RESUMEN
Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011-2020).
Asunto(s)
Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/tendencias , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pirazoles/química , Pirazoles/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor , Desarrollo de Medicamentos/historia , Inhibidores Enzimáticos/clasificación , Inhibidores Enzimáticos/uso terapéutico , Historia del Siglo XXI , Humanos , Inhibidores de Puntos de Control Inmunológico/química , Inhibidores de Puntos de Control Inmunológico/farmacología , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
During 1921 to 1922, a team effort by Banting, Macleod, Collip and Best isolated and purified insulin and demonstrated its life-giving properties, giving rise to the birth of insulin therapy. In the early years (1922-1950), priorities revolved around the manufacture of insulin to meet demand, improving purity to avoid allergic reactions, establishing insulin standards and increasing its duration of action to avoid multiple daily injections. Shortly after the emergence of insulin, Joslin and Allen advocated the need to achieve and maintain good glycaemic control to realize its full potential. Although this view was opposed by some during a dark period in the history of insulin, it was subsequently endorsed some 60 years later endorsed by the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study. Major scientific advances by the Nobel Laureates Sanger, Hodgkin, Yalow and Gilbert and also by Steiner have revolutionized the understanding of diabetes and facilitated major advances in insulin therapy. The more recent advent of recombinant technology over the last 40 years has provided the potential for unlimited source of insulin, and the ability to generate various insulin 'analogues', in an attempt to better replicate normal insulin secretory patterns. The emerging biosimilars now provide the opportunity to improve availability at a lower cost.
Asunto(s)
Desarrollo de Medicamentos , Insulina , Biosimilares Farmacéuticos , Diabetes Mellitus/tratamiento farmacológico , Desarrollo de Medicamentos/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/historia , Insulina/uso terapéutico , Insulina Regular Humana , Estudios ProspectivosRESUMEN
The first insulin preparation capable of consistently lowering blood glucose was developed in 1921. But 100 years later, blood glucose control with insulin in people with diabetes is nearly universally suboptimal, with essentially the same molecule still delivered by the same inappropriate subcutaneous injection route. Bypassing this route with oral administration appears to have become technologically feasible, accelerating over the past 50 years, either with packaged insulin peptides or by chemical insulin mimetics. Some of the problems of prospective unregulated absorption of insulin into the circulation from subcutaneous depots might be overcome with glucose-responsive insulins. Approaches to these problems could be modification of the peptide by adducts, or the use of nanoparticles or insulin patches, which deliver insulin according to glucose concentration. Some attention has been paid to targeting insulin preferentially to different organs, either by molecular engineering of insulin, or with adducts. But all these approaches still have problems in even beginning to match the responsiveness of physiological insulin delivery to metabolic requirements, both prandially and basally. As would be expected, for all these technically complex approaches, many examples of abandoned development can be found. Meanwhile, it is becoming possible to change the duration of action of subcutaneous injected insulin analogues to act even more rapidly for meals, and towards weekly insulin for basal administration. The state of the art of all these approaches, and the barriers to success, are reviewed here.
Asunto(s)
Desarrollo de Medicamentos , Insulina , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/historia , Vías de Administración de Medicamentos , Composición de Medicamentos/historia , Composición de Medicamentos/tendencias , Desarrollo de Medicamentos/historia , Desarrollo de Medicamentos/tendencias , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Insulina/administración & dosificación , Insulina/historia , Sistemas de Infusión de Insulina/historiaRESUMEN
This review provides a brief history of the advances of cellular analysis tools focusing on instrumentation, detection probes, and data analysis tools. The interplay of technological advancement and a deeper understanding of cellular biology are emphasized. The relevance of this topic to drug development is that the evaluation of cellular biomarkers has become a critical component of the development strategy for novel immune therapies, cell therapies, gene therapies, antiviral therapies, and vaccines. Moreover, recent technological advances in single-cell analysis are providing more robust cellular measurements and thus accelerating the advancement of novel therapies.Graphical abstract.
