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This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.
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Monoterpenos Acíclicos , Analgésicos , Capsaicina , Codeína , Dolor Facial , Dimensión del Dolor , Terpenos , Animales , Codeína/farmacología , Dolor Facial/inducido químicamente , Dolor Facial/tratamiento farmacológico , Monoterpenos Acíclicos/farmacología , Masculino , Dimensión del Dolor/efectos de los fármacos , Capsaicina/farmacología , Terpenos/farmacología , Analgésicos/farmacología , Ratones , Factores de Tiempo , Modelos Animales de Enfermedad , Reproducibilidad de los Resultados , Formaldehído , Ácido Glutámico , Resultado del Tratamiento , Nocicepción/efectos de los fármacos , Análisis de Varianza , Estadísticas no Paramétricas , Conducta Animal/efectos de los fármacosRESUMEN
This study investigated fluid removal strategies for critically ill patients with fluid overload on mechanical ventilation. Traditionally, a negative fluid balance (FB) is aimed for. However, this approach can have drawbacks. Here, we compared a new approach, namely removing fluids until patients become fluid responsive (FR) to the traditional empiric negative balance approach. Twelve patients were placed in each group (n = 24). FR assessment was performed using passive leg raising (PLR). Both groups maintained stable blood pressure and heart function during fluid management. Notably, the FR group weaned from the ventilator significantly faster than negative FB group (both for a spontaneous breathing trial (14 h vs. 36 h, p = 0.031) and extubation (26 h vs. 57 h, p = 0.007); the difference in total ventilator time wasn't statistically significant (49 h vs. 62 h, p = 0.065). Additionally, FR group avoided metabolic problems like secondary alkalosis and potential hypokalemia seen in the negative FB group. FR-guided fluid-removal in fluid overloaded mechanically ventilated patients was a feasible, safe, and maybe superior strategy in facilitating weaning and disconnection from mechanical ventilation than negative FB-driven fluid removal. FR is a safe endpoint for optimizing cardiac function and preventing adverse consequences during fluid removal.
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BACKGROUND: Norepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care. METHODS: We conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared. RESULTS: 4086 eligible patients with septic shock were identified, with a median age of 68 [57-78] years, an admission SOFA score of 7 [6-10], and lactate at diagnosis of 3.2 [2.4-5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12-0.42] µg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79-43)% and 67 (95% CI 80-47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 µg/kg/min threshold, predicted mortality was 54 (95% CI 52-56)% and 83 (95% CI 80-87)% for tartrate formulation and base molecule, respectively. CONCLUSIONS: Heterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.
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Norepinefrina , Choque Séptico , Humanos , Choque Séptico/tratamiento farmacológico , Choque Séptico/mortalidad , Anciano , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Norepinefrina/uso terapéutico , Norepinefrina/administración & dosificación , Vasoconstrictores/uso terapéutico , Vasoconstrictores/administración & dosificación , Estudios de CohortesRESUMEN
In this work, multicomponent trimethoprim-based pharmaceutical solid systems were developed by mechanochemistry, using coformers from the GRAS list and other active pharmaceutical ingredients. The choice of coformers took into account their potential to increase the aqueous solubility/dissolution rate of TMP or its antibacterial activity. All the binary systems were characterized by thermal analysis, powder X-ray diffraction and infrared spectroscopy, and 3 equimolar systems with FTIR pointing to salts, and 4 eutectic mixtures were identified. The intrinsic dissolution rate of TMP in combination with nicotinic acid (a salt) and with paracetamol (eutectic mixture) were 25% and 5% higher than for pure TMP, respectively. For both Gram-positive and -negative strains, the antibacterial activity of TMP with some of the coformers was improved, since the dosage used was lower than the TMP control. A significant increase in antibacterial activity against E. coli was found for the eutectic mixture with curcumin, with the best results being obtained for the eutectic and equimolar mixtures with ciprofloxacin. Combining trimethoprim with coformers offers an interesting alternative to using trimethoprim alone: multicomponent forms with enhanced TMP dissolution rates were identified, as well as combinations showing enhanced antibacterial activity relatively to the pure drug.
