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ETHNOPHARMACOLOGICAL RELEVANCE: Gelsemium dynamized dilutions (GDD) are known as a remedy for a wide range of behavioral and psychological symptoms of depression and anxiety at ultra-low doses, yet the underlying mechanisms of the mode of action of G. sempervirens itself are not well understood. AIM OF THE STUDY: The present study was designed to examine the neuroprotective effects of Gelsemium preparations in counteracting stress-related mitochondrial dysfunctions in neuronal cells. MATERIALS AND METHODS: We started by studying how serum deprivation affects the mitochondrial functions of human neuroblastoma (SH-SY5Y) cells. Next, we looked into the potential of various Gelsemium dilutions to improve cell survival and ATP levels. After identifying the most effective dilutions, 3C and 5C, we tested their ability to protect SH-SY5Y cells from stress-induced mitochondrial deficits. We measured total and mitochondrial superoxide anion radicals using fluorescent dyes dihydroethidium (DHE) and the red mitochondrial superoxide indicator (MitoSOX). Additionally, we assessed total nitric oxide levels with 4,5-diaminofluorescein diacetate (DAF-2DA), examined the redox state using pRA305 cells stably transfected with a plasmid encoding a redox-sensitive green fluorescent protein, and analyzed mitochondrial network morphology using an automated high-content analysis device, Cytation3. Furthermore, we investigated bioenergetics by measuring ATP production with a bioluminescence assay (ViaLighTM HT) and evaluated mitochondrial respiration (OCR) and glycolysis (ECAR) using the Seahorse Bioscience XF24 Analyzer. Finally, we determined cell survival using an MTT reduction assay. RESULTS: Our research indicates that Gelsemium dilutions (3C and 5C) exhibited neuroprotective effects by: - Normalizing total and mitochondrial superoxide anion radicals and total nitric oxide levels. - Regulating the mitochondrial redox environment and mitochondrial networks morphology. - Increasing ATP generation as well as OCR and ECAR levels, thereby reducing the viability loss induced by serum withdrawal stress. CONCLUSIONS: These findings highlight that dynamized Gelsemium preparations may have neuroprotective effects against stress-induced cellular changes in the brain by regulating mitochondrial functions, essential for the survival, plasticity, and function of neurons in depression.
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Supervivencia Celular , Mitocondrias , Neuronas , Fármacos Neuroprotectores , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Adenosina Trifosfato/metabolismo , Estrés Oxidativo/efectos de los fármacos , Óxido Nítrico/metabolismo , Extractos Vegetales/farmacología , Relación Dosis-Respuesta a Droga , Superóxidos/metabolismoRESUMEN
ETHNOPHARMACOLOGY RELEVANCE: Palm buds are a natural green resource of the forest, which are not only rich in nutrients but contain a large number of phenolic acids and flavonoids, among other components. It has a variety of biological activities such as antioxidant and uterine smooth muscle stimulation. AIM OF THE STUDY: To evaluate the safety of palm buds for use as a nutraceutical product and food by evaluating the toxicity, subacute toxicity and genotoxicity of the young palm buds. Also studied for its immune-enhancing activity. MATERIALS AND METHODS: Acute toxicity tests were performed in mice using the maximum tolerance method, and the manifestations of toxicity and deaths were recorded after administration of 10,000 mg/mL for 14 consecutive d (days) of observations. To assess subacute toxicity, mice were treated with palm buds (750, 1500, or 3000 mg/mL) daily for 28 days. The teratogenicity of palm buds was assessed by the Ames test, the mouse bone marrow cell micronucleus test, and the mouse spermatozoa malformation test. In addition, we evaluated the immune-enhancing ability of palm buds by the mouse carbon profile test, delayed-type metamorphosis reaction, and serum hemolysin assay. RESULTS: In the acute toxicity study, the Median Lethal Dose (LD50) was greater than 10,000 mg/kg bw in both male and female rats. There were also no deaths or serious toxicities in the subacute study. The no-observed-adverse-effect level (NOAEL) was 3000 mg/kg bw. However, the mice's food intake decreased after one week. The medium and high dose groups had a reducing effect on body weight in mice of both sexes. In addition, the changes in organ coefficients of the liver, kidney and stomach in male mice were significantly higher in the high-dose group (3.23 ± 0.35, 0.75 ± 0.05, 0.57 ± 0.05 g) than in the control group (2.94 ± 0.18, 0.58 ± 0.05, 0.50 ± 0.02 g). Hematological analyses showed