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1.
Theranostics ; 11(4): 1690-1702, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33408775

RESUMEN

The global outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a requirement for two pronged clinical interventions such as development of effective vaccines and acute therapeutic options for medium-to-severe stages of "coronavirus disease 2019" (COVID-19). Effective vaccines, if successfully developed, have been emphasized to become the most effective strategy in the global fight against the COVID-19 pandemic. Basic research advances in biotechnology and genetic engineering have already provided excellent progress and groundbreaking new discoveries in the field of the coronavirus biology and its epidemiology. In particular, for the vaccine development the advances in characterization of a capsid structure and identification of its antigens that can become targets for new vaccines. The development of the experimental vaccines requires a plethora of molecular techniques as well as strict compliance with safety procedures. The research and clinical data integrity, cross-validation of the results, and appropriated studies from the perspective of efficacy and potently side effects have recently become a hotly discussed topic. In this review, we present an update on latest advances and progress in an ongoing race to develop 52 different vaccines against SARS-CoV-2. Our analysis is focused on registered clinical trials (current as of November 04, 2020) that fulfill the international safety and efficacy criteria in the vaccine development. The requirements as well as benefits and risks of diverse types of SARS-CoV-2 vaccines are discussed including those containing whole-virus and live-attenuated vaccines, subunit vaccines, mRNA vaccines, DNA vaccines, live vector vaccines, and also plant-based vaccine formulation containing coronavirus-like particle (VLP). The challenges associated with the vaccine development as well as its distribution, safety and long-term effectiveness have also been highlighted and discussed.


Asunto(s)
/epidemiología , Desarrollo de Medicamentos/tendencias , Pandemias/prevención & control , /inmunología , Antígenos Virales/genética , Antígenos Virales/inmunología , /transmisión , Ensayos Clínicos como Asunto/estadística & datos numéricos , Aprobación de Drogas , Desarrollo de Medicamentos/estadística & datos numéricos , Humanos , Seguridad del Paciente , Factores de Tiempo , Resultado del Tratamiento , Proteínas Estructurales Virales/genética , Proteínas Estructurales Virales/inmunología
2.
MAbs ; 13(1): 1860476, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33459118

RESUMEN

In this 12th annual installment of the Antibodies to Watch article series, we discuss key events in antibody therapeutics development that occurred in 2020 and forecast events that might occur in 2021. The coronavirus disease 2019 (COVID-19) pandemic posed an array of challenges and opportunities to the healthcare system in 2020, and it will continue to do so in 2021. Remarkably, by late November 2020, two anti-SARS-CoV antibody products, bamlanivimab and the casirivimab and imdevimab cocktail, were authorized for emergency use by the US Food and Drug Administration (FDA) and the repurposed antibodies levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 in Russia and India, respectively. Despite the pandemic, 10 antibody therapeutics had been granted the first approval in the US or EU in 2020, as of November, and 2 more (tanezumab and margetuximab) may be granted approvals in December 2020.* In addition, prolgolimab and olokizumab had been granted first approvals in Russia and cetuximab saratolacan sodium was first approved in Japan. The number of approvals in 2021 may set a record, as marketing applications for 16 investigational antibody therapeutics are already undergoing regulatory review by either the FDA or the European Medicines Agency. Of these 16 mAbs, 11 are possible treatments for non-cancer indications and 5 are potential treatments for cancer. Based on the information publicly available as of November 2020, 44 antibody therapeutics are in late-stage clinical studies for non-cancer indications, including 6 for COVID-19, and marketing applications for at least 6 (leronlimab, tezepelumab, faricimab, ligelizumab, garetosmab, and fasinumab) are planned in 2021. In addition, 44 antibody therapeutics are in late-stage clinical studies for cancer indications. Of these 44, marketing application submissions for 13 may be submitted by the end of 2021. *Note added in proof on key events announced during December 1-21, 2020: margetuximab-cmkb and ansuvimab-zykl were approved by FDA on December 16 and 21, 2020, respectively; biologics license applications were submitted for ublituximab and amivantamab.


