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1.
Nutrients ; 13(11)2021 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-34836055

RESUMEN

Pancreatic cancer, the seventh most lethal cancer around the world, is considered complicated cancer due to poor prognosis and difficulty in treatment. Despite all the conventional treatments, including surgical therapy and chemotherapy, the mortality rate is still high. Therefore, the possibility of using natural products for pancreatic cancer is increasing. In this study, 68 natural products that have anti-pancreatic cancer effects reported within five years were reviewed. The mechanisms of anti-cancer effects were divided into four types: apoptosis, anti-metastasis, anti-angiogenesis, and anti-resistance. Most of the studies were conducted for natural products that induce apoptosis in pancreatic cancer. Among them, plant extracts such as Eucalyptus microcorys account for the major portion. Some natural products, including Moringa, Coix seed, etc., showed multi-functional properties. Natural products could be beneficial candidates for treating pancreatic cancer.


Asunto(s)
Productos Biológicos/uso terapéutico , Descubrimiento de Drogas/tendencias , Medicina Tradicional/tendencias , Neoplasias Pancreáticas/tratamiento farmacológico , Fitoterapia/tendencias , Inhibidores de la Angiogénesis , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Extractos Vegetales/farmacología
2.
Biochem Pharmacol ; 194: 114798, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34678227

RESUMEN

Drug affinity responsive target stability (DARTS) is a novel target discovery approach and is particularly adept at screening small molecule (SM) targets without requiring any structural modifications. The DARTS method is capable of revealing drug-target interactions from cells or tissues by tracking changes in the stability of proteins acting as receptors of bioactive SMs. Due to its simple operation and high efficiency, the DARTS method has been applied to uncover the drug-action mechanism. This review summarized analytical principles, protocols, validation approaches, applications, and challenges involved in the DARTS method. Due to the innate advantages of the DARTS method, it is expected to be a powerful tool to accelerate SM target discovery, especially for bioactive natural products with unknown mechanisms.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Animales , Sistemas de Liberación de Medicamentos/tendencias , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/tendencias , Estabilidad de Medicamentos , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Unión Proteica/fisiología , Bibliotecas de Moléculas Pequeñas/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-34445332

RESUMEN

More than 85% of pre-clinically tested drugs fail during clinical trials, which results in a long, inefficient and costly process, suggesting that animal models are often poor predictors of human biology [...].


Asunto(s)
Descubrimiento de Drogas/métodos , Células Madre Pluripotentes Inducidas/fisiología , Animales , Técnicas de Cultivo de Célula , Diferenciación Celular , Células Cultivadas , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Humanos , Células Madre Pluripotentes Inducidas/citología , Modelos Biológicos
4.
Methods ; 195: 29-43, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33962011

RESUMEN

Therapeutic approaches to COVID-19 treatment require appropriate inhibitors to target crucial proteins of SARS-CoV-2 replication machinery. It's been approximately 12 months since the pandemic started, yet no known specific drugs are available. However, research progresses with time in terms of high throughput virtual screening (HTVS) and rational design of repurposed, novel synthetic and natural products discovery by understanding the viral life cycle, immuno-pathological and clinical outcomes in patients based on host's nutritional, metabolic, and lifestyle status. Further, complementary and alternative medicine (CAM) approaches have also improved resiliency and immune responses. In this article, we summarize all the therapeutic antiviral strategies for COVID-19 drug discovery including computer aided virtual screening, repurposed drugs, immunomodulators, vaccines, plasma therapy, various adjunct therapies, and phage technology to unravel insightful mechanistic pathways of targeting SARS-CoV-2 and host's intrinsic, innate immunity at multiple checkpoints that aid in the containment of the disease.