that all the indices of the rats in each palm sprout dose group were within the normal range. The results of blood biochemical indicators showed that there was a significant reduction in TP in the blood of male mice in the high-dose group (44.6 ± 7.8 g/L) compared to the control group (58.3 ± 15.1 g/L). In histopathological analysis, none of the significant histopathological changes were observed. The results of the immunological experiment in mice showed that the liver coefficient and thymus coefficient of the high-dose group (8400 mg/kg) were significantly lower than the control group. There was no remarkable difference in auricle swelling between each dose palm bud group (1400, 2800, or 8400 mg/kg) and the control group. The anti-volume number of the high-dose group was significantly increased. CONCLUSION: Palm buds have non-toxic effects in vivo and have little effect on non-specific and cellular immunity in the test mice within the dose range of this experiment. The immunoenhancement in mice is mainly achieved through humoral immunity. In conclusion, our results suggest that palm buds are safe for use as healthcare products and food.
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Arecaceae , Pruebas de Toxicidad Aguda , Animales , Femenino , Masculino , Arecaceae/química , Ratones , Extractos Vegetales/toxicidad , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Factores Inmunológicos/toxicidad , Ratas , Pruebas de Toxicidad Subaguda , Relación Dosis-Respuesta a Droga , Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Proteínas Hemolisinas/toxicidad , Dosificación Letal MedianaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The popularity of herbal medicine is expanding globally due to the common belief that herbal products are natural and nontoxic. Thymelaea hirsuta leaves are traditionally used for the treatment of recurrent abortion in humans and animals. However, a lack of safety evaluation of the plant, particularly in pregnant women, raises serious concerns regarding its potential embryotoxic effects. AIM OF THE STUDY: Therefore, the present study investigated the safety of Thymelaea hirsuta leaves aqueous extract (THLE) during pregnancy and lactation following maternal rat treatment. MATERIALS AND METHODS: THLE phytochemical compounds were identified using high-performance liquid chromatography (HPLC). THLE was orally administered to pregnant rats and lactating dams at dosages of 0, 250, 500, and 1000 mg/kg/day. At the end of the study, dam s' and pups' body weights, serum biochemical and hematological indices, and histopathological changes were investigated. For the fetal observation and histopathological changes were also evaluated. RESULTS: Our findings revealed that THLE is rich in different phenolic and flavonoid compounds. However, biochemical and hormonal parameters such as ALT, AST, and prolactin were significantly increased in dams treated with a higher dosage of THLE when compared to the control dams (P ≤ 0.05). Additionally, external, visceral and skeletal examinations of fetuses revealed a marked increase of malformation rates in treated fetuses. CONCLUSIONS: The results revealed that higher oral dosing of THLE during pregnancy could affect embryonic development in rats, while lower doses are safe and can be used during pregnancy and lactation to attain its beneficial effects.
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Extractos Vegetales , Hojas de la Planta , Ratas Wistar , Thymelaeaceae , Animales , Extractos Vegetales/toxicidad , Extractos Vegetales/farmacología , Femenino , Embarazo , Ratas , Thymelaeaceae/química , Lactancia , Reproducción/efectos de los fármacos , Masculino , Relación Dosis-Respuesta a DrogaRESUMEN
INTRODUCTION: We have previously reported that genetically positive patients have a more profound early decrease in provocable left ventricular outflow tract gradient compared to genetically negative patients utilizing mavacamten in the first 12 weeks of therapy. METHODS AND RESULTS: In this current analysis, we found that genetically positive patients have less favorable remodeling as measured by left ventricular wall thickness regression when evaluated long-term as compared to genetically negative patients, despite an overall better early response to mavacamten. The majority of genetically positive patients were maintained on only 2.5 mg of mavacamten due to early robust response. CONCLUSION: We hypothesize that this lower dosing attenuated the long-term benefit of mavacamten in genetically positive patients. We believe that the long-term benefit of mavacamten on positive cardiac remodeling is dose-dependent and not solely related to the magnitude of left ventricular outflow gradient decrease.