Asunto(s)
Desarrollo de Medicamentos/tendencias , Citometría de Flujo/tendencias , Análisis de la Célula Individual/tendencias , Desarrollo de Medicamentos/historia , Desarrollo de Medicamentos/métodos , Citometría de Flujo/historia , Citometría de Flujo/métodos , Historia del Siglo XVI , Historia del Siglo XVII , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Microscopía/historia , Microscopía/métodos , Microscopía/tendencias , Análisis de la Célula Individual/historia , Análisis de la Célula Individual/métodosRESUMEN
The introduction of chlorpromazine and the work that ensued provided the foundation to reposition schizophrenia as a biological illness. The present paper follows the evolution of antipsychotics and their shift from 'typical' to 'atypical'. Atypicality is reviewed in reference to its original definition, clozapine's role, and developments that now leave the concept's utility in question. In a similar fashion, drug development is reviewed in the context of the illness' multiple symptom domains, as well as differences captured by clinical staging and phenotyping. Collectively, the evidence argues for a more nuanced approach to drug development that aligns with the illness' heterogeneity and complexity. Just as 'atypical' as a descriptor for antipsychotics may be outdated, it may be time to set aside the notion of developing drugs that treat 'schizophrenia'.
Asunto(s)
Antipsicóticos/historia , Desarrollo de Medicamentos/historia , Esquizofrenia/tratamiento farmacológico , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
The aim of this work is to identify the most influential initial clinical studies that fomented important developments in anesthesiology over the past 50 years. Studies fomenting new development can be selected using vastly different approaches and, therefore, might provide diverse outcomes. In the present work, two basic aspects of study assessments - the stage of development (eg, generation of idea, preclinical studies, clinical trials) and the method of selection (eg, committee vote, various types of citation analysis, method of finding the invention disclosure) - were chosen according to the following model. The stage of development: the initial clinical studies demonstrating the basic advantage of an innovation for providing anesthesia. The method: a combination of two factors - the study priority in terms of the time of its publication and the degree of its acknowledgement in the form of citation impact; the time of study publication was regarded as a primary factor, but only if the study's citation count was =/>20. The initial high-impact studies were selected for 16 drug-related topics (ketamine, isoflurane, etomidate, propofol, midazolam in anesthesia, vecuronium, alfentanil, atracurium, sevoflurane, sufentanil, rocuronium, desflurane, ropivacaine, remifentanil, dexmedetomidine in anesthesia, and sugammadex), and 9 technique-related topics (ultrasound-guided peripheral nerve block, capnography in anesthesia, target-controlled intravenous anesthesia, pulse oximetry in anesthesia, total intravenous anesthesia, transesophageal echocardiography in anesthesia, combined spinal-epidural anesthesia, and bispectral index). Twenty-five studies were designated the first high-impact studies (one for each topic); 16 are drug-related and 9 are technique-related. Half of the first high-impact studies had a citation count of =/>100, (range: 100 to 555). The citation count of the other half of high-impact studies did not reach the 100-citation threshold (range: 41 to 97). If a selected first high-impact study had a citation count <100, a next-on-timeline, additional study with citation count =/>100 was also selected; (range: 100 to 344). The present results show that an initial high-impact clinical study on a new development in anesthesiology can be determined and that related citations usually vary from one hundred to five hundred.
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Anestesia/historia , Anestesiología/historia , Ensayos Clínicos como Asunto/historia , Anestesia/métodos , Anestésicos/administración & dosificación , Anestésicos/historia , Animales , Desarrollo de Medicamentos/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Publicaciones/historia , Publicaciones/estadística & datos numéricosRESUMEN
With the improvements in relevant policies, laws, and regulations regarding drug clinical trials in China, the quantity and quality of drug clinical trials have gradually improved, and the development prospects of drug clinical trials for endocrine disorders and metabolism and nutrition disorders are promising. Based on information from the clinical trials from the online drug clinical trial registration platform of the National Medical Products Administration, we aimed to review and evaluate the development of clinical trials of drugs for endocrine disorders and metabolism and nutrition disorders in mainland China from 2010 to 2019, as well as the trends over time. A total of 861 trials were carried out on 254 types of drugs for endocrine disorders and metabolism and nutrition disorders, among which 531 (61.67%) involved endocrine disorders, and 330 (38.33%) addressed metabolism and nutrition disorders. The annual number of clinical trials has been increasing gradually, with a significant increase in 2017. Among them, the proportion of clinical trials with Chinese epidemiological characteristics was relatively large (Wu, Annual Report on Development Health Management and Health Industry in China, 2018). The largest number of trials were for diabetes drugs (55.63%), followed by trials of drugs for hyperlipidemia (19.4%) and those for hyperuricemia (7.9%). It was found that the geographical area of the leading units also showed obvious unevenness according to the analysis of the test unit data. Based on the statistics and evaluation of the data, comprehensive information is provided to support the cooperation of global pharmaceutical R&D companies and research units in China and the development of international multicenter clinical trials in China. This work additionally provides clinical trial units with a self-evaluation of scientific research competitiveness and hospital development strategies. At the same time, it provides a reference with basic data for sponsors and stakeholders in these trials to determine their development strategy goals.
