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1.
Drug Deliv ; 28(1): 325-342, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33517789

RESUMEN

The aim of the present study was to investigate the pharmacological mechanism of matrine in treatment of COVID-19 combined with liver injury. Potential targets related to matrine, COVID-19 and liver injury were identified from several databases. We constructed PPI network and screened the core targets according to the degree value. Then, GO and KEGG enrichment were carried out. Molecular docking technology was used to verify the affinity between matrine and the crystal structure of core target protein. Finally, real-time RT-PCR was used to detect the effects of matrine on hub gene expression in liver tissue of liver injury mice and lung tissue of lung injury mice to further confirm the results of network pharmacological analysis. The results show that six core targets including AKT1, TP53, TNF, IL6, BCL2L1 and ATM were identified. The potential therapeutic mechanism of matrine on COVID-19 combined with liver injury is closely related to regulate antiviral process, improve immune system and regulate the level of inflammatory factors. Molecular docking showed that matrine could spontaneously bind to the receptor protein and had strong binding force. Real-time RT-PCR demonstrated that matrine could significantly reduce the expression of AKT1, TP53, TNF, IL6 and ATM in mice with liver injury or lung injury (P < 0.05), and increase the expression of BCL2L1 to a certain extent (P > 0.05). Our results indicate that matrine can achieve simultaneous intervention of COVID-19 combined with liver injury by multi-dimensional pharmacological mechanism.


Asunto(s)
Alcaloides/farmacología , /epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Simulación del Acoplamiento Molecular/métodos , Quinolizinas/farmacología , Alcaloides/administración & dosificación , Animales , Antivirales/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Relación Dosis-Respuesta a Droga , Humanos , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Quinolizinas/administración & dosificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacos
2.
Epidemiol Psychiatr Sci ; 30: e13, 2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33568254

RESUMEN

AIMS: Lifestyle interventions are an important and viable approach for preventing cognitive deficits. However, the results of studies on alcohol, coffee and tea consumption in relation to cognitive decline have been divergent, likely due to confounds from dose-response effects. This meta-analysis aimed to find the dose-response relationship between alcohol, coffee or tea consumption and cognitive deficits. METHODS: Prospective cohort studies or nested case-control studies in a cohort investigating the risk factors of cognitive deficits were searched in PubMed, Embase, the Cochrane and Web of Science up to 4th June 2020. Two authors searched the databases and extracted the data independently. We also assessed the quality of the studies with the Newcastle-Ottawa scale. Stata 15.0 software was used to perform model estimation and plot the linear or nonlinear dose-response relationship graphs. RESULTS: The search identified 29 prospective studies from America, Japan, China and some European countries. The dose-response relationships showed that compared to non-drinkers, low consumption (<11 g/day) of alcohol could reduce the risk of cognitive deficits or only dementias, but there was no significant effect of heavier drinking (>11 g/day). Low consumption of coffee reduced the risk of any cognitive deficit (<2.8 cups/day) or dementia (<2.3 cups/day). Green tea consumption was a significant protective factor for cognitive health (relative risk, 0.94; 95% confidence intervals, 0.92-0.97), with one cup of tea per day brings a 6% reduction in risk of cognitive deficits. CONCLUSIONS: Light consumption of alcohol (<11 g/day) and coffee (<2.8 cups/day) was associated with reduced risk of cognitive deficits. Cognitive benefits of green tea consumption increased with the daily consumption.


Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Café/efectos adversos , Trastornos del Conocimiento/etiología , Disfunción Cognitiva/etiología , Consumo de Bebidas Alcohólicas/metabolismo , Café/metabolismo , Cognición , Trastornos del Conocimiento/epidemiología , Disfunción Cognitiva/epidemiología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Factores de Riesgo , Té/efectos adversos , Té/metabolismo
3.
Medicine (Baltimore) ; 100(4): e23930, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530193

