RESUMEN
Cardiovascular disease (CVD) is one of the leading causes of death worldwide, and its internal medicine treatments are mostly single/few-target chemical drugs. Long-term use of cardiovascular drugs for complex chronic diseases may lead to serious adverse drug reactions. Traditional Chinese medicine (TCM) has been used to treat heart diseases for thousands of years, helping to ease symptoms and prolong patients' lifespan in ancient China. TCM has the pharmacological characteristics of being multi-component, multi-target and multi-pathway, and the combined application of TCM and western medicine can be an alternative treatment for chronic and intractable diseases with high safety levels. This article reviewed the interactions and synergistic effect of TCM and cardiovascular drugs. In the treatment of arrhythmia, TCM combined with western medicine can more effectively regulate patients' cardiac electrophysiological characteristics, reduce the onsets of premature beat and heart rate variability, lower the levels of QT interval dispersion and serum inflammatory factors, alleviate clinical symptoms and TCM syndromes, and improve cardiac function with good safety levels. In the treatment of hypertension, integrative medicine can more steadily reduce blood pressure and levels of serum inflammatory factors and improve hemodynamic indexes and exercise tolerance, and it has high safety levels, especially for pregnant women. As for coronary heart disease, the combination of TCM and antiplatelet drugs may promote the absorption of each other. However, the interaction risk of pharmacokinetic mechanism between them is low at the dose of efficacy. Integrative medicine can reduce the level of N-terminal pro-brain natriuretic peptide, delay cardiac remodeling and improve heart function and quality of life for patients with heart failure with high safety levels.
Asunto(s)
Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Medicamentos Herbarios Chinos , Medicina Tradicional China , Humanos , Medicina Tradicional China/métodos , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacología , Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/farmacocinética , Enfermedades Cardiovasculares/tratamiento farmacológico , Interacciones de Hierba-Droga , Animales , Interacciones FarmacológicasRESUMEN
Dried Blood Spots (DBS) revolutionize therapeutic drug monitoring using LC-MS for the precise quantification of cardiovascular drugs (CDs), enabling personalized treatment adapted to patient-specific pharmacokinetics with minimal invasiveness. This study aims to achieve simultaneous quantification of eight CDs in DBS, overcoming physicochemical challenges. A two-step protein precipitation method was used for simple and precise sample preparation. The drugs were analyzed using LC-MS/MS in ESI positive-ion mode, showing high sensitivity and linearity, with a correlation coefficient (r2) exceeding 0.999, after being separated on a reversed-phase chromatography by gradient elution of DW-acetonitrile containing 0.1 % formic acid + 2 mM ammonium formate. The validation results indicate good selectivity, with no observed matrix effect and carry-over. The intra- and inter-day accuracy and precision were within 6 % for most drugs, except for digoxin and deslanoside at low therapeutic levels where the variation was within 20 %. Stability tests confirmed suitable DBS handling and storage conditions, indicating drug stability for at least 30 days at room temperature. The analysis of whole spot has demonstrated remarkable precision and reliability in all target drugs. The analysis of 3 mm internal diameter discs, punched in and out of DBS, presumed to contain 3 µL of blood, showed acceptable accuracy for most drugs, with less polar drugs like digoxin and deslanoside showing lower accuracy, indicating a need for further correction due to non-uniform drug distribution. Consequently, the developed LC-MS/MS method enables the quantification of multiple CDs in a single DBS analysis, while suggesting the potential for accuracy-based analysis.
