RESUMEN
Bacterial infections have emerged as a significant contributor to global mortality and morbidity rates. Herein, we introduce a dual fluorescence "turn-on" supramolecular sensor array composed of three assembled complexes (C1-C3), formed from three positively charged fluorophores (A1-A3) and one cucurbit[7]uril (CB[7]). The ability of this three-element array to simultaneously recognize 10 bacterial species within just 30 s was remarkable, boasting an impressive 100% accuracy. Additionally, the array excelled at distinguishing among various bacterial mixtures and enabled the quantitative detection of common bacterial strains. Notably, it has been skillfully applied to differentiate 10 bacterial samples in urine, achieving excellent differentiation and showcasing promising potential for medical diagnostic applications.
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Hidrocarburos Aromáticos con Puentes , Colorantes Fluorescentes , Imidazoles , Imidazoles/química , Hidrocarburos Aromáticos con Puentes/química , Colorantes Fluorescentes/química , Bacterias/aislamiento & purificación , Humanos , Espectrometría de Fluorescencia , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.
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Antineoplásicos , Proteínas de Ciclo Celular , Bibliotecas de Moléculas Pequeñas , Humanos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Proliferación Celular/efectos de los fármacos , Triazoles/química , Triazoles/farmacología , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Azepinas/farmacología , Azepinas/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Indolizinas/química , Indolizinas/farmacología , Línea Celular Tumoral , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ligandos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Proteínas Nucleares/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas que Contienen Bromodominio , Óxidos N-Cíclicos , Compuestos de PiridinioRESUMEN
BACKGROUNDS: A soluble guanylyl cyclase stimulator vericiguat has been shown to reduce cardiovascular mortality or hospitalization for heart failure in patients with worsening heart failure in the VICTORIA study. However, little is known about the effects of vericiguat on biventricular structure and function. METHODS AND RESULTS: A retrospective analysis of 63 consecutive patients with heart failure with reduced ejection fraction (HFrEF) who were treated with vericiguat was performed. Clinical data and echocardiographic parameters were compared between baseline and follow-up after the initiation of vericiguat. The median follow-up duration was 266 days. Treatment with vericiguat significantly reduced the plasma BNP levels (log-transformed) compared to baseline (2.46 ± 0.51 vs. 2.14 ± 0.58, p < 0.0001). Left ventricular end-diastolic volume index and left ventricular end-systolic volume index were significantly reduced (LVEDVI, 113.5 ± 46.3 vs. 103.6 ± 51.0, p = 0.0056; LVESVI, 82.0 ± 41.9 vs. 72.8 ± 44.7, p = 0.0077; respectively). The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, an indicator of right ventricle-pulmonary artery (RV-PA) coupling, increased significantly after the treatment (0.56 ± 0.29 vs. 0.92 ± 1.09, p < 0.0001). Univariate and multivariate analyses showed that the treatment effects of vericiguat on BNP levels, LV reverse remodeling, and RV-PA coupling were not correlated with the achievement of the quadruple therapy with beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid inhibitors, and sodium-glucose cotransporter-2 inhibitors, nor with worsening heart failure (WHF). CONCLUSION: Treatment with vericiguat improved adverse LV remodeling and RV-PA uncoupling in HFrEF patients. These effects were independent of WHF and achieving the quadruple therapy. Patients with HFrEF may benefit from early initiation of vericiguat to prevent biventricular adverse remodeling.
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Insuficiencia Cardíaca , Arteria Pulmonar , Pirimidinas , Volumen Sistólico , Humanos , Masculino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Femenino , Estudios Retrospectivos , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Anciano , Persona de Mediana Edad , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/diagnóstico por imagen , Resultado del Tratamiento , Pirimidinas/uso terapéutico , Estudios de Seguimiento , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Compuestos Heterocíclicos con 2 AnillosRESUMEN
BACKGROUND: Heart failure (HF) is a chronic-progressive disease. Once established, it is almost impossible to obtain a restitutio ad integrum of the cardiac function, but current strategies aim at slowing down the progression towards the terminal stages of the disease, which inevitably lead to the exitus. On the basis of these considerations, it appears clear that pharmacological interventions applied in this clinical condition should prevent first the development of the disease, by controlling the risk factors for HF thus reducing the onset of the disease, second slowing the disease evolution towards the terminal phases thus containing clinical symptoms and reducing the number of hospitalizations. In this scenario, the add-on therapy with vericiguat seems promising as reported in the VICTORIA study without affecting renal function. Several evidence indicates that renal arterial resistance index (RRI) seems to better reflect cardiovascular damage also in HF patients, thus affecting patients prognosis METHODS: In the present study we have analyzed the effect of vericiguat administration in 27 HF patients specifically evaluating RRI. RESULTS: Vericiguat signicantly reduces RRI. CONCLUSIONS: The findings of the present study seems to indicate that vericiguat, beyond its primary mechanism of action, might offer an additional advantage in HF patients.