RESUMEN

BACKGROUND: To investigate whether closed-loop systems under bispectral index anesthesia depth monitoring can reduce the intraoperative propofol dosage. METHODS: All randomized controlled trials (RCTs) on reducing propofol dosage under closed-loop systems were collected, and the literature was screened out, the abstracts and full texts were carefully read, and the references were tracked, data extraction and quality evaluation were conducted on the included research, and the RevMan5.3 software was used for meta-analysis. The main results were propofol and the incidence of adverse reactions such as hypertensive hypotension and postoperative cognitive dysfunction. A total of 879 cases were included in 8 articles, including 450 occurrences in the closed-loop system group and 429 cases in the open-loop system group. RESULTS: Compared with manual control, closed-loop systems under bispectral index anesthesia depth monitoring reduced the dose of propofol (MD: -0.62, 95% CI: -1.08--0.16, P = .008), with heterogeneity (I2 = 80%). Closed-loop systems significantly reduced the incidence of abnormal blood pressure (MD: -0.02, 95%CI: -0.05-0.01, P = .15, I2 = 74%) and postoperative cognitive dysfunction (MD: -0.08, 95% CI: -0.14 -0.01, P = .02, I2 = 94%). CONCLUSION: Bispectral index monitoring of propofol closed-loop target-controlled infusion system can reduce the amount of propofol, reduce the incidence of adverse reactions such as hypertensive or hypotension and postoperative cognitive dysfunction.


Asunto(s)
Anestésicos Intravenosos/uso terapéutico , Monitores de Conciencia , Propofol/uso terapéutico , Anestesia Intravenosa/métodos , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Complicaciones Cognitivas Postoperatorias/inducido químicamente , Propofol/administración & dosificación , Propofol/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto
4.
BMJ ; 372: n37, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536184

RESUMEN

OBJECTIVE: To assess the risk of meningioma associated with use of high dose cyproterone acetate, a progestogen indicated for clinical hyperandrogenism. DESIGN: Observational cohort study. SETTING: Data from SNDS, the French administrative healthcare database, between 2007 and 2015. PARTICIPANTS: 253 777 girls and women aged 7-70 years living in France who started cyproterone acetate between 2007 and 2014. Participants had at least one reimbursement for high dose cyproterone acetate and no history of meningioma or benign brain tumour, or long term disease status. Participants were considered to be exposed when they had received a cumulative dose of at least 3 g during the first six months (139 222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114 555 participants). 10 876 transgender participants (male to female) were included in an additional analysis. MAIN OUTCOME MEASURE: Surgery (resection or decompression) or radiotherapy for one or more intracranial meningiomas. RESULTS: Overall, 69 meningiomas in the exposed group (during 289 544 person years of follow-up) and 20 meningiomas in the control group (during 439 949 person years of follow-up) were treated by surgery or radiotherapy. The incidence of meningioma in the two groups was 23.8 and 4.5 per 100 000 person years, respectively (crude relative risk 5.2, 95% confidence interval 3.2 to 8.6; adjusted hazard ratio 6.6, 95% confidence interval 4.0 to 11.1). The adjusted hazard ratio for a cumulative dose of cyproterone acetate of more than 60 g was 21.7 (10.8 to 43.5). After discontinuation of cyproterone acetate for one year, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group. In a complementary analysis, 463 women with meningioma were observed among 123 997 already using cyproterone acetate in 2006 (risk of 383 per 100 000 person years in the group with the highest exposure in terms of cumulative dose). Meningiomas located in the anterior skull base and middle skull base, particularly the medial third of the middle skull base, involving the spheno-orbital region, appeared to be specific to cyproterone acetate. An additional analysis of transgender participants showed a high risk of meningioma (three per 14 460 person years; 20.7 per 100 000 person years). CONCLUSIONS: A strong dose-effect relation was observed between use of cyproterone acetate and risk of intracranial meningiomas. A noticeable reduction in risk was observed after discontinuation of treatment.


Asunto(s)
Antagonistas de Andrógenos/efectos adversos , Acetato de Ciproterona/efectos adversos , Neoplasias Meníngeas/inducido químicamente , Meningioma/inducido químicamente , Adolescente , Adulto , Anciano , Antagonistas de Andrógenos/administración & dosificación , Estudios de Casos y Controles , Niño , Acetato de Ciproterona/administración & dosificación , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Femenino , Francia/epidemiología , Humanos , Incidencia , Estudios Longitudinales , Neoplasias Meníngeas/epidemiología , Meningioma/epidemiología , Persona de Mediana Edad , Medición de Riesgo , Adulto Joven
5.
Anticancer Res ; 41(2): 687-697, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517273

