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1.
PLoS Med ; 18(8): e1003726, 2021 08.
Article in English | MEDLINE | ID: covidwho-1416857

ABSTRACT

Florian Naudet and co-authors propose a pathway involving registered criteria for evaluation and approval of new drugs.


Subject(s)
Drug Approval/methods , European Union , Drug Approval/organization & administration , Marketing , Pharmaceutical Preparations
2.
Expert Opin Drug Saf ; 20(12): 1559-1564, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1334105

ABSTRACT

Background: Remdesivir has been used for treating patients with moderate to severe coronavirus disease 2019 (COVID-19) although there is conflicting evidence regarding its usefulness. Data regarding its safety largely come from the clinical trials conducted to support its emergency use authorization (EUA). This study aimed to identify the adverse events of remdesivir with disproportionately high reporting using real-world data.Research design and methods: The adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) by health-care professionals for drugs that have received EUA or approved for the treatment of COVID-19 in the US were studied. Adisproportionality analysis was performed to determine adverse events more frequently reported with remdesivir compared with other COVID-19 drugs in the database.Results: Elevated liver enzymes, acute kidney injury, raised blood creatinine levels, bradycardia, cardiac arrest, and death had disproportionately higher reporting with remdesivir as asuspect drug compared with other drugs. There is no significant difference in the reporting of these events based on patient sex or age.Conclusions: Our study confirms the drug label information regarding liver enzyme elevation. The renal and cardiac safety signals identified necessitate reevaluation for potential drug-labeling changes.


Subject(s)
Acute Kidney Injury , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Bradycardia , COVID-19 , Drug-Related Side Effects and Adverse Reactions , Liver Function Tests , Acute Kidney Injury/chemically induced , Acute Kidney Injury/diagnosis , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Alanine/administration & dosage , Alanine/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Bradycardia/chemically induced , Bradycardia/diagnosis , COVID-19/complications , COVID-19/drug therapy , COVID-19/epidemiology , Drug Approval/methods , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Liver Function Tests/methods , Liver Function Tests/statistics & numerical data , Male , Middle Aged , SARS-CoV-2 , United States/epidemiology , United States Food and Drug Administration/statistics & numerical data
3.
PLoS One ; 16(7): e0255270, 2021.
Article in English | MEDLINE | ID: covidwho-1332008

ABSTRACT

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become the current health concern and threat to the entire world. Thus, the world needs the fast recognition of appropriate drugs to restrict the spread of this disease. The global effort started to identify the best drug compounds to treat COVID-19, but going through a series of clinical trials and our lack of information about the details of the virus's performance has slowed down the time to reach this goal. In this work, we try to select the subset of human proteins as candidate sets that can bind to approved drugs. Our method is based on the information on human-virus protein interaction and their effect on the biological processes of the host cells. We also define some informative topological and statistical features for proteins in the protein-protein interaction network. We evaluate our selected sets with two groups of drugs. The first group contains the experimental unapproved treatments for COVID-19, and we show that from 17 drugs in this group, 15 drugs are approved by our selected sets. The second group contains the external clinical trials for COVID-19, and we show that 85% of drugs in this group, target at least one protein of our selected sets. We also study COVID-19 associated protein sets and identify proteins that are essential to disease pathology. For this analysis, we use DAVID tools to show and compare disease-associated genes that are contributed between the COVID-19 comorbidities. Our results for shared genes show significant enrichment for cardiovascular-related, hypertension, diabetes type 2, kidney-related and lung-related diseases. In the last part of this work, we recommend 56 potential effective drugs for further research and investigation for COVID-19 treatment. Materials and implementations are available at: https://github.com/MahnazHabibi/Drug-repurposing.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pandemics/prevention & control , Comorbidity , Drug Approval/methods , Drug Repositioning/methods , Humans , Protein Interaction Maps/drug effects
5.
J Neurooncol ; 153(3): 375-381, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1279476