Asunto(s)
Fármacos Cardiovasculares , Pruebas con Sangre Seca , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Pruebas con Sangre Seca/métodos , Humanos , Reproducibilidad de los Resultados , Modelos Lineales , Cromatografía Liquida/métodos , Fármacos Cardiovasculares/sangre , Fármacos Cardiovasculares/farmacocinética , Límite de Detección , Monitoreo de Drogas/métodosRESUMEN
Despite major advances in cardiac research over the past three decades, cardiovascular disease (CVD) still remains the leading cause of morbidity and mortality in women and men worldwide. However, a major challenge for health care providers is that the current guidelines for cardiovascular drug therapies do not consider the impact of sex in the development of treatment plan for optimizing therapies for women. Clinical research in recent years suggests significant pharmacological and pharmacokinetic differences between females and males, which have been attributed in part to differences in body composition, plasma protein binding capacity, drug metabolism, and excretion. Herein, we provide a comprehensive review regarding sex-specific differences and drugs commonly used for CVDs in women and men. Understanding how sex-related differences influence drug efficacy and CVD outcomes is crucial for not only optimizing treatment strategies for women and men but also to encourage the implementation of specific guidelines that address sex difference as a consideration for the treatment of CVDs.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Caracteres Sexuales , Humanos , Enfermedades Cardiovasculares/tratamiento farmacológico , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/efectos adversos , Femenino , Factores Sexuales , Masculino , AnimalesRESUMEN
It is widely acknowledged that the ketogenic diet (KD) has positive physiological effects as well as therapeutic benefits, particularly in the treatment of chronic diseases. Maintaining nutritional ketosis is of utmost importance in the KD, as it provides numerous health advantages such as an enhanced lipid profile, heightened insulin sensitivity, decreased blood glucose levels, and the modulation of diverse neurotransmitters. Nevertheless, the integration of the KD with pharmacotherapeutic regimens necessitates careful consideration. Due to changes in their absorption, distribution, metabolism, or elimination, the KD can impact the pharmacokinetics of various medications, including anti-diabetic, anti-epileptic, and cardiovascular drugs. Furthermore, the KD, which is characterised by the intake of meals rich in fats, has the potential to impact the pharmacokinetics of specific medications with high lipophilicity, hence enhancing their absorption and bioavailability. However, the pharmacodynamic aspects of the KD, in conjunction with various pharmaceutical interventions, can provide either advantageous or detrimental synergistic outcomes. Therefore, it is important to consider the pharmacokinetic and pharmacodynamic interactions that may arise between the KD and various drugs. This assessment is essential not only for ensuring patients' compliance with treatment but also for optimising the overall therapeutic outcome, particularly by mitigating adverse reactions. This highlights the significance and necessity of tailoring pharmacological and dietetic therapies in order to enhance the effectiveness and safety of this comprehensive approach to managing chronic diseases.
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Dieta Cetogénica , Interacciones Alimento-Droga , Cetosis , Humanos , Disponibilidad Biológica , Fármacos Cardiovasculares/farmacocinética , Enfermedad Crónica/tratamiento farmacológico , Enfermedad Crónica/terapia , Interacciones Farmacológicas , Hipoglucemiantes/farmacocinética , Cetosis/metabolismoRESUMEN
BACKGROUND: Drug-coated balloons (DCBs) are important treatment options for coronary artery disease; however, randomised controlled trials comparing various DCB technologies are sparse, and further investigations are needed. AIMS: This preclinical study aimed to histologically and biologically compare the drug effects and safety of a low-dose paclitaxel-coated DCB (PCB; AGENT), a regular-dose PCB (SeQuent Please NEO) and a sirolimus-coated DCB (SCB; MagicTouch). METHODS: The DCBs were inflated in the healthy iliac arteries of 18 rabbits, which were euthanised after 28 days. The treated iliac arteries and distal skeletal muscles were histopathologically evaluated, and drug concentrations were measured. RESULTS: In the histopathological evaluation, the medial smooth muscle cell loss score regarding depth, an indicator of drug efficacy, was significantly higher with AGENT and SeQuent Please NEO than with MagicTouch (4.0 [3.6-4.0] vs 3.7 [3.7-4.0] vs 2.2 [2.0-2.4]), with significant differences in comparisons between AGENT and MagicTouch (p<0.01) and between SeQuent Please NEO and MagicTouch (p<0.01). AGENT and SeQuent Please NEO showed comparable drug concentrations in the treated artery (p=0.61). In contrast, the drug concentrations in distal skeletal muscles were the highest for MagicTouch, followed by SeQuent Please NEO and AGENT (28.07 [13.19-52.46] ng/mg vs 0.66 [0.22-3.76] ng/mg vs 0.25 [0.04-3.23] ng/mg, respectively). CONCLUSIONS: This study demonstrated that PCBs might have higher efficacy and lower drug concentrations in distal skeletal muscles than the MagicTouch SCB. The efficacy of the AGENT low-dose PCB and the SeQuent Please NEO regular-dose PCB was comparable.