RESUMEN

BACKGROUND/AIM: We investigated drugs that could sensitize P-glycoprotein (P-gp)-overexpressing drug-resistant cancer cells to vincristine (VIC) or eribulin treatment and assessed their associated mechanisms of action. MATERIALS AND METHODS: We investigated 15 bipolar drugs (quetiapine, risperidone, clozapine, asenapine, iloperidone, paliperidone, ziprasidone, trifluoperazine, loxapine succinate, pilocarpine, valproic acid, carbamazepine, levetiracetam, topiramate, and felbamate) to identify drugs with a sensitizing effect on VIC-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting (FACS), annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: We found that co-treatment with half the tested drugs (quetiapine, iloperidone, trifluoperazine, loxapine, risperidone, ziprasidone, or felbamate) at low doses could highly sensitize VIC-resistant KBV20C cells. With lower amounts of the bipolar drugs or VIC, we found that among the 15 bipolar drugs tested, 2 combinations (VIC-quetiapine and VIC-trifluoperazine) had much higher sensitization effects, suggesting that lower effective doses were sufficient for sensitizing P-gp-overexpressing resistant cells compared to those required with the other drugs. Furthermore, when we compared quetiapine and trifluoperazine to previously known bipolar drugs (fluphenazine, thioridazine, pimozide, or aripiprazole), we found that aripiprazole, administered at lower doses, had a much higher sensitization effect. We also demonstrated that co-treatment with another anti-mitotic drug (eribulin) increased the sensitization of KBV20C cells similar to VIC. We also found that aripiprazole had higher P-gp-inhibitory activity than the other bipolar drugs, indicating that this activity was involved in the higher level of VIC-aripiprazole sensitization. CONCLUSION: Co-treatment of anti-mitotic drug-resistant cancer cells with a low dose of aripiprazole had the strongest sensitization effect and is highly dependent on P-gp-inhibitory activity.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antipsicóticos/farmacología , Aripiprazol/farmacología , Reposicionamiento de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Furanos/farmacología , Cetonas/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Vincristina/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
6.
BMJ Case Rep ; 14(1)2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33414115

RESUMEN

Symptomatic drug-induced liver injury (DILI) is an uncommon problem. Direct DILI is dose-related, predictable with short latency (hour to days) and is generally associated with transient and reversible transaminitis without jaundice. Antimetabolites including methotrexate are a common cause for direct DILI. Hepatotoxicity associated with high-dose methotrexate (HD-MTX) is generally transient and includes reversible elevation of transaminase in up to 60% and associated hyperbilirubinaemia (≤grade 2) in 25% of courses and therefore is of no clinical significance. Severe grades of DILI with HD-MTX (grade ≥4) are extremely rare. We describe an adolescent with Burkitt leukaemia who had reversible grade 4 DILI including hyperbilirubinaemia postfirst course of HD-MTX. Rechallenge with two-third dose of HD-MTX in subsequent chemotherapeutic cycle did not cause recurrence of DILI.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Linfoma de Burkitt/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hiperbilirrubinemia/inducido químicamente , Metotrexato/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Niño , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Metotrexato/administración & dosificación , Índice de Severidad de la Enfermedad
7.
Postgrad Med ; 133(1): 1-9, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33423590

RESUMEN

Pregabalin is one of the first-line treatments approved for the management of neuropathic pain (NeP). While many patients benefit from treatment with pregabalin, they are often treated with suboptimal doses, possibly due to unfamiliarity around prescribing the drug and/or side effects that can occur with up-titration. This narrative review discusses key aspects of initiating, titrating, and managing patients prescribed pregabalin therapy, and addresses concerns around driving and the potential for abuse, as well as when to seek specialist opinion. To ensure that patients derive maximum therapeutic benefit from the drug, we suggest a 'low and slow' dosing approach to limit common side effects and optimize tolerability alongside patients' expectations. When requiring titration to higher doses, we recommend initiating 'asymmetric dosing,' with the larger dose in the evening. Fully engaging patients in order for them to understand the expected timeline for efficacy and side effects (including their resolution), can also help determine the optimal titration tempo for each individual patient. The 'low and slow' approach also recognizes that patients with NeP are heterogeneous in terms of their optimal therapeutic dose of pregabalin. Hence, it is recommended that general practitioners closely monitor patients and up-titrate according to pain relief and side effects to limit suboptimal dosing or premature discontinuation.