Asunto(s)
Ensayos Clínicos como Asunto/estadística & datos numéricos , Desarrollo de Medicamentos/tendencias , Enfermedades del Sistema Endocrino/tratamiento farmacológico , Enfermedades Metabólicas/tratamiento farmacológico , Trastornos Nutricionales/tratamiento farmacológico , China , Ensayos Clínicos como Asunto/historia , Desarrollo de Medicamentos/historia , Desarrollo de Medicamentos/estadística & datos numéricos , Historia del Siglo XXI , HumanosRESUMEN
Dengue is the most important arboviral disease world-wide with an estimated 400 million annual infections. Dengvaxia™ is a live attenuated tetravalent vaccine recently licensed for dengue seropositive individuals aged 9-45 years. There is great need for a dengue vaccine that could be given to dengue-naïve individuals and very young children. To that end, the U.S. NIH developed a live attenuated tetravalent dengue vaccine using an iterative approach evaluating the safety, infectivity, and immunogenicity of different candidates. This approach identified poor candidates who were then discarded from further evaluation. Each of the components of the tetravalent vaccine formulation is able to replicate to very low titer, inducing a homotypic immune response to each. The immune response elicited by the tetravalent vaccine is balanced, without immunodominance of one component. The vaccine was licensed by several manufacturers for development, including the Instituto Butantan which initiated a Phase 3 efficacy trial.
Asunto(s)
Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Dengue/prevención & control , Desarrollo de Medicamentos , Vacunas Atenuadas/inmunología , Dengue/historia , Dengue/inmunología , Dengue/virología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/genética , Vacunas contra el Dengue/historia , Virus del Dengue/genética , Desarrollo de Medicamentos/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Vacunas Atenuadas/historia , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/genética , Vacunas Combinadas/historia , Vacunas Combinadas/inmunologíaRESUMEN
DNA-like molecules called antisense oligonucleotides have opened new treatment possibilities for genetic diseases by offering a method of regulating gene expression. Antisense oligonucleotides are often used to suppress the expression of mutated genes which may interfere with essential downstream pathways. Since antisense oligonucleotides have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Mipomersen and inotersen are examples of recent FDA-approved antisense oligonucleotide gapmers used for the treatment of familial hypercholesterolemia and hereditary transthyretin amyloidosis, respectively. In addition, volanesorsen was conditionally approved in the EU for the treatment of adult patients with familial chylomicronemia syndrome (FCS) in 2019. Many others are being tested in clinical trials or under preclinical development. This chapter will cover the development of mipomersen and inotersen in clinical trials, along with advancement in gapmer treatments for cancer, triglyceride-elevating genetic diseases, Huntington's disease, myotonic dystrophy, and prion diseases.
Asunto(s)
Ensayos Clínicos como Asunto , Desarrollo de Medicamentos , Enfermedades Genéticas Congénitas/terapia , Oligonucleótidos Antisentido , Adulto , Ensayos Clínicos como Asunto/historia , Ensayos Clínicos como Asunto/métodos , Desarrollo de Medicamentos/historia , Desarrollo de Medicamentos/métodos , Enfermedades Genéticas Congénitas/genética , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Oligonucleótidos/síntesis química , Oligonucleótidos/uso terapéutico , Oligonucleótidos Antisentido/síntesis química , Oligonucleótidos Antisentido/uso terapéuticoRESUMEN
The field of neuromuscular and neurodegenerative diseases has been revolutionized by the advent of genetics and molecular biology to evaluate the pathogenicity, thereby providing considerable insight to develop suitable therapies. With the successful translation of antisense oligonucleotides (AOs) from in vitro into animal models and clinical practice, modifications are being continuously made to the AOs to improve the pharmacokinetics and pharmacodynamics. In order to activate RNase H-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed to have a phosphorothioate (PS) backbone flanked with the modified AOs on both sides. Antisense-mediated knockdown of mutated huntingtin is a promising therapeutic approach for Huntington's disease (HD), a devastating disorder affecting the motor and cognitive abilities. This chapter focuses on the modified gapmer AOs for the treatment of HD.