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Insuficiencia Cardíaca , Resistencia Vascular , Humanos , Masculino , Femenino , Anciano , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Persona de Mediana Edad , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Arteria Renal/efectos de los fármacos , Pirimidinas/administración & dosificación , Compuestos Heterocíclicos con 2 AnillosRESUMEN
The regulation of the cell membrane potential plays a crucial role in governing the transmembrane transport of various ions and cellular life processes. However, in situ and on-demand modulation of cell membrane potential for ion channel regulation is challenging. Herein, we have constructed a supramolecular assembly system based on water-soluble cationic oligo(phenylenevinylene) (OPV) and cucurbit[7]uril (CB[7]). The controllable disassembly of OPV/4CB[7] combined with the subsequent click reaction provides a step-by-step adjustable surface positive potential. These processes can be employed in situ on the plasma membrane to modulate the membrane potential on-demand for precisely controlling the activation of the transient receptor potential vanilloid 1 (TRPV1) ion channel and up-regulating exogenous calcium-responsive gene expression. Compared with typical optogenetics, electrogenetics, and mechanogenetics, our strategy provides a perspective supramolecular genetics toolbox for the regulation of membrane potential and downstream intracellular gene regulation events.
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Imidazoles , Potenciales de la Membrana , Imidazoles/química , Humanos , Hidrocarburos Aromáticos con Puentes/química , Polivinilos/química , Membrana Celular/metabolismo , Membrana Celular/química , Canales Catiónicos TRPV/metabolismo , Células HEK293 , Calcio/metabolismo , Calcio/química , Canales de Calcio/metabolismo , Canales de Calcio/química , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
A novel CB[6]-based supramolecular assembly [K(ANS)(CB[6])2(DMF)2(H2O)0.5] (1) (CB[6] = cucurbit[6]uril, ANS- = 8-amino-1-naphthalene sulfonic acid ion) was successfully synthesized under solvothermal condition. Performance studies have shown that 1 exhibited excellent chemical stability and recycling performance. Meanwhile, 1 exhibited remarkable potential as a fluorescence sensor for the detection of 2,4,6-trinitrophenol (TNP), 4-nitrophenol (4-NP), and rifampicin (RFP) in both aqueous environments and practical samples. This sensing capability is achieved through fluorescence quenching, which offers fast response times and exceptional sensitivity, with detection limits of 0.19 µM for both TNP and 4-NP, and 0.21 µM for RFP. Even more remarkably, an anti-counterfeiting ink based on 1 and a portable test hydrogel were devised for encrypting information and visually detecting using a smartphone application. This work has the potential to expand the utilization of CB[6]-based materials in optical applications.
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Antibacterianos , Hidrocarburos Aromáticos con Puentes , Imidazoles , Espectrometría de Fluorescencia , Hidrocarburos Aromáticos con Puentes/química , Espectrometría de Fluorescencia/métodos , Imidazoles/química , Antibacterianos/análisis , Antibacterianos/química , Nitrocompuestos/análisis , Nitrocompuestos/química , Límite de Detección , Colorantes Fluorescentes/química , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
In recent years, thanks to the advent of new classes of drugs (ARNI and SGLT2-i), the prognosis of patients suffering from heart failure with reduced ejection fraction (HFrEF) has gradually improved. Nonetheless, there is a residual risk that is not targeted by these therapies. Currently, it is recognized that vericiguat, an oral stimulator of soluble guanylate cyclase (sGC), can restore the NO-sGC-cGMP pathway, through stimulation and activation of sGC, aiming to increase cGMP levels with a reduction in heart failure-related oxidative stress and endothelial dysfunction. Even though the Victoria trial demonstrated that HFrEF patients in treatment with vericiguat showed a 10% reduction in the composite of cardiovascular mortality and rehospitalization for heart failure, statistically significantly reducing heart failure hospitalization, the international guidelines limit its use as a second-line drug for patients with worsening symptomatology despite optimized medical therapy. Furthermore, vericiguat has proved to be a valid therapeutic ally especially in those patients with comorbidities such that they cannot receive the classic four-pillar therapy of HF (in particular renal failure). In this review, the authors report on randomized clinical trials, substudies, and meta-analysis about vericiguat in HFrEF, emphasizing the strengths that would suggest the possible role of vericiguat as the fifth pillar of the HFrEF treatment, acknowledging that there are still gaps in the evidence that need to be clarified.