Asunto(s)
Analgésicos/administración & dosificación , Neuralgia/tratamiento farmacológico , Pregabalina/administración & dosificación , Pregabalina/efectos adversos , Factores de Edad , Analgésicos/uso terapéutico , Conducción de Automóvil , Comorbilidad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Cumplimiento de la Medicación , Dimensión del Dolor , Educación del Paciente como Asunto , Pregabalina/uso terapéutico , Factores Sexuales , Trastornos Relacionados con Sustancias/prevención & control
8.
Ecotoxicol Environ Saf ; 208: 111601, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396121

RESUMEN

Atrazine (ATZ) is among the most widely used herbicides in the world, and yet it has a potential to contaminate aquatic environments due to pesticide leaching from agricultural areas. In the Neotropical region, studies about the effects of this herbicide in native aquatic wildlife is scarce.Our study aimed at investigating the effects of a 30-day exposure to a commercial atrazine formulation on oxidative stress parameters, histopathology in testis and liver, and hormone levels in males and female of yellow-tailed tetra fish (Astyanax altiparanae). Adults were exposed to low but environmentally relevant concentrations of atrazine as follows: 0 (CTL-control), 0.5 (ATZ0.5), 1 (ATZ1), 2 (ATZ2) and 10 (ATZ10) µg/L. Our results showed decreased GST activity in gills in all groups of exposed animals and increased CAT activity in gills from the ATZ10 group. In the liver, there was an increase in lipid peroxidation in fish from ATZ1 and ATZ2 groups. Histological analysis of the liver showed increased percentage of sinusoid capillaries in ATZ2 fish, increased vascular congestion in ATZ1 and increased leukocyte infiltration in the ATZ10 group. Hepatocyte diameter analysis revealed a decrease in cell size in all groups exposed to ATZ, and a decrease in hepatocyte nucleus diameter in ATZ1, ATZ2 and ATZ10 groups. Endocrine parameters did not show significant changes following ATZ exposure, although an increase of triiodothyronine/thyroxine (T3/T4) ratio was observed in ATZ2 fish. Our results provide evidence that even low, environmentally relevant concentrations of ATZ produced oxidative damage and histological alterations in adult yellow-tailed tetra.


Asunto(s)
Atrazina/toxicidad , Characidae/metabolismo , Herbicidas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Atrazina/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Branquias/efectos de los fármacos , Branquias/metabolismo , Herbicidas/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , Contaminantes Químicos del Agua/metabolismo
9.
Ecotoxicol Environ Saf ; 208: 111603, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396123

RESUMEN

Chlorothalonil (CLT) is a broad spectrum, and non-systemic fungicide applied in foliar structures to prevent and treat pathogens. This compound reaches to aquatic environments and affects the biota. In this context, the main goal of this study was to assess the effects of CLT at biochemical, tissular, and individual levels of biological organization using the invasive bivalve Corbicula largillierti as a bioindicator species. Clams were exposed to different sublethal concentrations (0, 10, 20 and 50 µg. L-1 CLT) for 96 h. At biochemical level, the enzymatic activity (Glutathione-s-Transferase, Catalase, Acetyl-, Butiryl- and Carboxyl-esterases) and lipid peroxidation were measured in gills and the visceral mass. Also, the digestive gland morphometry through quantitative histological indexes was registered at the tissular level. Finally, filtering activity and burial behavior at the individual level were measured. At the highest CLT concentration, the most significant changes were observed in enzymatic activity (except for butyrylcholinesterase), lipid peroxidation and in digestive gland morphometry. It was also registered increases of the filtering activity and the latency time to burial. Most of the biomarkers assessed showed significant responses under CLT exposure. Therefore, taking into account that C. largillierti was affected by CLT, it can be expected that other species could be in a potential risk if this fungicide is present in freshwater systems.