ABSTRACT

OBJECTIVE: Contemporary management of patients with neuro-oncologic disease requires an understanding of approvals by the US Food and Drug Administration (FDA) related to nervous system tumors. To summarize FDA updates applicable to neuro-oncology practitioners, we sought to review oncology product approvals and Guidances that were pertinent to the field in the past year. METHODS: Oncology product approvals between January 1, 2020, and December 31, 2020, were reviewed for clinical trial outcomes involving tumors of the nervous system. FDA Guidances relevant to neuro-oncology were also reviewed. RESULTS: Five oncology product approvals described outcomes for nervous system tumors in the year 2020. These included the first regulatory approval for neurofibromatosis type 1: selumetinib for children with symptomatic, inoperable plexiform neurofibromas. Additionally, there were 4 regulatory approvals for non-central nervous system (CNS) cancers that described clinical outcomes for patients with brain metastases. These included the approval of tucatinib for metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer including patients with brain metastases, brigatinib for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and pralsetinib and selpercatinib for RET fusion-positive NSCLC. Finally, two FDA Guidances for Industry, "Cancer Clinical Trial Eligibility Criteria: Brain Metastases" and "Evaluating Cancer Drugs in Patients with Central Nervous System Metastases" were published to facilitate drug development for and inclusion of patients with CNS metastases in clinical trials. CONCLUSIONS: Despite the challenges of the past year brought on by the COVID-19 pandemic, progress continues to be made in neuro-oncology. These include first-of-their-kind FDA approvals and Guidances that are relevant to the management of patients with nervous system tumors.


Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Drug Approval/legislation & jurisprudence , Drug Approval/methods , Humans , United States , United States Food and Drug Administration
6.
Biochem Pharmacol ; 189: 114424, 2021 07.
Article in English | MEDLINE | ID: covidwho-1269238

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Three viral proteins, the spike protein (S) for attachment of virus to host cells, 3-chymotrypsin-like cysteine protease (Mpro) for digestion of viral polyproteins to functional proteins, and RNA-dependent-RNA-polymerase (RdRp) for RNA synthesis are the most critical proteins for virus infection and replication, rendering them the most important drug targets for both antibody and chemical drugs. Due to its low-fidelity polymerase, the virus is subject to frequent mutations. To date, the sequence data from tens of thousands of virus isolates have revealed hundreds of mutations. Although most mutations have a minimum consequence, a small number of non-synonymous mutations may alter the virulence and antigenicity of the mutants. To evaluate the effects of viral mutations on drug safety and efficacy, we reviewed the biochemical features of the three main proteins and their potentials as drug targets, and analyzed the mutation profiles and their impacts on RNA therapeutics. We believe that monitoring and predicting mutation-introduced protein conformational changes in the three key viral proteins and evaluating their binding affinities and enzymatic activities with the U.S. Food and Drug Administration (FDA) regulated drugs by using computational modeling and machine learning processes can provide valuable information for the consideration of drug efficacy and drug safety for drug developers and drug reviewers. Finally, we propose an interactive database for drug developers and reviewers to use in evaluating the safety and efficacy of U.S. FDA regulated drugs with regard to viral mutations.


Subject(s)
COVID-19/drug therapy , COVID-19/genetics , Mutation/genetics , RNA/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Animals , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , COVID-19/metabolism , Drug Approval/methods , Drug Development/methods , Drug Development/trends , Humans , RNA/metabolism , RNA/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism
7.
AAPS PharmSciTech ; 22(5): 172, 2021 Jun 07.
Article in English | MEDLINE | ID: covidwho-1261286