Asunto(s)
Desarrollo de Medicamentos , Enfermedad de Huntington/terapia , Oligonucleótidos Antisentido/síntesis química , Oligonucleótidos Antisentido/uso terapéutico , Animales , Desarrollo de Medicamentos/historia , Desarrollo de Medicamentos/métodos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Oligonucleótidos Antisentido/genéticaRESUMEN
Although technological advances in molecular genetics over the last few decades have greatly expedited the identification of mutations in many genetic diseases, the translation of the genetic mechanisms into a clinical setting has been quite challenging, with a minimum number of effective treatments available. The advancements in antisense therapy have revolutionized the field of neuromuscular disorders as well as lipid-mediated diseases. With the approval of splice-switching antisense oligonucleotide (AO) therapy for nusinersen and eteplirsen for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD), several modified AOs are now being evaluated in clinical trials for the treatment of a number of disorders. In order to activate RNase H-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed that have a PS backbone flanked with the modified AOs on both sides. Mipomersen (trade name Kynamro), a 2'-O-methoxyethyl (MOE) gapmer, was approved by the Food and Drug Administration (FDA) for the treatment of homozygous familial hypercholesterolemia (HoFH) in 2013. Volanesorsen, another 20-mer MOE gapmer has shown to be successful in lowering the levels of triglycerides (TGs) in several lipid disorders and has received conditional approval in the European Union for the treatment of Familial chylomicronemia syndrome (FCS) in May 2019 following successful results from phase II/III clinical trials. This chapter focuses on the clinical applications of gapmer AOs for genetic dyslipidemia and lipodystrophy.
Asunto(s)
Desarrollo de Medicamentos , Dislipidemias/terapia , Lipodistrofia/terapia , Oligonucleótidos Antisentido/síntesis química , Oligonucleótidos Antisentido/uso terapéutico , Animales , Desarrollo de Medicamentos/historia , Desarrollo de Medicamentos/métodos , Dislipidemias/genética , Terapia Genética/historia , Terapia Genética/métodos , Terapia Genética/tendencias , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lipodistrofia/genética , Morfolinos/síntesis química , Morfolinos/uso terapéutico , Oligonucleótidos/síntesis química , Oligonucleótidos/uso terapéutico , Oligonucleótidos Antisentido/genéticaRESUMEN
Vadadustat (VAFSEO®) is a prolyl hydroxylase inhibitor being developed by Akebia Therapeutics, Inc. (Akebia) for the treatment of anaemia associated with chronic kidney disease (CKD). Akebia is collaborating with Mitsubishi Tanabe Pharma Corporation on the development and commercialization of vadadustat in Japan and with Otsuka Pharmaceutical Co. Ltd on the development and commercialization of vadadustat in the USA, the EU and certain other territories. The drug is approved in Japan for use in adult patients with anaemia associated with CKD and regulatory submissions are planned in the USA and the EU. This article summarizes the milestones in the development of vadadustat leading to this first approval.
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Anemia/tratamiento farmacológico , Aprobación de Drogas/historia , Desarrollo de Medicamentos/historia , Glicina/análogos & derivados , Ácidos Picolínicos/uso terapéutico , Inhibidores de Prolil-Hidroxilasa/uso terapéutico , Adulto , Anemia/etiología , Ensayos Clínicos como Asunto/historia , Aprobación de Drogas/legislación & jurisprudencia , Aprobación de Drogas/estadística & datos numéricos , Desarrollo de Medicamentos/legislación & jurisprudencia , Glicina/historia , Glicina/farmacología , Glicina/uso terapéutico , Historia del Siglo XXI , Humanos , Japón , Ácidos Picolínicos/historia , Ácidos Picolínicos/farmacología , Inhibidores de Prolil-Hidroxilasa/historia , Inhibidores de Prolil-Hidroxilasa/farmacología , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Estados UnidosRESUMEN
The oncogenic transcription inhibitor lurbinectedin (ZEPZELCA™) is being developed by PharmaMar as a treatment for various cancers. The drug has been granted orphan drug status for the treatment of small cell lung cancer (SCLC) by regulatory authorities in multiple countries worldwide and was approved in the USA in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The US FDA and international regulators, including the Australian Therapeutic Goods Administration, are collaborating on the review of lurbinectedin under the Project Orbis initiative. Clinical investigation in other solid cancers is ongoing. This article summarizes the milestones in the development of lurbinectedin leading to this first approval for the treatment of metastatic SCLC.
