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Fármacos Anti-VIH , Farmacorresistencia Viral , Emtricitabina , Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Emtricitabina/uso terapéutico , Piridonas/uso terapéutico , Piperazinas/uso terapéutico , Tenofovir/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Hepatitis B/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/uso terapéutico , Masculino , Femenino , AmidasRESUMEN
BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.
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Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Tenofovir , Carga Viral , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Femenino , Adulto , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Carga Viral/efectos de los fármacos , Emtricitabina/uso terapéutico , VIH-1/efectos de los fármacos , VIH-1/genética , Adenina/análogos & derivados , Adenina/uso terapéutico , Piperazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Darunavir/uso terapéutico , Alanina/uso terapéutico , Alanina/análogos & derivados , Resultado del Tratamiento , ARN Viral , Sulfonamidas/uso terapéutico , Persona de Mediana Edad , Cobicistat/uso terapéutico , Reino Unido , Combinación de Medicamentos , Amidas , PiridonasRESUMEN
RATIONALE: Anesthetics are widely used for optimizing surgical conditions, postoperative pain management, and treating various chronic pain conditions. Tetracaine and decamethonium are representative drugs of local anesthetics and neuromuscular blocking agents, respectively. However, overdose and toxicity of the drugs always lead to serious adverse events. Thus, there is a strong demand for effective antidotes. METHODS: The binding interactions of amide naphthotubes with tetracaine and decamethonium were systematically studied using 1H NMR, ITC, and DFT calculations. The antidotal effects of amide naphthotube to tetracaine toxicity were assessed in vitro and in vivo, and the mechanism of detoxification was explored at a cellular level. Additionally, mouse models were established to evaluate the reversal activities of amide naphthotube on decamethonium-induced mortality and muscle relaxation, and the reversal mechanism was investigated through pharmacokinetic experiments. RESULTS: We have demonstrated that the anti-isomer of amide naphthotube exhibits significant binding affinities towards tetracaine (K a = 1.89×107 M-1) and decamethonium (K a = 1.01×107 M-1) in water. The host displayed good biocompatibility both in vitro and in vivo. The administration of amide naphthotube following tetracaine overdose in mouse models notably increased the overall survival rate, indicating its effective antidotal properties. The host could reverse the tetracaine-induced Na+ channels blockage at the cellular level. Moreover, the injection of amide naphthotube also reversed the mortality and paralysis induced by decamethonium in mouse models following a pharmacokinetic mechanism. CONCLUSION: An emerging artificial receptor, amide naphthotube, has strong binding affinities towards tetracaine and decamethonium. It functions as a supramolecular antidote for tetracaine poisoning and a reversal agent for decamethonium by selectively sequestering these compounds in vivo.
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Antídotos , Tetracaína , Animales , Tetracaína/farmacología , Tetracaína/química , Ratones , Antídotos/farmacología , Antídotos/química , Amidas/química , Amidas/farmacología , Masculino , Anestésicos Locales/farmacología , Anestésicos Locales/química , Humanos , Bloqueantes Neuromusculares/química , Bloqueantes Neuromusculares/farmacologíaRESUMEN
As an important small organic molecule, cyclopropane is widely used in drug design. In this paper, fifty-three amide derivatives containing cyclopropane were designed and synthesized by introducing amide groups and aryl groups into cyclopropane through the active splicing method, and their antibacterial and antifungal activities were evaluated in vitro. Among them, thirty-five compounds were new compounds, and eighteen compounds were known compounds (F14, F15, F18, F20-F26, F36, and F38-F44). Bioassay results disclosed that four, three, and nine of the compounds showed moderate activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, respectively. Three compounds were sensitive to Candida albicans, with excellent antifungal activity (MIC80 = 16 µg/mL). The molecular docking results show that compounds F8, F24, and F42 have good affinity with the potential antifungal drug target CYP51 protein.
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Amidas , Antifúngicos , Candida albicans , Ciclopropanos , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Staphylococcus aureus , Ciclopropanos/farmacología , Ciclopropanos/química , Ciclopropanos/síntesis química , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Candida albicans/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Escherichia coli/efectos de los fármacos , Relación Estructura-Actividad , Antiinfecciosos/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Estructura MolecularRESUMEN
Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFß inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.