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Remodelación Ventricular , Humanos , Remodelación Ventricular/efectos de los fármacos , Remodelación Ventricular/genética , Masculino , Femenino , Estudios de Seguimiento , Persona de Mediana Edad , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resultado del Tratamiento , Factores de Tiempo , Bencilaminas , Uracilo/análogos & derivadosRESUMEN
BACKGROUND: Corticosteroids are commonly used to treat COVID-19 patients with hypoxemia, and clinicians have adjusted the corticosteroid intensity on the basis of clinical needs. However, neither the optimal dose nor the duration of treatment has been recommended. OBJECTIVE: To investigate whether cumulative doses of corticosteroids, measured as dexamethasone-equivalent doses over the first 14 days, impact outcomes in patients with COVID-19 pneumonia. METHODS: We conducted a retrospective cohort study of COVID-19 pneumonia patients admitted between April 1st, 2020, and September 30th, 2021. The study focused on the type and dose of corticosteroid administered during the initial 14 days, clinical outcomes, and complications. The primary outcome was in-hospital mortality. RESULTS: Among 271 patients, the mean cumulative dexamethasone-equivalent dose was 158 (119.9-197.25) mg in survivors and 185 (131.7-222.0) mg in nonsurvivors. Univariate analysis revealed that the cumulative dexamethasone-equivalent dose was a risk factor for in-hospital mortality. However, this association did not hold true in the multivariate analysis. After the cumulative dexamethasone-equivalent dose was categorized into quartiles, the moderate dosage (126.01-165.00 mg) in the second quartile was found to be associated with the lowest in-hospital mortality (16.2%). Higher cumulative dexamethasone-equivalent doses were associated with longer hospital and ICU stays and fewer ventilator-free days (p < 0.001). Doses exceeding 165 mg were associated with an increased risk of hospital-acquired infections (p < 0.001). CONCLUSIONS: The cumulative dexamethasone-equivalent dose during the first 14 days is not associated with in-hospital mortality in hypoxemic COVID-19 patients. However, higher cumulative doses exceeding 165 mg are associated with an increased risk of in-hospital mortality and secondary hospital-acquired infections.
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Corticoesteroides , Tratamiento Farmacológico de COVID-19 , COVID-19 , Dexametasona , Mortalidad Hospitalaria , Hipoxia , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/efectos adversos , COVID-19/mortalidad , COVID-19/complicaciones , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Hipoxia/tratamiento farmacológico , SARS-CoV-2/aislamiento & purificación , Resultado del Tratamiento , Relación Dosis-Respuesta a Droga , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The clinical evidence for the effects of different doses of intranasal dexmedetomidine on emergence delirium/ emergence agitation (ED/EA) in children is lacking. METHODS: We searched the PubMed, EMBASE and Cochrane Library from the establishment of the databases until December 30, 2023. All randomized controlled trials that evaluated the effect of different dosage of intranasl dexamedetomidine in children younger than 18 years on postoperative ED/ EA were included. Data analysis was conducted using R 4.3.0. RESULTS: A total of 15 randomized controlled trials involving 1566 children were included. Compared to 0.5 µg/kg (RR = 4.81, 95%CI = 1.66-13.94), and normal saline (RR = 8.23, 95%CI = 4.63-14.65), intranasal dexmedetomidine at doses of 2 µg/kg significantly reduced the incidence of ED/ EA in children. 2 µg/kg was the most effective dosage in reducing the incidence of ED/ EA (Probability of rank = 0.75), the incidence of severe ED/ EA (Probability of rank = 0.45), and ED/ EA score (Probability of rank = 0.65). Moreover, intranasal dexmedetomidine at doses of 2 µg/kg significantly reduced the PACU pain compared to 0.5 µg/kg (RR = 0.42, 95%CI = -0.22-1.06), 1 µg/kg (RR = 0.18, 95%CI = -0.26-0.63), 1.5 µg/kg (RR = 1.00, 95%CI = -0.54-0.75), and normal saline (RR = 8.23, 95%CI = 4.63-14.65), with a probability of rank = 0.45. CONCLUSION: 2µg/kg intranasal dexmedetomidine is the optimum dose for reducing the occurrence of ED/ EA and postoperative pain. However, further research is required to verify our findings.