Asunto(s)
Corticoesteroides/administración & dosificación , Antivirales/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Vacunas contra la COVID-19/administración & dosificación , COVID-19/inmunología , Descubrimiento de Drogas/tendencias , Animales , COVID-19/prevención & control , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Ensayos Analíticos de Alto Rendimiento/tendencias , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Interferón alfa-2/administración & dosificación , Interleucina-6/antagonistas & inhibidores , Interleucina-6/inmunología
5.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33925625

RESUMEN

The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).


Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/fisiología , Enfermedades del Sistema Nervioso/terapia , Esclerosis Amiotrófica Lateral/terapia , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos , Humanos , Modelos Biológicos , Enfermedades Neurodegenerativas/terapia , Enfermedad de Parkinson/terapia , Preparaciones Farmacéuticas , Trasplante de Células Madre/métodos , Trasplante de Células Madre/tendencias
6.
Mol Pharmacol ; 99(4): 256-265, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33547249

RESUMEN

The high failure rate of drugs in the clinical pipeline is likely in part the result of inadequate preclinical models, particularly those for neurologic disorders and neurodegenerative disease. Such preclinical animal models often suffer from fundamental species differences and rarely recapitulate all facets of neurologic conditions, whereas conventional two-dimensional (2D) in vitro models fail to capture the three-dimensional spatial organization and cell-to-cell interactions of brain tissue that are presumed to be critical to the function of the central nervous system. Recent studies have suggested that stem cell-derived neuronal organoids are more physiologically relevant than 2D neuronal cultures because of their cytoarchitecture, electrophysiological properties, human origin, and gene expression. Hence there is interest in incorporating such physiologically relevant models into compound screening and lead optimization efforts within drug discovery. However, despite their perceived relevance, compared with previously used preclinical models, little is known regarding their predictive value. In fact, some have been wary to broadly adopt organoid technology for drug discovery because of the low-throughput and tedious generation protocols, inherent variability, and lack of compatible moderate-to-high-throughput screening assays. Consequently, microfluidic platforms, specialized bioreactors, and automated assays have been and are being developed to address these deficits. This mini review provides an overview of the gaps to broader implementation of neuronal organoids in a drug discovery setting as well as emerging technologies that may better enable their utilization. SIGNIFICANCE STATEMENT: Neuronal organoid models offer the potential for a more physiological system in which to study neurological diseases, and efforts are being made to employ them not only in mechanistic studies but also in profiling/screening purposes within drug discovery. In addition to exploring the utility of neuronal organoid models within this context, efforts in the field aim to standardize such models for consistency and adaptation to screening platforms for throughput evaluation. This review covers potential impact of and hurdles to implementation.


Asunto(s)
Descubrimiento de Drogas/métodos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Neuronas/efectos de los fármacos , Neuronas/fisiología , Organoides/efectos de los fármacos , Organoides/fisiología , Animales , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Enfermedades Neurodegenerativas/fisiopatología
7.
Drug Discov Today ; 26(4): 982-992, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33476566

RESUMEN

AI integration in plant-based traditional medicine could be used to overcome drug discovery challenges.


Asunto(s)
Inteligencia Artificial , Descubrimiento de Drogas , Medicina Tradicional/métodos , Fitoterapia/métodos , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Humanos
8.
Molecules ; 25(20)2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-33076254

RESUMEN

Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued efforts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature.


Asunto(s)
Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/tendencias , Bibliotecas de Moléculas Pequeñas/química , Interfaz Usuario-Computador , Algoritmos , Humanos , Ligandos , Simulación del Acoplamiento Molecular/métodos
9.
J Med Microbiol ; 69(8): 1040-1048, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32692643

RESUMEN

Given the increased reporting of multi-resistant bacteria and the shortage of newly approved medicines, researchers have been looking towards extreme and unusual environments as a new source of antibiotics. Streptomyces currently provides many of the world's clinical antibiotics, so it comes as no surprise that these bacteria have recently been isolated from traditional medicine. Given the wide array of traditional medicines, it is hoped that these discoveries can provide the much sought after core structure diversity that will be required of a new generation of antibiotics. This review discusses the contribution of Streptomyces to antibiotics and the potential of newly discovered species in traditional medicine. We also explore how knowledge of traditional medicines can aid current initiatives in sourcing new and chemically diverse antibiotics.


