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Profiles of Drug Substances,... 2023Remdesivir, marketed under the brand name Veklury, is an antiviral drug with a broad spectrum of activity. There were various countries where the use of Remdesivir for... (Review)
Review
Remdesivir, marketed under the brand name Veklury, is an antiviral drug with a broad spectrum of activity. There were various countries where the use of Remdesivir for the treatment of COVID-19 was authorized during the pandemic. Remdesivir was first designed to treat hepatitis C, but it was later tested for Ebola virus sickness and Marburg virus infections. Remdesivir is a prodrug designed to facilitate the intracellular transport of GS-441524 monophosphate and its subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase. The objective of this chapter is to provide a comprehensive review of Remdesivir (GS-5734), including its nomenclature, physiochemical properties, preparation methods, identification procedures, numerous qualitative and quantitative analytical techniques, ADME profiles, and pharmacological effects. In addition, the chapter provides a variety of chromatographic and spectroscopic techniques for separating brimonidine from other drugs in combination formulations.
Topics: Humans; COVID-19; SARS-CoV-2; COVID-19 Drug Treatment; Adenosine Monophosphate
PubMed: 37061276
DOI: 10.1016/bs.podrm.2022.11.003 -
Cell Research Mar 2020
Topics: Adenosine Monophosphate; Alanine; Animals; Antimalarials; Antiviral Agents; Betacoronavirus; Biological Assay; COVID-19; Chlorocebus aethiops; Chloroquine; Coronavirus Infections; Drug Discovery; Drug Evaluation, Preclinical; Humans; Middle East Respiratory Syndrome Coronavirus; Pneumonia, Viral; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; Sincalide; Vero Cells; COVID-19 Drug Treatment
PubMed: 32020029
DOI: 10.1038/s41422-020-0282-0 -
Biochemical Pharmacology Nov 2021Remdesivir (GS-5734, Veklury®) has remained the only antiviral drug formally approved by the US FDA for the treatment of Covid-19 (SARS-CoV-2 infection). Its key... (Review)
Review
Remdesivir (GS-5734, Veklury®) has remained the only antiviral drug formally approved by the US FDA for the treatment of Covid-19 (SARS-CoV-2 infection). Its key structural features are the fact that it is a C-nucleoside (adenosine) analogue, contains a 1'-cyano function, and could be considered as a ProTide based on the presence of a phosphoramidate group. Its antiviral spectrum and activity in animal models have been well established and so has been its molecular mode of action as a delayed chain terminator of the viral RdRp (RNA-dependent RNA polymerase). Its clinical efficacy has been evaluated, but needs to be optimized with regard to timing, dosage and duration of treatment, and route of administration. Safety, toxicity and pharmacokinetics need to be further addressed, and so are its potential combinations with other drugs such as corticosteroids (i.e. dexamethasone) and ribavirin.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; COVID-19; Drug Therapy, Combination; Humans; Protein Structure, Tertiary; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34678228
DOI: 10.1016/j.bcp.2021.114800 -
A&A Practice Nov 2019
Topics: Adenosine Monophosphate; Cardiopulmonary Bypass; Heparin; Humans; Kidney Failure, Chronic; Thrombocytopenia
PubMed: 31609718
DOI: 10.1213/XAA.0000000000001095 -
MMW Fortschritte Der Medizin Jun 2022
Review
Topics: Adenosine Monophosphate; Alanine; Hospitalization; Humans; COVID-19 Drug Treatment
PubMed: 35650486
DOI: 10.1007/s15006-022-1234-z -
Biochemical and Biophysical Research... Jan 2021Human coronaviruses (HCoV) were discovered in the 1960s and were originally thought to cause only mild upper respiratory tract diseases in immunocompetent hosts. This... (Review)
Review
Human coronaviruses (HCoV) were discovered in the 1960s and were originally thought to cause only mild upper respiratory tract diseases in immunocompetent hosts. This view changed since the beginning of this century, with the 2002 SARS (severe acute respiratory syndrome) epidemic and the 2012 MERS (Middle East respiratory syndrome) outbreak, two zoonotic infections that resulted in mortality rates of approximately 10% and 35%, respectively. Despite the importance of these pathogens, no approved antiviral drugs for the treatment of human coronavirus infections became available. However, remdesivir, a nucleotide analogue prodrug originally developed for the treatment of Ebola virus, was found to inhibit the replication of a wide range of human and animal coronaviruses in vitro and in preclinical studies. It is therefore not surprising that when the highly pathogenic SARS-CoV-2 coronavirus emerged in late 2019 in China, causing global health concern due to the virus strong human-to-human transmission ability, remdesivir was one of the first clinical candidates that received attention. After in vitro studies had shown its antiviral activity against SARS-CoV-2, and a first patient was successfully treated with the drug in the USA, a number of trials on remdesivir were initiated. Several had encouraging results, particularly the ACTT-1 double blind, randomized, and placebo controlled trial that has shown shortening of the time to recovery in hospitalized patients treated with remdesivir. The results of other trials were instead negative. Here, we provide an overview of remdesivir discovery, molecular mechanism of action, and initial and current clinical studies on its efficacy.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Drug Discovery; Hemorrhagic Fever, Ebola; Humans; COVID-19 Drug Treatment
PubMed: 33388129
DOI: 10.1016/j.bbrc.2020.11.043 -
Cell Jul 2020Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19...
Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; Catalytic Domain; Coronavirus RNA-Dependent RNA Polymerase; Cryoelectron Microscopy; Models, Chemical; Models, Molecular; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Transcription, Genetic; Viral Nonstructural Proteins; Virus Replication
PubMed: 32526208
DOI: 10.1016/j.cell.2020.05.034 -
Frontiers in Immunology 2022Adenosine is a purine nucleoside that, activation of distinct G protein-coupled receptors, modulates inflammation and immune responses. Under pathological conditions... (Review)
Review
Adenosine is a purine nucleoside that, activation of distinct G protein-coupled receptors, modulates inflammation and immune responses. Under pathological conditions and in response to inflammatory stimuli, extracellular ATP is released from damaged cells and is metabolized to extracellular adenosine. However, studies over the past 30 years provide strong evidence for another source of extracellular adenosine, namely the "cAMP-adenosine pathway." The cAMP-adenosine pathway is a biochemical mechanism mediated by ATP-binding cassette transporters that facilitate cAMP efflux and by specific ectoenzymes that convert cAMP to AMP (ecto-PDEs) and AMP to adenosine (ecto-nucleotidases such as CD73). Importantly, the cAMP-adenosine pathway is operative in many cell types, including those of the airways. In airways, β-adrenoceptor agonists, which are used as bronchodilators for treatment of asthma and chronic respiratory diseases, stimulate cAMP efflux and thus trigger the extracellular cAMP-adenosine pathway leading to increased concentrations of extracellular adenosine in airways. In the airways, extracellular adenosine exerts pro-inflammatory effects and induces bronchoconstriction in patients with asthma and chronic obstructive pulmonary diseases. These considerations lead to the hypothesis that the cAMP-adenosine pathway attenuates the efficacy of β-adrenoceptor agonists. Indeed, our recent findings support this view. In this mini-review, we will highlight the potential role of the extracellular cAMP-adenosine pathway in chronic respiratory inflammatory disorders, and we will explore how extracellular cAMP could interfere with the regulatory effects of intracellular cAMP on airway smooth muscle and innate immune cell function. Finally, we will discuss therapeutic possibilities targeting the extracellular cAMP-adenosine pathway for treatment of these respiratory diseases.
Topics: Adenosine; Adenosine Monophosphate; Asthma; Humans; Receptors, Adrenergic; Signal Transduction
PubMed: 35479074
DOI: 10.3389/fimmu.2022.866097 -
European Review For Medical and... Sep 2020Remdesivir is a nucleotide analogue prodrug that inhibits viral RNA polymerases. It has been recognized recently as a promising antiviral drug against a wide array of... (Review)
Review
OBJECTIVE
Remdesivir is a nucleotide analogue prodrug that inhibits viral RNA polymerases. It has been recognized recently as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV5). We aimed at determining which drugs used in dentistry interact with Remdesivir in order to avoid adverse reactions that may worsen the condition of patients with COVID-19.
MATERIALS AND METHODS
A literature review was conducted to identify potential drug interactions between remdesivir (used in the treatment of COVID-19) and drugs prescribed in dentistry. The search was made in the databases PubMed and MEDLINE and official websites using key terms remdesivir, drug interactions and dentistry for articles published up to 31st July 2020.
RESULTS
According to the articles reviewed, a total of 279 drugs interact with Remdesivir. Two major interactions have been reported, 277 moderate drug interactions, and one with alcohol/food. The drug interactions involving drugs prescribed in dentistry are all moderate drug interactions and are (according to drug group): (1) antibiotics: azithromycin, clavulanate, doxycycline, erythromycin, levofloxacin; (2) antifungals: clotrimazole, fluconazole, itraconazole, ketoconazole; (3) non-steroidal anti-inflammatories (NAIDS): celecoxib diclofenac, etodolac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, mefenamic acid, naproxen, piroxicam.
CONCLUSIONS
It is clinically necessary for oral health professionals to be aware of possible drug interactions that may occur between remdesivir and drugs commonly prescribed in dentistry in order to prevent adverse reactions that may even endanger the life of a patient with COVID-19.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Dentistry; Drug Interactions; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 33015819
DOI: 10.26355/eurrev_202009_23065 -
Shock (Augusta, Ga.) Aug 2020Ischemia and reperfusion injury following severe trauma or cardiac arrest are major causes of organ damage in intensive care patients. The brain is particularly...
Ischemia and reperfusion injury following severe trauma or cardiac arrest are major causes of organ damage in intensive care patients. The brain is particularly vulnerable because hypoxia rapidly damages neurons due to their heavy reliance on oxidative phosphorylation. Therapeutic hypothermia can reduce ischemia-induced brain damage, but cooling procedures are slow and technically difficult to perform in critical care settings. It has been previously reported that injection of naturally occurring adenosine 5'-monophosphate (AMP) can rapidly induce hypothermia in mice. We studied the underlying mechanisms and found that AMP transiently reduces the heart rate, respiratory rate, body temperature, and the consciousness of adult male and female C57BL/6J mice. Adding AMP to mouse or human neuronal cell cultures dose-dependently reduced the membrane potential (ΔΨm) and Ca signaling of mitochondria in these cells. AMP treatment increased intracellular AMP levels and activated AMP-activated protein kinase, which resulted in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and of mitochondrial and cytosolic Ca signaling in resting and stimulated neurons. Pretreatment with an intraperitoneal injection of AMP almost doubled the survival time of mice under hypoxic (6% O2) or anoxic (<1% O2) conditions when compared to untreated mice. These findings suggest that AMP induces a hypometabolic state that slows mitochondrial respiration, reduces oxygen demand, and delays the processes that damage mitochondria in the brain and other organs following hypoxia and reperfusion. Further examination of these mechanisms may lead to new treatments that preserve organ function in critical care patients.
Topics: Adenosine Monophosphate; Animals; Cells, Cultured; Female; Humans; Hypoxia; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mitochondria; Oxygen; Signal Transduction
PubMed: 31460871
DOI: 10.1097/SHK.0000000000001440