovascular/etiología , Hipertensión Renovascular/fisiopatología , Inyecciones Intravenosas , Masculino , Ratas , Ratas Wistar , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: Several studies suggest the importance of the interaction between the renin angiotensin and sympathetic nervous systems in blood pressure control, especially in clinical situations such as the metabolic syndrome. Previously, we have demonstrated changes in noradrenergic hypothalamic control of blood pressure in an animal model of insulin resistance and hypertension. The aim of the present study was to evaluate the effects of the interaction between the noradrenergic and angiotensinergic systems on hypothalamic blood pressure regulation in fructose hypertensive rats. METHODS: In control (C) and fructose-fed hypertensive (F) rats, we studied: 1) the effects of hypothalamic perfusion of irbesartan (AT(1) angiotensin receptor antagonist, 50 and 500 microg ml(-1)) and metoprolol (beta(1) adrenergic receptor antagonist, 10 and 100 microg ml(-1)) on blood pressure, heart rate and noradrenaline intrahypothalamic levels, by means of the microdialysis technique; and 2) the effects of intrahypothalamic microinjection of angiotensin II alone or after metoprolol pre-administration, on blood pressure and heart rate. RESULTS: Meanwhile irbesartan perfusion did not modify neither mean arterial pressure (MAP) nor heart rate or noradrenaline hypothalamic levels in the C group, its highest dose diminished MAP (DeltaMAP: F: - 16.3+/-1 mm Hg, p<0.05) and noradrenaline levels (% of basal levels: 58+/-7%, p<0.05) in the F group, without affecting heart rate. Intrahypothalamic perfusion of metoprolol diminished MAP only in the F group (DeltaMAP: F: -12.1+/-1.1 mm Hg, p<0.05), but did not modify heart rate in both groups. On the other hand, it diminished noradrenaline hypothalamic levels in C (% of basal levels: 53+/-6%, p<0.05) but not in the F group. The pressor response to angiotensin II microinjection was increased in F rats (DeltaMAP: F: 13.3+/-1.5 mm Hg vs. C: 6.9+/-1.8 mm Hg; p<0.05). Previous administration of metoprolol markedly abolished this increment. CONCLUSIONS: Our results suggest the existence of an increase in AT(1) and beta(1) adrenergic receptors tone in the hypothalamus of F rats, which could be related to the increase in blood pressure present in this experimental model. On the other hand, considering that the enhanced pressor response to angiotensin II intrahypothalamic injection in F rats was abolished by previous administration of a beta(1) adrenergic receptor antagonist, these results would indicate that beta(1) adrenergic receptors activation participates in the pressor response to angiotensin II in this experimental model of insulin resistance and hypertension.
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Fructosa/farmacología , Hipertensión/inducido químicamente , Hipotálamo/fisiología , Receptores Adrenérgicos/efectos de los fármacos , Receptores de Angiotensina/efectos de los fármacos , Animales , Antihipertensivos/farmacología , Compuestos de Bifenilo/farmacología , Hipotálamo/efectos de los fármacos , Resistencia a la Insulina , Irbesartán , Masculino , Metoprolol/farmacología , Modelos Animales , Ratas , Ratas Sprague-Dawley , Tetrazoles/farmacologíaRESUMEN
OBJECTIVE: the aim of this relative bioavailability study was to determine the rate and extent of absorption of Alikal Dolor (effervescent powder containing paracetamol 500 mg/sodium bicarbonate 2318 mg)--test formulation (T) in relation to Parageniol (paracetamol 500 mg coated tablets)--reference formulation (R). METHODS: 18 healthy volunteers (10 male and 8 female aged between 21 and 46 years) received, after 2 h of standardized breakfast, a single oral dose with 220 ml of water, in an open, randomized, crossover study, with a 7-day wash-out period. Paracetamol concentrations were established at 0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 90 min and at 2, 4, 6, 8 and 10 h postdose by HPLC with an ultraviolet detector. RESULTS: the regression coefficient determined for paracetamol calibration curves was 0.9983 +/- 0.0034 and the working range was from 0.2 to 50 microg/ml. The quantification limit was 0.2 microg/ml. The rate of absorption was significantly greater (p < 0.03) for T (T(max) = 20.4 min) compared with R (T(max) = 38.4 min). Extent of absorption over the first 30 min postdose AUC((0-30 min)) was 4.21-fold greater (p < 0.03) for T compared with R, without differences between C(max.) The 90% CI on the geometric mean for C(max), AUC((0-10 h)) and AUC((0-)) ratios (T/R) were within the limits of 0.80-1.25, indicating both formulations were bioequivalent with respect to these parameters. CONCLUSION: paracetamol was absorbed at least twice as fast from T-containing sodium bicarbonate compared with R. This pharmacokinetic feature could prove crucial from the therapeutic point of view as it would allow a lower latency in the action time of paracetamol in producing its analgesic and antithermal effect.
