Dual strategy to improve the oral bioavailability of efavirenz employing nanomicelles and curcumin as a bio-enhancer.

The present investigation was focused on the development of Soluplus®-based nanomicelles (NMs) (10 % w/v) loaded with Efavirenz (EFV) (5 mg/mL) and Curcumin (natural bio-enhancer) (CUR) (5, 10 and 15 mg/mL) to improve the oral bioavalability of EFV. Micellar formulations were obtained employing an acetone-diffusion technique. Apparent aqueous solubility was increased up to ∼1250-fold and 25,000-fold for EFV and CUR, respectively. Drug-loaded nanoformulations showed an excellent colloidal stability with unimodal size distribution and PDI values < 0.30. In vitro drug release was 41.5 % (EFV) and 2.6 % (CUR) from EFV-CUR-NMs over 6 h in simulated gastrointestinal fluids. EFV-CUR-loaded NMs resulted as safe nanoformulations according to the in vitro cytocompatibility assays in Caco-2 cells. Furthermore, CUR bio-enhancer activity was demonstrated for those nanoformulations. A CUR concentration of 15 mg/mL produced a significant (p < 0.05) increment (2.64-fold) of relative EFV oral bioavailability. Finally, the active role of the lymphatic system in the absorption process of EFV, after its oral administration was assessed in a comparative pharmacokinetic study in presence and absence of cycloheximide, a lymphatic transport inhibitor. Overall our EFV-CUR-NMs denoted their potential as a novel nanotechnological platform, representing a step towards an optimized "nano-sized" therapy for AIDS patients.

Meningeal cryptococcosis and SARS-CoV-2 infection in people living with HIV/AIDS. / Criptococosis meníngea e infección por SARS-CoV-2 en personas con VIH/SIDA

INTRODUCTION: Fungal infections in patients with COVID-19 was one of the most debated topics during the pandemic. OBJECTIVES: To analyze the clinical characteristics and evolution of people living with HIV/AIDS and coinfection with cryptococcus and COVID-19 (group A) or without it (group B). MATERIALS AND METHODS: This is an analytical and retrospective study. We reviewed medical records of patients with meningeal cryptococcosis between April 2020 and May 2021. RESULTS: We studied 65 people living with HIV/AIDS and with cryptococcosis infection diagnosed from April 2020 to May 2021. Fifteen patients with HIV/AIDS suffered from cryptococcosis and COVID-19, and out of these, 14 presented meningitis (group A), while 28 suffered from meningeal cryptococcosis, but did not have COVID-19 (group B). CONCLUSIONS: No statistically significant differences were observed between the two groups (A and B) considering: intracranial hypertension, presence of Cryptococcus antigens in cerebrospinal fluid, sensorium deterioration or mortality. The detection of Cryptococcus antigens in serum by lateral flow assay was highly effective to rapidly diagnose cryptococcosis in patients with HIV/AIDS who also developed COVID-19. Patients of both groups consulted for cryptoccocosis sometime after, in comparison with the pre-pandemic cases related to this infection.

Introducción: Las infecciones fúngicas en pacientes con COVID-19 fue uno de los temas más debatidos durante la pandemia. Objetivo: Analizar las características clínicas y la evolución de personas con VIH/SIDA que presentaron la asociación de criptococosis meníngea y COVID-19 (grupo A), y compararlas con aquellas personas con VIH/SIDA que padecieron criptococosis meníngea, pero sin infección de COVID-19 (grupo B). Materiales y métodos: Se realizó un estudio analítico y retrospectivo en el que se revisaron las historias clínicas de pacientes que padecieron criptococosis meníngea entre abril de 2020 y mayo de 2021. Resultados: Se estudiaron 65 pacientes con HIV/SIDA y con criptococosis, diagnosticados entre abril de 2020 y mayo de 2021 (63 habían desarrollado sida y 2 eran negativos para VIH). De estos, 15 de los pacientes con sida padecían criptococosis y COVID-19, y 14 presentaban meningitis (grupo A), mientras que 28 pacientes padecieron criptococosis meníngea, pero no tuvieron COVID-19 (grupo B). Conclusiones: No se observaron diferencias estadísticamente significativas, entre los dos grupos, respecto a la hipertensión intracraneal, la presencia de antígenos de criptoccoco en líquido cefalorraquídeo, el deterioro del sensorio o la mortalidad. La detección de antígenos de Cryptococcus en suero por ensayo de flujo lateral fue efectiva para diagnosticar rápidamente criptococosis en personas con VIH/sida y con infección de COVID-19. Se observó que los pacientes de ambos grupos consultaron tarde por criptococosis en comparación con los casos prepandémicos de esta infección.

