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1.
N Engl J Med ; 381(17): 1609-1620, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31475794

RESUMEN

BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).


Asunto(s)
Aminobutiratos/administración & dosificación , Antagonistas de Receptores de Angiotensina/administración & dosificación , Enfermedades Cardiovasculares/mortalidad , Insuficiencia Cardíaca/tratamiento farmacológico , Hospitalización/estadística & datos numéricos , Neprilisina/antagonistas & inhibidores , Tetrazoles/administración & dosificación , Valsartán/administración & dosificación , Anciano , Aminobutiratos/efectos adversos , Angioedema/inducido químicamente , Antagonistas de Receptores de Angiotensina/efectos adversos , Método Doble Ciego , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipotensión/inducido químicamente , Masculino , Persona de Mediana Edad , Calidad de Vida , Factores Sexuales , Método Simple Ciego , Volumen Sistólico , Tetrazoles/efectos adversos , Valsartán/efectos adversos
2.
Lancet ; 394(10199): 672-683, 2019 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-31448738

RESUMEN

BACKGROUND: A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease. METHODS: The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle-eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome-occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)-was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985. FINDINGS: Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study-3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5-92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55-0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49-0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51-1·12; pinteraction=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33-0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up-ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group. INTERPRETATION: Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs. FUNDING: Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou.


Asunto(s)
Fármacos Cardiovasculares/administración & dosificación , Enfermedades Cardiovasculares/prevención & control , Combinación de Medicamentos , Prevención Secundaria/métodos , Adulto , Anciano , Anticolesterolemiantes/administración & dosificación , Antihipertensivos/administración & dosificación , Aspirina/administración & dosificación , Atorvastatina/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , LDL-Colesterol/efectos de los fármacos , Diabetes Mellitus/epidemiología , Enalapril/administración & dosificación , Femenino , Humanos , Hidroclorotiazida/administración & dosificación , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Valsartán/administración & dosificación
3.
Pharm Res ; 36(8): 117, 2019 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-31161271

RESUMEN

PURPOSE: To investigate the mechanism of enhancing solubility and bioavailability of water-insoluble drug, valsartan (VAL), with being mega-loaded by cyclodextrin metal organic framework (CD-MOF). METHODS: VAL was successfully mega-loaded into CD-MOF by magnetic agitation of VAL in ethanolic solution. Characterizations including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), synchrotron radiation-based Fourier transform-infrared spectroscopy (SR-FTIR) 13C solid-state nuclear magnetic resonance spectroscopy ( 13C SS-NMR), nitrogen gas adsorption, and small-angle X-ray scattering (SAXS) were carried out to confirm the mechanism and incorporation behavior of VAL in CD-MOF. Ball milling process combined with molecular modeling was also used to confirm the mechanism. Improvement of bioavailability in vivo was confirmed by pharmacokinetic experiment in beagles. RESULTS: As a carrier with payload 150% higher than conventional CD complexation, CD-MOF included molecules of VAL as complexations in the chambers of (γ-CD)2, and nanoclusters in the confined spherical cages of (γ-CD)6 confirmed by SAXS and 13C SS-NMR. Ball milling combined with molecular modeling inferred that the reduced release rate of the milled CD-MOF with ultrahigh drug payload was mainly due to the partial aggregation of the VAL nanoclusters. The molecules of VAL as nanoclusters in the cages of (γ-CD)6 are critical in dramatically improving the apparent solubility (39.5-fold) and oral bioavailability (1.9-fold) of VAL in contrast to γ-CD inclusion. CONCLUSIONS: The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.