Asunto(s)
Paclitaxel , Sirolimus , Animales , Conejos , Paclitaxel/administración & dosificación , Sirolimus/administración & dosificación , Enfermedad de la Arteria Coronaria/terapia , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/métodos , Materiales Biocompatibles Revestidos , Arteria Ilíaca/efectos de los fármacos , Arteria Ilíaca/patología , Masculino , Modelos Animales de Enfermedad , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/farmacocinéticaRESUMEN
BACKGROUND: Dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been approved for improving glycemic control and reducing the risk of cardiovascular (CV) adverse events. This study compared the pharmacokinetic (PK) profiles, safety, and immunogenicity of LY05008, a biosimilar candidate, to a licensed product dulaglutide in healthy Chinese male subjects. RESEARCH DESIGN AND METHODS: In this double-blind, open-label, parallel-group study, healthy Chinese male subjects were randomized 1:1 to receive either LY05008 or dulaglutide subcutaneously. Primary study endpoints were PK parameters such as the area under the concentration-time curve (AUC) from time zero to infinity (AUC0 - ∞), AUC from time zero to the last quantifiable concentration (AUC0-t), and maximum serum concentration (Cmax). Safety and immunogenicity profiles were also included for data analysis. RESULTS: 82 subjects were randomized to receive LY05008 (n = 41) or dulaglutide (n = 41). The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUC0 - ∞, AUC0-t and Cmax of LY05008 to dulaglutide were all within the bioequivalence limits of 80%-125%. Other PK parameters, safety, and immunogenicity profiles were comparable across the two treatment groups. CONCLUSION: This study demonstrated PK similarity of LY05008, a dulaglutide biosimilar, to dulaglutide in healthy Chinese male subjects, with comparable safety and immunogenicity data. TRIAL REGISTRATION: The trial is registered at the Chinese Clinical Trial Registry (Identifier No. ChiCTR2200066519).
Asunto(s)
Biosimilares Farmacéuticos , Fármacos Cardiovasculares , Agonistas Receptor de Péptidos Similares al Glucagón , Hipoglucemiantes , Humanos , Masculino , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/metabolismo , Biosimilares Farmacéuticos/farmacocinética , Método Doble Ciego , Pueblos del Este de Asia , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/farmacología , Equivalencia Terapéutica , Voluntarios Sanos , Agonistas Receptor de Péptidos Similares al Glucagón/efectos adversos , Agonistas Receptor de Péptidos Similares al Glucagón/farmacocinética , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacocinética , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Péptidos Similares al Glucagón/análogos & derivadosRESUMEN
OBJECTIVE: The purpose of this study was to determine the impact of varying inflation parameters on paclitaxel delivery and retention using a commercially available DCB. BACKGROUND: Drug-coated balloons (DCB) have become the standard treatment for peripheral artery disease. Clinical data suggest that varying DCB delivery parameters directly impact patient outcome. Differences in delivery parameters can potentially alter the retention of the drug coating on DCBs. METHODS: Harvested porcine carotid arteries were utilized in an ex vivo pulsatile flow bioreactor system. The DCBs were then deployed at a DCB-to-artery ratio of 1:1 or 1.25:1, an inflation time of 30 seconds or 1 minute and transit time of 30 seconds or 3 minutes. The amount of drug retention in arterial tissue was evaluated by pharmacokinetic analysis at 1 hour and 1 day post DCB deployment. RESULTS: Arterial paclitaxel levels were found to be less at an inflation ratio of 1:1 with 3-minute transit time as compared to 30 seconds of transit time at 1 hour (12.3 ± 1.6 ng/mg vs. 391 ± 139 ng/mg, P = .036). At 1-day, DCBs deployed at a ratio of 1:1 resulted in less drug retention as compared to 1.25:1 (61.3 ± 23.1 ng/mg vs. 404 ± 195 ng/mg, P = .013). CONCLUSION: Arterial paclitaxel retention is reduced with extended transit times and sub-optimal expansion of the balloon. Optimization of delivery parameters can serve as an effective strategy to enhance clinical DCB outcomes.