Asunto(s)
Corbicula/efectos de los fármacos , Monitoreo del Ambiente/métodos , Agua Dulce/química , Fungicidas Industriales/toxicidad , Nitrilos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Biomarcadores/metabolismo , Catalasa/metabolismo , Corbicula/enzimología , Relación Dosis-Respuesta a Droga , Fungicidas Industriales/análisis , Branquias/efectos de los fármacos , Branquias/enzimología , Glutatión Transferasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Nitrilos/análisis , Contaminantes Químicos del Agua/análisis
10.
Ecotoxicol Environ Saf ; 208: 111609, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396129

RESUMEN

With the wide application of neodymium oxide nanoparticles (NPs-Nd2O3) in various fields, their health hazards have aroused public concern in recent years. However, data regarding the cytotoxicity of NPs-Nd2O3 is limited. In this study, we investigated the function and mechanism of long-chain non-coding RNAs (lncRNAs) in NPs-Nd2O3-induced airway inflammation. Treatment with NPs-Nd2O3 induced an inflammatory response in human bronchial epithelial cells (16HBE) by upregulating the expression of interleukin-6 (IL-6) and interleukin-8 (IL-8). The levels of LDH and intracellular ROS in the cells treated by various doses of NPs-Nd2O3 also increased significantly. After treatment with 10 µg/ml NPs-Nd2O3, RNA microarray and real-time quantitative polymerase chain reaction (qRT-PCR) showed a significant upregulation of lncRNA loc105377478. Functional experiments suggested lncRNA loc105377478 enhanced the expression of IL-6, IL-8 and ROS in NPs-Nd2O3-treated 16HBE cells, and it was further demonstrated that lncRNA loc105377478 promoted the activation of NF-κB by negatively regulating ADIPOR1 expression. Moreover, the expression of IL-6 and IL-8 in NPs-Nd2O3-treated 16HBE cells was regulated by lncRNA loc105377478, which was mediated by the NF-κB signaling pathway. In conclusion, lncRNA loc105377478 promotes NF-κB activation by negatively regulating ADIPOR1 expression, thereby upregulating the expression of IL-6 and IL-8 in 16HBE cells treated with NPs-Nd2O3.


Asunto(s)
Células Epiteliales/efectos de los fármacos , FN-kappa B/metabolismo , Nanopartículas/química , Nanopartículas/toxicidad , Neodimio/toxicidad , Óxidos/toxicidad , ARN Largo no Codificante/genética , Receptores de Adiponectina/metabolismo , Bronquios/efectos de los fármacos , Bronquios/inmunología , Bronquios/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Relación Dosis-Respuesta a Droga , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Humanos , Inflamación , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neodimio/química , Óxidos/química , Transducción de Señal , Regulación hacia Arriba
11.
Nat Commun ; 12(1): 81, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33398055

RESUMEN

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.


Asunto(s)
/inmunología , Modelos Animales de Enfermedad , Hurones/inmunología , /inmunología , Animales , Anticuerpos Antivirales/inmunología , /farmacología , Relación Dosis-Respuesta a Droga , Femenino , Pulmón/inmunología , Pulmón/patología , ARN Viral/aislamiento & purificación , Replicación Viral/efectos de los fármacos , Replicación Viral/inmunología , Esparcimiento de Virus/efectos de los fármacos , Esparcimiento de Virus/inmunología
12.
Anticancer Res ; 41(1): 1-7, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419794

RESUMEN

Chemoradiotherapy (CRT) refers to the combined administration of both chemotherapy and radiotherapy as an anticancer treatment. Over the years, CRT has become an established treatment for a diverse range of locally advanced solid tumours. The rationale for CRT is based on the two concepts of spatial cooperation and in-field cooperation, whereby the end goal is to achieve synergistic antitumour effects from the combination of both treatment modalities. CRT offers notable patient survival benefits and local disease control without significant long-term toxicities. Although the enhancement of cytotoxic effects inevitably increases damage to normal tissues as well as tumour cells, if the damage to normal tissue is lesser than that to tumour cells, CRT is still deemed beneficial. Thus, the search to optimise dose, timings and fractionation of CRT is of particular interest. Considering the recent success achieved with anticancer immunotherapies including immune checkpoint inhibitors, the combination of CRT and immunotherapy has emerged as an exciting field of research with the potential for significant clinical benefit. This report outlines the rationale underlying CRT and discusses its advantages through clinical examples focusing on anal, cervical, non-small-cell lung cancer and bladder cancer.