Asunto(s)
Anticuerpos/uso terapéutico , Antivirales/uso terapéutico , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/tendencias , Reposicionamiento de Medicamentos/tendencias , /efectos de los fármacos , Animales , Anticuerpos/efectos adversos , Antivirales/efectos adversos , /virología , Difusión de Innovaciones , Aprobación de Drogas , Predicción , Interacciones Huésped-Patógeno , Humanos , /inmunología
3.
Yakugaku Zasshi ; 141(1): 1-13, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390437

RESUMEN

Chemical biology and structural development studies performed at The University of Tokyo during 1977-2020 are outlined chronologically. The studies are divided into three parts, i.e., (i) chemical biology of chemical carcinogenesis and molecular design of anti-tumor agents, (ii) structural development studies on biological response modifiers, and (iii) studies on so-called dramatype drug discovery focusing on pharmacological chaperones and protein knockdown-inducers. The first part describes analysis of DNA modification by Glu-P-1, which is a typical carcinogenic heterocyclic amine found in cooked foods, as well as molecular design of DNA-cleaving agents with anti-tumor properties. The second part deals with structural development studies of nuclear receptor ligands and various biological response modifiers derived from thalidomide, including the ligand superfamily concept and the multi-template strategy. The third part describes pharmacological chaperones that should be useful for the treatment of protein misfolding diseases, including Niemann-Pick type C disease and retinitis pigmentosa, and a protein knockdown strategy aimed at degradation of neurodegenerative-disease-causing polyglutamic aggregative proteins.


Asunto(s)
Antineoplásicos , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Factores Inmunológicos , Química Orgánica , Diseño de Fármacos , Técnicas de Silenciamiento del Gen , Humanos , Ligandos , Chaperonas Moleculares/uso terapéutico , Ácido Poliglutámico , Pliegue de Proteína , Deficiencias en la Proteostasis/tratamiento farmacológico , Talidomida/química , Factores de Tiempo , Tokio , Universidades
4.
J Pharmacol Exp Ther ; 376(1): 12-20, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33115823

RESUMEN

Faced with the health and economic consequences of the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the biomedical community came together to identify, diagnose, prevent, and treat the novel disease at breathtaking speeds. The field advanced from a publicly available viral genome to a commercialized globally scalable diagnostic biomarker test in less than 2 months, and first-in-human dosing with vaccines and repurposed antivirals followed shortly thereafter. This unprecedented efficiency was driven by three key factors: 1) international multistakeholder collaborations, 2) widespread data sharing, and 3) flexible regulatory standards tailored to meet the urgency of the situation. Learning from the remarkable success achieved during this public health crisis, we are proposing a biomarker-centric approach throughout the drug development pipeline. Although all therapeutic areas would benefit from end-to-end biomarker science, efforts should be prioritized to areas with the greatest unmet medical needs, including neurodegenerative diseases, chronic lower respiratory diseases, metabolic disorders, and malignant neoplasms. SIGNIFICANCE STATEMENT: Faced with the unprecedented threat of the severe acute respiratory syndrome coronavirus 2 pandemic, the biomedical community collaborated to develop a globally scalable diagnostic biomarker (viral DNA) that catalyzed therapeutic development at breathtaking speeds. Learning from this remarkable efficiency, we propose a multistakeholder biomarker-centric approach to drug development across therapeutic areas with unmet medical needs.


Asunto(s)
Antivirales/uso terapéutico , Defensa Civil/tendencias , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/tendencias , Animales , Biomarcadores/análisis , /genética , Defensa Civil/métodos , Desarrollo de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Marcadores Genéticos/genética , Humanos , Pandemias
5.
Adv Drug Deliv Rev ; 169: 168-189, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33316346

RESUMEN

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented effort toward the development of an effective and safe vaccine. Aided by extensive research efforts into characterizing and developing countermeasures towards prior coronavirus epidemics, as well as recent developments of diverse vaccine platform technologies, hundreds of vaccine candidates using dozens of delivery vehicles and routes have been proposed and evaluated preclinically. A high demand coupled with massive effort from researchers has led to the advancement of at least 31 candidate vaccines in clinical trials, many using platforms that have never before been approved for use in humans. This review will address the approach and requirements for a successful vaccine against SARS-CoV-2, the background of the myriad of vaccine platforms currently in clinical trials for COVID-19 prevention, and a summary of the present results of those trials. It concludes with a perspective on formulation problems which remain to be addressed in COVID-19 vaccine development and antigens or adjuvants which may be worth further investigation.


Asunto(s)
Adyuvantes Inmunológicos/síntesis química , /prevención & control , Desarrollo de Medicamentos/métodos , /efectos de los fármacos , Adyuvantes Inmunológicos/uso terapéutico , Animales , /uso terapéutico , Composición de Medicamentos/métodos , Composición de Medicamentos/tendencias , Desarrollo de Medicamentos/tendencias , Humanos , Proteínas Recombinantes/síntesis química , Proteínas Recombinantes/uso terapéutico , /inmunología
6.
Sci China Life Sci ; 63(12): 1833-1849, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33355886

RESUMEN

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection is a critical determinant for patients' outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.