Asunto(s)
Antibacterianos/aislamiento & purificación , Descubrimiento de Drogas/tendencias , Microbiología del Suelo , Streptomyces/metabolismo , Animales , Antibacterianos/biosíntesis , Cuevas/química , Invertebrados/química , Medicina Tradicional , Péptido Sintasas/metabolismo , Plantas Medicinales/química , Sintasas Poliquetidas/metabolismo , Poríferos/química , Streptomyces/química , Streptomyces/enzimología
10.
Eur Rev Med Pharmacol Sci ; 24(13): 7462-7474, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32706086

RESUMEN

OBJECTIVE: Although highly successful, the medical R&D model is failing at improving people's health due to a series of flaws and defects inherent to the model itself. A new collective intelligence, incorporating human and artificial intelligence (AI) could overcome these obstacles. Because AI will play a key role in this new collective intelligence, it is necessary that those involved in healthcare have a general knowledge of how these technologies work. With this comprehensive review, we intend to provide it. MATERIALS AND METHODS: A broad-ranging search has been undertaken on institutional and non-institutional websites in order to identify relevant papers, comments and reports. RESULTS: We firstly describe the flaws and defects of the current R&D biomedical model and how the generation of a new collective intelligence will result in a better and wiser medicine through a truly personalized and holistic approach. We, then, discuss the new forms of data collection and data processing and the different types of artificial learning and their specific algorithms. Finally, we review the current uses and applications of AI in the biomedical field and how these can be expanded, as well as the limitations and challenges of applying these new technologies in the medical field. CONCLUSIONS: This colossal common effort based on a new collective intelligence will exponentially improve the quality of medical research, resulting in a radical change for the better in the healthcare model. AI, without replacing us, is here to help us achieve the ambitious goal set by the WHO in the Alma Ata declaration of 1978: "Health for All".


Asunto(s)
Inteligencia Artificial/tendencias , Diagnóstico por Computador/tendencias , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/tendencias , Terapia Asistida por Computador/tendencias , Toma de Decisiones Clínicas , Técnicas de Apoyo para la Decisión , Difusión de Innovaciones , Predicción , Humanos
11.
Theranostics ; 10(16): 7034-7052, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32641977

RESUMEN

This review provides an update for the international research community on the cell modeling tools that could accelerate the understanding of SARS-CoV-2 infection mechanisms and could thus speed up the development of vaccines and therapeutic agents against COVID-19. Many bioengineering groups are actively developing frontier tools that are capable of providing realistic three-dimensional (3D) models for biological research, including cell culture scaffolds, microfluidic chambers for the culture of tissue equivalents and organoids, and implantable windows for intravital imaging. Here, we review the most innovative study models based on these bioengineering tools in the context of virology and vaccinology. To make it easier for scientists working on SARS-CoV-2 to identify and apply specific tools, we discuss how they could accelerate the discovery and preclinical development of antiviral drugs and vaccines, compared to conventional models.


Asunto(s)
Antivirales/aislamiento & purificación , Antivirales/farmacología , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/prevención & control , Vacunas Virales/aislamiento & purificación , Vacunas Virales/farmacología , Betacoronavirus/química , Betacoronavirus/genética , Betacoronavirus/inmunología , Bioingeniería/métodos , Bioingeniería/tendencias , Reactores Biológicos , COVID-19 , Vacunas contra la COVID-19 , Técnicas de Cultivo de Célula , Simulación por Computador , Infecciones por Coronavirus/inmunología , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Evaluación de Medicamentos/métodos , Evaluación de Medicamentos/tendencias , Farmacorresistencia Viral , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/inmunología , Humanos , Modelos Biológicos , Organoides/citología , Organoides/virología , Neumonía Viral/inmunología , SARS-CoV-2 , Nanomedicina Teranóstica
12.
J Med Chem ; 63(10): 5242-5256, 2020 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-32255647