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Insuficiencia Cardíaca , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/fisiología , Volumen Sistólico/efectos de los fármacos , Pirimidinas/uso terapéutico , Pirrolidinas/uso terapéutico , Resultado del Tratamiento , Guanilil Ciclasa Soluble/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos Heterocíclicos con 2 AnillosRESUMEN
Vericiguat, a soluble guanylate cyclase stimulator known for augmenting cyclic guanosine monophosphate production, has garnered substantial clinical attention in patients with systolic heart failure. Despite its proven efficacy, discerning the specific subset of individuals who can enjoy clinical advantages from vericiguat therapy in contemporary real-world clinical practice, particularly among the individuals undergoing "quadruple medical therapy" comprising administration of a beta-blocker, angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose co-transporter 2 inhibitor, remains an unresolved query. This study involved patients undergoing 3-month vericiguat therapy alongside complete quadruple medical therapy in a contemporary real-world clinical practice. Baseline characteristics associated with the primary outcome, defined as a reduction in serum NT pro-B-type natriuretic peptide (BNP) levels over the 3-month therapeutic duration, were scrutinized. A cohort of 24 patients (median age: 66 years; 20 males) were included. All participants diligently adhered to the 3-month vericiguat therapy in conjunction with the quadruple medical regimen. A higher baseline systolic blood pressure emerged as an independent factor linked to the primary outcome, yielding an adjusted odds ratio of 1.31 (95% confidence interval: 1.03-1.65, P = 0.026) at a threshold of 105 mmHg. This threshold notably stratified the trajectories of serum NT pro-BNP levels during the 3-month vericiguat therapy. In conclusion, preservation of baseline systolic blood pressure emerged as a pivotal determinant for reaping the clinical benefits from mid-term vericiguat therapy among patients with systolic heart failure receiving quadruple medical therapy.
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Quimioterapia Combinada , Insuficiencia Cardíaca Sistólica , Péptido Natriurético Encefálico , Humanos , Masculino , Femenino , Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Insuficiencia Cardíaca Sistólica/fisiopatología , Anciano , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Resultado del Tratamiento , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Fragmentos de Péptidos/sangre , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Neprilisina/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 AnillosRESUMEN
Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.
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Quimioterapia Combinada , Insuficiencia Cardíaca , Ivabradina , Volumen Sistólico , Humanos , Ivabradina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Pirimidinas/uso terapéutico , Urea/análogos & derivados , Urea/uso terapéutico , Benzazepinas/uso terapéutico , Benzazepinas/farmacología , Compuestos Heterocíclicos con 2 AnillosRESUMEN
Host-guest complex has attracted much attention because of their fantastic capability. Accurate prediction of their binding affinity and enthalpy is essential to the rational design of guest molecules. The attach-pull-release (APR) method proposed by Henriksen et al. (J. Chem. Theory Comput., 2015, 11:4377.) shows good prediction capability of binding affinity especially for host-guest system. In order to further evaluate the performance of APR method in practice, we have conducted the calculations on the macrocycle cucurbit [7]urils (CB7) encapsulated with four structurally similar alkaloids (berberine, coptisine, epiberberine and palmatine) with two force fields (GAFF and GAFF2) and three water models (TIP3P, SPC/E and OPC). Compared to the experimental data, the calculation by the combination of GAFF2 and SPC/E force field presents the best performance, of which the Pearson correlation coefficients (R2) is 0.95, and the root-mean-square-deviation is 3.04 kcal/mol. While the predictions from GAFF force field all overestimated the binding affinity, suggesting a systematic error may be involved. Comparison of calculation also indicates that the accuracy of prediction was susceptible to the combination of force field. Therefore, it would be necessary to repeat the simulation with different combination of force fields in practice.