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Angioplastia de Balón , Fármacos Cardiovasculares , Enfermedad Arterial Periférica , Animales , Fármacos Cardiovasculares/farmacocinética , Materiales Biocompatibles Revestidos , Arteria Femoral , Paclitaxel , Enfermedad Arterial Periférica/terapia , Preparaciones Farmacéuticas , Porcinos , Resultado del TratamientoRESUMEN
BACKGROUND: The chemokine CXCL12 and its two receptors (CXCR4 and CXCR7) are involved in inflammation and hematopoietic cell trafficking. This study was designed to investigate molecular docking interactions of four popular cardiovascular-active natural compounds; curcumin, resveratrol, quercetin, and eucalyptol; with these receptors and to predict their drug-like properties. We hypothesize that these compounds can modify CXCL12/CXCR4/CXCR7 pathway offering benefits for coronary artery disease patients. METHODS: Docking analyses were carried and characterized by Molecular Environment (MOE) software. Protein Data Bank ( http://www.rcsb.org/ ) has been retrieved from protein structure generation and crystal structures of CXCR4 and CXCR7 receptors (PDB code = 3ODU and 6K3F). The active sites of these receptors were evaluated and extracted from full protein and molecular docking protocol was done for compounds against them. The presented parameters included docking scores, ligand binding efficiency, and hydrogen bonding. The pharmacokinetic/toxic properties (ADME/T) were calculated using SwissADME, ProTox-II, and Pred-hERG softwares to predict drug-like properties of the compounds. The thermochemical and molecular orbital analysis, and molecular dynamics simulations were also done. RESULTS: All compounds showed efficient interactions with the CXCR4 and CXCR7 receptors. The docking scores toward proteins 3ODU of CXCR4 and 6K3F of CXCR7 were - 7.71 and - 7.17 for curcumin, - 5.97 and - 6.03 for quercetin, - 5.68 and - 5.49 for trans-resveratrol, and - 4.88 and - 4.70 for (1 s,4 s)-eucalyptol respectively indicating that all compounds, except quercetin, have more interactions with CXCR4 than with CXCR7. The structurally and functionally important residues in the interactive sites of docked CXCR4-complex and CXCR7-complex were identified. The ADME analysis showed that the compounds have drug-like properties. Only (1 s,4 s)-Eucalyptol has potential weak cardiotoxicity. The results of thermochemical and molecular orbital analysis and molecular dynamics simulation validated outcomes of molecular docking study. CONCLUSIONS: Curcumin showed the top binding interaction against active sites of CXCR4 and CXCR7 receptors, with the best safety profile, followed by quercetin, resveratrol, and eucalyptol. All compounds demonstrated drug-like properties. Eucalyptol has promising potential because it can be used by inhalation or skin massage. To our knowledge, this is the first attempt to find binding interactions of these natural agents with CXCR4 and CXCR7 receptors and to predict their druggability.
Asunto(s)
Productos Biológicos , Fármacos Cardiovasculares , Simulación de Dinámica Molecular , Receptores CXCR4 , Receptores CXCR , Transducción de Señal , Productos Biológicos/farmacocinética , Fármacos Cardiovasculares/farmacocinética , Humanos , Simulación del Acoplamiento MolecularRESUMEN
The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares/metabolismo , GMP Cíclico/metabolismo , Péptidos Natriuréticos/metabolismo , Receptores del Factor Natriurético Atrial , Anciano , Regulación Alostérica , Animales , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacología , Células Cultivadas , Femenino , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Receptores del Factor Natriurético Atrial/química , Receptores del Factor Natriurético Atrial/efectos de los fármacos , Receptores del Factor Natriurético Atrial/metabolismoRESUMEN
Shengxian Decotion (SXT), a well-known Traditional Chinese Medicine (TCM) formula composed of Astragali Radix, Bupleuri Radix, Cimicifugae Rhizoma, Anemarrhenae Rhizoma and Platycodonis Radix, is clinically considered as an effective formula against cardiovascular diseases. However, the exact effective substance of SXT in treating chronic heart failure (CHF) still remains unclear. In the current study, we investigated the benefit of SXT in doxorubicin (DOX)-induced CHF rats and established a UHPLC-MS/MS method to simultaneously determine 18 key compounds in a subsequent comparative pharmacokinetic study in normal and CHF rats. Histopathological studies, transmission electron microscopy, and echocardiography were applied to assess the therapeutic effect of SXT on DOX-induced CHF rats, which indicated that SXT significantly ameliorated DOX-induced CHF, similar to enalapril. In addition, we successfully established a UHPLC-MS/MS method to determine the pharmacokinetics of the components in rat plasma, which was validated with good linearity, inter-day and intra-day precisions and accuracies, matrix effects, extraction recovery, and stability values. Our results showed that only astragaloside IV showed increased plasma exposure in the CHF rats, while saikosaponin A, quercetin, timosaponin B-II, ferulic acid, isoferulic acid and formononetin decreased compared to their pharmacokinetic characteristics in the normal and CHF rats. This study demonstrates that SXT enjoys obvious therapeutic effect on DOX-induced CHF rats, and the altered metabolism of some compounds in SXT is affected by the pathological state of CHF rats. Our findings provide a better understanding of the in vivo exposure to complex compounds of SXT, supporting effective substance screening and further investigation of the therapeutic mechanism.