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Antibacterianos , Escherichia coli , Solubilidad , Trimetoprim , Trimetoprim/química , Trimetoprim/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Acetaminofén/química , Acetaminofén/farmacología , Curcumina/química , Curcumina/farmacología , Difracción de Rayos X/métodos , Química Farmacéutica/métodos , Ciprofloxacina/química , Ciprofloxacina/farmacología , Liberación de FármacosRESUMEN
Candida species are frequently implicated in the development of both superficial and invasive fungal infections, which can impact vital organs. In the quest for novel strategies to combat fungal infections, there has been growing interest in exploring synthetic and semi-synthetic products, particularly chromone derivatives, renowned for their antimicrobial properties. In the analysis of the antifungal activity of the compound (E)-benzylidene-chroman-4-one against Candida, in silico and laboratory tests were performed to predict possible mechanisms of action pathways, and in vitro tests were performed to determine antifungal activity (MIC and MFC), to verify potential modes of action on the fungal cell membrane and wall, and to assess cytotoxicity in human keratinocytes. The tested compound exhibited predicted affinity for all fungal targets, with the highest predicted affinity observed for thymidylate synthase (-102.589 kJ/mol). MIC and CFM values ranged from 264.52 µM (62.5 µg/mL) to 4232.44 µM (1000 µg/mL). The antifungal effect likely occurs due to the action of the compound on the plasma membrane. Therefore, (E)-benzylidene-chroman-4-one showed fungicidal-like activity against Candida spp., possibly targeting the plasma membrane.
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Given the increasing pressure on water bodies, it is imperative to explore sustainable methodologies for wastewater treatment and reuse. The simultaneous presence of multiples contaminants in complex wastewater, such as the liquid effluents from biogas plants, can compromise biological treatment effectiveness for reclaiming water. Vertical subsurface flow constructed wetlands were established as low-cost decentralized wastewater treatment technologies to treat the liquid fraction of digestate from municipal organic waste with metals, antibiotics, and antibiotic resistance genes, to allow its reuse in irrigation. Twelve lab-scale planted constructed wetlands were assembled with gravel, light expanded clay aggregate and sand, testing four different treating conditions (liquid digestate spiked with oxytetracycline, sulfadiazine, or ofloxacin, at 100 µg/ L, or without dosing) during 3 months. Physicochemical parameters (pH, chemical oxygen demand (COD), nutrients, metals, and antibiotics), the microbial communities dynamics (through 16S high-throughput sequencing) and antibiotic resistance genes removal (qPCR) were monitored in influents and effluents. Systems removed 85.8%-96.9% of organic matter (as COD), over 98.1% of ammonium and phosphate ions, and 69.3%-99.4% of nitrate and nitrite ions, with no significant differences between the presence or absence of antibiotics. Removal of Fe, Mn, Zn, Cu, Pb and Cr exceeded 82% in all treatment cycles. The treatment also removed oxytetracycline, sulfadiazine and ofloxacin over 99%, and decreased intl1, tetA, tetW, sul1 and qnrS gene copies. Nonetheless, after 3 months of ofloxacin dosing, qnrS gene started being detected. Removal processes relied on high HRT (14 days) and various mechanisms including sorption, biodegradation, and precipitation. Microbial community diversity in liquid digestate changed significantly after treatment in constructed wetlands with a decrease in the initial Firmicutes dominance, but with no clear effect of antibiotics on the microbial community structure. Removals above 85% and 94% were observed for Streptococcus and Clostridium, respectively. Results suggest that vertical subsurface flow constructed wetlands were a suitable technology for treating the liquid digestate to reuse it in irrigation agricultural systems, contributing to the circular bioeconomy concept. However, a more profound understanding of effective wastewater treatment strategies is needed to avoid antibiotic resistance genes dissemination.
