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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 -
Tierarztliche Praxis. Ausgabe K,... Jun 2022
Topics: Alanine; Animals; Dog Diseases; Dogs; Lymphoma; Purines
PubMed: 35790170
DOI: 10.1055/a-1843-1662 -
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 -
Nutrients Mar 2022Cockscomb hydrolysate was found to have neurite outgrowth-promoting activity in PC12 cells. To investigate the neurite outgrowth-promoting compounds derived from...
Cockscomb hydrolysate was found to have neurite outgrowth-promoting activity in PC12 cells. To investigate the neurite outgrowth-promoting compounds derived from cockscomb hydrolysate, bioassay-guided purification was carried out. Purified active fractions were obtained by liquid-liquid partition, followed by column chromatography. High-performance liquid chromatography and proton nuclear magnetic resonance analyses of the purified active fractions clarified that the main compounds are threonine, alanine, valine, and methionine. By screening for 20 kinds of amino acids, it was shown that valine and methionine, but not threonine and alanine, have neurite outgrowth-promoting activity. The results of activity evaluation of the mixture of amino acids indicated that alanine enhanced the activity of valine and that the mixture of valine and methionine showed a higher ratio of neurite formation than did each of them alone. On the other hand, dipeptides formed by valine and methionine showed weak neurite outgrowth-promoting activity. A mixture of threonine, alanine, valine, and methionine at the same concentrations as those in cockscomb hydrolysate showed neurite outgrowth-promoting activity comparable to that of cockscomb hydrolysate although threonine, alanine, valine, and methionine alone did not show activity at their concentrations in cockscomb hydrolysate. Therefore, the strong neurite outgrowth-promoting activity of cockscomb hydrolysate was considered to be due to the synergistic effect of threonine, alanine, valine, and methionine.
Topics: Alanine; Amino Acids; Animals; Methionine; Neurites; Neuronal Outgrowth; PC12 Cells; Rats; Threonine; Valine
PubMed: 35406035
DOI: 10.3390/nu14071422 -
Amino Acids Jun 2021Plants catalyze the biosynthesis of a large number of non-protein amino acids, which are usually toxic for other organisms. In this review, the chemistry and metabolism... (Review)
Review
Plants catalyze the biosynthesis of a large number of non-protein amino acids, which are usually toxic for other organisms. In this review, the chemistry and metabolism of N-heterocyclic non-protein amino acids from plants are described. These N-heterocyclic non-protein amino acids are composed of β-substituted alanines and include mimosine, β-pyrazol-1-yl-L-alanine, willardiine, isowillardiine, and lathyrine. These β-substituted alanines consisted of an N-heterocyclic moiety and an alanyl side chain. This review explains how these individual moieties are derived from their precursors and how they are used as the substrate for biosynthesizing the respective N-heterocyclic non-protein amino acids. In addition, known catabolism and possible role of these non-protein amino acids in the actual host is explained.
Topics: Alanine; Amino Acids, Diamino; Plants; Uracil
PubMed: 33950299
DOI: 10.1007/s00726-021-02990-0 -
BMJ (Clinical Research Ed.) Nov 2020
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; Randomized Controlled Trials as Topic; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33234523
DOI: 10.1136/bmj.m4560 -
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 -
Expert Opinion on Therapeutic Patents Apr 2021: The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 represents a serious health issue worldwide, with more than 61 million cases and more than 1.4 million... (Review)
Review
: The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 represents a serious health issue worldwide, with more than 61 million cases and more than 1.4 million deaths since the beginning of the epidemic near the end of 2019. The scientific community strongly responded to this emergency situation with massive research efforts, mostly focused on diagnosis and clinical investigation of therapeutic solutions. In this scenario, drug repurposing played a crucial role in accelerating advanced clinical testing and shortening the time to access the regulatory review.: This review covers the main and most successful drug repurposing approaches from a design, clinical, and regulatory standpoint. Available patents on repurposed drugs are also discussed.: Drug repurposing proved highly successful in response to the current pandemic, with remdesivir becoming the first specific antiviral drug approved for the treatment of COVID-19. In parallel, a number of drugs such as corticosteroids and low molecular weight heparin (LMWH) are used to treat hospitalized COVID-19 patients, while clinical testing of additional therapeutic options is ongoing. It is reasonably expected that these research efforts will deliver optimized and specific therapeutic tools that will increase the preparedness of health systems to possible future epidemics.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Drug Repositioning; Female; Humans; Male; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33283567
DOI: 10.1080/13543776.2021.1861248 -
European Journal of Internal Medicine Aug 2022The clinical progression of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to critical illness is associated with a systemic and uncontrolled... (Review)
Review
The clinical progression of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to critical illness is associated with a systemic and uncontrolled inflammatory response of the innate and adaptive immunity with the release of a plethora of proinflammatory cytokines termed "cytokine storm". In the absence of an effective treatment, many off-label agents from the armamentarium of rheumatology are used. Here, from the perspective of a rheumatologist, we will discuss the current therapeutic strategies in critically ill patients with SARS-CoV-2 pneumonia. Thus, we will discuss the agents that aim to target viral entry and its replication into the host cell and those focusing and targeting the inflammatory response. In this setting, many agents have been used with promising results but, not all have been approved by the International Authorities and Institutions. In the first step (viral entry), SARS-CoV-2 monoclonal antibodies and remdesivir have been approved to be used and, in the second step, corticosteroids along with interleukin-6 inhibitors, or Janus Kinase inhibitors are currently used.
Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Alanine; Antibodies, Monoclonal; Critical Illness; Cytokine Release Syndrome; Cytokines; Humans; Rheumatology; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35610165
DOI: 10.1016/j.ejim.2022.05.014 -
Journal of Infection and Chemotherapy :... Jan 2023Healthcare-associated COVID-19 among vulnerable patients leads to disproportionate morbidity and mortality. Early pharmacologic intervention may reduce negative sequelae... (Review)
Review
Healthcare-associated COVID-19 among vulnerable patients leads to disproportionate morbidity and mortality. Early pharmacologic intervention may reduce negative sequelae and improve survival in such settings. This study aimed to describe outcome of patients with healthcare-associated COVID-19 who received early short-course remdesivir therapy. We reviewed the characteristics and outcome of hospitalized patients who developed COVID-19 during an outbreak that involved two wards at a non-acute care hospital in Japan and received short-course remdesivir. Forty-nine patients were diagnosed with COVID-19, 34 on a comprehensive inpatient rehabilitation ward and 15 on a combined palliative care and internal medicine ward. Forty-seven were symptomatic and 46 of them received remdesivir. The median age was 75, and the median Charlson comorbidity index was 6 among those who received it. Forty-one patients had received one or two doses of mRNA vaccines, while none had received a third dose. Most patients received 3 days of remdesivir. Of the patients followed up to 14 and 28 days from onset, 41/44 (95.3%) and 35/41(85.4%) were alive, respectively. Six deaths occurred by 28 days in the palliative care/internal medicine ward and two of them were possibly related to COVID-19. Among those who survived, the performance status was unchanged between the time of onset and at 28 days.
Topics: Humans; Aged; SARS-CoV-2; Antiviral Agents; Alanine; Delivery of Health Care; Hospitals; COVID-19 Drug Treatment
PubMed: 36113848
DOI: 10.1016/j.jiac.2022.08.025