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Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/uso terapéutico , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Animales , Astragalus propinquus , Cromatografía Líquida de Alta Presión , Enfermedad Crónica , Electrocardiografía/efectos de los fármacos , Insuficiencia Cardíaca/inducido químicamente , Masculino , Espectrometría de Masas , Medicina Tradicional China , Ratas , Ratas Sprague-Dawley , Saponinas/sangre , Triterpenos/sangreRESUMEN
Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr1]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr1]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr1]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.
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Receptores de Apelina/agonistas , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/farmacocinética , Péptidos y Proteínas de Señalización Intercelular/farmacología , Animales , Área Bajo la Curva , Fármacos Cardiovasculares/síntesis química , Diseño de Fármacos , Semivida , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Macaca fascicularis , Estructura Molecular , Pirimidinonas/química , Pirimidinonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that is currently in clinical development for the treatment of heart failure. The absorption and disposition of [14C]OM (60 µCi) were studied after a single intravenous infusion (35 mg over 1 hour) or oral solution dose (35 mg) in 14 healthy male subjects. Mean recovery of the administered [14C]OM dose was 85.1% and 86.5% over 336 hours for the intravenous and oral routes, respectively. After intravenous dosing, 47.8% and 37.3% of the dose was recovered in urine and feces, respectively; after oral dosing, 48.6% and 38.0% was recovered in urine and feces, respectively. Unchanged OM accounted for a minor percentage of radioactivity in urine (mean 7.7% of dose) and feces (mean 4.1% of dose) across all subjects. The major metabolites recovered in urine and feces were M3 (decarbamoylation product) and sequential metabolite M4 (lactam of M3), which accounted for means of 26.5% and 11.6% of the administered dose, respectively. The CYP4 family of enzymes was primarily responsible for the formation of M3 based on in vitro studies. Other metabolic pathways accounted for 14.9% of the administered dose. In pooled plasma, OM, M3, and M4 accounted for 83.8%, 6.0%, and 3.3% of the total [14C]OM-related materials. No other plasma metabolites constituted more than 3% of the administered dose. The bioavailability for OM solution was 93.5% after rapid and extensive absorption. SIGNIFICANCE STATEMENT: This study characterized the absorption and disposition of OM, a novel small molecule being developed for the treatment of heart failure. OM was primarily cleared through metabolism by the CYP4 family through oxidative cleavage of a terminal carbamate moiety that resembles hydrolysis.
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Familia 4 del Citocromo P450/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Eliminación Hepatobiliar/fisiología , Absorción Intestinal/fisiología , Eliminación Renal/fisiología , Urea/análogos & derivados , Administración Intravenosa , Administración Oral , Adulto , Disponibilidad Biológica , Biotransformación , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/farmacocinética , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Urea/administración & dosificación , Urea/farmacocinéticaRESUMEN
Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h-1, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were IC 50 = 475 (11), IC 50 = 4.01 (5.4), EC 50 = 50.6 (93), and IC 50 = 47.8 (16), and efficacies (%RSE within parentheses) were I max = 0.944 (1.7), Imax = 1.00 (1.3), E max = 0.195 (9.9), and Imax = 0.745 (4.6) for ivabradine, sildenafil, dofetilide, and pimobendan. Hill parameters were estimated with good precision and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach integrating data from different studies and compounds for refined preclinical safety margin assessment. SIGNIFICANCE STATEMENT: A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure, and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), wherein system- (turnover rates) and drug-specific parameters (e.g., potencies and efficacies) were sought. The model-predicted equilibrium concentration-biomarker response relationships and was used for safety assessment (predictions of 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval.
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Biomarcadores Farmacológicos/sangre , Presión Sanguínea , Fármacos Cardiovasculares/toxicidad , Frecuencia Cardíaca , Animales , Cardiotoxicidad/sangre , Cardiotoxicidad/etiología , Cardiotoxicidad/fisiopatología , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/farmacocinética , Ivabradina/administración & dosificación , Ivabradina/farmacocinética , Ivabradina/toxicidad , Masculino , Fenetilaminas/administración & dosificación , Fenetilaminas/farmacocinética , Fenetilaminas/toxicidad , Piridazinas/administración & dosificación , Piridazinas/farmacocinética , Piridazinas/toxicidad , Ratas , Ratas Wistar , Citrato de Sildenafil/administración & dosificación , Citrato de Sildenafil/farmacocinética , Citrato de Sildenafil/toxicidad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidadRESUMEN
Los inhibidores del cotransportador de sodio-glucosa tipo 2 (iSGLT2) fueron incialmente desarrollados para el tratamiento de la diabetes por su actividad hipoglucemiante. Sin embargo, a la luz de los estudios clínicos más recientes, están revolucionando el abordaje de la enfermedad cardiovascular (CV) en el paciente diabético. En el año 2015, el ensayo clínico EMPA-REG OUTCOME nos demuestra por primera vez que la empagliflozina -un fármaco considerado «antidiabético»- reduce la mortalidad CV y por cualquier causa, además de eventos CV mayores, hospitalización por IC y progresión de enfermedad renal. Posteriormente, otros estudios clínicos con agentes del mismo grupo farmacológico, CANVAS, con canagliflozina y DECLARE-TIMI-58 con dapagliflozina, corroboran la exitencia de los beneficios CV asociados a la inhibición del receptor SGLT2. Los beneficios observados los sitúan más allá de simples agentes hipoglucemiantes, con un demostrado efecto cardionefroprotector en la enfermedad aterosclerótica, insuficiencia cardiaca, mortalidad total, mortalidad cardiovascular y progresión de insuficiencia renal. Actualmente ya son una realidad en pacientes diabéticos de alto y muy alto riesgo cardiovascular, mientras su evidencia en el paciente no diabético es cada vez mayor. Asistimos, por tanto, a un cambio de paradigma y posiblemente al nacimiento de una nueva especialidad, la cardio-endocrinología, con la implicación de nuevos tratamientos que deben ser considerados más que sólo fármacos antidiabéticos
The sodium-glucose co-transporter 2 inhibitors (SGLT2i) were first conceived to treat type 2 diabetes due to their hypoglycaemic effect. However, due to an increasing number of studies, SGLT2i are changing the way we treat, and understand, diabetes, and cardiovascular risk, in general. The EMPA-REG OUTCOME clinical trial, in 2015, showed for the first time that empagliflozine - a glucose lowering agent - lowers the risk of death from cardiovascular causes and death from any cause. Also, this SGLT2i lowered hospital admission for heart failure and delayed renal function worsening. From then on, other clinical trials with SGLT2i such as CANVAS (canagliflozin) and DECLARE-TIMI-58 (dapagliflozin) confirmed these positive effects. With a proven and non-related glucose-lowering effect on heart failure, overall death, cardiovascular death, and renal function, SGLT2i stands out among the rest of anti-diabetic drugs. Since its role in treating patients with heart failure and type 2 diabetes has been undoubtedly established, new studies are paving the way for non-diabetic patients as well. A potential paradigm shift is being witnessed and, probably, the dawn of a new field, cardio-endocrinology, which involves new and far-reaching pharmacological agents
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Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Hipoglucemiantes/farmacocinética , Fármacos Cardiovasculares/farmacocinética , Insuficiencia Cardíaca/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
A sensitive and robust method has been developed using an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay to quantify Tat-K13, a novel interfering peptide for the treatment of ischemic stroke, in human plasma. Automated solid-phase extraction on a Waters Oasis WCX (30 µm, 10 mg) 96-well plate was used to extract Tat-K13 from human plasma and the extracts were separated on a Waters Acquity CSH column (2.1 × 50 mm i.d., 1.7 µm) with a gradient elution method by mobile phase A (nonafluoropentanoic acid-acetic acid-water, 1:2:1000, v/v/v) and B (nonafluoropentanoic acid-acetic acid-water-acetonitrile, 1:2:100:900, v/v/v/v). The method was fully validated following international bioanalytical guidelines and showed good linearity from 2.10 to 1,050 ng/ml. The method was successfully applied to investigate the clinical pharmacokinetics of Tat-K13 in health volunteers. Rapid elimination of Tat-K13 from the body was observed, with half-life ranging from 0.26 to 0.78 h across different dose levels. The exposure of Tat-K13 was approximately dose-dependent in terms of the area under the concentration-time curve and peak concentration.
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Fármacos Cardiovasculares , Cromatografía Líquida de Alta Presión/métodos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Péptidos , Espectrometría de Masas en Tándem/métodos , Adolescente , Adulto , Fármacos Cardiovasculares/sangre , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/uso terapéutico , Humanos , Persona de Mediana Edad , Péptidos/sangre , Péptidos/farmacocinética , Péptidos/uso terapéutico , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Ivabradine is a unique agent that is distinct from beta-blockers and calcium channel blockers as it reduces heart rate without affecting myocardial contractility or vascular tone. Ivabradine is a use-dependent inhibitor targeting the sinoatrial node. It is approved for use in the United States as an adjunct therapy for heart rate reduction in patients with heart failure with reduced ejection fraction. In this scenario, ivabradine has demonstrated improved clinical outcomes due to reduction in heart failure readmissions. However, there has been conflicting evidence from prospective studies and randomized controlled trials for its use in stable ischemic heart disease regarding efficacy in symptom reduction and mortality benefit. Ivabradine may also play a role in the treatment of patients with inappropriate sinus tachycardia, who often cannot tolerate beta-blockers and/or calcium channel blockers. In this review, we highlight the evidence for the nuances of using ivabradine in heart failure, stable ischemic heart disease, and inappropriate sinus tachycardia to raise awareness for its vital role in the treatment of select populations.
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Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Ivabradina/farmacología , Ivabradina/uso terapéutico , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacocinética , Humanos , Ivabradina/efectos adversos , Ivabradina/farmacocinética , Isquemia Miocárdica/tratamiento farmacológico , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Volumen Sistólico/efectos de los fármacos , Taquicardia Sinusal/tratamiento farmacológicoRESUMEN
Interventional therapies such as drug-eluting stents (DES) and drug-coated balloons (DCB) have significantly improved the clinical outcomes of patients with coronary occlusions in recent years. Despite this marked improvement, ischemic cardiovascular disease remains the most common cause of death worldwide. To address this, research efforts are focused on improving the safety and efficacy of the next generation of these devices. However, current experimental methods are unable to account for the influence of atherosclerotic lesions on drug uptake and retention. Therefore, in this study, we used an integrated approach utilizing both in vitro and in silico methods to assess the performance of DCB therapy. This approach was validated against existing in vivo results before being used to numerically estimate the effect of the atheroma. A bolus release of sirolimus was observed with our coating matrix. This, coupled with the rapid saturation of specific and non-specific binding sites observed in our study, indicated that increasing the therapeutic dose coated onto the balloons might not necessarily result in greater uptake and/or retention. Additionally, our findings alluded to an optimal exposure time, dependent on the coating matrix, for the DCBs to be expanded against the vessel. Moreover, our findings suggest that a biphasic drug release profile might be beneficial for establishing and maintaining the saturation of bindings sites within severely occluded vessels. Ultimately, we have demonstrated that computational methods may be capable of assessing the efficacy of DCB therapy as well as predict the influence of atherosclerotic lesions on said efficacy.
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Angioplastia Coronaria con Balón/instrumentación , Aterosclerosis/complicaciones , Fármacos Cardiovasculares/farmacocinética , Oclusión Coronaria/cirugía , Reestenosis Coronaria/prevención & control , Stents Liberadores de Fármacos , Aterosclerosis/patología , Fármacos Cardiovasculares/administración & dosificación , Simulación por Computador , Oclusión Coronaria/complicaciones , Oclusión Coronaria/patología , Reestenosis Coronaria/patología , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Relación Dosis-Respuesta a Droga , Liberación de Fármacos , Humanos , Modelos Cardiovasculares , Sirolimus/administración & dosificación , Sirolimus/farmacocinética , Resultado del TratamientoRESUMEN
PURPOSE: Major depressive disorder (MDD) and anxiety disorders (AD) are both highly prevalent among individuals with arrhythmia, ischemic heart disease, heart failure, hypertension, and dyslipidemia. There should be increased support for MDD and AD diagnosis and treatment in individuals with cardiac diseases, because treatment rates have been low. However, cardiac-psychiatric drug interaction can make pharmacologic treatment challenging. METHODS: The objective of the present systematic review was to investigate cardiac-psychiatric drug interactions in three different widely used pharmacological databases (Micromedex, Up to Date, and ClinicalKey). RESULTS: Among 4914 cardiac-psychiatric drug combinations, 293 significant interactions were found (6.0%). When a problematic interaction is detected, it may be easier to find an alternative cardiac medication (32.6% presented some interaction) than a psychiatric one (76.9%). Antiarrhythmics are the major class of concern. The most common problems produced by these interactions are related to cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest), increased exposure of cytochrome P450 2D6 (CYP2D6) substrates, or reduced renal clearance of organic cation transporter 2 (OCT2) substrates and include hypertensive crisis, increased risk of bleeding, myopathy, and/or rhabdomyolysis. CONCLUSION: Unfortunately, there is considerable inconsistency among the databases searched, such that a clinician's discretion and clinical experience remain invaluable tools for the management of patients with comorbidities present in psychiatric and cardiac disorders. The possibility of an interaction should be considered. With a multidisciplinary approach, particularly involving a pharmacist, the prescriber should be alerted to the possibility of an interaction. MDD and AD pharmacologic treatment in cardiac patients could be implemented safely both by cardiologists and psychiatrists. TRIAL REGISTRATION: PROSPERO Systematic Review Registration Number: CRD42018100424.
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Antipsicóticos/farmacología , Fármacos Cardiovasculares/farmacología , Enfermedades Cardiovasculares/tratamiento farmacológico , Bases de Datos Farmacéuticas/estadística & datos numéricos , Trastorno Depresivo Mayor/tratamiento farmacológico , Antipsicóticos/efectos adversos , Antipsicóticos/farmacocinética , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacocinética , Enfermedades Cardiovasculares/epidemiología , Citocromo P-450 CYP2D6/efectos de los fármacos , Trastorno Depresivo Mayor/epidemiología , Interacciones Farmacológicas , Humanos , Tasa de Depuración Metabólica , Transportador 2 de Cátion Orgánico/efectos de los fármacosRESUMEN
Ivabradine and its metabolite both demonstrate heart rate-reducing effect (If current inhibitors) and undergo CYP3A4 metabolism. The purpose of this study was to develop a joint parent-metabolite physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict the PK and PD of ivabradine and its metabolite following intravenous (i.v.) or oral administration (alone or co-administered with CYP3A4 inhibitors). Firstly, a parent-metabolite disposition model was developed and optimised using individual plasma concentration-time data following i.v. administration of ivabradine or metabolite within a Bayesian framework. Secondly, the model was extended and combined with a mechanistic intestinal model to account for oral absorption and drug-drug interactions (DDIs) with CYP3A4 inhibitors (ketoconazole, grapefruit juice). Lastly, a PD model was linked to the PBPK model to relate parent and metabolite PK to heart rate (HR) reduction. The disposition model described successfully parent-metabolite PK following i.v. administration. Following integration of a gut model, the PBPK model adequately predicted plasma concentration profiles and the DDI risk (92% and 85% of predicted AUC+inhibitor/AUCcontrol and Cmax+inhibitor/Cmaxcontrol for ivabradine and metabolite within the prediction limits). Ivabradine-metabolite PBPK model was linked to PD by using the simulated unbound parent-metabolite concentrations in the heart. This approach successfully predicted the effects of both entities on HR (observed vs predicted - 7.7/- 5.9 bpm and - 15.8/- 14.0 bpm, control and ketoconazole group, respectively). This study provides a framework for PBPK/PD modelling of a parent-metabolite and can be scaled to other populations or used for investigation of untested scenarios (e.g. evaluation of DDI risk in special populations).
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Fármacos Cardiovasculares/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Ivabradina/farmacocinética , Modelos Biológicos , Administración Intravenosa , Administración Oral , Adulto , Área Bajo la Curva , Teorema de Bayes , Fármacos Cardiovasculares/administración & dosificación , Simulación por Computador , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Interacciones Farmacológicas , Enterocitos , Femenino , Jugos de Frutas y Vegetales/efectos adversos , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Absorción Intestinal/fisiología , Ivabradina/administración & dosificación , Cetoconazol/administración & dosificación , Cetoconazol/farmacocinética , Masculino , Distribución TisularRESUMEN
The natural isomers of resveratrol, cis- and trans-resveratrol, are natural phenolic substances synthetized via the shikimate pathway and found in many sources, including grapes, peanuts, blackberries, pistachios, cacao, cranberries, and jackfruits. They have functional and pharmacological properties such as anticarcinogenic, antidiabetic, anti-inflammatory, and cardioprotective activities. The aim of this article is to review the data published on resveratrol and its isomers, and their biosynthesis in plants, food sources, health and toxic effects, and the excretion of their metabolites. Due to its contribution to the promotion of human health, it is convenient to gather more knowledge about its functional properties, food sources, and the interactions with the human body during the processes of eating, digestion, absorption, biotransformation, and excretion, to combine this information to improve the understanding of these substances.