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Acetaminofén/química , Acetaminofén/farmacocinética , Alimentos , Bicarbonato de Sodio/química , Bicarbonato de Sodio/farmacocinética , Adulto , Disponibilidad Biológica , Química Farmacéutica/métodos , Estudios Cruzados , Femenino , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Masculino , Persona de Mediana Edad , Polvos , ComprimidosRESUMEN
Activation of alpha(2)-adrenoceptors in the anterior hypothalamic area (AHA) decreases sympathetic nervous system activity and blood pressure. The aim of the present study was to evaluate activity of pre- and postsynaptic alpha(2)-adrenoceptors in the AHA of fructose hypertensive rats (F), an animal model of insulin resistance and hypertension. The AHA of Control (C) and F anaesthetized rats was perfused with Ringer solution in the absence or presence of clonidine (100 or 300 microg ml(-1)) using reverse microdialysis. Clonidine effects on mean arterial pressure (MAP) and heart rate (HR), and on hypothalamic noradrenaline levels were measured along perfusion time. Noradrenaline extracellular levels in the AHA were significantly diminished in F hypertensive rats compared to C animals. The depressor effect of intrahypothalamic perfusion of clonidine on MAP was enhanced in F rats compared with C animals. Intrahypothalamic perfusion of clonidine reduced HR only in F rats. The effect of clonidine on noradrenaline hypothalamic extracellular levels was enhanced in F rats. These results suggest, in our experimental conditions, the existence of an increased responsiveness of pre- and postsynaptic alpha(2)-adrenoceptors in the AHA of F hypertensive rats. This fact could be a consequence of a compensatory supersensitivity of alpha-adrenoceptors due to a decrease in noradrenaline release from nerve terminals located in the AHA.
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Fructosa/efectos adversos , Hipertensión/fisiopatología , Hipotálamo Anterior/metabolismo , Resistencia a la Insulina/fisiología , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Clonidina/farmacología , Dieta , Hipertensión/inducido químicamente , Hipotálamo Anterior/efectos de los fármacos , Masculino , Microdiálisis , Norepinefrina/análisis , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/efectos de los fármacosRESUMEN
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.
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Anticonvulsivantes/farmacocinética , Carbamazepina/análogos & derivados , Administración Oral , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Área Bajo la Curva , Biotransformación , Calibración , Carbamazepina/administración & dosificación , Carbamazepina/sangre , Carbamazepina/farmacocinética , Química Farmacéutica , Cromatografía Líquida de Alta Presión/normas , Estudios Cruzados , Semivida , Humanos , Modelos Lineales , Masculino , Tasa de Depuración Metabólica , Modelos Biológicos , Oxcarbazepina , Valores de Referencia , Reproducibilidad de los Resultados , Proyectos de Investigación , Equivalencia TerapéuticaRESUMEN
INTRODUCTION: The aim of the present work was to study the applicability of a modified E(max) pharmacodynamic model for the pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. METHODS: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized SHR and WKY rats for simultaneous determination of unbound plasma concentrations of diltiazem and their effects on mean arterial pressure (MAP) and heart rate (HR) after the intravenous application of 1 and 3 mg kg(-1) of the drug. Correlation between diltiazem plasma levels and their cardiovascular effects was established by fitting the data to a conventional and modified E(max) model. RESULTS: Volume of distribution and clearance of diltiazem was greater in SHR than in WKY animals. A proportional increase of area under curve with dose increment was observed in WKY animals but not in SHR. A good correlation between plasma unbound concentrations of diltiazem and their hypotensive and chronotropic effects was found in both experimental groups using both PK-PD models. The application of the modified E(max) model for PK-PD modeling of diltiazem allowed a more accurate and precise estimation of PK-PD parameters than the E(max) equation do. Chronotropic effect of 3 mg kg(-1) diltiazem was lower in SHR compared to WKY animals. Initial sensitivity (S(0)) to diltiazem chronotropic effect was greater in SHR with regards to WKY animals after administration of 1 mg kg(-1). S(0) to diltiazem hypotensive effect was greater in SHR with regards to WKY animals after administration of both doses of diltiazem. DISCUSSION: Microdialysis sampling is a useful technique for the pharmacokinetic study and pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem. The modified E(max) model allows an accurate estimation of drug sensitivity in conditions when maximal pharmacological response can not be attained. Genetic hypertension induced changes in the pharmacokinetic and PK-PD behavior of diltiazem suggesting that SHR is an interesting animal model for pre-clinical evaluation of calcium channel blockers.