RESUMEN

Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67-84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of 45 in complex with human BRD4 BD1 at a high resolution of 2.0 Å has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Cromonas/administración & dosificación , Cromonas/química , Descubrimiento de Drogas/métodos , Factores de Transcripción/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Proteínas de Ciclo Celular/metabolismo , Línea Celular Transformada , Cromonas/farmacología , Cristalización/métodos , Cristalización/tendencias , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Factores de Transcripción/metabolismo
13.
Antioxid Redox Signal ; 33(5): 329-331, 2020 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-32122175

RESUMEN

NADPH oxidases (Noxs) represent an original pharmacological target because they are the only enzymes whose main function is to produce reactive oxygen species. It is also a double target with the need for stimulation in chronic granulomatosis and inhibition reported in other pathologies (vascular, cancerous, neurological, etc.). The complexity of the involvement of Noxs in pathophysiology has not yet made it possible to obtain a drug that effectively inhibits these enzymes at the clinical level. This issue of the Forum aims to take stock of the obstacles and limitations to the development of these inhibitors both in their preclinical and clinical evaluation.


Asunto(s)
Descubrimiento de Drogas/tendencias , Inhibidores Enzimáticos/farmacología , NADPH Oxidasas/antagonistas & inhibidores , Animales , Estudios Clínicos como Asunto , Descubrimiento de Drogas/historia , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Historia del Siglo XXI , Humanos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
14.
Adv Parasitol ; 107: 201-282, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32122530

RESUMEN

The use of chemotherapeutic drugs is the main resource against clinical giardiasis due to the lack of approved vaccines. Resistance of G. duodenalis to the most used drugs to treat giardiasis, metronidazole and albendazole, is a clinical issue of growing concern and yet unknown impact, respectively. In the search of new drugs, the completion of the Giardia genome project and the use of biochemical, molecular and bioinformatics tools allowed the identification of ligands/inhibitors for about one tenth of ≈150 potential drug targets in this parasite. Further, the synthesis of second generation nitroimidazoles and benzimidazoles along with high-throughput technologies have allowed not only to define overall mechanisms of resistance to metronidazole but to screen libraries of repurposed drugs and new pharmacophores, thereby increasing the known arsenal of anti-giardial compounds to some hundreds, with most demonstrating activity against metronidazole or albendazole-resistant Giardia. In particular, cysteine-modifying agents which include omeprazole, disulfiram, allicin and auranofin outstand due to their pleiotropic activity based on the extensive repertoire of thiol-containing proteins and the microaerophilic metabolism of this parasite. Other promising agents derived from higher organisms including phytochemicals, lactoferrin and propolis as well as probiotic bacteria/fungi have also demonstrated significant potential for therapeutic and prophylactic purposes in giardiasis. In this context the present chapter offers a comprehensive review of the current knowledge, including commonly prescribed drugs, causes of therapeutic failures, drug resistance mechanisms, strategies for the discovery of new agents and alternative drug therapies.


Asunto(s)
Resistencia a Medicamentos , Giardiasis/tratamiento farmacológico , Terapias Complementarias/tendencias , Biología Computacional/tendencias , Descubrimiento de Drogas/tendencias , Giardiasis/terapia , Humanos
16.
Biochem Soc Trans ; 48(1): 271-280, 2020 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-31985743

RESUMEN

Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical studies that can trace their origins to a fragment-based screen. The challenges associated with implementing an FBDD approach are many and diverse, ranging from the library design to developing methods for identifying weak affinity compounds. In this article, we give an overview of current progress in fragment library design, fragment to lead optimisation and on the advancement in techniques used for screening. Finally, we will comment on the future opportunities and challenges in this field.


Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Bibliotecas de Moléculas Pequeñas/química , Cristalografía por Rayos X , Aprobación de Drogas , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/tendencias , Humanos , Espectroscopía de Resonancia Magnética , Unión Proteica
17.
J Med Chem ; 63(9): 4430-4444, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-31913033

RESUMEN

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.


Asunto(s)
Química Farmacéutica , Descubrimiento de Drogas/métodos , Química Farmacéutica/tendencias , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Publicaciones
18.
Neuropharmacology ; 167: 107702, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-31301334

RESUMEN

The epilepsies are a complex group of disorders that can be caused by a myriad of genetic and acquired factors. As such, identifying interventions that will prevent development of epilepsy, as well as cure the disorder once established, will require a multifaceted approach. Here we discuss the progress in scientific discovery propelling us towards this goal, including identification of genetic risk factors and big data approaches that integrate clinical and molecular 'omics' datasets to identify common pathophysiological signatures and biomarkers. We discuss the many animal and cellular models of epilepsy, what they have taught us about pathophysiology, and the cutting edge cellular, optogenetic, chemogenetic and anti-seizure drug screening approaches that are being used to find new cures in these models. Finally, we reflect on the work that still needs to be done towards identify at-risk individuals early, targeting and stopping epileptogenesis, and optimizing promising treatment approaches. Ultimately, developing and implementing cures for epilepsy will require a coordinated and immense effort from clinicians and basic scientists, as well as industry, and should always be guided by the needs of individuals affected by epilepsy and their families. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Descubrimiento de Drogas/métodos , Epilepsia/terapia , Terapia Genética/métodos , Animales , Anticonvulsivantes/farmacología , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/fisiología , Epilepsia/diagnóstico , Epilepsia/genética , Terapia Genética/tendencias , Humanos
19.
Neuropharmacology ; 167: 107750, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-31469995

RESUMEN

Since 1993, over 20 new anti-seizure drugs (ASDs) have been identified in well-established animal seizure and epilepsy models and subsequently demonstrated to be clinically effective in double-blinded, placebo-controlled clinical trials in patients with focal onset seizures. All clinically-available ASDs on the market today are effective in at least one of only three preclinical seizure and epilepsy models: the acute maximal electroshock (MES), the acute subcutaneous pentylenetetrazol (scPTZ) test, or the kindled rodent with chronic evoked seizures. Thus, it reasons that preclinical ASD discovery does not need significant revision to successfully identify ASDs for the symptomatic treatment of epilepsy. Unfortunately, a significant need still persists for more efficacious and better tolerated ASDs. This is particularly true for those patients whose seizures remain drug resistant. This review will focus on the continued utility of the acute MES and scPTZ tests, as well as the kindled rodent for current and future ASD discovery. These are the only "clinically validated" rodent models to date and been heavily used in the search for novel and more efficacious ASDs. This is to say that promising ASDs have been brought to the clinic on the basis of efficacy in these particular seizure and epilepsy models alone. This review also discusses some of the inherent advantages and limitations of these models relative to existing and emerging preclinical models. It then offers insight into future efforts to develop a preclinical model that will advance a truly transformative therapy for the symptomatic treatment of difficult to treat focal onset epilepsy. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Modelos Animales de Enfermedad , Descubrimiento de Drogas/métodos , Epilepsia/tratamiento farmacológico , Excitación Neurológica/fisiología , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/farmacología , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Humanos , Excitación Neurológica/efectos de los fármacos , Pentilenotetrazol/toxicidad , Reproducibilidad de los Resultados , Convulsiones/inducido químicamente , Convulsiones/fisiopatología
20.
Front Med ; 14(1): 30-42, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31858368

RESUMEN

Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.


Asunto(s)
Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/aislamiento & purificación , Descubrimiento de Drogas/métodos , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/prevención & control , Animales , Anticuerpos Neutralizantes/inmunología , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos , VIH-1 , Humanos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
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