ABSTRACT

Vaccination development and production was an essential question for the prevention and global control of COVID-19. The strong support from governing authorities such as Operation Warp Speed and robust funding has led to the development and authorization of the tozinameran (BNT162b2) vaccine. The BNT162b2 vaccine is a lipid nanoparticle-encapsulated mRNA that encodes for SARS-CoV-2 spike protein, the main site for neutralizing antibodies. Once it binds with the host cells, the lipid nanoparticles enable the transfer of the RNA, causing S antigens' expression of the SARS-CoV-2, conferring immunity. The vaccine is administered as a 2-dose regime 21 days apart for individuals 16 years and older. Pfizer-BioNTech's BNT162b2 vaccine was the first candidate to receive FDA-Emergency Use Authorization (EUA) on December 11, 2020. During phase 2/3 clinical trials, 95% efficacy was reported among 37,706 participants over the age of 16 who received the BNT162b2 vaccination; additionally, 52% efficacy was noted 12 days following the administration of the first dose of BNT162b2, reflecting early protection of COVID-19. The BNT162b2 vaccine has exhibited 100% efficacy in clinical trials of adolescents between the ages of 12 and 15. Clinical trials in pregnant women and children under the age of 12 are expected to also exhibit promising results. This review article encompasses tozinameran (BNT162b2) vaccine journey, summarizing the BNT162b1 and BNT162b2 vaccines from preclinical studies, clinical trial phases, dosages, immune response, adverse effects, and FDA-EUA.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Clinical Trials as Topic/methods , Drug Approval/methods , SARS-CoV-2/drug effects , Animals , Antibodies, Neutralizing/drug effects , Antibodies, Neutralizing/metabolism , COVID-19/epidemiology , COVID-19/metabolism , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/metabolism , Clinical Trials as Topic/legislation & jurisprudence , Drug Approval/legislation & jurisprudence , Drug Evaluation, Preclinical/methods , Exanthema/chemically induced , Female , Humans , Male , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Vaccination/legislation & jurisprudence , Vaccination/methods
8.
Clin Pharmacol Ther ; 111(3): 551-558, 2022 03.
Article in English | MEDLINE | ID: covidwho-1241501

ABSTRACT

The development of drugs for coronavirus disease 2019 (COVID-19) is a global challenge. In Japan, remdesivir was approved in May 2020 for COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In February 2021, a vaccine against COVID-19 was approved. These two approvals were made using the Special Approval for Emergency system in Japan. This Japanese system was started in 2010 and has been used to approve four drugs to date, including remdesivir and the Pfizer COVID-19 vaccine. This paper discusses future challenges for Japan's Special Approval for Emergency system and organizes what can be learned from experiences to date. As a result, I would like to point Out the following issues. (i) Special Approval for Emergency is a system for approving drugs approved overseas, not a system for approving drugs originally developed in Japan. A system to approve drugs that have not been approved in foreign countries needs to be considered. (ii) In the Special Approval for Emergency system, it is necessary to ensure that postmarketing activities are conducted in accordance with the Risk Management Plan and the conditions of approval, to disclose the results in a timely and speedy manner, and to judge the appropriateness of continued approval based on the results of postmarketing activities.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Approval/legislation & jurisprudence , COVID-19/epidemiology , Drug Approval/methods , Drug and Narcotic Control/legislation & jurisprudence , Emergencies , Europe , Humans , Japan , Risk Management , United States , United States Food and Drug Administration
13.
Drug Deliv Transl Res ; 11(4): 1309-1315, 2021 08.
Article in English | MEDLINE | ID: covidwho-1053116

ABSTRACT

One year after the first human case of SARS-CoV-2, two nanomedicine-based mRNA vaccines have been fast-tracked, developed, and have received emergency use authorization throughout the globe with more vaccine approvals on the heels of these first two. Several SARS-CoV-2 vaccine compositions use nanotechnology-enabled formulations. A silver lining of the COVID-19 pandemic is that the fast-tracked vaccine development for SARS-CoV-2 has advanced the clinical translation pathway for nanomedicine drug delivery systems. The laboratory science of lipid-based nanoparticles was ready and rose to the clinical challenge of rapid vaccine development. The successful development and fast tracking of SARS-CoV-2 nanomedicine vaccines has exciting implications for the future of nanotechnology-enabled drug and gene delivery; it demonstrates that nanomedicine is necessary and critical to the successful delivery of advanced molecular therapeutics such as nucleic acids, it is establishing the precedent of safety and the population effect of phase four clinical trials, and it is laying the foundation for the clinical translation of more complex, non-lipid nanomedicines. The development, fast-tracking, and approval of SARS-CoV-2 nanotechnology-based vaccines has transformed the seemingly daunting challenges for clinically translating nanomedicines into measurable hurdles that can be overcome. Due to the tremendous scientific achievements that have occurred in response to the COVID-19 pandemic, years, perhaps even decades, have been streamlined for certain translational nanomedicines.