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Dioxoles , Fibrosis , Infarto del Miocardio , Piridinas , Ingeniería de Tejidos , Animales , Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Infarto del Miocardio/metabolismo , Infarto del Miocardio/genética , Ratones , Humanos , Piridinas/farmacología , Piridinas/uso terapéutico , Ingeniería de Tejidos/métodos , Dioxoles/farmacología , Dioxoles/uso terapéutico , Miocardio/patología , Miocardio/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Modelos Animales de Enfermedad , Transducción de Señal , Masculino , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Remodelación Ventricular/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Corazón/fisiopatología , Corazón/efectos de los fármacos , AmidasRESUMEN
In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 µg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 µg/mL and against the E. faecalis strain with a MIC of 0.125 µg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.
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Antibacterianos , Girasa de ADN , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Inhibidores de Topoisomerasa II , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Humanos , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/síntesis química , Girasa de ADN/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Enterococcus faecalis/efectos de los fármacos , Pirroles/farmacología , Pirroles/química , Pirroles/síntesis química , Amidas/farmacología , Amidas/química , Amidas/síntesis química , Escherichia coli/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacosRESUMEN
Monkeypox (MPXV) is one of the infectious viruses which caused morbidity and mortality problems in these years. Despite its danger to public health, there is no approved drug to stand and handle MPXV. On the other hand, drug repurposing is a promising screening method for the low-cost introduction of approved drugs for emerging diseases and viruses which utilizes computational methods. Therefore, drug repurposing is a promising approach to suggesting approved drugs for the MPXV. This paper proposes a computational framework for MPXV antiviral prediction. To do this, we have generated a new virus-antiviral dataset. Moreover, we applied several machine learning and one deep learning method for virus-antiviral prediction. The suggested drugs by the learning methods have been investigated using docking studies. The target protein structure is modeled using homology modeling and, then, refined and validated. To the best of our knowledge, this work is the first work to study deep learning methods for the prediction of MPXV antivirals. The screening results confirm that Tilorone, Valacyclovir, Ribavirin, Favipiravir, and Baloxavir marboxil are effective drugs for MPXV treatment.
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Antivirales , Aprendizaje Profundo , Reposicionamiento de Medicamentos , Monkeypox virus , Antivirales/farmacología , Monkeypox virus/efectos de los fármacos , Reposicionamiento de Medicamentos/métodos , Pirazinas/farmacología , Simulación del Acoplamiento Molecular , Dibenzotiepinas , Amidas/farmacología , Ribavirina/farmacología , Triazinas/farmacología , Mpox/tratamiento farmacológico , Mpox/virología , Humanos , Aprendizaje Automático , Morfolinas , PiridonasRESUMEN
This narrative review provides an overview of current knowledge on the impact of nutritional strategies on chronic craniofacial pain associated with temporomandibular disorders (TMDs). Individuals experiencing painful TMDs alter their dietary habits, avoiding certain foods, possibly due to chewing difficulties, which might lead to nutrient deficiencies. Our literature investigation revealed that the causal links between nutritional changes and craniofacial pain remain unclear. However, clinical and preclinical studies suggest that nutraceuticals, including vitamins, minerals, polyphenols, omega-3 fatty acids, isoprenoids, carotenoids, lectins, polysaccharides, glucosamines, and palmitoylethanolamides, could have beneficial effects on managing TMDs. This is described in 12 clinical and 38 preclinical articles since 2000. Clinical articles discussed the roles of vitamins, minerals, glucosamine, and palmitoylethanolamides. The other nutraceuticals were assessed solely in preclinical studies, using TMD models, mostly craniofacial inflammatory rodents, with 36 of the 38 articles published since 2013. Our investigation indicates that current evidence is insufficient to assess the efficacy of these nutraceuticals. However, the existing data suggest potential for therapeutic intervention in TMDs. Further support from longitudinal and randomized controlled studies and well-designed preclinical investigations is necessary to evaluate the efficacy of each nutraceutical intervention and understand their underlying mechanisms in TMDs.
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Dolor Crónico , Suplementos Dietéticos , Dolor Facial , Trastornos de la Articulación Temporomandibular , Trastornos de la Articulación Temporomandibular/dietoterapia , Humanos , Dolor Facial/dietoterapia , Dolor Facial/etiología , Dolor Crónico/dietoterapia , Dolor Crónico/terapia , Animales , Ácidos Grasos Omega-3/administración & dosificación , Glucosamina/administración & dosificación , Vitaminas/administración & dosificación , Amidas , Etanolaminas , Ácidos PalmíticosRESUMEN
Prenatal exposure to dibutyl phthalate (DBP) has been reported to cause erectile dysfunction (ED) in adult offspring rats. However, its underlying mechanisms are not fully understood. Previously, we found that DBP activates the RhoA/ROCK pathway in the male reproductive system. This study investigated how prenatal exposure to DBP activates the RhoA/ROCK signalling pathway, leading to ED in male rat offspring. Pregnant rats were stratified into DBP-exposed and NC groups, with the exposed group receiving 750 milligrams per kilogram per day (mg/kg/day) of DBP through gavage from days 14-18 of gestation. DBP exposure activated the RhoA/ROCK pathway in the penile corpus cavernosum (CC) of descendants, causing smooth muscle cell contraction, fibrosis, and apoptosis, all of which contribute to ED. In vitro experiments confirmed that DBP induces apoptosis and RhoA/ROCK pathway activation in CC smooth muscle cells. Treatment of DBP-exposed offspring with the ROCK inhibitor Y-27632 for 8 weeks significantly improved smooth muscle cell condition, erectile function, and reduced fibrosis. Thus, prenatal DBP exposure induces ED in offspring through RhoA/ROCK pathway activation, and the ROCK inhibitor Y-27632 shows potential as an effective treatment for DBP-induced ED.
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Apoptosis , Dibutil Ftalato , Disfunción Eréctil , Efectos Tardíos de la Exposición Prenatal , Ratas Sprague-Dawley , Transducción de Señal , Quinasas Asociadas a rho , Animales , Dibutil Ftalato/toxicidad , Masculino , Quinasas Asociadas a rho/metabolismo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Embarazo , Femenino , Transducción de Señal/efectos de los fármacos , Disfunción Eréctil/inducido químicamente , Disfunción Eréctil/metabolismo , Ratas , Apoptosis/efectos de los fármacos , Proteína de Unión al GTP rhoA/metabolismo , Pene/efectos de los fármacos , Pene/metabolismo , Fibrosis , Piridinas/farmacología , Piridinas/toxicidad , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Amidas , Proteínas de Unión al GTP rhoRESUMEN
The main focus of the present research is to design network hydrogels derived from natural polymers to promote a sustainable future. Multifunctional hydrogels were prepared by combining sterculia gum (SG), phosphorester -cyclic amide polymers for bio-medical applications including drug delivery (DD). The antibiotic drug ceftriaxone was incorporated into hydrogels to enhance wound healing potential. The surface morphology of copolymers was investigated by using FESEM and AFM techniques. FTIR and 13C NMR spectroscopic techniques provided insight into the formation of network structures. In FTIR analysis, distinctive bands were identified: at 1649 cm-1 attributed to CO stretching of the cyclic amide of PVP, at 1147 cm-1 and 974 cm-1 representing PO stretching and P-O-C of poly(BMEP), respectively. In the 13C NMR spectrum, a prominent peak at 63.272 ppm revealed the presence of (O-CH2) linkage of poly(BMEP). XRD demonstrated amorphous characteristics of hydrogels. The interactions of copolymer with blood, bio-membrane and encapsulated drug illustrated their biocompatibility, bio-adhesion and controlled DD properties. The dressings expressed a hemolytic index value of 2.58 ± 0.03 %. The hydrogels exhibited mucoadhesive character, revealed from the adhesion force of 50.0 ± 5 mN needed to separate polymer dressing from the mucosa. Dressings exhibited antioxidant properties and displayed 33.73 ± 0.3 % radical scavenging in the DPPH assay. Protein adsorption test of copolymer illustrated 9.48 ± 0.970 % of albumin adsorption. The tensile strength of the dressing was found 0.54 ± 0.03 N mm-2 while the burst strength 9.92 ± 0.27 N was observed. The sustained release of the drug was provided by supra-molecular interactions. Drug release followed a non-Fickian diffusion mechanism and the release profile was best described by the Higuchi kinetic model. Additionally, hydrogel dressings revealed permeability to H2O vapors and O2 and antimicrobial activity. These findings suggest the suitability of sterculia gum-based hydrogels for DD uses.
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Hidrogeles , Sterculia , Hidrogeles/química , Hidrogeles/síntesis química , Sterculia/química , Amidas/química , Humanos , Materiales Biocompatibles/química , Portadores de Fármacos/química , Liberación de Fármacos , Antibacterianos/química , Antibacterianos/farmacología , Sistemas de Liberación de Medicamentos , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/síntesis químicaRESUMEN
Palmitoylethanolamide (PEA) is a highly lipophilic molecule with low solubility, making absorption difficult. Recent techniques like micronisation, ultra-micronisation and combining PEA with solvents have improved their bioavailability and stability. Our study analysed particle size differences and absorption kinetics using specific solvents (PEAΩ and PEA DynoΩ) over time (0.5 h-6 h) in a dose-dependent manner (200 mg-1800 mg). The results showed that PEAΩ and PEA DynoΩ achieved 82-63% absorption at 3 h, compared to 30-60% for micronised, ultra-micronised PEA and a commercial product, highlighting the optimal dose range of 300 mg-600 mg. In addition, a 3D model of the peripheral nerve was utilised to explain the efficacy after gut passage and support the most effective dose (300 mg or 600 mg) achieved at the gut level. PEAΩ and PEA DynoΩ, which are associated with better intestinal bioavailability compared to PEA-micronised, PEA ultra-micronised and a commercial product, have allowed not only a reduction in the inflammatory context but also an improvement of peripheral nerve well-being by increasing specific markers like MPZ (26-36% vs. 8-15%), p75 (25-32% vs. 13-16%) and NRG1 (22-29.5% vs. 11-14%). These results highlight the potential of advanced PEA formulations to overcome solubility challenges and maintain in vitro efficacy, modulating peripheral nerve well-being.
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Amidas , Etanolaminas , Ácidos Palmíticos , Ácidos Palmíticos/química , Ácidos Palmíticos/farmacología , Etanolaminas/química , Amidas/química , Humanos , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Suplementos Dietéticos , Animales , Nervios Periféricos/efectos de los fármacos , Tamaño de la PartículaRESUMEN
Fibromyalgia is characterized by chronic widespread pain, fatigue, and sleep disturbances. Recent theories attribute fibromyalgia to central sensitization syndromes, suggesting altered nociceptive processing leads to hyperalgesia and allodynia. Standardized effective treatments are currently lacking. Palmitoylethanolamide and melatonin have shown pain-relieving effects in chronic pain conditions, including fibromyalgia, with excellent safety. Our open-label study assessed the impact of a daily combination of 1200 mg of palmitoylethanolamide and 0.2 mg of melatonin on pain, sleep, and quality of life in fibromyalgia patients. Between June 2023 and March 2024, 50 patients (2016 ACR criteria) were treated and evaluated at baseline, 1 month, 3 months, and 4 months (1 month discontinuation). The assessments included VAS for pain, ISI for insomnia, HAQ for health assessments, and a tender points evaluation. The patients, averaging 54.12 years old with a 3:1 female-to-male ratio, showed significant improvements in VAS, ISI, and HAQ scores relative to their own baselines and a reduction in tender points at 1 and 3 months, which was maintained at 4 months. No adverse events were reported. This study is the first to demonstrate the efficacy of a palmitoylethanolamide and melatonin combination as an adjunct therapy in fibromyalgia, highlighting its potential to reduce pain and improve sleep and quality of life.
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Amidas , Combinación de Medicamentos , Etanolaminas , Fibromialgia , Melatonina , Ácidos Palmíticos , Calidad de Vida , Humanos , Melatonina/administración & dosificación , Fibromialgia/tratamiento farmacológico , Femenino , Ácidos Palmíticos/administración & dosificación , Ácidos Palmíticos/uso terapéutico , Persona de Mediana Edad , Proyectos Piloto , Masculino , Etanolaminas/administración & dosificación , Amidas/administración & dosificación , Adulto , Anciano , Sueño/efectos de los fármacos , Resultado del Tratamiento , Dimensión del Dolor , Manejo del Dolor/métodos , Dolor Crónico/tratamiento farmacológicoRESUMEN
BACKGROUND: It was reported that either shorter programmed intermittent epidural bolus (PIEB) intervals or high-speed bolus can produce more extensive epidural spread. We hypothesized that a combination of shortened time interval and increased speed of epidural bolus might further improve analgesic effect and therefore reduce the hourly volume for epidural labour analgesia. METHODS: This double-blind dose-finding study used a biased coin up-and-down sequential allocation method to determine the 90% effective bolus volume of ropivacaine combined with sufentanil while using the push pump at a rate of 400 mL/hr and interval of 30 min to provide effective analgesia without breakthrough pain. We used 0.1% ropivacaine with 0.4 µg/mL sufentanil, with bolus volumes ranging from 3 to 6 mL. The first patient was assigned a volume of 3 mL, and the remaining volumes were assigned according to the biased coin-up-and-down method. RESULTS: The estimated 90% effective volume (EV90) of ropivacaine combined with sufentanil for epidural labour analgesia at a time interval of 30 min was 4.88 mL (95% confidence interval 4.83-5.38). CONCLUSIONS: The optimum bolus volume of ropivacaine with sufentanil while using push pump at a time interval of 30 min is approximately 5 mL. It could probably further reduce the hourly bolus volume for epidural labour analgesia.
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Amidas , Analgesia Epidural , Analgesia Obstétrica , Anestésicos Locales , Ropivacaína , Sufentanilo , Humanos , Ropivacaína/administración & dosificación , Sufentanilo/administración & dosificación , Método Doble Ciego , Femenino , Analgesia Epidural/métodos , Embarazo , Adulto , Anestésicos Locales/administración & dosificación , Analgesia Obstétrica/métodos , Amidas/administración & dosificación , Analgésicos Opioides/administración & dosificación , Relación Dosis-Respuesta a Droga , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Liver disease imposes a significant medical burden that persists due to a shortage of liver donors and an incomplete understanding of liver disease progression. Hepatobiliary organoids (HBOs) could provide an in vitro mini-organ model to increase the understanding of the liver and may benefit the development of regenerative medicine. METHODS: In this study, we aimed to establish HBOs with bile duct (BD) structures and mature hepatocytes (MHs) using human chemically induced liver progenitor cells (hCLiPs). hCLiPs were induced in mature cryo-hepatocytes using a small-molecule cocktail of TGF-ß inhibitor (A-83-01, A), GSK3 inhibitor (CHIR99021, C), and 10% FBS (FAC). HBOs were then formed by seeding hCLiPs into ultralow attachment plates and culturing them with a combination of small molecules of Rock-inhibitor (Y-27632) and AC (YAC). RESULTS: These HBOs exhibited bile canaliculi of MHs connected to BD structures, mimicking bile secretion and transportation functions of the liver. The organoids showed gene expression patterns consistent with both MHs and BD structures, and functional assays confirmed their ability to transport the bile analogs of rhodamine-123 and CLF. Functional patient-specific HBOs were also successfully created from hCLiPs sourced from cirrhotic liver tissues. CONCLUSIONS: This study demonstrated the potential of human HBOs as an efficient model for studying hepatobiliary diseases, drug discovery, and personalized medicine.
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Conductos Biliares , Hígado , Organoides , Piridinas , Células Madre , Humanos , Organoides/metabolismo , Organoides/efectos de los fármacos , Conductos Biliares/metabolismo , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Células Madre/citología , Piridinas/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/citología , Pirimidinas/farmacología , Amidas/farmacología , Diferenciación Celular/efectos de los fármacos , Pirazoles , TiosemicarbazonasRESUMEN
Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.
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Antineoplásicos , Ácidos Cafeicos , Alcohol Feniletílico , Humanos , Ácidos Cafeicos/farmacología , Ácidos Cafeicos/química , Ácidos Cafeicos/síntesis química , Células HeLa , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacología , Alcohol Feniletílico/química , Alcohol Feniletílico/síntesis química , Agua/química , Línea Celular Tumoral , Amidas/farmacología , Amidas/química , Supervivencia Celular/efectos de los fármacosRESUMEN
M64HCl, which has drug-like properties, is a water-soluble Focal Adhesion Kinase (FAK) activator that promotes murine mucosal healing after ischemic or NSAID-induced injury. Since M64HCl has a short plasma half-life in vivo (less than two hours), it has been administered as a continuous infusion with osmotic minipumps in previous animal studies. However, the effects of more transient exposure to M64HCl on monolayer wound closure remained unclear. Herein, we compared the effects of shorter M64HCl treatment in vitro to continuous treatment for 24 hours on monolayer wound closure. We then investigated how long FAK activation and downstream ERK1/2 activation persist after two hours of M64HCl treatment in Caco-2 cells. M64HCl concentrations immediately after washing measured by mass spectrometry confirmed that M64HCl had been completely removed from the medium while intracellular concentrations had been reduced by 95%. Three-hour and four-hour M64HCl (100 nM) treatment promoted epithelial sheet migration over 24 hours similar to continuous 24-hour exposure. 100nM M64HCl did not increase cell number. Exposing cells twice with 2-hr exposures of M64HCl during a 24-hour period had a similar effect. Both FAK inhibitor PF-573228 (10 µM) and ERK kinase (MEK) inhibitor PD98059 (20 µM) reduced basal wound closure in the absence of M64HCl, and each completely prevented any stimulation of wound closure by M64HCl. Rho kinase inhibitor Y-27632 (20 µM) stimulated Caco-2 monolayer wound closure but no further increase was seen with M64HCl in the presence of Y-27632. M64HCl (100 nM) treatment for 3 hours stimulated Rho kinase activity. M64HCl decreased F-actin in Caco-2 cells. Furthermore, a two-hour treatment with M64HCl (100 nM) stimulated sustained FAK activation and ERK1/2 activation for up to 16 and hours 24 hours, respectively. These results suggest that transient M64HCl treatment promotes prolonged intestinal epithelial monolayer wound closure by stimulating sustained activation of the FAK/ERK1/2 pathway. Such molecules may be useful to promote gastrointestinal mucosal repair even with a relatively short half-life.