Meningeal cryptococcosis and SARS-CoV-2 infection in people living with HIV/AIDS

Introduction. Fungal infections in patients with COVID-19 was one of the most debated topics during the pandemic. Objectives. To analyze the clinical characteristics and evolution of people living with HIV/ AIDS and coinfection with cryptococcus and COVID-19 (group A) or without it (group B). Materials and methods. This is an analytical and retrospective study. We reviewed medical records of patients with meningeal cryptococcosis between April 2020 and May 2021. Results. We studied 65 people living with HIV/AIDS and with cryptococcosis infection diagnosed from April 2020 to May 2021. Fifteen patients with HIV/AIDS suffered from cryptococcosis and COVID-19, and out of these, 14 presented meningitis (group A), while 28 suffered from meningeal cryptococcosis, but did not have COVID-19 (group B). Conclusions. No statistically significant differences were observed between the two groups (A and B) considering: intracranial hypertension, presence of Cryptococcus antigens in cerebrospinal fluid, sensorium deterioration or mortality. The detection of Cryptococcus antigens in serum by lateral flow assay was highly effective to rapidly diagnose cryptococcosis in patients with HIV/AIDS who also developed COVID-19. Patients of both groups consulted for cryptoccocosis sometime after, in comparison with the pre-pandemic cases related to this infection.

Introducción. Las infecciones fúngicas en pacientes con COVID-19 fue uno de los temas más debatidos durante la pandemia. Objetivo. Analizar las características clínicas y la evolución de personas con VIH/SIDA que presentaron la asociación de criptococosis meníngea y COVID-19 (grupo A), y compararlas con aquellas personas con VIH/SIDA que padecieron criptococosis meníngea, pero sin infección de COVID-19 (grupo B). Materiales y métodos. Se realizó un estudio analítico y retrospectivo en el que se revisaron las historias clínicas de pacientes que padecieron criptococosis meníngea entre abril de 2020 y mayo de 2021. Resultados. Se estudiaron 65 pacientes con HIV/SIDA y con criptococosis, diagnosticados entre abril de 2020 y mayo de 2021 (63 habían desarrollado sida y 2 eran negativos para VIH). De estos, 15 de los pacientes con sida padecían criptococosis y COVID-19, y 14 presentaban meningitis (grupo A), mientras que 28 pacientes padecieron criptococosis meníngea, pero no tuvieron COVID-19 (grupo B). Conclusiones. No se observaron diferencias estadísticamente significativas, entre los dos grupos, respecto a la hipertensión intracraneal, la presencia de antígenos de criptoccoco en líquido cefalorraquídeo, el deterioro del sensorio o la mortalidad. La detección de antígenos de Cryptococcus en suero por ensayo de flujo lateral fue efectiva para diagnosticar rápidamente criptococosis en personas con VIH/sida y con infección de COVID-19. Se observó que los pacientes de ambos grupos consultaron tarde por criptococosis en comparación con los casos prepandémicos de esta infección.

Nebivolol is more effective than atenolol for blood pressure variability attenuation and target organ damage prevention in L-NAME hypertensive rats.

ß-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional ß-blockers compared with other antihypertensive drugs. It is unknown whether third-generation ß-blockers share the limitations of traditional ß-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor ß (TGF-ß), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional ß-blockers must not be carried forward to third-generation ß-blockers.