Asunto(s)
Quimioradioterapia , Neoplasias/terapia , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Toma de Decisiones Clínicas , Terapia Combinada , Manejo de la Enfermedad , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Humanos , Neoplasias/diagnóstico , Neoplasias/mortalidad , Especificidad de Órganos , Resultado del Tratamiento
13.
Anticancer Res ; 41(1): 91-99, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419802

RESUMEN

BACKGROUND/AIM: Small-cell lung cancer (SCLC) is aggressive and confers poor prognosis. Although SCLC shows more response to chemotherapy than other types of lung cancer, it is difficult to cure because of its frequent recurrence. New drugs and molecular targets need to be identified. MATERIALS AND METHODS: We investigated the effect of nelfinavir, an HIV protease inhibitor, on SCLC cells and in preclinical treatment studies using SCLC patient-derived xenograft (PDX) mouse models. RESULTS: Nelfinavir inhibited SCLC cell proliferation and induced cell death in vitro, which was caused by induction of the unfolded protein response (UPR), inhibition of mammalian/mechanistic target of rapamycin (mTOR) activation, and reduction in the expression of SCLC-related molecules such as achaete-scute homolog 1 (ASCL1). In vivo, nelfinavir inhibited the growth of SCLC PDX tumors, which correlated with the induction of UPR and reduced expression of ASCL1. CONCLUSION: Nelfinavir is highly effective in SCLC in vitro and in vivo, suggesting possible incorporation of nelfinavir into clinical trials for patients with SCLC.


Asunto(s)
Antineoplásicos/farmacología , Reposicionamiento de Medicamentos , Nelfinavir/farmacología , Animales , Antineoplásicos/uso terapéutico , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Nelfinavir/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Serina-Treonina Quinasas TOR/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Anticancer Res ; 41(1): 137-149, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419807

RESUMEN

BACKGROUND/AIM: Conventional viability tests, help to screen the cellular effects of candidate molecules, but the endpoint of these measurements lacks sufficient information regarding the molecular aspects. A non-invasive, easy-to-setup live-cell microscopic method served to in-depth analysis of mechanisms of potential anticancer drugs. MATERIALS AND METHODS: The proposed method combining the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test with time-lapse scanning microscopy (TLS), provided additional data related to the cell-cycle and the dynamic properties of cell morphology. Apoptotic and necrotic events became detectable with these methods. RESULTS: Quantification of the results was assisted by image analysis of the acquired image sequences. After demonstrating the potential of the TLS method, a series of experiments compared the in vitro effect of a known and a newly synthesized nucleoside analogue. CONCLUSION: The proposed approach provided a more in-depth insight into the cellular processes that can be affected by known chemotherapeutic agents including nucleoside analogues rather than applying repeated individual treatments.


Asunto(s)
Antineoplásicos/farmacología , Nucleósidos/farmacología , Sales de Tetrazolio , Tiazoles , Imagen de Lapso de Tiempo , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Microscopía , Nucleósidos/análogos & derivados , Imagen de Lapso de Tiempo/métodos
15.
Anticancer Res ; 41(1): 259-268, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419820

RESUMEN

BACKGROUND/AIM: Quinazolinone is a privileged chemical structure employed for targeting various types of cancer. This study aimed to demonstrate the antitumor activity of synthesized 6,7-disubstituted-2-(3-fluorophenyl) quinazolines (HoLu-11 to HoLu-14). MATERIALS AND METHODS: The cytotoxicity was assessed by the sulforhodamine B (SRB) assay. The cell cycle was examined by flow cytometry. The expression levels of cell cycle- and apoptosis-related proteins were estimated by western blotting. A xenograft animal model was used to explore the antitumor effects of HoLu-12. RESULTS: Among four synthetic quinazolinone derivatives, HoLu-12 significantly reduced the viability of oral squamous cell carcinoma (OSCC) cells. HoLu-12 induced G2/M arrest and increased the expression of cyclin B, histone H3 (Ser10) phosphorylation, and cleaved PARP, indicating that HoLu-12 could induce mitotic arrest and then apoptosis. Moreover, the combination of HoLu-12 and 5-fluorouracil (5-FU) displayed synergistic toxic effect on OSCC cells. HoLu-12 significantly inhibited tumor growth in vivo. CONCLUSION: HoLu-12 induces mitotic arrest and leads to apoptosis of OSCC cells. Furthermore, HoLu-12 alone or in combination with 5-FU is a potential therapeutic agent for OSCC.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Quinazolinonas/farmacología , Animales , Antineoplásicos/química , Carcinoma de Células Escamosas , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Citometría de Flujo , Fluorouracilo/farmacología , Humanos , Ratones , Mitosis/efectos de los fármacos , Neoplasias de la Boca , Quinazolinonas/química , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Trials ; 22(1): 2, 2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397432