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Administración Intranasal , Dexmedetomidina , Delirio del Despertar , Agitación Psicomotora , Ensayos Clínicos Controlados Aleatorios como Asunto , Dexmedetomidina/administración & dosificación , Dexmedetomidina/uso terapéutico , Humanos , Delirio del Despertar/prevención & control , Niño , Agitación Psicomotora/prevención & control , Agitación Psicomotora/tratamiento farmacológico , Metaanálisis en Red , Relación Dosis-Respuesta a Droga , Preescolar , Hipnóticos y Sedantes/administración & dosificación , Adolescente , LactanteRESUMEN
BACKGROUND: Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. METHODS: Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2µg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a » log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q0 and α. RESULTS: Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT2AR activation decreased Q0 in female rats but increased Q0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. CONCLUSION: DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT2AR activation sex-dependently alters opioid reinforcement.
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Anfetaminas , Fentanilo , Ratas Sprague-Dawley , Autoadministración , Animales , Masculino , Femenino , Fentanilo/farmacología , Ratas , Anfetaminas/farmacología , Caracteres Sexuales , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Relación Dosis-Respuesta a Droga , Analgésicos Opioides/farmacología , Alucinógenos/farmacologíaRESUMEN
Due to their exceptional physicochemical features, green synthesized silver nanoparticles (AgNPs) have been of considerable interest in cancer treatment. In the present study, for the first time, we aimed to green synthesize AgNPs from Euphorbia retusa and explore their anticancer potential on human breast cancer (MCF-7) cells. First, the green synthesized AgNPs (EU-AgNPs) were well characterized by UV-visible spectroscopy, Fourier transmission infrared (FTIR) spectrum, XRD, scanning and transmission electron microscopy (SEM and TEM), and EDX techniques. The characterization data exhibited that EU-AgNPs were spherical in shape and crystalline in nature with an average size of 17.8 nm. FTIR results established the presence of active metabolites in EU-AgNPs. Second, the anticancer effect of EU-AgNPs was evaluated against MCF-7 cells by MTT and neutral red uptake (NRU) assays. Moreover, morphological changes, ROS production, MMP, and apoptotic marker genes were also studied upon exposure to cytotoxic doses of EU-AgNPs. Our results showed that EU-AgNPs induce cytotoxicity in a concentration-dependent manner, with an IC50 value of 40 µg/mL. Morphological changes in MCF-7 cells exposed to EU-AgNPs also confirm their cytotoxic effects. Increased ROS and decreased MMP levels revealed that EU-AgNPs induced oxidative stress and mitochondrial membrane dysfunction. Moreover, ROS-mediated apoptosis was confirmed by elevated levels of proapoptotic marker genes (p53, Bax, caspase-3, and caspase-9) and reduced levels of an antiapoptotic gene (Bcl-2). Altogether, these findings suggested that EU-AgNPs could induce potential anticancer effects through ROS-mediated apoptosis in MCF-7 cells.