Asunto(s)
Antihipertensivos/administración & dosificación , Ciclodextrinas/química , Estructuras Metalorgánicas/química , Nanopartículas/química , Valsartán/administración & dosificación , Animales , Antihipertensivos/farmacocinética , Disponibilidad Biológica , Perros , Liberación de Fármacos , Solubilidad , Valsartán/farmacocinética
4.
J Microencapsul ; 36(1): 10-20, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30719944

RESUMEN

The study was aimed to prepare a co-amorphous system of valsartan (VAL) with vanillin (VAN) for improving its solubility and dissolution followed by its confinement in mesoporous silica particles (MSPs) to stabilise the co-amorphous system and prevent its recrystallization. Amorphous VAL and VAN were obtained through quench-cooling and VAL/VAN binary co-amorphous system (VAL/VAN-CAS) was prepared through solvent evaporation technique. The particle size and morphology of VAL/VAN-CAS-MSPs were studied using scanning electron microscopy (SEM) and solid-state characterisation was performed by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The in vitro dissolution was investigated by dialysis bag diffusion method. SEM analysis revealed irregular shaped VAL/VAN-CAS-MSPs with a size range of 5-25 µm, while outcomes of DSC and XRPD confirmed the formation of VAL/VAN-CAS. The in vitro dissolution profiles demonstrated a significantly increased dissolution in first 60 minutes from VAL/VAN-CAS (∼68%) and VAL/VAN-CAS-MSPs (∼76%) compared to powder VAL (∼25%).


Asunto(s)
Antihipertensivos/química , Benzaldehídos/química , Portadores de Fármacos/química , Dióxido de Silicio/química , Valsartán/química , Antihipertensivos/administración & dosificación , Benzaldehídos/administración & dosificación , Cristalización , Liberación de Fármacos , Aromatizantes/administración & dosificación , Aromatizantes/química , Porosidad , Solubilidad , Valsartán/administración & dosificación
5.
AAPS PharmSciTech ; 20(1): 35, 2019 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-30604045

RESUMEN

The main purpose of the study was to develop valsartan floating tablets (VFT) via non-effervescent technique using low density polypropylene foam powder, carbopol, and xanthan gum by direct compression. Before compression, the particulate powdered mixture was evaluated for pre-compression parameters. The prepared valsartan tablets were evaluated for post-compression parameters, swelling index, floating lag time, in vitro buoyancy studies, and in vitro and in vivo X-ray imaging studies in albino rabbits. The result of all formulations for pre- and post-compression parameters were within the limits of USP. FTIR and DSC studies revealed no interaction between the drug and polymers used. The prepared floating tablets had good swelling and floating capabilities for more than 12 h with zero floating lag time. The release of valsartan from optimized formulation NF-2 showed sustained release up to 12 h; which was found to be non-Fickian release. Moreover, the X-ray imaging of optimized formulation (NF-2) revealed that tablet was constantly floating in the stomach region of the rabbit, thereby indicating improved gastric retention time for more than 12 h. Consequently, all the findings and outcomes have showed that developed valsartan matrix tablets could be effectively used for floating drug delivery system.


Asunto(s)
Química Farmacéutica/métodos , Polipropilenos/síntesis química , Polipropilenos/metabolismo , Valsartán/síntesis química , Valsartán/metabolismo , Animales , Antihipertensivos/síntesis química , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Liberación de Fármacos , Polipropilenos/administración & dosificación , Polvos , Conejos , Estómago/diagnóstico por imagen , Estómago/efectos de los fármacos , Estómago/fisiología , Comprimidos , Valsartán/administración & dosificación
6.
J Oncol Pharm Pract ; 25(5): 1231-1234, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29945530

RESUMEN

BACKGROUND: Sacubitril/valsartan has been shown to significantly reduce cardiovascular mortality and hospitalizations due to heart failure in adult patients with reduced ejection fraction when compared to enalapril. To the best of our knowledge, the combination of sacubitril (neprilysin inhibitor) and valsartan (angiotensin receptor blocker) has not been evaluated in patients with chemotherapy-induced cardiomyopathy, as these patients were excluded from the recent pivotal trial, PARADIGM-HF. However, current guidelines for the evaluation and management of cardiovascular complications of cancer therapy, published by the Canadian Cardiovascular Society, direct clinicians to the Canadian Cardiovascular Society Heart Failure Guidelines for the management of cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction (e.g. >10% reduction from baseline or left ventricular ejection fraction <53%), which could include the use of sacubitril/valsartan. METHODS: Retrospective descriptive comparative case study of two patients treated with sacubitril/valsartan. RESULTS: We present data from two patients who experienced anthracycline-induced cardiomyopathy and were successfully managed with sacubitril/valsartan after suboptimal responses to traditional evidence-based heart failure therapies. Both patients demonstrated some recovery of function and normalization of N-terminal pro B-type natriuretic peptide levels. Sacubitril/valsartan was well tolerated with minimal side effects. To date, neither patient has required hospitalization or additional clinic interventions for heart failure. CONCLUSIONS: While further large scale studies are required to determine a comprehensive safety and efficacy profile, we report two cases of anthracycline-induced cardiomyopathy survivors managed with sacubitril/valsartan with minimal side effects and no hospitalizations.