RESUMEN

OBJECTIVE: General: To assess the virucidal efficacy of povidone iodine (PVP-I) on COVID-19 virus located in the nasopharynx Specific: i. To evaluate the efficacy of povidone iodine (PVP-I) to removeCOVID-19 virus located in the nasopharynx ii. To assess the adverse events of PVP-I TRIAL DESIGN: This is a single-center, open-label randomized clinical trial with a 7-arm parallel-group design. PARTICIPANTS: The study will be conducted at Dhaka Medical College Hospital, Dhaka, Bangladesh. INCLUSION CRITERIA: All RT-PCR-confirmed COVID-19 cases aged between 15-90 years with symptoms for the past 4 days will be screened. Those who give informed consent, are willing to participate, and accept being randomized to any assigned group will also be considered for final inclusion. EXCLUSION CRITERIA: Patients with known sensitivity to PVP-I aqueous antiseptic solution or any of its listed excipients or previously diagnosed thyroid disease or who had a history of chronic renal failure: stage ≥3 by estimated glomerular filtration rate (eGFR) Modification of Diet in Renal Disease (MDRD) or had acute renal failure (KDIGO ≥stage 2: creatinine ≥2 times from the baseline) or patients who required invasive or noninvasive ventilation or planned within the next 6 hours were considered for exclusion. Moreover, lactating or pregnant women will also be restricted to include here. INTERVENTION AND COMPARATOR: This RCT consist of seven arms: Arm-1 (intervention group): will receive povidone iodine (PVP-I) nasal irrigation (NI) at a concentration of 0.4% Arm-2 (intervention group): will receive PVP-I nasal irrigation at a concentration of 0.5% Arm-3 (intervention group): will receive PVP-I nasal irrigation at a concentration of 0.6%. Arm-4 (intervention group): will receive PVP-I nasal spray (NS) at a concentration of 0.5%. Arm-5 (intervention group): will receive PVP-I nasal spray at a concentration of 0.6%. Arm-6 (placebo comparator group): will receive distilled water through NI Arm-7 (Placebo comparator group): will receive distilled water through NS The intervention arms will be compared to the placebo comparator arms. Other supportive and routine care will be the same in both groups. MAIN OUTCOMES: The primary outcome is the proportion of cases that remain COVID-19 positive following the intervention. It will be assessed from 1 minutes to 15 minutes after the intervention. Any occurrence of adverse effects following the intervention will be documented as a secondary outcome. RANDOMIZATION: The assignment to the study (intervention) or control (comparator) group will be allocated in equal numbers through randomization using random number generation in Microsoft Excel by a statistician who is not involved in the trial. The allocation scheme will be made by an independent statistician using a sealed envelope. The participants will be allocated immediately after the eligibility assessment and consenting procedures. BLINDING (MASKING): This is an open-label clinical trial, and no blinding or masking will be performed. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 189 confirmed cases of COVID-19 will be randomized into seven groups. In each arm, a total of 27 participants will be recruited. TRIAL STATUS: The current trial protocol is Version 1.5 from September 10, 2020. Recruitment began September 30, 2020 and is anticipated to be completed, including data analysis by February 28, 2021. TRIAL REGISTRATION: The trial protocol has been registered in the ClinicalTrials.gov on September 16, 2020. NCT Identifier number: NCT04549376 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Antiinfecciosos Locales/administración & dosificación , Nasofaringe/virología , Povidona Yodada/administración & dosificación , /efectos de los fármacos , Administración Intranasal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bangladesh , /virología , Ensayos Clínicos Fase II como Asunto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Lavado Nasal (Proceso) , Rociadores Nasales , Nasofaringe/efectos de los fármacos , Placebos/administración & dosificación , Placebos/efectos adversos , Povidona Yodada/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Adulto Joven
17.
Nat Commun ; 12(1): 269, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431834

RESUMEN

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.