Asunto(s)
Carbolinas/administración & dosificación , Aprobación de Drogas/historia , Desarrollo de Medicamentos/historia , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adulto , Australia , Carbolinas/efectos adversos , Carbolinas/historia , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Esquema de Medicación , Aprobación de Drogas/estadística & datos numéricos , Desarrollo de Medicamentos/legislación & jurisprudencia , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/historia , Historia del Siglo XXI , Humanos , Infusiones Intravenosas , Producción de Medicamentos sin Interés Comercial/historia , Producción de Medicamentos sin Interés Comercial/legislación & jurisprudencia , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
Asunto(s)
Decitabina/uso terapéutico , Aprobación de Drogas/historia , Desarrollo de Medicamentos/historia , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Uridina/análogos & derivados , Administración Oral , Adulto , Canadá , Ensayos Clínicos como Asunto/historia , Decitabina/historia , Decitabina/farmacología , Aprobación de Drogas/legislación & jurisprudencia , Aprobación de Drogas/estadística & datos numéricos , Combinación de Medicamentos , Desarrollo de Medicamentos/legislación & jurisprudencia , Historia del Siglo XXI , Humanos , Estados Unidos , United States Food and Drug Administration , Uridina/historia , Uridina/farmacología , Uridina/uso terapéuticoAsunto(s)
Productos Biológicos/farmacología , Desarrollo de Medicamentos/historia , Fitoterapia/historia , Segunda Guerra Mundial , Analgésicos Opioides/farmacología , Antibacterianos/farmacología , Antimaláricos/farmacología , Etnobotánica/historia , Historia del Siglo XX , Humanos , Morfina/farmacología , Penicilinas/farmacología , Quinina/farmacología , Heridas Relacionadas con la Guerra/complicaciones , Heridas Relacionadas con la Guerra/terapiaRESUMEN
Since the birth of biotechnology, hundreds of biotherapeutics have been developed and approved by the US Food and Drug Administration (FDA) for human use. These novel medicines not only bring significant benefit to patients but also represent precision tools to interrogate human disease biology. Accordingly, much has been learned from the successes and failures of hundreds of high-quality clinical trials. In this review, we discuss general and broadly applicable themes that have emerged from this collective experience. We base our discussion on insights gained from exploring some of the most important target classes, including interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), IL-6, IL-12/23, IL-17, IL-4/13, IL-5, immunoglobulin E (IgE), integrins and B cells. We also describe current challenges and speculate about how emerging technological capabilities may enable the discovery and development of the next generation of biotherapeutics.
Asunto(s)
Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Terapia Biológica , Desarrollo de Medicamentos , Animales , Productos Biológicos/historia , Terapia Biológica/historia , Terapia Biológica/métodos , Biotecnología/historia , Biotecnología/métodos , Ensayos Clínicos como Asunto , Desarrollo de Medicamentos/historia , Descubrimiento de Drogas/historia , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients.
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Fármacos Cardiovasculares/historia , Desarrollo de Medicamentos/historia , Estado de Salud , Insuficiencia Cardíaca/historia , Fármacos Cardiovasculares/farmacología , Aprobación de Drogas/historia , Insuficiencia Cardíaca/tratamiento farmacológico , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Estados UnidosAsunto(s)
Enfermedades Neurodegenerativas/historia , Neurociencias/historia , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/historia , Desarrollo de Medicamentos/historia , Inglaterra , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Retratos como AsuntoRESUMEN
Animal experiments have served to improve our knowledge on diseases and treatment approaches since ancient times. Today, animal experiments are widely used in medical, biomedical and veterinary research, and are essential means of drug development and preclinical testing, including toxicology and safety studies. Recently, great efforts have been made to replace animal experiments with in vitro organoid culture methods and in silico predictions, in agreement with the 3R strategy to "reduce, refine and replace" animals in experimental testing, as outlined by the European Commission. Here we present a mini-review on the development of animal testing, as well as on alternative in vitro and in silico methods, that may at least partly replace animal experiments in the near future.