Desarrollo de implantes subcutáneos de liberación controlada de Carvedilol para la reducción sostenida de la presión arterial en modelos experimentales de hipertensión arterial / Development of Subcutaneous Implants of Controlled Release Formulations of Carvedilol for Sustained Blood Pressure Reduction in Experimental Models of Hypertension

RESUMEN Objetivo: El objetivo del presente estudio fue el desarrollo y la evaluación farmacocinética y farmacodinámica de la liberación in vivo de implantes subcutáneos de carvedilol capaces de aportar niveles tisulares estables en modelos experimentales de hipertensión arterial. La incorporación del polímero hidrofílico SoluPlus (SP) en los implantes PCL:SP 150:150 y 50:250 favorece un incremento de la liberación de carvedilol dado que aporta concentraciones plasmáticas en el rango de 100-200 ng/mL durante 2 semanas, lo que tiene como resultado una reducción sostenida de la presión arterial sistólica indirecta en animales SHR. Material y métodos: Se prepararon implantes subcutáneos de poli (epsilon-caprolactona) (PCL) con diferentes proporciones del polímero hidrofílico SoluPlus (300:0; 250:50; 150:150 y 50:250 mg) cargados con 100 mg de carvedilol. Se evaluó el perfil plasmático y el efecto sobre la presión arterial sistólica (PAS) luego del implante de cada formulación en el tejido subcutáneo de ratas espontáneamente hipertensas (REH) macho. Resultados: Las formulaciones PCL:SP 50:250 y 150:150 aportaron niveles en el rango de 100-200 ng/mL. Las formulaciones PCL:SP 250:50 y 300:0 aportaron concentraciones inferiores de carvedilol comprendidas en el rango de los 0-100 ng/mL durante el transcurso del tratamiento. Los animales espontáneamente hipertensos tratados con PCL:SP 50:250 y 150:150 experimentaron un descenso significativo de la presión arterial sistólica (PCL:SP 50:250: DPAS: -36,6 ± 2,0 mmHg; PCL:SP150:150: 35,7 ± 2,2 mmHg; p <0,05 vs. basal). Conclusiones: La incorporación del polímero hidrofílico SoluPlus en los implantes PCL:SP 150:150 y 50:250 favorece un incremento de la liberación de carvedilol, ya que aporta concentraciones plasmáticas del β-bloqueante que aseguran una reducción sostenida de la PAS indirecta en animales espontáneamente hipertensos.

ABSTRACT Objective: The aim of this study was the development and pharmacokinetic/pharmacodynamic evaluation of the in vivo release of subcutaneous implants of carvedilol capable of providing stable tissue levels in experimental models of hypertension. Methods: The subcutaneous implants were prepared with poly (epsilon-caprolactone) (PCL) and different proportions of the SoluPlus (SP) hydrophilic polymer (300:0; 250:50; 150:150 and 50:250 mg) loaded with 100 mg carvedilol. The plasma profile and the effect on systolic blood pressure (SBP) after subcutaneous implantation of each formulation was evaluated in male spontaneously hypertensive rats (SHR). Results: The PCL:SP 50:250 and 150:150 formulations provided levels ranging from 100 to 200 ng/mL and the PCL:SP 250:50 and 300:0 formulations provided lower concentrations of carvedilol ranging from 0 to 100 ng/mL during the treatment period. Spontaneously hypertensive animals treated with the PCL:SP 50:250 y 150:150 implants presented a significant decrease in SBP (PCL:SP 50:250: DPAS: -36.6 ± 2.0 mm Hg; PCL:SP150:150: -35.7 ± 2.2 mmHg; p <0.05 vs. baseline values) Conclusions: The incorporation of the SoluPlus hydrophilic polymer in PC:SP 150:150 and 50:250 implants increases the release of carvedilol, since it provides plasma concentrations ranging from 100 to 200 ng/ml, resulting in a sustained reduction of indirect SBP in SHR.

Effects of third-generation ß-blockers, atenolol or amlodipine on blood pressure variability and target organ damage in spontaneously hypertensive rats.

BACKGROUND: ß-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection. METHOD: Considering the differences in the pharmacological properties of ß-blockers, the present work compared the effects of third-generation ß-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RESULTS: Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-ß, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine. CONCLUSION: Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating ß-blockers, as atenolol, in hypertension must not be translated to third-generation ß-blockers.

Factors influencing hepatic metabolism of antihypertensive drugs: impact on clinical response.

INTRODUCTION: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management. Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including ß-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered. Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific ß-blockers, calcium channel blockers, and angiotensin receptor blockers.