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This study retrospectively examined the hemodynamic effects of passive leg raising (PLR) in mechanically ventilated patients during fluid removal before spontaneous breathing trials. In previous studies, we noticed varying cardiac responses after PLR completion, particularly in positive tests. Using a bioreactance monitor, we recorded and analyzed hemodynamic parameters, including stroke volume and cardiac index (CI), before and after PLR in post-acute ICU patients. We included 27 patients who underwent 60 PLR procedures. In preload-unresponsive patients, no significant CI changes were observed (CI_t-6 = 3.7 [2.6; 4.7] mL/min/m2 vs. CI_t9 = 3.3 [2.5; 3.4] mL/min/m2; p = 0.306), while in preload-responsive patients, two distinct CI response types to PLR were identified: a transient peak with immediate return to baseline (CI_t-6 = 2.7 [2.5; 3.1] mL/min/m2 vs. 3.3 [2.6; 3.8] L/min/m2; p = 0.119) and a sustained CI elevation lasting beyond the PLR maneuver (CI_t-6 = 2.8 [2.3; 2.9] L/min/m2 vs. 3.3 [2.8; 3.9] ml/min/m2; p = 0.034). The latter was particularly noted when ΔCI during PLR exceeded 25%. Our findings suggest that in certain preload-responsive patients, PLR can induce a more sustained increase in CI, indicating a possible persistent hemodynamic effect. This effect could be due to a combination of autotransfusion and sympathetic activation affecting venous return and vascular tone. Further research in larger cohorts and more comprehensive hemodynamic assessments are warranted to validate these observations and elucidate the possible underlying mechanisms.The Fluid unLoading On Weaning (FLOW) study was prospectively registered under the ID NCT04496583 on 2020-07-29 at ClinicalTrials.gov.
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Fungal infections represent a serious health problem worldwide. The study evaluated the antifungal activity of 4-chlorobenzyl p-coumarate, an unprecedented semi-synthetic molecule. Docking molecular and assay experiments were conducted to determine the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC), mode of action, effect on growth, fungal death kinetics, drug association, effects on biofilm, micromorphology, and against human keratinocytes. The investigation included 16â strains of Candida spp, including C. albicans, C. krusei, C. glabrata, C. tropicalis, C. dubliniensis, C. lusitaniae, C. utilis, C. rugosa, C. guilhermondi, and C. parapsilosis. Docking analysis predicted affinity between the molecule and all tested targets. MIC and MFC values ranged from 3.9â µg/mL (13.54â µM) to 62.5â µg/mL (217.01â µM), indicating a probable effect on the plasma membrane. The molecule inhibited growth from the first hour of testing. Association with nystatin proved to be indifferent. All concentrations of the molecule reduced fungal biofilm. The compound altered fungal micromorphology. The tested compound exhibited an IC50 of 7.90±0.40â µg/mL (27.45±1.42â µM) for keratinocytes. 4-chlorobenzyl p-coumarate showed strong fungicidal effects, likely through its action on the plasma membrane and alteration of fungal micromorphology, and mildly cytotoxic to human keratinocytes.