Subject(s)
COVID-19 Vaccines/administration & dosage , Drug Approval/methods , Nanomedicine/methods , Nanotechnology/methods , Vaccines, Synthetic/administration & dosage , COVID-19/epidemiology , COVID-19/genetics , COVID-19/prevention & control , COVID-19 Vaccines/genetics , Clinical Trials, Phase IV as Topic/methods , Humans , Nanomedicine/trends , Nanotechnology/trends , RNA, Messenger/administration & dosage , RNA, Messenger/genetics , SARS-CoV-2/genetics , Vaccines, Synthetic/genetics
17.
Nucleic Acids Res ; 49(D1): D1160-D1169, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-910390

ABSTRACT

DrugCentral is a public resource (http://drugcentral.org) that serves the scientific community by providing up-to-date drug information, as described in previous papers. The current release includes 109 newly approved (October 2018 through March 2020) active pharmaceutical ingredients in the US, Europe, Japan and other countries; and two molecular entities (e.g. mefuparib) of interest for COVID19. New additions include a set of pharmacokinetic properties for ∼1000 drugs, and a sex-based separation of side effects, processed from FAERS (FDA Adverse Event Reporting System); as well as a drug repositioning prioritization scheme based on the market availability and intellectual property rights forFDA approved drugs. In the context of the COVID19 pandemic, we also incorporated REDIAL-2020, a machine learning platform that estimates anti-SARS-CoV-2 activities, as well as the 'drugs in news' feature offers a brief enumeration of the most interesting drugs at the present moment. The full database dump and data files are available for download from the DrugCentral web portal.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Databases, Pharmaceutical/statistics & numerical data , Drug Approval/statistics & numerical data , Drug Discovery/statistics & numerical data , Drug Repositioning/statistics & numerical data , SARS-CoV-2/drug effects , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , COVID-19/epidemiology , COVID-19/virology , Drug Approval/methods , Drug Discovery/methods , Drug Repositioning/methods , Epidemics , Europe , Humans , Information Storage and Retrieval/methods , Internet , Japan , SARS-CoV-2/physiology , United States
20.
Drug Resist Updat ; 53: 100719, 2020 12.
Article in English | MEDLINE | ID: covidwho-645153

ABSTRACT

In December 2019, a novel SARS-CoV-2 coronavirus emerged, causing an outbreak of life-threatening pneumonia in the Hubei province, China, and has now spread worldwide, causing a pandemic. The urgent need to control the disease, combined with the lack of specific and effective treatment modalities, call for the use of FDA-approved agents that have shown efficacy against similar pathogens. Chloroquine, remdesivir, lopinavir/ritonavir or ribavirin have all been successful in inhibiting SARS-CoV-2 in vitro. The initial results of a number of clinical trials involving various protocols of administration of chloroquine or hydroxychloroquine mostly point towards their beneficial effect. However, they may not be effective in cases with persistently high viremia, while results on ivermectin (another antiparasitic agent) are not yet available. Interestingly, azithromycin, a macrolide antibiotic in combination with hydroxychloroquine, might yield clinical benefit as an adjunctive. The results of clinical trials point to the potential clinical efficacy of antivirals, especially remdesivir (GS-5734), lopinavir/ritonavir, and favipiravir. Other therapeutic options that are being explored involve meplazumab, tocilizumab, and interferon type 1. We discuss a number of other drugs that are currently in clinical trials, whose results are not yet available, and in various instances we enrich such efficacy analysis by invoking historic data on the treatment of SARS, MERS, influenza, or in vitro studies. Meanwhile, scientists worldwide are seeking to discover novel drugs that take advantage of the molecular structure of the virus, its intracellular life cycle that probably elucidates unfolded-protein response, as well as its mechanism of surface binding and cell invasion, like angiotensin converting enzymes-, HR1, and metalloproteinase inhibitors.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Drug Approval/methods , SARS-CoV-2/drug effects , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/metabolism , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/metabolism , Antimalarials/administration & dosage , Antimalarials/metabolism , Antiviral Agents/metabolism , COVID-19/metabolism , Clinical Trials as Topic/methods , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/metabolism , Drug Therapy, Combination , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/metabolism , SARS-CoV-2/metabolism , United States/epidemiology
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