What is the Real Efficacy of Beta-Blockers for the Treatment of Essential Hypertension?

OBJECTIVE: This review covers the pharmacokinetics and pharmacodynamic of ß-blockers, the rationale for their use, some recent controversies in its use for managing hypertension, as well as, the beneficial properties of the third-generation ß-blockers beyond hypertension. BACKGROUND: The efficacy and safety of ß-blockers in the treatment of hypertension and other cardiovascular diseases have been established during more than 50 years of clinical experience. Recent updates of clinical guidelines have downgraded the use of ß-blockers for the treatment of uncomplicated hypertension to second and third line therapy. It is a well-known fact that ß-blockers exhibit heterogeneous pharmacokinetic and pharmacodynamic properties that clearly influence their clinical efficacy and tolerability in the management of essential hypertension. Conventional nonvasodilating ß-blockers (atenolol and metoprolol) are inferior to first-line antihypertensive agents in terms of cardioprotection due to lower ability to reduce central blood pressure and its variability and the adverse effects on glycemic and lipid metabolism. CONCLUSION: New vasodilating ß-blockers, mainly carvedilol and nebivolol, show enhanced hemodynamic and metabolic properties, which probably result in a higher prevention of major cardiovascular events in hypertensive patients. Despite head-to-head clinical trials comparing the effects of vasodilating vs nonvasodilating ß-blockers on hard clinical endpoints are lacking, the current evidence suggests that third-generation ß-blockers are superior to conventional ß-blockers for the prevention of cardiovascular events in patients with essential hypertension. Moreover, beyond their antihypertensive properties, third-generation ß-blockers also have pleiotropic, antioxidant and antiinflammatory effects that warrant a "promissory new era" of this newly group.

Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability.

The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor ß, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor ß, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats.

Advances in therapy for the prevention of HIV transmission from mother to child.

INTRODUCTION: Actually, ~17.8 million women and 1.8 million children (<15 years) are currently infected with the Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS). Particularly, the majority of pediatric infections (>90%) resulted from 'HIV mother-to-child transmission' (MTCT), both in pregnancy, labour, delivery and later by breastfeeding. Due to its high pediatric incidence, MTCT represents a public health concern. Areas covered: In this review, we focus on available treatments and antiretroviral drugs recommended by the World Health Organization, and the main clinical investigations in antiretroviral pharmacotherapy to prevent the MTCT. Expert opinion: The MTCT has been improved dramatically in the last few years mainly due to prophylactic perinatal antiretroviral therapy for pregnant women living with HIV. However, there is still a milestone to reach since HIV MTCT remains as a public health challenge associated with MTCT though breastfeeding (post-natal transmission). In this context, different strategies could be employed as an attempt to reduce pediatric HIV infections. One of them involves the improvement of patient adherence to the HIV therapy. One possible solution is the development of novel long-acting formulations for prophylaxis of mothers and children, and a second possible solution is increase the inclusion of mothers and infants in care programs to more effectively prevent the vertical transmission.

Novel carvedilol paediatric nanomicelle formulation: in-vitro characterization and in-vivo evaluation.

OBJECTIVES: Carvedilol (CAR) is a poorly water-soluble beta-blocker. Its encapsulation within nanomicelles (NMs) could improve drug solubility and its oral bioavailability, allowing the development of a paediatric liquid CAR formulation with commercially available copolymers: D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(vinyl caprolactam)-poly(vinyl acetate)-poly(ethylene glycol) (Soluplus® ). METHODS: Drug-loaded NMs were prepared by copolymer and CAR dispersion in distilled water. Micellar size and morphology were characterized by dynamic light scattering and transmission electron microscopy, respectively. In-vitro drug permeation studies were evaluated by conventional gut sac method. In-vivo CAR oral bioavailability from NMs dispersions and drug control solution was evaluated in Wistar rats. KEY FINDINGS: Carvedilol apparent aqueous solubility was increased (up to 60.4-folds) after its encapsulation within NMs. The micellar size was ranged between 10.9 and 81.9 nm with a monomodal size distribution. There was a significant enhancement of CAR relative oral bioavailability for both copolymers vs a micelle-free drug solution (P < 0.05). This improvement was higher for TPGS-based micelles (4.95-fold) in accordance with the in-vitro CAR permeation results. CONCLUSIONS: The present investigation demonstrates the development of highly concentrated CAR liquid micellar formulation. The improvement on drug oral bioavailability contributes to the potential of this NMs formulation to enhance CAR paediatric treatment.