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Antifúngicos , Biopelículas , Candida , Pruebas de Sensibilidad Microbiana , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Humanos , Biopelículas/efectos de los fármacos , Candida/efectos de los fármacos , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Queratinocitos/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Ácidos Cumáricos/farmacología , Ácidos Cumáricos/química , Ácidos Cumáricos/síntesis química , Supervivencia Celular/efectos de los fármacosRESUMEN
BACKGROUND: Assessment of dynamic parameters to guide fluid administration is one of the mainstays of current resuscitation strategies. Each test has its own limitations, but passive leg raising (PLR) has emerged as one of the most versatile preload responsiveness tests. However, it requires real-time cardiac output (CO) measurement either through advanced monitoring devices, which are not routinely available, or echocardiography, which is not always feasible. Analysis of the hepatic vein Doppler waveform change, a simpler ultrasound-based assessment, during a dynamic test such as PLR could be useful in predicting preload responsiveness. The objective of this study was to assess the diagnostic accuracy of hepatic vein Doppler S and D-wave velocities during PLR as a predictor of preload responsiveness. METHODS: Prospective observational study conducted in two medical-surgical ICUs in Chile. Patients in circulatory failure and connected to controlled mechanical ventilation were included from August to December 2023. A baseline ultrasound assessment of cardiac function was performed. Then, simultaneously, ultrasound measurements of hepatic vein Doppler S and D waves and cardiac output by continuous pulse contour analysis device were performed during a PLR maneuver. RESULTS: Thirty-seven patients were analyzed. 63% of the patients were preload responsive defined by a 10% increase in CO after passive leg raising. A 20% increase in the maximum S wave velocity after PLR showed the best diagnostic accuracy with a sensitivity of 69.6% (49.1-84.4) and specificity of 92.8 (68.5-99.6) to detect preload responsiveness, with an area under curve of receiving operator characteristic (AUC-ROC) of 0.82 ± 0.07 (p = 0.001 vs. AUC-ROC of 0.5). D-wave velocities showed worse diagnostic accuracy. CONCLUSIONS: Hepatic vein Doppler assessment emerges as a novel complementary technique with adequate predictive capacity to identify preload responsiveness in patients in mechanical ventilation and circulatory failure. This technique could become valuable in scenarios of basic hemodynamic monitoring and when echocardiography is not feasible. Future studies should confirm these results.
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Geopropolis resins are produced by stingless bees (Meliponinae), developed from the collection of resinous materials, waxes and exudates, from the flora of the region where stingless bees are present, in addition to the addition of clay or earth in its composition. Several biological activities are attributed to Ethanol Extracts of Geopropolis (EEGP). The bioactive properties are associated with the complex chemical composition that the samples have. This work aims to evaluate the biological activities of the EEGP, in order to contribute with a natural therapeutic alternative, to face infections, mainly those caused by resistant strains of Staphylococcus aureus. The EEGP MIC tests showed antibacterial activity against two strains of S. aureus, both at concentrations of 550â µg/mL. The MBC performed with the inhibition values showed that the EEGP has bacteriostatic activity in both strains. Biofilm inhibition rates exhibited an average value greater than 65 % at the highest concentration. The EEGP antioxidant potential test showed good antioxidant activity (IC50) of 11.05±1.55â µg/mL. In the cytotoxicity test against HaCat cells, after 24â hours, EEGP induced cell viability at the three tested concentrations (550â µg/mL: 81.68±3.79 %; 1100â µg/mL: 67.10±3.76 %; 2200â µg/mL: 67.40±1.86 %). In view of the above, the safe use of EEGP from the brazilian northeast could be proven by the cytotoxicity test, and its use as an antioxidant and antibacterial agent has proven to be effective, as an alternative in combating oxidative stress and microorganisms such as S.â aureus, which, through the spread and ongoing evolution of drug resistance, generates an active search for effective solutions.
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Antibacterianos , Biopelículas , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus , Staphylococcus aureus/efectos de los fármacos , Animales , Abejas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Humanos , Biopelículas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Própolis/química , Própolis/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Relación Dosis-Respuesta a DrogaRESUMEN
A positive fluid balance may evolve to fluid overload and associate with organ dysfunctions, weaning difficulties, and increased mortality in ICU patients. We explored whether individualized fluid management, assessing fluid responsiveness via a passive leg-raising maneuver (PLR) before a spontaneous breathing trial (SBT), is associated with less extubation failure in ventilated patients with a high fluid balance admitted to the ICU after liver transplantation (LT). We recruited 15 LT patients in 2023. Their postoperative fluid balance was +4476 {3697, 5722} mL. PLR maneuvers were conducted upon ICU admission (T1) and pre SBT (T2). Cardiac index (CI) changes were recorded before and after each SBT (T3). Seven patients were fluid-responsive at T1, and twelve were responsive at T2. No significant differences occurred in hemodynamic, respiratory, and perfusion parameters between the fluid-responsive and fluid-unresponsive patients at any time. Fluid-responsive patients at T1 and T2 increased their CI during SBT from 3.1 {2.8, 3.7} to 3.7 {3.4, 4.1} mL/min/m2 (p = 0.045). All fluid-responsive patients at T2 were extubated after the SBTs and consolidated extubation. Two out of three of the fluid-unresponsive patients experienced weaning difficulties. We concluded that fluid-responsive patients post LT may start weaning earlier and achieve successful extubation despite a high postoperative fluid balance. This highlights the profound impact of personalized assessments of cardiovascular state on critical surgical patients.