Asunto(s)
Anticuerpos Antivirales/biosíntesis , /inmunología , /inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Neutralizantes/uso terapéutico , Infecciones Asintomáticas , /aislamiento & purificación , China , Desarrollo de Medicamentos/tendencias , Interacciones Microbiota-Huesped/inmunología , Humanos , Inmunidad Humoral , Inmunización Pasiva , Inmunoglobulinas Intravenosas/uso terapéutico , Modelos Inmunológicos , Pandemias , /prevención & control , Seroconversión
10.
Emerg Microbes Infect ; 9(1): 2379-2380, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33059515

RESUMEN

This commentary provides an overview and links to presentations of a recent virtual congress series organized by the International Society for Vaccines (ISV) focused on COVID-19 vaccines. The series provided the academic community and vaccine developers as well as the wider general public with balanced information of the global response and resources for COVID-19 vaccines under development featuring: 1) NGOs and the regulatory perspective, 2) the status of vaccine development efforts, and 3) panel discussions to present and discuss challenges. ISV is a non-profit scientific organization whose members work on all areas relevant to vaccines. ISV plans to host additional virtual symposia including regional meetings and incorporating other topics along with COVID-19 vaccines.


Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/prevención & control , Vacunas Virales/inmunología , Betacoronavirus/genética , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Desarrollo de Medicamentos/tendencias , Humanos , Neumonía Viral/epidemiología , Neumonía Viral/virología , Vacunas Virales/administración & dosificación , Vacunas Virales/genética
11.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(4): 419-424, 2020 Aug 25.
Artículo en Chino | MEDLINE | ID: mdl-32985153

RESUMEN

Narcolepsy is the most common cause of excessive daytime sleepiness (EDS) following obstructive sleep apnea. Its treatment aims to reduce EDS and cataplexy, improve nighttime sleep disturbance, sleep paralysis and sleep-related hallucinations. Pitolisant (a histamine H3 receptor antagonist) and solriamfetol (a norepinephrine reuptake inhibitor) have recently been approved effective for narcolepsy in the United States and the European Union. Pitolisant has proved to be effective for both EDS and cataplexy. Besides being effective on EDS, solriamfetol seems to have advantages in abuse potential and withdrawal syndrome. As potential treatments for EDS and cataplexy associated with narcolepsy, several new drugs are being developed and tested. These new drugs include new hydroxybutyrate preparations (controlled release sodium hydroxybutyrate FT218, low sodium hydroxybutyrate JZP-258), selective norepinephrine reuptake inhibitor (AXS-12), and modafinil combined with astroglial junction protein inhibitor (THN102). This paper reviews the recently approved drugs and potential treatments for narcolepsy.


Asunto(s)
Carbamatos/uso terapéutico , Narcolepsia/tratamiento farmacológico , Fenilalanina/análogos & derivados , Piperidinas/uso terapéutico , Cataplejía/tratamiento farmacológico , Desarrollo de Medicamentos/tendencias , Humanos , Fenilalanina/uso terapéutico
16.
Aliment Pharmacol Ther ; 52(4): 619-636, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32638417

RESUMEN

BACKGROUND: Patients with non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, are at higher risk of cardiovascular disease (CVD) and associated mortality. Therefore, it is important to understand how new therapies for non-alcoholic steatohepatitis (NASH) may impact CVD risk factors in these patients. AIMS: To summarise the effects of drug therapies on lipid and lipoprotein levels in patients with NASH and provide insight into the potential mechanisms for the observed changes. METHODS: PubMed searches of the literature were performed and results were compiled. RESULTS: Recent clinical trials have highlighted the safety and efficacy of drug candidates for the treatment of NASH. Several agents have shown improvements in the histological features of NASH and liver function. Pioglitazone, a drug that is currently available for type 2 diabetes and may be useful for NASH, exhibits beneficial effects on lipids. However, agents such as farnesoid X receptor agonists, which are in development for NASH, may adversely affect circulating lipids and lipoproteins. CONCLUSIONS: NASH is a multi-system disease with a disproportionate CVD burden. Current and future drugs for NASH have had variable impact on the atherogenic risk profile. Potential co-administration of a statin may help mitigate the negative impact of some of these therapies on lipid and lipoprotein levels.


Asunto(s)
Aterosclerosis/etiología , Hipolipemiantes/uso terapéutico , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Aterosclerosis/epidemiología , Aterosclerosis/prevención & control , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/tendencias , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Hígado/fisiología , Pruebas de Función Hepática , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/patología , Pioglitazona/uso terapéutico , Factores de Riesgo
17.
Leg Med (Tokyo) ; 47: 101761, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32702607