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Alcaloides , Hidrocarburos Aromáticos con Puentes , Simulación de Dinámica Molecular , Termodinámica , Alcaloides/química , Hidrocarburos Aromáticos con Puentes/química , Imidazoles/química , Agua/química , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
KRAS G12D is the most common oncogenic mutation identified in several types of cancer. Therefore, design of inhibitors targeting KRAS G12D represents a promising strategy for anticancer therapy. MRTX1133 is a highly potent inhibitor (approximate experiment Kd ≈ 0.0002 nM) of KRAS G12D and is currently in Phase 1/2 study, however, pathways of the compound binding to KRAS G12D has remained unknown, and the mechanism underlying the complicated dynamic process are challenging to capture experimentally, which hinder the structure-based anti-cancer drug design. Here, using MRTX1133 as a probe, unbiased molecular dynamics (MD) was used to simulate the process of MRTX1133 spontaneously binding to KRAS G12D. In six of 42 independent MD simulation (a total of 99 µs), MRTX1133 was observed to successfully associate with KRAS G12D. The kinetically metastable states refer to the potential pathways of MRTX1133 binding to KRAS G12D were revealed by Markov state models (MSM) analysis. Additionally, 8 key residues that are essential for MRTX1133 recognition and tight binding at the preferred low energy states were identified by MM/GBSA analysis. In sum, this study provides a new perspective on understanding the pathways and mechanism of MRTX1133 binding to KRAS G12D.
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Cadenas de Markov , Simulación de Dinámica Molecular , Unión Proteica , Proteínas Proto-Oncogénicas p21(ras) , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Humanos , Mutación , Compuestos Heterocíclicos con 2 Anillos , NaftalenosRESUMEN
New photostable and bright supramolecular complexes based on cucurbit[7]uril (CB7) host and diketopyrrolopyrole (DPP) guest dyes having two positively charged 4-(trimethylammonio)phenyl groups were prepared and characterized. The dye core displays large Stokes shift (in H2O, abs./emission max. 480/550â nm; ϵ~19 000, τfl>4 ns), strong binding with the host (~560â nM Kd) and a linker affording fluorescence detection of bioconjugates with antibody and nanobody. Combination of protein-functionalized DPP dye with CB7 improves photostability and affords up to 12-fold emission gain. Two-color confocal and stimulated emission depletion (STED) microscopy with 595â nm or 655â nm STED depletion lasers shows that the presence of CB7 not only leads to improved brightness and image quality, but also results in DPP becoming cell-permeable.
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Hidrocarburos Aromáticos con Puentes , Colorantes Fluorescentes , Imidazoles , Pirroles , Imidazoles/química , Hidrocarburos Aromáticos con Puentes/química , Pirroles/química , Colorantes Fluorescentes/química , Humanos , Microscopía Fluorescente , Estructura Molecular , Fluorescencia , Microscopía Confocal , Compuestos Heterocíclicos con 2 Anillos , Cetonas , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
Vericiguat is an oral soluble guanylate cyclase stimulator and enhances the cyclic guanosine monophosphate pathway independently of nitric oxide as well as synergistically in normal- and low-nitric oxide conditions. This review describes the pharmacokinetic and pharmacodynamic profile of vericiguat and summarizes the effect of vericiguat on cardiac electrophysiology and population pharmacokinetic/pharmacodynamic relationships. Vericiguat demonstrates virtually complete absorption and increased exposure with food. Vericiguat has high oral bioavailability when taken with food (93.0%) with dose-proportional pharmacokinetics in healthy volunteers. Vericiguat has slightly less than dose-proportional pharmacokinetics with a slight decrease in bioavailability at higher doses in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Vericiguat is a low-clearance drug, with a half-life of approximately 20 h in healthy volunteers and 30 h in patients with HFrEF. Most drug metabolism is achieved by glucuronidation. Vericiguat has pharmacodynamic effects as expected from its pharmacological mechanism of action (i.e., relaxation of the