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BACKGROUND: Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response. METHODS: Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80-85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions). RESULTS: CRT decreased significantly with both tests (from 5 [3.5-7.6] to 4 [2.4-5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3-5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after the VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin. CONCLUSIONS: Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.
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The pathogenic nature of infections caused by Candida spp. underscores the necessity for novel therapeutic agents. Extracts of Schinopsis brasilienses Engl are \ a promising source of agents with antifungal effects. This study aimed to assess the antifungal potential of the leaf extract of S. brasilienses. The antifungal activity was evaluated by determining the minimum inhibitory concentrations and fungicide concentrations (MIC and MFC). The antibiofilm potential was assessed by counting colony-forming units/mL. The study examined the inhibition kinetics of fungal growth and potential synergism between gallic acid or the extract and nystatin using the Checkerboard method. Cytotoxicity was evaluated through the MTT assay. The extract exhibited antifungal effect against all tested strains, with MIC and MFC ranging from 31.25-250 µg/mL. Gallic acid, the main isolated compound, displayed a MIC of 2000 µg/mL. The extract of S. brasilienses at 31.25 µg/mL inhibited the formation of biofilm by C. albicans and significantly reduced the mass of mature biofilm after 24 and 48 h (p < 0. 05). At a concentration of 125 µg/mL, the extract demonstrated significant inhibition of fungal growth after 6 hours. The combination of gallic acid or extract with nystatin did not exhibit synergistic or antagonistic effect. Furthermore, the extract did not induce cytotoxicity to a human cell line. The extract of S. brasiliensis demonstrates antifungal activity against Candida, generally exhibiting fungicidal action and capacity to inhibit biofilm formation as well as reduce mature biofilms. Additionally, the extract showed low cytotoxicity to human cells.
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Anacardiaceae , Candida , Humanos , Antifúngicos , Nistatina , Candida albicans , Biopelículas , Ácido Gálico , Extractos VegetalesRESUMEN
The integration of abscisic acid (ABA) into a chitosan-alginate gel blend unveils crucial insights into the formation and stability of these two substances. ABA, a key phytohormone in plant growth and stress responses, is strategically targeted for controlled release within these complexes. This study investigates the design and characterization of this novel controlled-release system, showcasing the potential of alginate-chitosan gel blends in ABA delivery. Computational methods, including molecular dynamics simulations, are employed to analyze the structural effects of microencapsulation, offering valuable insights into complex behavior under varying conditions. This paper focuses on the controlled release of ABA from these complexes, highlighting its strategic importance in drug delivery systems and beyond. This controlled release enables targeted and regulated ABA delivery, with far-reaching implications for pharmaceuticals, agriculture, and plant stress response studies. While acknowledging context dependency, the paper suggests that the liberation or controlled release of ABA holds promise in applications, urging further research and experimentation to validate its utility across diverse fields. Overall, this work significantly contributes to understanding the characteristics and potential applications of chitosan-alginate complexes, marking a noteworthy advancement in the field of controlled-release systems.
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BACKGROUND: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission. METHODS: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected. RESULTS: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals. CONCLUSIONS: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices.
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Hiperemia , Sepsis , Humanos , Persona de Mediana Edad , Anciano , Enfermedad Crítica/epidemiología , Enfermedad Crítica/terapia , Estudios Prospectivos , Estudios Transversales , Hiperemia/complicaciones , Sepsis/complicaciones , Fluidoterapia/métodosRESUMEN
Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.