Asunto(s)
Antimaláricos/uso terapéutico , Descubrimiento de Drogas , Malaria/tratamiento farmacológico , Malaria/transmisión , Pandemias , Aedes/parasitología , Animales , Antimaláricos/química , Antimaláricos/farmacología , Análisis por Conglomerados , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estadios del Ciclo de Vida/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/parasitología , Malaria/epidemiología , Masculino , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo
18.
Artículo en Inglés | MEDLINE | ID: mdl-33466469

RESUMEN

There is growing interest in Phase I dose-finding studies studying several doses of more than one agent simultaneously. A number of combination dose-finding designs were recently proposed to guide escalation/de-escalation decisions during the trials. The majority of these proposals are model-based: a parametric combination-toxicity relationship is fitted as data accumulates. Various parameter shapes were considered but the unifying theme for many of these is that typically between 4 and 6 parameters are to be estimated. While more parameters allow for more flexible modelling of the combination-toxicity relationship, this is a challenging estimation problem given the typically small sample size in Phase I trials of between 20 and 60 patients. These concerns gave raise to an ongoing debate whether including more parameters into combination-toxicity model leads to more accurate combination selection. In this work, we extensively study two variants of a 4-parameter logistic model with reduced number of parameters to investigate the effect of modelling assumptions. A framework to calibrate the prior distributions for a given parametric model is proposed to allow for fair comparisons. Via a comprehensive simulation study, we have found that the inclusion of the interaction parameter between two compounds does not provide any benefit in terms of the accuracy of selection, on average, but is found to result in fewer patients allocated to the target combination during the trial.


Asunto(s)
Ensayos Clínicos Fase III como Asunto , Modelos Logísticos , Proyectos de Investigación , Teorema de Bayes , Relación Dosis-Respuesta a Droga , Humanos , Dosis Máxima Tolerada , Tamaño de la Muestra
19.
In Vivo ; 35(1): 653-661, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33402523

RESUMEN

BACKGROUND/AIM: To investigate the efficacy (prognosis, coagulation/inflammation biomarkers) and safety (bleeding events) of different anticoagulation dosages in COVID-19 inpatients. PATIENTS AND METHODS: COVID-19 inpatients (Athens, Greece) were included. The "Enhanced dose THRomboprophylaxis in Admissions (ETHRA)" protocol was applied in certain Departments, suggesting the use of intermediate anticoagulation dosage. The primary endpoint was a composite of intubation/venous thromboembolism/death. Inflammation/coagulation parameters were assessed. RESULTS: Among 127 admissions, 95 fulfilled the inclusion criteria. Twenty-one events (4 deaths, 17 intubations) were observed. Regression analysis demonstrated significant reduction of events with intermediate or therapeutic dosage [HR=0.16 (95%CI=0.05-0.52) p=0.002; HR=0.17 (0.04-0.71) p=0.015, respectively]. D-Dimer values were higher in those who met the composite endpoint. Intermediate dosage treatment was associated with decreased values of ferritin. Three patients (3%) had minor hemorrhagic complications. CONCLUSION: Anticoagulation treatment (particularly intermediate dosage) appears to have positive impact on COVID-19 inpatients' prognosis by inhibiting both coagulation and inflammatory cascades.


Asunto(s)
Anticoagulantes/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Hospitalización/estadística & datos numéricos , Tromboembolia Venosa/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/administración & dosificación , /virología , Relación Dosis-Respuesta a Droga , Femenino , Grecia , Humanos , Pacientes Internos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Tromboembolia Venosa/sangre
20.
JAMA ; 325(7): 632-644, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33475701

RESUMEN

Importance: Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19. Objective: To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19. Design, Setting, and Participants: The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020. Interventions: Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156). Main Outcomes and Measures: The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19-related hospitalization, an emergency department [ED] visit, or death at day 29). Results: Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was -3.72 for 700 mg, -4.08 for 2800 mg, -3.49 for 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, -0.35 to 0.52; P = .69) for 700 mg, -0.27 (95% CI, -0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, -0.13 to 0.76; P = .16) for 7000 mg, and -0.57 (95% CI, -1.00 to -0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19-related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment. Conclusions and Relevance: Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point. Trial Registration: ClinicalTrials.gov Identifier: NCT04427501.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Antivirales/administración & dosificación , /aislamiento & purificación , Carga Viral/efectos de los fármacos , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Neutralizantes/efectos adversos , Antivirales/efectos adversos , /virología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
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