Comparación de la respuesta antihipertensiva aguda al telmisartán y al irbesartán en ratas espontáneamente hipertensas / Comparison of the Acute Antihypertensive Response to Telmisartán and Irbesartán in Spontaneously Hypertensive Rats

Introducción: El telmisartán y el irbesartán, dos de los principales antagonistas del receptor AT1 disponibles para el control de enfermedades cardiovasculares, difieren en sus propiedades farmacológicas, incluyendo el tiempo de disociación desde el receptor AT1 y la capacidad de activar otros receptores, con potencial impacto en su eficacia clínica relativa. Objetivo: Comparar la respuesta cardiovascular aguda de la administración de una dosis única de irbesartán o de telmisartán en ratas espontáneamente hipertensas. Material y métodos: Se utilizaron 24 ratas espontáneamente hipertensas macho de 250-275 g, a las que se les canuló la arteria carótida y la vena femoral para la medición directa de la presión arterial media (PAM) y la administración de irbesartán 3-6 mg/kg o de telmisartán 0,5-1 mg/kg. Se estimó el cambio en la PAM, la frecuencia cardíaca y la variabilidad de la presión arterial a corto plazo y latido-a-latido. Resultados: Aunque ambos antagonistas redujeron la PAM, el telmisartán indujo una respuesta antihipertensiva más prolongada que el irbesartán, evidenciada por mayor reducción de la PAM luego de 180 minutos (-33,3% ± 4,1% vs. -16,3% ± 4%; p < 0,05). El telmisartán y el irbesartán atenuaron de manera prolongada la variabilidad de la presión arterial a corto plazo, sin diferencias entre ambos grupos experimentales. En el nivel de dosis más bajo, el telmisartán disminuyó en mayor medida la frecuencia cardíaca y la variabilidad latido-a-latido en los diferentes dominios de frecuencia en comparación con el irbesartán. Conclusiones: En ratas espontáneamente hipertensas, la administración de telmisartán induce un efecto antihipertensivo más prolongado y una respuesta bradicardizante mayor que el irbesartán. El análisis espectral de la variabilidad latido-a-latido sugiere que el telmisartán, en la dosis más baja, atenúa en mayor medida la actividad simpática vascular en comparación con el irbesartán.

Background: Telmisartan and irbesartan, two of the main AT1 receptor antagonists available for the control of cardiovascular diseases, differ in their pharmacological properties, including time of dissociation from the AT receptor and the ability to activate other receptors, with potential impact on their relative clinical efficacy Objectives: The aim of this study was to compare the acute cardiovascular response to single dose administration of irbesartan or telmisartan in spontaneously hypertensive rats. Methods: Twenty-four male spontaneously hypertensive rats, weighting 250-275 g, were used. The carotid artery and femoral vein were cannulated for direct mean arterial pressure measurement (MAP) and irbesartan 3-6 mg/kg or telmisartan 0.5-1 mg/kg administration. Changes in MAP, heart rate and short-term and beat-to-beat blood pressure variability were estimated. Results: Although both antagonists reduced MAP, telmisartan induced a longer antihypertensive response than irbesartan, evidenced by greater MAP reduction after 180 min (-33.3%±4.1% vs. -16.3%±4%; p<0.05). Telmisartan and irbesartan induced sustained reduction of short-term blood pressure variability without significant differences between both experimental groups. At the lower dose level, telmisartan produced greater decrease of heart rate and beat-to-beat blood pressure variability at the different frequency domains compared with irbesartan. Conclusions: In spontaneously hypertensive rats, telmisartan administration induces a more persistent antihypertensive response and a greater bradycardic response than irbesartan. Spectral analysis of beat-to-beat blood pressure variability suggests that low dose telmisartan produces greater attenuation of vascular sympathetic activity compared with irbesartan.