smooth muscles in the vasculature leading to changes in hemodynamics). In the VICTORIA trial (NCT02861534), which enrolled patients with HFrEF, no meaningful exposure-response relationships for the incidence of symptomatic hypotension or syncope were evident. There were no significant imbalances in the incidence of undesirable hemodynamic-related effects (symptomatic hypotension and syncope) in subgroups with HFrEF defined by sex, age, race, and renal impairment. In addition, most patients achieved the 10-mg target dose per the blood pressure-guided titration regimen. No dose adjustments due to body weight, age, sex, race, or hepatic/renal impairment are necessary in adult patients with HFrEF. Observed and predicted changes in vericiguat exposure when co-administered with perpetrator drugs were small and not clinically meaningful. In addition, vericiguat has low potential as a perpetrator to affect exposure and/or pharmacodynamic effects of drugs commonly prescribed in patients with heart failure; therefore, no dose adjustment of these drugs is required in patients taking vericiguat. There is limited experience on the combined use of vericiguat with long-acting nitrates in patients with HFrEF. The ongoing VICTOR trial (NCT05093933), which is investigating vericiguat in patients with HFrEF, permits the co-administration of long-acting nitrates. Combined use of vericiguat and phosphodiesterase type-5 inhibitors has not been studied in patients with HFrEF and is therefore not recommended because of the potential increased risk for symptomatic hypotension. Vericiguat was not associated with electrophysiological abnormalities in preclinical and clinical studies up to the approved dose of 10 mg at steady state. Vericiguat is approved for the treatment of recently decompensated patients with worsening HFrEF. Vericiguat's safety and efficacy profile in patients with HFrEF will be further characterized by the VICTOR trial (NCT05093933) in adults without recent decompensation and in a pediatric population with HF due to left ventricular systolic dysfunction (VALOR trial, NCT05714085).
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Insuficiencia Cardíaca , Humanos , Administración Oral , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Semivida , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Compuestos Heterocíclicos con 2 Anillos , Pirimidinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Pirimidinas/efectos adversos , Ensayos Clínicos como AsuntoRESUMEN
OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.
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Artritis Reumatoide , Azetidinas , Teorema de Bayes , Inhibidores de las Cinasas Janus , Metaanálisis en Red , Piperidinas , Pirimidinas , Humanos , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Azetidinas/uso terapéutico , Azetidinas/efectos adversos , Purinas/uso terapéutico , Purinas/efectos adversos , Pirroles/uso terapéutico , Pirroles/efectos adversos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Niacinamida/efectos adversos , Benzamidas/uso terapéutico , Benzamidas/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Triazoles/uso terapéutico , Triazoles/efectos adversos , Triazoles/administración & dosificación , Adamantano/análogos & derivados , Piridinas , Valina/análogos & derivadosRESUMEN
DNA hydrogels have been demonstrated with the advantages of good stability, easy modification, and extraordinary biocompatibility, which enables their great application prospects in biosensing, tissue engineering, and biomedicine. Based on the host-guest recognition properties of cucurbit[8]uril (CB[8]), we proposed a general method for constructing functional supramolecular DNA nanogels. Guest molecules have been conjugated into the DNA building units, which could be further crosslinked with CB[8] to construct supramolecular DNA nanogels. At the same time, the aptamer has also been modified into the hydrogel network to achieve cell targeting. These supramolecular DNA nanogels have been demonstrated with a controllable size and multiple stimuli responses, in addition to the excellent biocompatibility, stability and good targeting drug transport ability. Such a host-guest based strategy will provide a molecular library as a "toolbox" for the functionalization of DNA nanogels.