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Antineoplásicos , Apoptosis , Neoplasias de la Mama , Tecnología Química Verde , Nanopartículas del Metal , Mitocondrias , Especies Reactivas de Oxígeno , Plata , Humanos , Plata/química , Plata/farmacología , Nanopartículas del Metal/química , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células MCF-7 , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Euphorbia/química , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacosRESUMEN
Background: Yujiang Paidu Decoction (YJPD) has demonstrated clinical efficacy in the treatment of chronic rhinosinusitis. However, the effects and mechanisms of the YJPD on chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. Purpose: This study aimed to elucidate the potential mechanism of action of YJPD in the treatment of CRSwNP based on network pharmacology, transcriptomics and experiments. Methods: A CRSwNP mouse model was established using ovalbumin (OVA) and staphylococcus aureus enterotoxin B (SEB) for 12 weeks and the human nasal epithelial cell (HNEpC) model was induced with IL-13 in vitro. Behavioral tests, scanning electron microscopy (SEM), micro-CT and pathological change of nasal tissues were observed to investigate the therapeutic effects of YJPD. Network pharmacology and transcriptomics were launched to explore the pharmacological mechanisms of YJPD in CRSwNP treatment. Finally, an ELISA, immunofluorescence, RT-qPCR, Western blotting and Tunel were performed for validation. Results: Different doses of YJPD intervention effectively alleviated rubbing and sneezing symptoms in CRSwNP mice. Additionally, YJPD significantly reduced abnormal serological markers, structural damage of the nasal mucosa, inflammatory cell infiltration, goblet cell increases, and inhibited OVA-specific IgE levels and the secretion of Th2 cytokines such as IL-4, IL-5, and IL-13. Moreover, transcriptomics and network pharmacology analyses indicated that YJPD may exert anti-inflammatory and anti-apoptotic effects by inhibiting the MAPK/AP-1 signaling pathway. The experimental findings supported this conclusion, which was further corroborated by similar results observed in IL13-induced HNEpCs in vitro. Conclusion: YJPD could alleviate inflammatory status and epithelial apoptosis by inhibiting aberrant activation of MAPK/AP-1 signaling pathway. This finding provides a strong basis for using YJPD as a potential treatment in CRSwNP.
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Medicamentos Herbarios Chinos , Pólipos Nasales , Farmacología en Red , Rinitis , Sinusitis , Animales , Sinusitis/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Ratones , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/patología , Enfermedad Crónica , Humanos , Rinitis/tratamiento farmacológico , Rinitis/metabolismo , Rinitis/patología , Transcriptoma/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Masculino , Relación Dosis-Respuesta a Droga , Células Cultivadas , RinosinusitisRESUMEN
Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.
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Homeostasis , Isoindoles , Pruebas de Sensibilidad Microbiana , Compuestos de Organoselenio , Oxidación-Reducción , Estreptomicina , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Animales , Ratones , Homeostasis/efectos de los fármacos , Estreptomicina/farmacología , Antituberculosos/farmacología , Antituberculosos/química , Mycobacterium marinum/efectos de los fármacos , Azoles/farmacología , Azoles/química , Relación Dosis-Respuesta a Droga , Antibacterianos/farmacología , Antibacterianos/química , Relación Estructura-Actividad , Estructura Molecular , Ratones Endogámicos BALB CRESUMEN
Benchmark dose analysis aims to estimate the level of exposure to a toxin associated with a clinically significant adverse outcome and quantifies uncertainty using the lower limit of a confidence interval for this level. We develop a novel framework for benchmark dose analysis based on monotone additive dose-response models. We first introduce a flexible approach for fitting monotone additive models via penalized B-splines and Laplace-approximate marginal likelihood. A reflective Newton method is then developed that employs de Boor's algorithm for computing splines and their derivatives for efficient estimation of the benchmark dose. Finally, we develop a novel approach for calculating benchmark dose lower limits based on an approximate pivot for the nonlinear equation solved by the estimated benchmark dose. The favorable properties of this approach compared to the Delta method and a parameteric bootstrap are discussed. We apply the new methods to make inferences about the level of prenatal alcohol exposure associated with clinically significant cognitive defects in children using data from six NIH-funded longitudinal cohort studies. Software to reproduce the results in this paper is available online and makes use of the novel semibmd R package, which implements the methods in this paper.