Effects of Chronic Carvedilol administration on blood Pressure Variability and target Organ injury in rats with sinoaortic Denervation / Efectos de la administración crónica de carvedilol sobre la variabilidad de la presión arterial y el daño de órgano blanco en ratas con desnervación sinoaórtica

background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both in hyperten-sive and normotensive subjects, so its reduction should be considered as a new therapeutic goal. Objective: The aim of this study was to evaluate the effect of long-term oral carvedilol treatment on blood pressure, blood pressure variability and target organ injury in the left ventricle and thoracic aorta in a model of blood pressure liability. Methods: Twelve male Wistar rats submitted to sinoaortic denervation were treated during 8 weeks with a single dose of carvedilol 30 mg/kg or vehicle. At the end of treatment, echocardiographic evaluation and blood pressure and short-term variability measure-ments were performed. Left ventricular and thoracic aortic weights were determined and histological samples were prepared from both tissues. Metalloproteinase MMP-2 and transforming growth factor β (TGF-β) were quantified in the left ventricle and thoracic aorta. results: Carvedilol reduced systolic blood pressure and its variability in sinoaortic-denervated rats compared with the control group (126±5 vs. 142±11 mmHg, p<0.05; SD: 2.9±0.5 vs. 6.0±0.5 mmHg; p<0.05). A lower amount of connective tissue was found in carvedilol-treated animals. The expression of TGF-β decreased in both organs after carvedilol treatment. Conclusions: Chronic carvedilol treatment significantly reduces systolic blood pressure and its short-term variability in sinoaortic-denervated rats, decreasing the degree of left ventricular fibrosis.

introducción: El incremento en la variabilidad de la presión arterial resulta un nuevo factor de riesgo para el desarrollo de daño de órgano blanco en individuos tanto hipertensos como normotensos, por lo que se postula que su reducción debe considerarse una posible nueva meta terapéutica. Objetivos: Evaluar el efecto del tratamiento a largo plazo con carvedilol sobre la presión arterial, su variabilidad y el daño de órgano blanco en el ventrículo izquierdo y la aorta torácica en el modelo de la labilidad de presión. Material y métodos: Se incluyeron 12 ratas Wistar macho sometidas a desnervación sinoaórtica, las cuales fueron tratadas durante 8 semanas con una única administración diaria de carvedilol 30 mg/kg o vehículo. Finalizado el tratamiento se realizó la medición de la presión arterial y de la variabilidad a corto plazo y la evaluación ecocardiográfica. Se determinó el peso del ventrículo y de la aorta torácica y se realizaron preparados histológicos sobre ambos tejidos. Se cuantificó la expresión de metaloproteinasa 2 (MMP-2) y factor de crecimiento transformante β (TGF-β) en el ventrículo izquierdo y la aorta torácica. resultados: El carvedilol redujo la presión arterial sistólica y su variabilidad en las ratas con desnervación sinoaórtica en comparación con el grupo control (126 ± 5 vs. 142 ± 11 mm Hg, p < 0,05; DE: 2,9 ± 0,5 vs. 6,0 ± 0,5 mm Hg; p < 0,05). Se evidenció menor cantidad de tejido conectivo en los animales tratados con carvedilol. La expresión de TGF-β se encuentra disminuida en ambos órganos luego del tratamiento con carvedilol. Conclusiones: El tratamiento crónico con carvedilol reduce significativamente la presión arterial y su variabilidad a corto plazo en ratas con desnervación sinoaórtica, disminuyendo el grado de fibrosis del ventrículo izquierdo.

Perfil farmacocinético y farmacodinámico del nebivolol en un modelo experimental de síndrome metabólico / Pharmacokinetic and Pharmacodynamic Profile of Nebivolol in an Animal Model of Metabolic Syndrome