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Diltiazem/farmacocinética , Microdiálisis/métodos , Modelos Biológicos , Algoritmos , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacocinética , Área Bajo la Curva , Presión Sanguínea/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Soluciones para Diálisis/análisis , Diltiazem/administración & dosificación , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especificidad de la EspecieRESUMEN
Objetivo: Evaluar el papel del área hipotalámica anterior en la regulación de la presión arterial en un modelo en ratas de hipertensión arterial (HTA) e insulinorresistencia. Material y métodos: Se utilizaron ratas Sprague-Dawley macho (n = 72) que fueron divididas en dos grupos: F,fructosa (10 por ciento p/v por 6 semanas) y C, grupo control. Se canuló la arteria carótida izquierda para la medición de la presión arterial media (PAM) y la frecuencia cardíaca (FC). Se colocó una sonda de microdiálisis en el área hipotalámica anterior (AHA) para la perfusión de yohimbina (10 y 100 µg/ml) o de clonidina (100 y 300 µg/ml), antagonista y agonista α2-adrenérgicos, respectivamente, y se evaluaron los cambios hemodinámicos. Resultados: Los animales del grupo F presentaron niveles mayores de presión arterial sistólica que los del grupo C (F: 131 ± 3 mm Hg versus C: 112 ± 4 mm Hg; p < 0,05). La perfusión intrahipotalámica de yohimbina indujo un incremento en la PAM en C, en tanto que no modificó los valores en F. No se encontraron cambios en la FC en ninguno de los grupos. La clonidina en dosis de 100 µg/ml indujo una disminución de la PAM sólo en F, mientras que en dosis de300 µg/ml la disminuyó en ambos grupos y fue mayor en F que en C. Sólo la clonidina en dosis de 300 µg/ml disminuyó la FC en el grupo F, sin modificar los valores en C. Conclusiones: Existiría un tono α2-adrenérgico menor en el AHA de las ratas F, que podría relacionarse con el incremento de la presión arterial presente en este grupo. Por otra parte, la respuesta exacerbada a la clonidina en F evidenciaría la existencia de una supersensibilidad de receptores adrenérgicos hipotalámicos, posiblemente como consecuencia de niveles extracelulares reducidos de noradrenalina en el AHA en este modelo de HTA e insulinorresistencia.
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Animales , Masculino , Ratas , Hipertensión , Hipotálamo , Resistencia a la Insulina/fisiología , Fructosa/administración & dosificación , Microdiálisis , Ratas Sprague-Dawley , Receptores AdrenérgicosRESUMEN
The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45 mg kg(-1), i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30 mg kg(-1), i.v.) 30 min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2 mg kg(-1)). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration, C(max): 2.7+/-0.3 microg ml(-1), p<0.05 versus C rats) than in C animals (C(max): 5.3+/-0.9 microg ml(-1)). Control rats pre-treated with NIMO showed similar results (C(max): 4.5+/-0.8 microg ml(-1)) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (C(max): 6.8+/-1.0 microg ml(-1), p<0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Resistencia a Medicamentos/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Nimodipina/farmacología , Fenitoína/agonistas , Ácido 3-Mercaptopropiónico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Anticonvulsivantes/agonistas , Anticonvulsivantes/farmacocinética , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Convulsivantes , Modelos Animales de Enfermedad , Resistencia a Medicamentos/fisiología , Epilepsia/inducido químicamente , Epilepsia/metabolismo , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatología , Masculino , Microdiálisis , Nimodipina/uso terapéutico , Fenitoína/farmacocinética , Ratas , Ratas WistarRESUMEN
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.
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Antagonistas Adrenérgicos beta/farmacología , Corazón/efectos de los fármacos , Metoprolol/farmacología , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Modelos Lineales , Contracción Miocárdica/efectos de los fármacos , Norepinefrina/antagonistas & inhibidores , Norepinefrina/farmacología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Vasoconstrictores/antagonistas & inhibidores , Vasoconstrictores/farmacologíaRESUMEN
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.