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Mucosa Intestinal , Cicatrización de Heridas , Humanos , Cicatrización de Heridas/efectos de los fármacos , Células CACO-2 , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Movimiento Celular/efectos de los fármacos , Piridinas/farmacología , Animales , Amidas/farmacologíaRESUMEN
Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.
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Inhibidores de la Angiogénesis , Antineoplásicos , Apoptosis , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Moduladores de Tubulina , Tubulina (Proteína) , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Humanos , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Tubulina (Proteína)/metabolismo , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/síntesis química , Apoptosis/efectos de los fármacos , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Descubrimiento de Drogas , Animales , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Ratones , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacosRESUMEN
During the pandemic, Favipiravir (FVP) and Molnupiravir (MPV) have been widely used for COVID-19 treatment, leading to their presence in the environment. A green synchronous spectrofluorimetric method was developed to simultaneously detect them in environmental water, human plasma, and binary mixtures. Maximum fluorescence intensity was achieved at pH 8, with MPV exhibiting two peaks at 300 and 430 nm, and FVP showing one peak at 430 nm. A fluorescence subtraction method effectively removed interference, enabling direct determination of MPV at 300 nm and FVP at 430 nm. The method showed linearity within 2-13 ng/mL for FVP and 50-600 ng/mL for MPV, with recoveries of 100.35% and 100.12%, respectively. Limits of detection and quantification were 0.19 and 0.57 ng/mL for FVP and 10.52 and 31.88 ng/mL for MPV. Validation according to ICH and FDA guidelines yielded acceptable results. The method demonstrated good recoveries of FVP and MPV in pharmaceuticals, tap water and Nile water (99.62% ± 0.96% and 99.69% ± 0.64%) as per ICH guidelines and spiked human plasma (94.87% ± 2.111% and 94.79% ± 1.605%) following FDA guidelines, respectively. Its environmental friendliness was assessed using Green Analytical Procedure Index (GAPI) and the Analytical Greenness Metric (AGREE) tools.
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Amidas , Antivirales , Pirazinas , Espectrometría de Fluorescencia , Pirazinas/análisis , Pirazinas/sangre , Pirazinas/química , Amidas/análisis , Amidas/química , Amidas/sangre , Espectrometría de Fluorescencia/métodos , Humanos , Antivirales/análisis , Antivirales/sangre , Uridina/análisis , Uridina/sangre , Límite de Detección , Citidina/análisis , Citidina/sangre , Citidina/análogos & derivados , Tratamiento Farmacológico de COVID-19 , Mercaptopurina/sangre , Mercaptopurina/análisis , SARS-CoV-2 , HidroxilaminasRESUMEN
Herein, we report the synthesis of new compounds with demonstrated anticancer properties based on the 2,3,4,9-tetrahydro-1H-carbazole scaffold. The Fischer indolization method was used to close the heterocyclic motif. The synthesis method's scope and limitations were thoroughly assessed through a series of experiments. Biological assays revealed that two thioamide compounds exhibited significant anticancer activity against MCF-7, HTC116, and A596 cell lines. Comprehensive in vitro profiling included evaluation of cell cytotoxicity, morphological alterations, colony formation and cell adhesion in 3D cultures, cell cycle analysis, DNA damage induction, impact on mitochondria, and apoptosis. Ex ovo studies further demonstrated these compounds' potential to inhibit angiogenic processes. Our results indicate that the newly developed compounds activate processes leading to DNA damage and disruption of mitochondrial function.
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Antineoplásicos , Apoptosis , Carbazoles , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Tioamidas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Carbazoles/farmacología , Carbazoles/química , Carbazoles/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Tioamidas/química , Tioamidas/farmacología , Tioamidas/síntesis química , Estructura Molecular , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Relación Dosis-Respuesta a Droga , Línea Celular TumoralRESUMEN
BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.