Con el objetivo en este estudio de evaluar los efectos cardiovasculares y la farmacocinética del nebivolol en ratas hipertensas por sobrecarga de fructosa y en ratas control, se registraron los efectos de la administración intravenosa de nebivolol, 3 mg/kg o 10 mg/kg, sobre la presión arterial, la frecuencia cardíaca y la variabilidad de la presión arterial a corto plazo y latido-a-latido, y se evaluó la farmacocinética enantioselectiva a partir del análisis de la concentración plasmática de los enantiómeros d-nebivolol y l-nebivolol. La variabilidad de la presión arterial a corto plazo y latido-a-latido se evaluó mediante la desviación estándar y el análisis espectral del registro de la presión arterial, respectivamente. El estado hipertensivo alteró la farmacocinética del nebivolol, evidenciado por una reducción en el aclaramiento del nebivolol en el grupo fructosa respecto del grupo control luego de la administración de la dosis más alta. El efecto antihipertensivo del nebivolol fue similar en ambos grupos, en tanto que el efecto bradicardizante fue mayor en las ratas del grupo control. Aunque no se observaron diferencias significativas en la variabilidad de la presión arterial latido-a-latido, la reducción de la variabilidad de la presión arterial a corto plazo inducida por el nebivolol fue significativamente superior en las ratas del grupo fructosa en comparación con los animales normotensos (-57,9% ± 11,8% vs. -19,6% ± 9,2%; p < 0,05). En conclusión, si bien el nebivolol reduce la presión arterial y la variabilidad de la presión arterial en ambos grupos, no se encontraron diferencias significativas en las ratas con sobrecarga de fructosa en cuanto a la farmacocinética y los efectos cardiovasculares, a excepción de una eficacia bradicardizante menor y una reducción mayor de la variabilidad de la presión arterial a corto plazo.

The cardiovascular and pharmacokinetic effects of nebivolol were evaluated in hypertensive fructose-fed and control rats, analyzing the effect of intravenously administered nebivolol 3 or 10 mg/kg on blood pressure, heart rate, and short-term and beat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers was evaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressure spectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction of nebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensive effect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Although no significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showed greater reduction after nebivolol administration in fructose-fed rats compared to control normotensive animals (-57.9%±11.8% vs.-19.6%±9.2%; p<0.05). In conclusion, although nebivolol reduces blood pressure and blood pressure variability in both groups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, except for lower bradycardic efficacy and greater reduction in short-term blood pressure variability.

Drugs affecting blood pressure variability: an update.

Blood pressure variability (BPV) is considered nowadays a novel risk factor for cardiovascular disease. Clinical evidences support that short-term and long-term BPV independently contribute to target organ damage, cardiovascular events and mortality in patients with hypertension or diabetes. Attenuation of excessive fluctuations of systolic and diastolic BPV has been suggested as an additional therapeutic target in cardiovascular prevention. A growing number of preclinical and clinical studies have focused in the assessment of drug effects or other interventions on the different types of BPV and their contribution in the prevention of cardiovascular events. Prospective clinical trials have shown that antihypertensive classes differ in their ability to control excessive BP fluctuations with an impact in clinical outcomes. Current evidences suggest that calcium channel blockers are more effective than other blood pressure lowering drugs for the reduction of short-term, mid-term and long-term BPV. In order to increase actual knowledge regarding the therapeutic significance of BPV in cardiovascular disease, there is a need for additional clinical studies specifically designed for the study of the relevance of short-term and long-term BPV control by antihypertensive drugs.

Models for evaluating the pharmacokinetics and pharmacodynamics for ß-blockers.

INTRODUCTION: ß-blocker therapy plays an important role in the treatment of various diseases, including hypertension, myocardial infarction and heart failure. Although all ß-blockers shared their ability to competitively block ß1-adrenoceptor, this therapeutic class showed great heterogeneity in their pharmacokinetic (PK) and pharmacodynamic (PD) properties. AREAS COVERED: The present review describes the models used for PK and PK/PD evaluation of ß-blockers and their applicability in preclinical and clinical studies. PK behavior of different ß-blockers has been studied by means of individual compartmental and population PKs, allowing the estimation of relevant PK parameters and factors involved in intersubject variability. Different PK/PD models have been developed for the in vivo estimation of PD parameters of different cardiovascular effects of ß-blockers. EXPERT OPINION: PK models and PK/PD modeling have clearly contributed to characterization of the PK and PD properties of ß-blockers. Differences in cardiovascular actions between classical ß-blockers and vasodilatory ß-blockers need to be further studied in order to confirm the clinical benefits of the new-generation of ß-blockers. PK/PD modeling may contribute to clarify the importance of heterogeneity of PK and PD properties of ß-blockers potentially improving the selection of the adequate agent and dose regimen in the treatment of cardiovascular diseases.