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Relación Dosis-Respuesta a Droga , Modelos Estadísticos , Humanos , Benchmarking , Femenino , Algoritmos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Simulación por Computador , Niño , Interpretación Estadística de Datos , Funciones de VerosimilitudRESUMEN
BACKGROUND: Oxaliplatin, a major drug in metastatic colorectal cancer (mCRC), is responsible for cumulative, dose-limiting peripheral neuropathy (PN). Whether the hepatic arterial infusion (HAI) route can limit oxaliplatin-induced PN in comparison with the intravenous (IV) route has not been specifically explored so far. METHODS: We compared the frequency and severity of PN in oxaliplatin-naive patients with mCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (ACCORD 04, CHOICE, OSCAR, and PACHA-01 trials) or by IV route (FFCD 2000-05 trial). We retrieved anonymized, prospectively collected data from trial databases for the ACCORD 04, CHOICE, and FFCD 2000-05 trials and through a review of Gustave Roussy patients' electronic medical records for PACHA-01 and OSCAR trials. The primary endpoint was the incidence of clinically significant PN (grades 2 to 4) according to the cumulative dose of oxaliplatin received. Secondary endpoints were time to onset of neuropathy as a function of the cumulative dose of oxaliplatin, discontinuation of oxaliplatin for neurotoxicity, and safety. RESULTS: A total of 363 patients were included (IV, 300; HAI, 63). In total, 180 patients in the IV group (60%) and 30 patients in the HAI group (48%) developed clinically significant PN, with no significant difference between the two groups (p = 0.23). No difference was shown in the time to onset of PN either (p = 0.23). CONCLUSION: The administration of oxaliplatin HAI rather than IV in the treatment of mCRC does not reduce the incidence, precocity, and severity of PN.
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Antineoplásicos , Neoplasias Colorrectales , Arteria Hepática , Infusiones Intraarteriales , Compuestos Organoplatinos , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico , Humanos , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Masculino , Femenino , Infusiones Intraarteriales/métodos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Persona de Mediana Edad , Infusiones Intravenosas , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Adulto , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Metástasis de la Neoplasia , Relación Dosis-Respuesta a DrogaRESUMEN
The neurohormone oxytocin (OT) has been proposed as a treatment for alcohol and nicotine use disorders. The aim of the present study was to examine whether intravenous (IV) OT decreases alcohol oral self-administration and consumption in nonhuman primates under a 6-h alcohol access procedure as well as alcohol and nicotine (IV) self-administration under 6-h concurrent access conditions. The subjects were five male baboons (Papio anubis) that self-administered oral alcohol (4% w/v) during 6-h sessions under a fixed ratio 3 (FR3) schedule per drink. Baseline levels of alcohol self-administration were established and then OT treatment was initiated. A single dose of OT (20, 40, 80, 120 IU, IV) or its vehicle (saline) was administered before and again in the middle of the 6-h drinking session for 5 consecutive days (total oxytocin dose of 40, 80, 160, 240 IU/day). After each 5-day treatment, baseline levels of alcohol self-administration were reestablished before the next 5-day OT treatment. In addition, the effect of OT on concurrent alcohol and IV nicotine self-administration was explored in 3 of the baboons where alcohol and nicotine were concurrently available during the 6-hr session each under an FR3 schedule for each drug. Establishment of baseline self-administration and 5-day OT treatments were completed as in the alcohol only study. There was a significant overall reduction in alcohol consumption with OT compared to placebo. On post-hoc analysis, after correcting for multiple comparisons, the 40 and 80 IU doses of OT significantly reduced alcohol consumption compared with vehicle, and consumption did not vary significantly within each 5-day treatment period. OT, qualitatively, also reduced the coadministration of both alcohol and nicotine in each baboon for at least one of the OT doses administered. These results underscore the therapeutic potential of oxytocin as a treatment of alcohol use disorder and possibly, co-use of nicotine.
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Consumo de Bebidas Alcohólicas , Etanol , Nicotina , Oxitocina , Autoadministración , Animales , Oxitocina/administración & dosificación , Oxitocina/farmacología , Masculino , Etanol/administración & dosificación , Nicotina/administración & dosificación , Papio , Relación Dosis-Respuesta a Droga , Papio anubisRESUMEN
OBJECTIVE: Accumulating experimental evidence has shown that resveratrol supplementation is effective for treating diabetic nephropathy (DN) in animal models. In this systematic review and meta-analysis, we assessed the effects and multiple mechanisms of resveratrol in animal models of DN. METHODS: Before September 2023, preclinical literature was systematically searched and screened across PubMed, Web of Science, EMBASE, and the Cochrane Library. Forty-two studies were included, and the risk of bias tool from SYRCLE was used to assess the methodological quality. Pooled overall effect sizes of the results were generated by STATA 16.0. RESULTS: The overall results provide preliminary evidence that the consumption of resveratrol can significantly reduce the mesangial index, glomerular basement membrane thickness, glomerular hypertrophy, serum creatinine, blood urea nitrogen, 24-h urinary protein, blood glucose, kidney index, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels. In contrast, the levels of albumin and high-density lipoprotein cholesterol are significantly increased. However, resveratrol did not significantly reduce creatinine clearance or glycated hemoglobin levels. Dose-response analysis revealed that resveratrol was most effective at improving kidney function and reducing DN when administered at lower doses of ≤15 mg/kg/day or higher doses of 100-200 mg/kg/day, with significant improvements in biochemical kidney injury markers and a better effect on dysglycemia. CONCLUSIONS: The benefits of resveratrol in DN are likely due to its anti-inflammatory, antioxidant, metabolic regulatory, and autophagy-promoting effects. To confirm these findings for clinical use, further large-scale, long-term, high-quality preclinical trials are warranted to accurately assess the anti-DN effects and safety of resveratrol.
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Nefropatías Diabéticas , Resveratrol , Resveratrol/farmacología , Resveratrol/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Animales , Progresión de la Enfermedad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Antioxidantes/farmacología , Antioxidantes/uso terapéuticoRESUMEN
Crystalline silica has emerged as a prominent occupational toxicant over extended periods, leading to the development of lung disease and cancer. The objective of this investigation is to establish a benchmark dose (BMD) for crystalline silica micro and nanoparticles based on the dehydrogenase activity of the A549 lung-cell line. The impact of exposure to crystalline silica micro-particles (C-SiO2 MPs) and crystalline silica nanoparticles (C-SiO2 NPs) on A549 epithelial lung cells was examined for durations of 24 and 72 h to evaluate cell viability using the MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay. The determination of dose-response and BMD was carried out through the BMD software v 3.2. The findings reveal a dose-dependent relationship between cell viability and both C-SiO2 MPs and -NPs. The BMDL values for 24 h treatment of C-SiO2 MPs and -NPs were determined to be 2.26 and 0.97 µg/ml, respectively, based on exponential models. Correspondingly, these values were found to be 1.17 and 0.85 µg/ml for the 72 h treatment. This investigation underscores the significance of particle size as a contributing factor in assessing occupational health risks. Moreover, the utilization of BMDL can facilitate the determination of more precise values for occupational exposures by considering various parameters associated with particle presence.
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Supervivencia Celular , Nanopartículas , Dióxido de Silicio , Dióxido de Silicio/química , Humanos , Células A549 , Nanopartículas/toxicidad , Nanopartículas/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Tamaño de la Partícula , Pulmón/efectos de los fármacos , Pulmón/patología , BenchmarkingRESUMEN
BACKGROUND: With the ban on the use of antibiotics in poultry nutrition, the opinion of nutritionists turned to their alternatives. Garlic and mushroom are the two important phytobiotic compounds in poultry nutrition. OBJECTIVES: This experiment was done to investigate the effect of garlic powder (GP) and mushroom powder (MP) on the growth performance, meat quality, serum lipid profile, and intestinal morphology of broilers. METHODS: Five hundred and seventy-six one-day-old male Ross 308 broiler chicks were assigned to eight treatments with six replications based on a completely randomized design in a factorial arrangement of 4*2 with four levels of GP (0.00, 0.50, 1.00, 1.50%) and two levels of MP (0.00, 1.00%). RESULTS: No significant effects of GP and MP on the performance were observed. With increasing levels of GP in the diets, the lightness and redness of breast meat decreased and increased, respectively (p < 0.05). The effect of increasing the amount of GP on the reduction of total cholesterol level was similar in the absence or presence of MP. With increasing levels of GP in the diets, the villus height (VH) and VH to crypt depth ratio (VH: CD) increased. The use of MP in the diets significantly increased VH and VH: CD (p < 0.05). CONCLUSION: The addition of GP and MP to the broilers' diets did not have any negative effect on the performance. These pharmaceutic herbs improved intestinal morphology. In addition, increasing the level of GP amended the meat color and reduced the level of serum cholesterol.