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Helicobacter pylori , Helicobacter pylori/metabolismo , Ureasa/metabolismo , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Urea/farmacologíaRESUMEN
Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α2-adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs.
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Monoterpenos Acíclicos , Analgésicos , Simulación del Acoplamiento Molecular , Monoterpenos Acíclicos/química , Monoterpenos Acíclicos/farmacología , Monoterpenos Acíclicos/metabolismo , Analgésicos/química , Analgésicos/farmacología , Analgésicos/metabolismo , Humanos , Simulación por Computador , Animales , Dolor/tratamiento farmacológico , Dolor/metabolismo , Monoterpenos/química , Monoterpenos/farmacologíaRESUMEN
Aspergillus niger causes infections such as otitis and pulmonary aspergillosis in immunocompromised individuals. Treatment involves voriconazole or amphotericin B, and due to the increase in fungal resistance, the search for new compounds with antifungal activity has intensified. In the development of new drugs, cytotoxicity and genotoxicity assays are important, as they allow predicting possible damage that a molecule can cause, and in silico studies predict the pharmacokinetic properties. The aim of this study was to verify the antifungal activity and the mechanism of action of the synthetic amide 2-chloro-N-phenylacetamide against Aspergillus niger strains and toxicity. 2-Chloro-N-phenylacetamide showed antifungal activity against different strains of Aspergillus niger with minimum inhibitory concentrations between 32 and 256 µg/mL and minimum fungicides between 64 and 1024 µg/mL. The minimum inhibitory concentration of 2-chloro-N-phenylacetamide also inhibited conidia germination. When associated with amphotericin B or voriconazole, 2-chloro-N-phenylacetamide had antagonistic effects. Interaction with ergosterol in the plasma membrane is the probable mechanism of action.2-Chloro-N-phenylacetamide has favorable physicochemical parameters, good oral bioavailability and absorption in the gastrointestinal tract, crosses the blood-brain barrier and inhibits CYP1A2. At concentrations of 50 to 500 µg/mL, it has little hemolytic effect and a protective effect for type A and O red blood cells, and in the cells of the oral mucosa it promotes little genotoxic change. It is concluded that 2-chloro-N-phenylacetamide has promising antifungal potential, favorable pharmacokinetic profile for oral administration and low cytotoxic and genotoxic potential, being a promising candidate for in vivo toxicity studies.
Asunto(s)
Antifúngicos , Aspergilosis , Aspergillus , Humanos , Antifúngicos/toxicidad , Anfotericina B/toxicidad , Voriconazol/toxicidad , Voriconazol/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Acetanilidas/uso terapéutico , Pruebas de Sensibilidad MicrobianaRESUMEN
INTRODUCTION: Brain tumors have high morbidity and mortality rates, accounting for 1.4% of all cancers. Gliomas are the most common primary brain tumors in adults. Currently, several therapeutic approaches are used; however, they are associated with side effects that affect patients'quality of life. Therefore, further studies are needed to develop novel therapeutic protocols with a more favorable side effect profile. In this context, cannabinoid compounds may serve as potential alternatives. OBJECTIVE: This study aimed to review the key enzymatic targets involved in glioma pathophysiology and evaluate the potential interaction of these targets with four cannabinoid derivatives through molecular docking simulations. METHODS: Molecular docking simulations were performed using four cannabinoid compounds and six molecular targets associated with glioma pathophysiology. RESULTS: Encouraging interactions between the selected enzymes and glioma-related targets were observed, suggesting their potential activity through these pathways. In particular, cannabigerol showed promising interactions with epidermal growth factor receptors and phosphatidylinositol 3- kinase, while Δ-9-tetrahydrocannabinol showed remarkable interactions with telomerase reverse transcriptase. CONCLUSION: The evaluated compounds exhibited favorable interactions with the analyzed enzymatic targets, thus representing potential candidates for further in vitro and in vivo studies.