Asunto(s)
Aminobutiratos/administración & dosificación , Antraciclinas/efectos adversos , Cardiomiopatías/tratamiento farmacológico , Tetrazoles/administración & dosificación , Valsartán/administración & dosificación , Anciano , Cardiomiopatías/inducido químicamente , Quimioterapia Combinada , Femenino , Humanos , Estudios Retrospectivos
7.
Int J Cardiol ; 278: 84-87, 2019 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-30449692

RESUMEN

OBJECTIVES: In the VAL-SERVE (Valsartan in Systemic Right Ventricle) trial, three-year valsartan treatment improved systemic ventricular function only in symptomatic patients with congenitally or with an atrial switch corrected transposition of the great arteries. The aim of the current study was to investigate the longer-term clinical outcomes after valsartan treatment. METHODS: From 2006 to 2009, 88 adults were randomly allocated 1:1 to either valsartan or placebo for three consecutive years. Endpoints were defined as overall survival and freedom from clinical events (arrhythmia, heart failure, tricuspid valve surgery, death). RESULTS: Cardiac drug use and median follow-up after trial close-out (8.3 years) was similar between the randomization groups. Six patients (valsartan n = 3, placebo n = 3) died in 364 and 365 person-years (P = 0.999). No difference in the composite or separate clinical endpoints was found between the randomization groups, with corresponding long-term event-free survival rates of 50% and 34%. Nevertheless, in symptomatic patients valsartan significantly reduced the risk for events compared to placebo (HR 0.37, 95% CI 0.17-0.92). Analysis for repeated events and on-treatment analysis with any renin-angiotensin-aldosterone-system-inhibitor did not alter these results. CONCLUSIONS: Valsartan treatment in systemic RV patients did not result in improved survival at longer-term follow-up, but was associated with decreased risk of events in symptomatic patients.


Asunto(s)
Antihipertensivos/administración & dosificación , Valsartán/administración & dosificación , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/mortalidad , Adulto , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Derecha/diagnóstico , Adulto Joven
8.
Am J Physiol Heart Circ Physiol ; 316(3): H446-H458, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30499710

RESUMEN

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg-1·wk-1), or 3) SNT (40 mg·kg-1·day-1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Antineoplásicos/toxicidad , Sistema Renina-Angiotensina , Disfunción Ventricular/prevención & control , Amidas/administración & dosificación , Amidas/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Animales , Antihipertensivos/administración & dosificación , Bevacizumab/toxicidad , Cardiotoxicidad , Fumaratos/administración & dosificación , Fumaratos/uso terapéutico , Hidralazina/administración & dosificación , Hidralazina/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Perindopril/administración & dosificación , Perindopril/uso terapéutico , Sunitinib/toxicidad , Valsartán/administración & dosificación , Valsartán/uso terapéutico , Disfunción Ventricular/tratamiento farmacológico , Disfunción Ventricular/etiología
9.
Ann Pharmacother ; 53(4): 402-412, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30449127

RESUMEN

DATA SOURCES: A PubMed (1966 to October 2018) search was conducted using the following keywords: nebivolol, valsartan, and hypertension (HTN). Additional sources were identified by references. STUDY SELECTION AND DATA EXTRACTION: Articles written in English were included if they evaluated the pharmacology, pharmacokinetics, efficacy, safety, or place in therapy of nebivolol/valsartan in human subjects. DATA SYNTHESIS: Most patients with HTN require combination therapy; however, ß-adrenergic antagonists and AII type 1 receptor blockers have been considered less effective because of overlapping mechanisms of action. A phase III, randomized trial demonstrated that nebivolol/valsartan produced statistically significant blood pressure (BP) lowering as compared with monotherapy with the individual components or placebo. Substudy analyses confirmed this among subgroups and demonstrated that nebivolol/valsartan decreased plasma renin and aldosterone levels. One trial reported continued BP lowering at 52 weeks. Another study showed that nebivolol/valsartan had similar additivity scores as compared with other antihypertensive combinations. Relevance to Patient Care and Clinical Practice: This review discusses drug information, efficacy, and safety of nebivolol/valsartan and discusses its clinical relevance as a novel combination product in managing patients with HTN. CONCLUSION: Nebivolol/valsartan combination may offer a benefit to patients with an indication for both classes who desire to decrease pill burden. Although BP lowering was statistically significant in comparison to the individual components as monotherapy, the combination does not offer clinically significant benefits that would elevate its place in HTN management.


Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Nebivolol/uso terapéutico , Valsartán/uso terapéutico , Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Ensayos Clínicos Fase III como Asunto , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nebivolol/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Renina/sangre , Comprimidos , Resultado del Tratamiento , Valsartán/administración & dosificación
10.
Eur J Pharm Sci ; 128: 103-111, 2019 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-30508581

RESUMEN

Simultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675 mg/day) vs. placebo, sacubitril (360 mg/day), valsartan (900 mg/day), and benazepril (5 mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n = 18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on Day 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on Day 5. Compared with placebo, sacubitril/valsartan (675 mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675 mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675 mg administration was similar to that observed with valsartan 900 mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.


Asunto(s)
Aldosterona/metabolismo , Aminobutiratos/farmacología , GMP Cíclico/sangre , Sistema Renina-Angiotensina/fisiología , Tetrazoles/farmacología , Angiotensina I/sangre , Angiotensina II/sangre , Antagonistas de Receptores de Angiotensina/farmacología , Animales , Estudios Cruzados , GMP Cíclico/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Femenino , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Masculino , Péptidos Natriuréticos/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sodio en la Dieta , Valsartán/administración & dosificación , Valsartán/farmacología
11.
Pharm. care Esp ; 21(3): 179-185, 2019. tab
Artículo en Español | IBECS | ID: ibc-185111

RESUMEN

Paciente de 69 años que acude a la farmacia a retirar su medicación. Recientemente ha sido diagnosticado de hipertensión y lleva 20 días en tratamiento con valsartán 160mg. Refiere que no quiere retirar uno de sus tratamientos para la diabetes porque sufre hipoglucemias al tomar el tratamiento con la comida, por lo que no toma la medicación al mediodía. El paciente tiene pautado: sitagliptina 100mg (0/1/0), Repaglinida 1mg (1/2/1), Tamsulosina 0.4mg (0/0/1) y Valsartán 160mg (1/0/0). El valsartán es sustrato del OATP1B1 a la vez que un inhibidor de éste y la repaglinida también. Esto causa una elevación plasmática de la repaglinida, ya que no puede ser metabolizada al tener bloqueado el transportador, lo que explicaría la hipoglucemia. Se le comunica al médico la sospecha de interacción y procede al cambio de medicación del paciente. Sustituye la repaglinida por metformina, lo que lleva al paciente a normalizar su glucemia y a seguir con la tensión controlada


A 69-year-old patient comes to the pharmacist to get his medication. He was recently diagnosed with hypertension and has been taken Valsartan 160mg during the last 20 days. He explains that he does not want to get one of his medicines for his diabetes because he suffers hypoglycemia when he takes the treatment while eating so he does not take it at noon. The patient is prescribed: sitagliptina 100mg (0/1/0), Repaglinida 1mg (1/2/1), Tamsulosina 0.4mg (0/0/1) and Valsartan 160mg (1/0/0). Valsartan is an OATP1B1 substrate and an inhibitor of it too, just as repaglinide. This causes a repaglinide plasma elevation because the transporter is blocked and the repaglinide can not be metabolized. Thus, there is a hypoglycemia. Repaglinide is replaced by Metformina. As a result, the glycaemia’s patient is stabilized and the blood pressure keeps controlled


Asunto(s)
Humanos , Valsartán/administración & dosificación , Proteínas Transportadoras de Solutos/análisis , Hipoglucemiantes/administración & dosificación , Interacciones de Drogas , Hipertensión/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico
12.
J Toxicol Sci ; 43(11): 685-695, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30405001

RESUMEN

We investigated the viability of a combined repeated dose toxicity study, including toxicokinetics (TK), in common marmosets according to the ICH-S4, ICH-S3A and ICH-S7A Guidelines using valsartan as test article whose non-clinical repeated dose toxicity studies had been conducted using this species for regulatory purpose. Valsartan was administered orally to 3 animals/sex at 200 mg/kg/day for 2 weeks. In addition to the routine parameters in repeated dose toxicity studies, safety pharmacology parameters (examinations of the central nervous, respiratory and cardiovascular systems) were also evaluated. The Plasma Micro Sampling Toxicokinetics (PMS-TK) method required ultrasensitive quantitation, was employed to evaluate the relationship between toxic changes and plasma concentrations as well as the effects of frequent blood sampling in individual animals. In valsartan, toxic findings (a deteriorated physical condition; moribundity of one male and one female on Day 14; sporadic vomitus; decreases in body weights and food consumption; decreases in erythrocytic parameters; and renal changes such as an increase in urea nitrogen, dilation of the tubules and hypertrophy of the tubular epithelium) were similar and plasma concentrations comparable to the results in the approval information. Furthermore, no side effects caused by frequent blood sampling were confirmed in the negative control group. Consequently, a combined repeated dose toxicity study including TK analysis using the PMS-TK method is viable in common marmosets and contributes to animal welfare.


Asunto(s)
Pruebas de Toxicidad/métodos , Valsartán/toxicidad , Administración Oral , Bienestar del Animal , Animales , Peso Corporal/efectos de los fármacos , Callithrix , Ingestión de Alimentos/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Femenino , Masculino , Toxicocinética , Valsartán/administración & dosificación , Valsartán/sangre , Vómitos/inducido químicamente
13.
Pharm Dev Technol ; 23(10): 1168-1176, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30320540

RESUMEN

The objective of this study was to investigate the effect of the physiological parameters (pH, buffer capacity, and ionic strength) of the gastrointestinal (GI) fluid on the dissolution behavior of the class II weakly acidic (BCS class IIa) drug valsartan. A series of in vitro dissolution studies was carried out on Diovan® immediate release tablets using media that cover the physiological range of pH (1.2-7.8), buffer capacity (0-0.047 M/ΔpH), and ionic strength (0-0.4 mol/L) of the GI fluid during fasted and fed states using the conventional USP II apparatus. Valsartan exhibited pH- and buffer capacity-dependent dissolution behavior, where valsartan release was slow and incomplete in media simulating gastric fluid with low pH, and fast and complete in media simulating intestinal fluid with high pH. In addition, the rate of valsartan release increased with increasing the buffer capacity of the dissolution medium. In water and NaCl solutions, valsartan release was incomplete and the dissolution profiles were similar regardless of the ionic strength of the medium, indicating an ionic strength-independent dissolution behavior. These results highlight the significant effect of the physiological parameters of the GI fluid on the dissolution behavior of BCS class IIa drugs.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Antihipertensivos/química , Contenido Digestivo/química , Valsartán/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Antihipertensivos/administración & dosificación , Tampones (Química) , Humanos , Concentración de Iones de Hidrógeno , Concentración Osmolar , Solubilidad , Comprimidos , Valsartán/administración & dosificación
14.
Med Sci Monit ; 24: 6892-6899, 2018 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-30266894

RESUMEN

BACKGROUND We tested the concept of improving arterial wall characteristics by treatment with a very low-dose combination of fluvastatin and valsartan (low-flu/val) in stable, post-myocardial infarction (MI) patients. MATERIAL AND METHODS We enrolled 36 post-MI middle-aged males in the treatment (n=20) or control (n=16) group receiving low-flu/val (10 mg/20 mg) or placebo, respectively. The parameters of endothelial function (flow-mediated dilatation (FMD), reactive hyperemia index), and arterial stiffness (carotid-femoral pulse wave velocity (cf-PWV), local carotid PWV, and beta stiffness coefficient) were measured before and after 30 days of therapy, and 10 weeks later. RESULTS Treatment with low-flu/val improved FMD from 3.1±1.3% to 4.8±1.5% (p<0.001; by 54.8%) and cf-PWV from 7.8±1.1 to 6.7±1.5 m/s (p<0.01; by 14.1%) without affecting either lipids or blood pressure. In the treatment group, FMD and/or cf-PWV significantly improved in 17 patients, but the improvements did not correlate. The benefits obtained were still detectable 10 weeks after complete treatment cessation. No changes were obtained in the control group. No other vascular parameters changed. CONCLUSIONS Low-flu/val added "on top of" optimal therapy substantially improves endothelial function and arterial stiffness in post-MI patients. Since these improved parameters are well-known predictors of future coronary events, such treatment could decrease cardiovascular risk. Further studies are therefore warranted.


Asunto(s)
Infarto del Miocardio/tratamiento farmacológico , Valsartán/administración & dosificación , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Arteria Braquial/efectos de los fármacos , Arteria Braquial/fisiopatología , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Método Doble Ciego , Quimioterapia Combinada , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Fluvastatina/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Proyectos Piloto , Rigidez Vascular/efectos de los fármacos
15.
Medicine (Baltimore) ; 97(37): e12329, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30212981

RESUMEN

BACKGROUND: To determine whether the effectiveness and safety of fixed-dose combinations (FDCs) of amlodipine orotate/valsartan (AML/VAL) 5/160 mg are noninferior to those of valsartan/hydrochlorothiazide (VAL/HCTZ) 160/12.5 mg in hypertensive patients with inadequate response to valsartan 160 mg monotherapy. METHODS: This 8-week, active-controlled, parallel-group, fixed-dose, multicenter, double-blind randomized controlled, and noninferiority trial was conducted at 17 cardiovascular centers in the Republic of Korea. Eligible patients had mean sitting diastolic blood pressure (msDBP) ≥90 mm Hg despite monotherapy with valsartan 160 mg for 4 weeks. Patients were randomly assigned to treatment with AML/VAL 5/160 mg FDC (AML/VAL) group or VAL/HCTZ 160/12.5 mg FDC (VAL/HCTZ) group once daily for 8 weeks. A total of 238 patients were enrolled (AML/VAL group, n = 121; VAL/HCTZ group, n = 117), of whom 228 completed the study. RESULTS: At 8 weeks after randomization, msDBP was significantly decreased in both groups (-9.44 ±â€Š0.69 mm Hg in the AML/VAL group and -7.47 ±â€Š0.71 mm Hg in the VAL/HCTZ group, both P < .001 vs baseline). Between group difference was -1.96 ±â€Š1.00 mm Hg, indicating that AML/VAL 5/160 mg FDC was not inferior to VAL/HCTZ 160/12.5 mg FDC at primary efficacy endpoint. Control rate of BP defined as the percentage of patients achieving mean sitting SBP (msSBP) <140 mm Hg or msDBP <90 mm Hg (target BP) from baseline to week 8 was significantly higher in the AML/VAL group than that in the VAL/HCTZ group (84.3% [n = 102] in the AML/VAL group vs 71.3% [n = 82] in the VAL/HCTZ group, P = .016). At 8 weeks after randomization, mean uric acid level was significantly increased in the VAL/HCTZ group compared to that at baseline (0.64 ±â€Š0.08 mg/dL; P < .001). However, it was slightly decreased from baseline in the AML/VAL group (-0.12 ±â€Š0.08 mg/dL; P = .085). The intergroup difference was significant (P < .001). CONCLUSION: The effectiveness and safety AML/VAL 5/160 mg FDC are noninferior to those of VAL/HCTZ 160/12.5 mg FDC in patients with hypertension inadequately controlled by valsartan 160 mg monotherapy.


Asunto(s)
Combinación Amlodipino y Valsartán/administración & dosificación , Antihipertensivos/administración & dosificación , Hipertensión Esencial/tratamiento farmacológico , Hidroclorotiazida/administración & dosificación , Valsartán/administración & dosificación , Anciano , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
16.
Sci Rep ; 8(1): 12765, 2018 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-30143653

RESUMEN

Food is a known primary role to the exposure of the drugs orally administered. Since each animal may have unique food taking pattern and it is difficult to manipulate the food taking to animals, there lacks rationalized protocol for the food effects in pre-clinic study. The objective of this study was to identify the beagle food taking patterns and demonstrate their effects on bioavailability in valsartan. Herein, four types of food taking patterns of beagle were identified via inter-day and intra-day analysis, and named as Persisting, Pulsing, Postponing, Pushing ("4P Modes"), respectively, which were also validated by principal component analysis (PCA). Interestingly, food intake resulted in a reduced area under the concentration-time curve (AUC0-12h), maximum concentration (Cmax) and absorption rate, whilst the reduction varied in "4P Modes" of food taking. General considerations in the design of experiment for food effect to the bioavailability in beagles have been established as: to recognize the food taking patterns in each animal, to confirm the inter-day stability of the food taking behaviors, to trace the food taking patterns in parallel with plasma sampling. In conclusion, the right animals with proper food taking patterns should be assessed and selected for pre-clinic bioavailability evaluations.


Asunto(s)
Perros/fisiología , Conducta Alimentaria/fisiología , Absorción Fisiológica , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Femenino , Interacciones Alimento-Droga , Masculino , Análisis de Componente Principal , Valsartán/administración & dosificación , Valsartán/farmacocinética , Valsartán/farmacología
18.
J. physiol. biochem ; 74(3): 467-478, ago. 2018. tab, graf, ilus
Artículo en Inglés | IBECS | ID: ibc-179000

RESUMEN

Despite the effectiveness of renin-angiotensin blockade in retarding diabetic nephropathy progression, a considerable number of patients still develop end-stage renal disease. The present investigation aims to evaluate the protective potential of FPS-ZM1, a selective inhibitor of receptor for advanced glycation end products (RAGE), alone and in combination with valsartan, an angiotensin receptor blocker, against glomerular injury parameters in streptozotocin-induced diabetic rats. FPS-ZM1 at 1 mg/kg (i.p.), valsartan at 100 mg/kg (p.o.), and their combination were administered for 4 weeks, starting 2 months after diabetes induction in rats. Tests for kidney function, glomerular filtration barrier, and podocyte slit diaphragm integrities were performed. Combined FPS-ZM1/valsartan attenuated diabetes-induced elevations in renal levels of RAGE and phosphorylated NF-κB p65 subunit. It ameliorated glomerular injury due to diabetes by increasing glomerular nephrin and synaptopodin expressions, mitigating renal integrin-linked kinase (ILK) levels, and lowering urinary albumin, collagen type IV, and podocin excretions. FPS-ZM1 also improved renal function as demonstrated by decreasing levels of serum cystatin C. Additionally, the combination also alleviated indices of renal inflammation as revealed by decreased renal monocyte chemoattractant protein 1 (MCP-1) and chemokine (C-X-C motif) ligand 12 (CXCL12) expressions, F4/80-positive macrophages, glomerular TUNEL-positive cells, and urinary alpha-1-acid glycoprotein (AGP) levels. These findings underline the benefits of FPS-ZM1 added to valsartan in alleviating renal glomerular injury evoked by diabetes in streptozotocin rats and suggest FPS-ZM1 as a new potential adjunct to the conventional renin-angiotensin blockade


No disponible


Asunto(s)
Humanos , Masculino , Ratas , Benzamidas/uso terapéutico , Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/prevención & control , Barrera de Filtración Glomerular , Valsartán/uso terapéutico , Insuficiencia Renal/prevención & control , Administración Oral , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Biomarcadores , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/fisiopatología , Barrera de Filtración Glomerular/metabolismo , Barrera de Filtración Glomerular/patología , Valsartán/administración & dosificación
20.
Drug Dev Ind Pharm ; 44(12): 1905-1917, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29969042

RESUMEN

The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a 'One factor at a time (OFAT)' approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.


Asunto(s)
Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Desarrollo de Medicamentos , Investigación Farmacéutica/métodos , Valsartán/química , Preparaciones de Acción Retardada/administración & dosificación , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Excipientes , Concentración de Iones de Hidrógeno , Modelos Químicos , Proyectos de Investigación , Comprimidos , Valsartán/administración & dosificación
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