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Microdiálisis , Farmacología/métodos , Pruebas de Toxicidad/métodos , Anestesia , Animales , Sistemas de Liberación de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Lipólisis/efectos de los fármacos , Músculos/metabolismo , Perfusión , Farmacocinética , Piel/efectos de los fármacos , Distribución TisularRESUMEN
The objective of the present work was to study the cardiovascular actions of the intrahypothalamic injection of Ang-(1-7) and its effects on the pressor response to Ang II in spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) animals. In anaesthetized SH and WKY rats, a carotid artery was cannulated for mean arterial pressure (MAP) measurement and a stainless-steel needle was inserted into the anterior hypothalamus for drug administration. The cardiovascular effects of the intrahypothalamic administration of Ang-(1-7) were determined in SH and WKY rats. In SH rats, the effect of irbesartan and D-Ala-Ang-(1-7) on Ang-(1-7) cardiovascular effect was also evaluated. Ang II was administered in the hypothalamus of SH and WKY rats and changes in blood pressure and heart rate were measured followed by the administration of Ang II, Ang II+Ang-(1-7) or Ang II+D-Ala-Ang-(1-7). Ang-(1-7) did not the change basal MAP in WKY rats, but induced a pressor response in SH animals. Whilst the co-administration of D-Ala-Ang-(1-7) did not affect the response to Ang-(1-7), the previous administration of irbesartan prevented the effect of the peptide. The intrahypothalamic injection of Ang II induced a significantly greater pressor response in SH animals compared to normotensive rats. The co-administration of Ang-(1-7) with Ang II did not affect the pressor response to Ang II in the WKY group. In SH rats, whilst the co-administration of Ang-(1-7) with Ang II reduced the pressor response to Ang II, the concomitant application of D-Ala-Ang-(1-7) with Ang II increased the pressor response to the octapeptide after 5 and 10 min of intrahypothalamic administration. In conclusion, our result demonstrated that the biologically active peptide Ang-(1-7) did not participate in the hypothalamic blood pressure regulation of WKY animals. In SH rats, Ang-(1-7) exerted pleiotropic effects on blood pressure regulation. High dose of the heptapeptide produced a pressor response because of an unspecific action by activation of AT1 receptors. The concomitant administration of lower doses of Ang-(1-7) with Ang II reduced the pressor response to the octapeptide. Finally, the effect of AT(1-7) antagonist on Ang II pressor response suggested that hypothalamic formed Ang-(1-7) are implicated in the regulation of the cardiovascular effects of Ang II.
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Angiotensina I/farmacología , Antihipertensivos/farmacología , Sistema Cardiovascular/efectos de los fármacos , Hipotálamo/metabolismo , Fragmentos de Péptidos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
The present work addressed possible alterations in the pharmacokinetics and the in vivo pharmacodynamic of metoprolol (MET) in spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) animals by means of the microdialysis technique. The correlation between MET unbound plasma concentrations and its pharmacological effects, such as heart rate and blood pressure change, was also examined in SH and WKY rats by the application of a PK-PD model. MET dialysate concentrations and its chronotropic and blood pressure effect were determined during 3 h after the administration of 3 and 10 mg.kg(-1) of the drug. A PK-PD model with a separate effect compartment was used to analyse the data. A good correlation between plasma MET concentrations and its hypotensive and chronotropic effect was found in all experimental groups. Although a greater maximal effect (E(max)) for the antihypertensive effect of MET was observed in SH rats (WKY: E(max): -17+/-1 mmHg; SH: E(max): -28+/-4 mmHg; P<0.05 versus WKY rats), no differences were found in the concentration yielding half-maximal response (IC(50)) comparing SH (IC(50): 583+/-146 ng x ml(-1)) and WKY animals (IC(50): 639+/-187 ng x ml(-1)). The bradycardic effect of MET was greater in SH rats (E(max): -29+/-1%, P<0.05 versus WKY rats) than in WK animals (E(max): -22+/-2%), but no differences were observed in the IC(50) comparing both experimental groups (WKY: IC(50): 187+/-53 ng x ml(-1); SH: IC(50): 216+/-62 ng x ml(-1)). Pharmacokinetic analysis shows that the volume of distribution of MET was greater in SH rats (Vd: 3.4+/-0.5 l, P<0.05 versus WKY rats) with regard to Wistar Kyoto (WKY) animals (Vd: 1.9+/-0.2 l). The results suggest that the pharmacokinetic behaviour of metoprolol are modified in SH rats, resulting in an increased volume of distribution. A greater maximal efficacy to the hypotensive effect of metoprolol was observed in SH rats, suggesting participation of beta-adrenoceptors in the maintenance of the hypertension. Also, a greater chronotropic response to metoprolol was found in the hypertensive group compared with WKY animals, suggesting that, at least in part, the greater cardiac effect of metoprolol explained the enhanced hypotensive response of the beta blocker in the SH animals.