Enantioselective pharmacokinetics and cardiovascular effects of nebivolol in L-NAME hypertensive rats.

The cardiovascular effects and pharmacokinetics of nebivolol were assessed in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive and normotensive control rats. Male Wistar rats were randomly divided to drink tap water (control) or L-NAME solution for 2 weeks. The effects of nebivolol (3 or 10 mg kg(-1) i.v.) on blood pressure (BP), heart rate and BP variability (BPV) were recorded in awake L-NAME and control rats. Short-term and beat-to-beat BPV was assessed by the s.d. and spectral analysis of the BP recordings. Nebivolol pharmacokinetics was studied by means of traditional blood sampling. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; the clearance and the volume of distribution of l-nebivolol were significantly greater than those of the d-enantiomer. The hypotensive response to nebivolol was significantly enhanced in L-NAME rats (Δmean arterial pressure (MAP): -16.1±1.1%, P<0.05 vs. control rats) compared with normotensive animals (ΔMAP: -1.4±2.1%). An analysis of the beat-to-beat BPV showed a greater reduction in VLF BPV in the L-NAME compare with the control rats. Nebivolol significantly reduced the low-frequency/high-frequency ratio in hypertensive L-NAME animals compared with normotensive rats. Short-term BPV was markedly reduced by nebivolol in both experimental groups, although the attenuation of the s.d. of BP recording was greater in L-NAME rats. In conclusion, the hypotensive efficacy of nebivolol is significantly enhanced in L-NAME rats compared with normotensive animals, which is most likely due to a greater reduction in vascular sympathetic activity. Nebivolol markedly attenuated short-term BPV in both experimental groups, suggesting that ß-blockers with additional pharmacological actions provide beneficial cardiovascular effects by controlling high BP and its short-term variability.

Acute effects of third generation ß-blockers on short-term and beat-to-beat blood pressure variability in sinoaortic-denervated rats.

An increase in blood pressure variability (BPV) contributes to the development of target organ damage associated with hypertension. Treatment with conventional ß-blockers, such as atenolol, has been associated with an increase in BPV; however, the extrapolation of these results to third generation ß-blockers with pleiotropic effects seems to be inappropriate. The cardiovascular effects of third generation ß-blockers, carvedilol and nebivolol, were assessed in sinoaortic-denervated rats (SAD) and compared with the second generation ß-blocker atenolol and the calcium channel blocker verapamil, with a special focus on short-term BPV. Male SAD rats were acutely treated with carvedilol, nebivolol, atenolol or verapamil at two different doses, and the effects on blood pressure and BPV were recorded. Short-term BPV was assessed by the s.d. of BP recordings. Beat-to-beat BPV was studied using spectral analysis to assess the vascular sympatholytic activity of carvedilol and nebivolol by estimating the effects of these drugs on the ratio of low frequency (LF) to high frequency (HF) BPV (LF/HF ratio). Nebivolol, carvedilol and the calcium channel blocker verapamil significantly attenuated short-term BPV at both doses in SAD animals, and there were no differences between the drugs. Conversely, atenolol did not modify baseline s.d. values at either dose. Carvedilol and nebivolol significantly reduced the LF/HF ratio in SAD rats compared with the effects of atenolol and verapamil, suggesting the ability of the third generation ß-blockers to reduce vascular sympathetic activity. In conclusion, third generation ß-blockers induce a marked reduction in short-term BPV in SAD rats compared to atenolol. Moreover, the ability of carvedilol and nebivolol to reduce short-term BPV in SAD rats is equivalent to that of verapamil, suggesting that these ß-blockers may have an additional beneficial effect through their control of short-term variability to a similar extent to calcium channel blockers.

Effect of nebivolol on beat-to-beat and short-term blood pressure variability in spontaneously hypertensive rats.

Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.

Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability.

The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg(-1) (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic-pharmacodynamic (PK-PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg(-1) compared with WKY rats. PK-PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E (max), -27.6 ± 3.9%; p < 0.05) compared with WKY group (E (max), -13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E (max), -45.5 ± 5.0%; p < 0.05) with regard to WKY group (E (max), -17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.