RESUMEN

On the battlefields of Syria, many innocent civilians have been killed or injured by sarin poisoning. In Malaysia in February 2017, a North Korean man was assassinated with VX at Kuala Lumpur International Airport. In the face of such threats, a more effective antidote against organophosphonate acetylcholinesterase (AChE) inhibitors is needed, one that can freely penetrate into the central nervous system (CNS) through the blood-brain barrier (BBB). In the 1995 Tokyo subway sarin attack, which produced more than 6,000 victims, 2-pyridinealdoxime methiodide was the most commonly used antidote in hospitals, but it was unable to prevent CNS damage and no other oximes have been approved for use in Japan. Ultimately, 12 people died, and many victims had severe neurological injuries or sequelae. Although more than 25 years have passed since the incident, progress has been slow in the development of a new antidote that can penetrate the BBB, restore AChE activity in the CNS, and definitely prevent brain injury. From the perspectives of countering terrorism and protecting innocent people from nerve agent attacks, the search for nerve agent antidotes should be accelerated with the goals of improving both survival and quality of life. This review gives an overview of a series of our studies on the development of a new antidote since the Tokyo subway sarin attack and emphasizes that there is unfortunately still no promising antidote for saving the CNS in Japan.


Asunto(s)
Antídotos , Terrorismo Químico , Sustancias para la Guerra Química/envenenamiento , Inhibidores de la Colinesterasa/envenenamiento , Desarrollo de Medicamentos , Vías Férreas , Sarín/envenenamiento , Barrera Hematoencefálica/metabolismo , Terrorismo Químico/prevención & control , Sustancias para la Guerra Química/metabolismo , Inhibidores de la Colinesterasa/metabolismo , Desarrollo de Medicamentos/tendencias , Humanos , Compuestos de Pralidoxima , Sarín/metabolismo , Factores de Tiempo , Tokio
18.
Theranostics ; 10(17): 7821-7835, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32685022

RESUMEN

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently become a pandemic. As the sudden emergence and rapid spread of SARS-CoV-2 is endangering global health and the economy, the development of strategies to contain the virus's spread are urgently needed. At present, various diagnostic kits to test for SARS-CoV-2 are available for use to initiate appropriate treatment faster and to limit further spread of the virus. Several drugs have demonstrated in vitro activity against SARS-CoV-2 or potential clinical benefits. In addition, institutions and companies worldwide are working tirelessly to develop treatments and vaccines against COVID-19. However, no drug or vaccine has yet been specifically approved for COVID-19. Given the urgency of the outbreak, we focus here on recent advances in the diagnostics, treatment, and vaccine development for SARS-CoV-2 infection, helping to guide strategies to address the current COVID-19 pandemic.


Asunto(s)
Betacoronavirus , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Vacunas Virales , Antivirales/aislamiento & purificación , Antivirales/uso terapéutico , Betacoronavirus/genética , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Técnicas de Laboratorio Clínico/tendencias , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/terapia , Desarrollo de Medicamentos/tendencias , Humanos , Inmunización Pasiva/tendencias , Pandemias/prevención & control , Neumonía Viral/diagnóstico , Neumonía Viral/prevención & control , Neumonía Viral/terapia , Nanomedicina Teranóstica/tendencias , Vacunas Virales/aislamiento & purificación , Vacunas Virales/farmacología
19.
J Toxicol Sci ; 45(7): 365-371, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32612005

RESUMEN

Over the last decade, combination of drugs in all stages of pharmaceutical development has accelerated availability of promising new therapies for difficult to treat diseases. Safety assessment of combined drugs to be tested in humans can occur at a critical path prior to proceeding in clinical testing. A recent survey by The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ DruSafe) summarized member companies' approaches to combination safety strategies. In addition, feedback from Health Authorities (HAs) support a case-by-case scientific approach in assessing combination products' safety in accordance with the International Council on Harmonization (ICH) guidelines. Here, we present Pfizer's drug combination safety approach for various therapeutic areas (TA) including inflammation and immunology, metabolic, and anti-cancer products. There is no one-size-fits-all approach; rather, our main considerations include: strength of the existing clinical safety data for the individual compounds, common target organs, the potential for a synergistic effect, potential drug-drug interaction, routes of administration of each product and disease indications. No formal toxicity studies are considered necessary for anti-cancer drugs, while safety endpoints may be collected in preclinical pharmacology studies especially when the combined drugs present a novel mechanism. Combination safety studies when conducted for non-cancer indications can range from 2 to 13-weeks in duration, conducted usually in rodents, with dosages of individual molecules within clinical pharmacologic ranges. A case-by-case strategy guided by scientific rationale and in close collaboration with HAs remains the best approach to decide on the design and conduct of combination safety studies.


Asunto(s)
Desarrollo de Medicamentos , Toxicología/métodos , Toxicología/tendencias , Animales , Biomarcadores Farmacológicos , Desarrollo de Medicamentos/tendencias , Interacciones Farmacológicas , Humanos , Seguridad
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