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ADN , ADN/química , Humanos , Nanogeles/química , Sistemas de Liberación de Medicamentos , Imidazoles/química , Hidrogeles/química , Hidrocarburos Aromáticos con Puentes/química , Portadores de Fármacos/química , Materiales Biocompatibles/química , Materiales Biocompatibles/síntesis química , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
Pure organic phosphorescence resonance energy transfer is a research hotspot. Herein, a single-molecule phosphorescence resonance energy transfer system with a large Stokes shift of 367 nm and near-infrared emission is constructed by guest molecule alkyl-bridged methoxy-tetraphenylethylene-phenylpyridines derivative, cucurbit[n]uril (n = 7, 8) and ß-cyclodextrin modified hyaluronic acid. The high binding affinity of cucurbituril to guest molecules in various stoichiometric ratios not only regulates the topological morphology of supramolecular assembly but also induces different phosphorescence emissions. Varying from the spherical nanoparticles and nanorods for binary assemblies, three-dimensional nanoplate is obtained by the ternary co-assembly of guest with cucurbit[7]uril/cucurbit[8]uril, accompanying enhanced phosphorescence at 540 nm. Uncommonly, the secondary assembly of ß-cyclodextrin modified hyaluronic acid and ternary assembly activates a single intramolecular phosphorescence resonance energy transfer process derived from phenyl pyridines unit to methoxy-tetraphenylethylene function group, enabling a near-infrared delayed fluorescence at 700 nm, which ultimately applied to mitochondrial targeted imaging for cancer cells.
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Transferencia Resonante de Energía de Fluorescencia , Ácido Hialurónico , Imidazoles , beta-Ciclodextrinas , beta-Ciclodextrinas/química , Humanos , Ácido Hialurónico/química , Imidazoles/química , Transferencia Resonante de Energía de Fluorescencia/métodos , Hidrocarburos Aromáticos con Puentes/química , Nanopartículas/química , Estilbenos/química , Piridinas/química , Células HeLa , Nanotubos/química , Mitocondrias/metabolismo , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
Gene expression technology has become an indispensable tool for elucidating biological processes and developing biotechnology. Cell-free gene expression (CFE) systems offer a fundamental platform for gene expression-based technology, in which the reversible and programmable control of transcription can expand its use in synthetic biology and medicine. This study shows that CFE can be controlled via the host-guest interaction of cucurbit[7]uril (CB[7]) with N6-guest-modified adenosines. These adenosine derivatives were conveniently incorporated into the DNA strand using a post-synthetic approach and formed a selective and stable base pair with complementary thymidine in DNA. Meanwhile, alternate addition of CB[7] and the exchanging guest molecule induced the reversible formation of a duplex structure through the formation and dissociation of a bulky complex on DNA. The kinetics of the reversibility was fine-tuned by changing the size of the modified guest moieties. When incorporated into a specific region of the T7 promoter sequence, the guest-modified adenosines enabled tight and reversible control of in vitro transcription and protein expression in the CFE system. This study marks the first utility of the host-guest interaction for gene expression control in the CFE system, opening new avenues for developing DNA-based technology, particularly for precise gene therapy and DNA nanotechnology.
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Adenosina , Hidrocarburos Aromáticos con Puentes , ADN , Imidazoles , Imidazoles/química , Adenosina/química , Adenosina/análogos & derivados , Hidrocarburos Aromáticos con Puentes/química , ADN/química , Sistema Libre de Células , Regiones Promotoras Genéticas , Expresión Génica , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , ImidazolidinasRESUMEN
Heart failure with reduced ejection fraction (HFrEF) represents an emerging epidemic, particularly affecting frail, older, and multimorbid patients. Current therapy for the management of HFrEF includes four different classes of disease-modifying drugs, commonly referred to as 'four pillars', which target the neurohormonal system that is overactivated in HF and contributes to its progression. These classes of drugs include ß-blockers, inhibitors of the renin-angiotensin-aldosterone system, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Unfortunately, these agents cannot be administered as frequently as needed to older patients because of poor tolerability and comorbidities. In addition, although these drugs have dramatically increased the survival expectations of patients with HF, their residual risk of rehospitalization and death at 5 years remains considerable. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, was reported to exert beneficial effects in patients with worsening HF, including older subjects, reducing the rate of both hospitalizations and deaths, with limited adverse effects and drug interaction. In this narrative review, we present the current state of art on vericiguat, with a particular focus on elderly and frail patients.
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Insuficiencia Cardíaca , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/efectos de los fármacos , Anciano , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Compuestos Heterocíclicos con 2 AnillosRESUMEN
Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The ß-cyclodextrin (ß-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by ß-CD, due to the low binding constant between PX and ß-CD (â¼100 M-1). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between ß-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (Cmax) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile.