RESUMO
Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.
Assuntos
Receptores de Apelina , Fármacos Cardiovasculares , Desenho de Fármacos , Receptores de Apelina/agonistas , Receptores de Apelina/química , Receptores de Apelina/ultraestrutura , Microscopia Crioeletrônica , Proteínas de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Humanos , Fármacos Cardiovasculares/químicaRESUMO
Global health concerns persist due to the multifaceted nature of heart diseases, which include lifestyle choices, genetic predispositions, and emerging post-COVID complications like myocarditis and pericarditis. This broadens the spectrum of cardiovascular ailments to encompass conditions such as coronary artery disease, heart failure, arrhythmias, and valvular disorders. Timely interventions, including lifestyle modifications and regular medications such as antiplatelets, beta-blockers, angiotensin-converting enzyme inhibitors, antiarrhythmics, and vasodilators, are pivotal in managing these conditions. In drug development, topological indices play a critical role, offering cost-effective computational and predictive tools. This study explores modified reverse degree topological indices, highlighting their adjustable parameters that actively shape the degree sequences of molecular drugs. This feature makes the approach suitable for datasets with unique physicochemical properties, distinguishing it from traditional methods that rely on fixed degree approaches. In our investigation, we examine a dataset of 30 drug compounds, including sotagliflozin, dapagliflozin, dobutamine, etc., which are used in the treatment of cardiovascular diseases. Through the structural analysis, we utilize modified reverse degree indices to develop quantitative structure-property relationship (QSPR) models, aiming to unveil essential understandings of their characteristics for drug development. Furthermore, we compare our QSPR models against the degree-based models, clearly demonstrating the superior effectiveness inherent in our proposed method.
Assuntos
Fármacos Cardiovasculares , Relação Quantitativa Estrutura-Atividade , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacologia , Fenômenos Químicos , HumanosRESUMO
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.
Assuntos
Fármacos Cardiovasculares , Doenças Cardiovasculares/metabolismo , GMP Cíclico/metabolismo , Peptídeos Natriuréticos/metabolismo , Receptores do Fator Natriurético Atrial , Idoso , Regulação Alostérica , Animais , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacologia , Células Cultivadas , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Receptores do Fator Natriurético Atrial/química , Receptores do Fator Natriurético Atrial/efeitos dos fármacos , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress in Apln-/y aorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater in Apln-/y mice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture in Apln-/y mice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) in Ldlr-/- mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.
Assuntos
Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/patologia , Apelina/metabolismo , Neprilisina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Angiotensina II/administração & dosagem , Enzima de Conversão de Angiotensina 2 , Animais , Aorta Abdominal/citologia , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/etiologia , Apelina/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Miócitos de Músculo Liso , Neprilisina/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Peptidil Dipeptidase A/metabolismo , Fenilefrina/administração & dosagem , Cultura Primária de Células , Proteólise/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genéticaRESUMO
BACKGROUND: Growing evidence shows that scientific collaboration plays a crucial role in transformative innovation in the life sciences. For example, contemporary drug discovery and development reflects the work of teams of individuals from academic centers, the pharmaceutical industry, the regulatory science community, health care providers, and patients. However, public understanding of how collaborations between academia and industry catalyze novel target identification and first-in-class drug discovery is limited. RESULTS: We perform a comprehensive network analysis on a large scientific corpus of collaboration and citations (97,688 papers with 1,862,500 citations from 170 million scientific records) to quantify the success trajectory of innovative drug development. By focusing on four types of cardiovascular drugs, we demonstrate how knowledge flows between institutions to highlight the underlying contributions of many different institutions in the development of a new drug. We highlight how such network analysis could help to increase industrial and governmental support, and improve the efficiency or accelerate decision-making in drug discovery and development. CONCLUSION: We demonstrate that network analysis of large public databases can identify and quantify investigator and institutional relationships in drug discovery and development. If broadly applied, this type of network analysis may help to enhance public understanding of and support for biomedical research, and could identify factors that facilitate decision-making in first-in-class drug discovery among academia, the pharmaceutical industry, and healthcare systems.
Assuntos
Pesquisa Biomédica/estatística & dados numéricos , Fármacos Cardiovasculares/química , Desenvolvimento de Medicamentos , Descoberta de Drogas , Análise de Rede Social , Indústria Farmacêutica/estatística & dados numéricosRESUMO
There is a continuous need for novel microbial natural products to fill the drying-up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N-ribityl 5,6-dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non-canonical PKS/NRPS gene cluster, whereas the origin of N-ribityl 5,6-dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C-N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.
Assuntos
Benzimidazóis/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Isoxazóis/uso terapêutico , Animais , Benzimidazóis/química , Fármacos Cardiovasculares/química , Isoxazóis/química , Estrutura Molecular , Myxococcus/química , Peixe-ZebraRESUMO
We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.
Assuntos
Adenosina/metabolismo , Fármacos Cardiovasculares/farmacologia , Estenose Coronária/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Ranolazina/farmacologia , 5'-Nucleotidase/química , 5'-Nucleotidase/metabolismo , Animais , Sítios de Ligação , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Células Cultivadas , Estenose Coronária/metabolismo , Estenose Coronária/fisiopatologia , Modelos Animais de Doenças , Cães , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Ligação Proteica , Conformação Proteica , Ranolazina/química , Ranolazina/metabolismo , Relação Estrutura-Atividade , Regulação para Cima , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
OBJECTIVE: Peripheral artery disease is the second most common cardiovascular disease. It can often occur in complex form when there is a presence of long, diffuse, and multiple lesions. Current treatments use either single long drug-coated balloons (DCBs) or multiple DCBs; however, treatment success is limited. The purpose of this study was to investigate the preclinical feasibility of our multiple-release Tailored Medical Devices DCB (MR-TMD-DCB) to treat multiple arterial segments using a single DCB. METHODS: The MR-TMD-DCBs were developed using a two-layer coating approach. The DCBs were developed in a certified Current Good Manufacturing Practices facility using presterilized materials and reagent and then characterized for coating morphology, thermal and chemical changes, and in vitro particulate shedding. The drug loss, tissue uptake, and undelivered drug amounts were analyzed using an in vitro peripheral artery flow model and explanted pig arteries. Then, an in vivo survival study was performed using a healthy porcine model to measure the short-term drug uptake (seven swine; 14 treatments at day 1) and retention (seven swine; 14 treatments at day 7) in two different arterial segments after treatment with a single MR-TMD-DCB. RESULTS: The coating on the MR-TMD-DCB was smooth and homogeneous with paclitaxel molecularly dispersed in its amorphous state. A negligible number of particulates were shed from the MR-TMD-DCB coating. A similar amount of drug was accurately delivered into two separate explanted arteries using a single MR-TMD-DCB during the in vitro flow model testing (707 ± 109 ng/mg in the first explanted artery and 783 ± 306 ng/mg in the second explanted artery). The MR-TMD-DCB treatment resulted in equivalent drug amounts in the two arterial segments at day 1 (63 ± 19 ng/mg in the first treatment site and 59 ±19 ng/mg in the second treatment site) and at day 7 (9 ± 6 ng/mg in the first treatment site and 10 ± 6 ng/mg in the second treatment site). In addition, the drug levels at each time point were in the clinically relevant range to prevent neointimal hyperplasia. CONCLUSIONS: The MR-TMD-DCBs provided equivalent and clinically relevant drug retention levels into two different arterial segments. Thus, MR-TMD-DCBs can be used to accurately deliver drug into multiple arterial segments with the use of a single DCB. The clinical outcomes of these findings need further investigation. Future long-term pharmacokinetics and safety studies will be performed to evaluate the safety and efficacy of the MR-TMD-DCB.
Assuntos
Angioplastia com Balão/instrumentação , Fármacos Cardiovasculares/administração & dosagem , Paclitaxel/administração & dosagem , Doença Arterial Periférica/terapia , Animais , Fármacos Cardiovasculares/química , Materiais Revestidos Biocompatíveis , Modelos Animais de Doenças , Paclitaxel/química , Material Particulado , Suínos , Grau de Desobstrução VascularRESUMO
OBJECTIVES: The aim of this study is to improve local-drug delivery efficiency and tissue absorption using the ultrasound (US)-responsible drug coating based on a newly developed US-controlled paclitaxel release balloon. BACKGROUND: Low availability of the drug coating remains a major concern of the current drug coated balloon (DCB). The goal of this study is to develop a method to use an US-responsible paclitaxel-loaded microcapsules (PM) as the main content of balloon drug coating to enhance bioavailability of DCB. METHODS: An US-controlled paclitaxel release balloon is designed and fabricated based on the US-responsible paclitaxel-loaded poly (lactic-co-glycolic acid) (PLGA) microcapsules. Rapid exchange percutaneous transluminal coronary angioplasty (PTCA) balloon catheters were coated with the PM. The deployment processes of the paclitaxel-loaded microcapsules coated balloons (PMCB) under US, PMCB without US and a homogenous matrix of paclitaxel and iopromide coated balloon (PICB) were then placed in healthy and stent implanted porcine coronary arteries. RESULTS: In vitro release assay demonstrated an ability of US (1 MHz, 1.22 W/cm2 , 1 minute) to affect the release kinetics of paclitaxel from PM by inducing a 76 ± 5.4% increase in the rate of release. The paclitaxel content in target vessels are 203 ± 37 µg/g for PMCB under US, 85 ± 23 µg/g for PMCB without US, and 107 ± 31 µg/g for PICB 1-hr post-surgery. The availability of the drug for the PMCB reaches 27% under US. CONCLUSIONS: The US-controlled paclitaxel release balloon significantly improved the drug content of the target vessels in the porcine model.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Cateteres Cardíacos , Fármacos Cardiovasculares/administração & dosagem , Materiais Revestidos Biocompatíveis , Vasos Coronários/metabolismo , Paclitaxel/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ondas Ultrassônicas , Animais , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacocinética , Preparações de Ação Retardada , Portadores de Fármacos , Liberação Controlada de Fármacos , Masculino , Paclitaxel/química , Paclitaxel/farmacocinética , Solubilidade , Sus scrofaRESUMO
With the increasing insight into molecular mechanisms of cardiovascular disease, a promising solution involves directly delivering genes, cells, and chemicals to the infarcted myocardium or impaired endothelium. However, the limited delivery efficiency after administration fails to reach the therapeutic dose and the adverse off-target effect even causes serious safety concerns. Controlled drug release via external stimuli seems to be a promising method to overcome the drawbacks of conventional drug delivery systems (DDSs). Microbubbles and magnetic nanoparticles responding to ultrasound and magnetic fields respectively have been developed as an important component of novel DDSs. In particular, several attempts have also been made for the design and fabrication of dual-responsive DDS. This review presents the recent advances in the ultrasound and magnetic fields responsive DDSs in cardiovascular application, followed by their current problems and future reformation.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Magnetismo , Nanopartículas de Magnetita , Microbolhas , Ultrassom , Animais , Fármacos Cardiovasculares/química , Preparações de Ação Retardada , Composição de Medicamentos , Técnicas de Transferência de Genes , Terapia Genética , Humanos , Campos MagnéticosRESUMO
Atherosclerosis is a chronic disease characterized by lipid accumulation and chronic inflammation of the arterial wall, which is the pathological basis for coronary heart disease, cerebrovascular disease and thromboembolic disease. Currently, there is a lack of low-cost therapeutic agents that effectively slow the progression of atherosclerosis. Therefore, the development of new drugs is urgently needed. The research and development of marine-derived drugs have gained increasing interest from researchers across the world. Many marine organisms provide a rich material basis for the development of atherosclerotic drugs. This review focuses on the latest technological advances in the structures and mechanisms of action of marine-derived anti-atherosclerotic substances and the challenges of the application of these substances including marine polysaccharides, proteins and peptides, polyunsaturated fatty acids and small molecule compounds. Here, we describe the theoretical basis of marine biological resources in the treatment of atherosclerosis.
Assuntos
Organismos Aquáticos/química , Aterosclerose/tratamento farmacológico , Fármacos Cardiovasculares/farmacologia , Ácidos Graxos Insaturados/farmacologia , Polissacarídeos/farmacologia , Proteínas/farmacologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/isolamento & purificação , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/isolamento & purificação , Humanos , Estrutura Molecular , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Proteínas/química , Proteínas/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin's prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin's ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin's mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.
Assuntos
Miosinas Cardíacas/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Miosinas/efeitos dos fármacos , Ureia/análogos & derivados , Animais , Técnicas Biossensoriais , Miosinas Cardíacas/química , Miosinas Cardíacas/isolamento & purificação , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/química , Bovinos , Galinhas , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Cinética , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Miocárdio/patologia , Miosinas/química , Fosfatos/química , Fosfatos/metabolismo , Coelhos , Ureia/administração & dosagem , Ureia/químicaRESUMO
Cardiac glycosides (CGs) are a class of naturally occurring steroid-like compounds, and members of this class have been in clinical use for more than 1500 years. They have been used in folk medicine as arrow poisons, abortifacients, heart tonics, emetics, and diuretics as well as in other applications. The major use of CGs today is based on their ability to inhibit the membrane-bound Na+/K+-ATPase enzyme, and they are regarded as an effective treatment for congestive heart failure (CHF), cardiac arrhythmia and atrial fibrillation. Furthermore, increasing evidence has indicated the potential cytotoxic effects of CGs against various types of cancer. In this review, we highlight some of the structural features of this class of natural products that are crucial for their efficacy, some methods of isolating these compounds from natural resources, and the structural elucidation tools that have been used. We also describe their physicochemical properties and several modern biotechnological approaches for preparing CGs that do not require plant sources.
Assuntos
Cardenolídeos/química , Cardenolídeos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacologia , Diuréticos/química , Diuréticos/farmacologia , HumanosRESUMO
Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only Food and Drug Administration (FDA)-approved therapy for ischemic stroke. The attempts to develop new treatments for acute ischemic stroke meet costly and spectacularly disappointing results, which requires both long time and high costs, whereas repurposing of safe existing drugs to new indications provides a cost-effective and not time-consuming alternative. Vascular protection is a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases (CVD) and ischemic cerebrovascular disease (ICD). Vascular function related biological processes and pathways maybe the critical associations between CVD and ICD. In this study, a multi-database, in silico target identification, gene function enrichment, and network pharmacology analysis integration approach was proposed and applied to investigate the FDA-approved CVD drugs repurposing for ICD. A list of 119 candidate drugs can be obtained for further investigation of their potential in ICD treatment. As a pleiotropic drug with multi-target, carvedilol was set an example to investigate its promising potential for ICD therapy. Our results indicated that the mode of action of carvedilol for ICD treatment may tightly associated with vascular function regulation and the mechanism is multi-target and multi-signaling pathway related. The disease-disease association network-assisted prediction needs further investigations. In summary, the proposed methods herein may provide a promising alternative to inferring novel disease indications for known drugs.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/genética , Reposicionamento de Medicamentos , Redes Reguladoras de Genes/genética , Isquemia Encefálica/genética , Fármacos Cardiovasculares/química , Bases de Dados Factuais , HumanosRESUMO
Catechin, the name of which is derived from catechu of the extract of Acacia catechu L [...].
Assuntos
Antioxidantes/química , Catequina/química , Chá/química , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/isolamento & purificação , Camellia sinensis/química , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/isolamento & purificação , Catequina/isolamento & purificação , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Isomerismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificaçãoRESUMO
Oral liquid formulations are compounded by pharmacists to meet the needs of patients when a suitable commercially available product is not available. To minimize the errors associated with measuring multiple excipients and to enhance the shelf-life of the medicines, commercially available suspending bases are commonly used. This review aims to compare the stability and shelf life of commercially available extemporaneous formulation to traditional formulation methods. Five (5) databases were searched (Pubmed, SCOPUS, Science direct, Embase, and EBSCOhost). Twelve articles, comprising of seven cardiovascular medications (amiodarone, captopril, carvedilol, furosemide, nifedipine, sotalol, and valsartan), met the study inclusion criteria and were reviewed. Chemical stability of the drugs was comparable between the two formulation methods except for furosemide, captopril, and valsartan. The traditional compounding method provided superior stability for furosemide (90 vs. 14 days) and captopril (50 vs. 14 days), while the commercial vehicles provided superior stability for valsartan (90 vs. 14 days). Physical stability tests indicated that sedimentation does occur with both formulation methods. Microbial studies within the data were lacking and further research can be undertaken in this area. This review highlights the importance of assessing the suitability of compounding ingredients prior to preparation of the formulation.
Assuntos
Fármacos Cardiovasculares/química , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Excipientes/química , Administração Oral , Fármacos Cardiovasculares/administração & dosagem , Armazenamento de Medicamentos , HumanosRESUMO
Although improvements in timing and approach for early reperfusion with acute coronary syndromes have occurred, myocardial injury culminating in a myocardial infarction (MI) remains a common event. Although a multifactorial process, an imbalance between the induction of proteolytic pathways, such as matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinase (TIMPs), has been shown to contribute to this process. In the present study, a full-length TIMP-3 recombinant protein (rTIMP-3) was encapsulated in a specifically formulated hyaluronic acid (HA)-based hydrogel that contained MMP-cleavable peptide cross-links, which influenced the rate of rTIMP-3 release from the HA gel. The effects of localized delivery of this MMP-sensitive HA gel (HAMMPS) alone and containing rTIMP-3 (HAMMPS/rTIMP-3) were examined in terms of the natural history of post-MI remodeling. Pigs were randomized to one of the following three different groups: MI and saline injection (MI/saline group, 100-µl injection at nine injection sites, n = 7), MI and HAMMPS injection (MI/HAMMPS group; 100-µl injection at nine injection sites, n = 7), and MI and HAMMPS/rTIMP-3 injection (MI/HAMMPS/rTIMP-3 group; 20-µg/100-µl injection at nine injection sites, n = 7). Left ventricular (LV) echocardiography was serially performed up to 28 days post-MI. LV dilation, as measured by end-diastolic volume, and the degree of MI wall thinning were reduced by ~50% in the HAMMPS/rTIMP-3 group ( P < 0.05). Furthermore, indexes of heart failure progression post-MI, such as LV filling pressures and left atrial size, were also attenuated to the greatest degree in the HAMMPS/rTIMP-3 group. At 28 days post-MI, HAMMPS/rTIMP-3 caused a relative reduction in the transcriptional profile for myofibroblasts as well as profibrotic pathways, which was confirmed by subsequent histochemistry. In conclusion, these findings suggest that localized delivery of a MMP-sensitive biomaterial that releases a recombinant TIMP holds promise as a means to interrupt adverse post-MI remodeling. NEW & NOTEWORTHY The present study targeted a myocardial matrix proteolytic system, matrix metalloproteinases (MMPs), through the use of a recombinant tissue inhibitor of MMPs incorporated into a MMP-sensitive hydrogel, which was regionally injected using a large animal model of myocardial infarction. Left ventricular geometry and function and indexes of myocardial remodeling were improved with this approach and support the advancement of localized therapeutic strategies that specifically target the myocardial matrix.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Sulfato de Dextrana/química , Portadores de Fármacos , Ventrículos do Coração/efeitos dos fármacos , Ácido Hialurônico/química , Infarto do Miocárdio/tratamento farmacológico , Inibidor Tecidual de Metaloproteinase-3/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Fármacos Cardiovasculares/química , Preparações de Ação Retardada , Sulfato de Dextrana/análogos & derivados , Modelos Animais de Doenças , Composição de Medicamentos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Perfilação da Expressão Gênica/métodos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Ácido Hialurônico/análogos & derivados , Hidrogéis , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Proteínas Recombinantes/administração & dosagem , Inibidor Tecidual de Metaloproteinase-3/química , Transcrição Gênica/efeitos dos fármacos , TranscriptomaRESUMO
In the present study, the interaction of human serum albumin (HSA) with some cardiovascular drugs (CARs) under physiological conditions was investigated via the fluorescence spectroscopic and Fourier transform infrared spectroscopy. The CAR included Captopril, Timolol, Propranolol, Atenolol, and Amiodarone. Cardiovascular drugs can effectively quench the endogenous fluorescence of HSA by static quenching mechanism. The fluorescence quenching of HSA is mainly caused by complex formation of HSA with CAR. The binding reaction of CAR with HSA can be concluded that hydrophobic and electrostatic interactions are the main binding forces in the CAR-HSA system. The results showed that CAR strongly quenched the intrinsic fluorescence of HSA through a static quenching procedure, and nonradiation energy transfer happened within molecules. Fourier transform infrared spectroscopy absorption studies showed that the secondary structure was changed according to the interaction of HSA and CAR. The binding reaction of CAR with HSA can be concluded that hydrophobic and electrostatic interactions are the main binding forces in the CAR-HSA system. The results obtained herein will be of biological significance in pharmacology and clinical medicines.
Assuntos
Fármacos Cardiovasculares/química , Ligação Proteica/efeitos dos fármacos , Albumina Sérica Humana/química , Amiodarona/química , Amiodarona/farmacologia , Atenolol/química , Atenolol/farmacologia , Captopril/química , Captopril/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Propranolol/química , Propranolol/farmacologia , Albumina Sérica Humana/efeitos dos fármacos , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Timolol/química , Timolol/farmacologiaRESUMO
OBJECTIVE: The purpose of this study was to investigate the newly developed drug-coated balloon (DCB) using polyethylene oxide (PEO) as a platform and to compare it directly with a commercially available DCB in a preclinical experimental setting. METHODS: The PEO balloon was characterized for coating morphology and degree of paclitaxel (PAT) crystallinity. PAT tissue levels were then measured up to 30 days in a healthy porcine model (10 swine, 20 vessels) after treatment with either a PEO balloon or a commercially available DCB. An in vitro bench-top model was used to compare the particulates released from the PEO balloon and commercially available DCB. RESULTS: The coating on the PEO balloon was smooth and homogeneous with PAT in its amorphous state. From the porcine survival study, the PAT tissue levels were comparable between PEO balloon and commercially available DCB after 7 days of treatment. Both the PEO balloon and the commercially available DCB retained therapeutic drug up to 30 days. During the simulated in vitro model, the PEO balloon shed significantly fewer particulates that were smaller than those of the commercially available DCB. Most important, the PEO balloon shed 25 times fewer large particulates than the commercially available DCB. CONCLUSIONS: The amorphous PAT in the PEO balloon provided comparable drug tissue retention levels to those of the commercially available DCB and fewer particulates. Thus prepared PEO balloon proved to be safe and effective in the preclinical experimental setting. The clinical outcomes of these findings need further investigation.
Assuntos
Angioplastia com Balão/instrumentação , Fármacos Cardiovasculares/administração & dosagem , Materiais Revestidos Biocompatíveis , Portadores de Fármacos , Artéria Ilíaca/efeitos dos fármacos , Paclitaxel/administração & dosagem , Polietilenoglicóis/química , Dispositivos de Acesso Vascular , Animais , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacocinética , Cristalização , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Artéria Ilíaca/metabolismo , Artéria Ilíaca/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Tamanho da Partícula , Coelhos , Solubilidade , Propriedades de Superfície , Sus scrofa , Distribuição TecidualRESUMO
Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling cardiovascular functions and water balance. Because the in vivo apelin half-life is in the minute range, we aimed to identify metabolically stable apelin-17 (K17F) analogs. We generated P92 by classic chemical substitutions and LIT01-196 by original addition of a fluorocarbon chain to the N terminus of K17F. Both analogs were much more stable in plasma (half-life >24 h for LIT01-196) than K17F (4.6 min). Analogs displayed a subnanomolar affinity for the apelin receptor and behaved as full agonists with regard to cAMP production, ERK phosphorylation, and apelin receptor internalization. Ex vivo, these compounds induced vasorelaxation of rat aortas and glomerular arterioles, respectively, precontracted with norepinephrine and angiotensin II, and increased cardiac contractility. In vivo, after intracerebroventricular administration in water-deprived mice, P92 and LIT01-196 were 6 and 160 times, respectively, more efficient at inhibiting systemic vasopressin release than K17F. Administered intravenously (nmol/kg range) in normotensive rats, these analogs potently increased urine output and induced a profound and sustained decrease in arterial blood pressure. In summary, these new compounds, which favor diuresis and improve cardiac contractility while reducing vascular resistances, represent promising candidates for the treatment of heart failure and water retention/hyponatremic disorders.-Gerbier, R., Alvear-Perez, R., Margathe, J.-F., Flahault, A., Couvineau, P., Gao, J., De Mota, N., Dabire, H., Li, B., Ceraudo, E., Hus-Citharel, A., Esteoulle, L., Bisoo, C., Hibert, M., Berdeaux, A., Iturrioz, X., Bonnet, D., Llorens-Cortes, C. Development of original metabolically stable apelin-17 analogs with diuretic and cardiovascular effects.