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Agaricus , Alimentación Animal , Pollos , Dieta , Ajo , Intestinos , Carne , Animales , Pollos/sangre , Pollos/fisiología , Pollos/crecimiento & desarrollo , Pollos/anatomía & histología , Agaricus/química , Ajo/química , Masculino , Alimentación Animal/análisis , Dieta/veterinaria , Carne/análisis , Intestinos/efectos de los fármacos , Intestinos/anatomía & histología , Lípidos/sangre , Distribución Aleatoria , Polvos , Fenómenos Fisiológicos Nutricionales de los Animales/efectos de los fármacos , Suplementos Dietéticos/análisis , Relación Dosis-Respuesta a DrogaRESUMEN
Introduction: Infantile Hemangioma (IH) is a prevalent benign vascular tumor affecting approximately 5-10% of infants. Its underlying pathogenesis remains enigmatic, and current therapeutic approaches show limited effectiveness. Our study aimed to discover potential IH-associated therapeutics through a transcriptomic, computational drug repurposing methodology. Methods: Utilizing the IH-specific dataset GSE127487 from the Gene Expression Omnibus, we identified differentially expressed genes (DEGs) and conducted weighted gene coexpression network analysis (WGCNA). Subsequently, a protein-protein interaction (PPI) network was constructed to obtain the top 100 hub genes. Drug candidates were sourced from the Connectivity Map (CMap) and Comparative Toxicogenomics Database (CTD). Results: Our analysis revealed 1203 DEGs and a significant module of 1780 mRNAs strongly correlated with IH. These genes were primarily enriched in the PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling pathway. After creating a PPI network of overlapping genes, we filtered out the top 100 hub genes. Ultimately, 44 non-toxic drugs were identified through the CMap and CTD databases. Twelve molecular-targeting agents (belinostat, chir 99021, dasatinib, entinostat, panobinostat, sirolimus, sorafenib, sunitinib, thalidomide, U 0126, vorinostat, and wortmannin) may be potential candidates for IH therapy. Moreover, in vitro experiments demonstrated that entinostat, sorafenib, dasatinib, and sirolimus restricted the proliferation and migration and initiated apoptosis in HemEC cells, thereby underscoring their potential therapeutic value. Conclusion: Our investigation revealed that the pathogenic mechanism underlying IH might be closely associated with the PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling pathways. Furthermore, we identified twelve molecular-targeting agents among the predicted drugs that show promise as therapeutic candidates for IH.
Transcriptomic analysis used to discover potential therapeutics for Infantile Hemangioma (IH). Key IH-related pathways: PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling identified. Identified 44 non-toxic drugs as potential IH therapies via CMap and CTD. Twelve molecular agents show potential as IH therapy candidates. In vitro studies confirmed entinostat, sorafenib, dasatinib, and sirolimus inhibit HemEC cell proliferation and induce apoptosis.
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Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Hemangioma , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Hemangioma/tratamiento farmacológico , Hemangioma/patología , Hemangioma/genética , Proliferación Celular/efectos de los fármacos , Lactante , Simulación por Computador , Apoptosis/efectos de los fármacos , Mapas de Interacción de Proteínas/efectos de los fármacos , Reposicionamiento de Medicamentos , Relación Dosis-Respuesta a DrogaRESUMEN
We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.