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FEBS Open Bio Jun 2022Influenza A and B viruses are among the most prominent human respiratory pathogens. About 3-5 million severe cases of influenza are associated with 300 000-650 000... (Review)
Review
Influenza A and B viruses are among the most prominent human respiratory pathogens. About 3-5 million severe cases of influenza are associated with 300 000-650 000 deaths per year globally. Antivirals effective at reducing morbidity and mortality are part of the first line of defense against influenza. FDA-approved antiviral drugs currently include adamantanes (rimantadine and amantadine), neuraminidase inhibitors (NAI; peramivir, zanamivir, and oseltamivir), and the PA endonuclease inhibitor (baloxavir). Mutations associated with antiviral resistance are common and highlight the need for further improvement and development of novel anti-influenza drugs. A summary is provided for the current knowledge of the approved influenza antivirals and antivirals strategies under evaluation in clinical trials. Preclinical evaluations of novel compounds effective against influenza in different animal models are also discussed.
Topics: Animals; Antiviral Agents; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Models, Animal; Oseltamivir
PubMed: 35451200
DOI: 10.1002/2211-5463.13416 -
Journal of Medicinal Chemistry Oct 2022Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By... (Review)
Review
Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.
Topics: Humans; Neuraminidase; Zanamivir; Oseltamivir; N-Acetylneuraminic Acid; Enzyme Inhibitors; Sialic Acids; Antiviral Agents; Biological Products
PubMed: 36252951
DOI: 10.1021/acs.jmedchem.2c01258 -
Science Immunology Jun 2023The immune system eliminates pathogen intruders such as viruses and bacteria. To recruit immune effectors to virus-infected cells, we conjugated a small molecule, the...
The immune system eliminates pathogen intruders such as viruses and bacteria. To recruit immune effectors to virus-infected cells, we conjugated a small molecule, the influenza neuraminidase inhibitor zanamivir, to a nanobody that recognizes the kappa light chains of mouse immunoglobulins. This adduct was designed to achieve half-life extension of zanamivir through complex formation with the much-larger immunoglobulins in the circulation. The zanamivir moiety targets the adduct to virus-infected cells, whereas the anti-kappa component simultaneously delivers polyclonal immunoglobulins of indeterminate specificity and all isotypes. Activation of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity promoted elimination of influenza neuraminidase-positive cells. A single dose of the conjugate protected mice against influenza A or B viruses and was effective even when given several days after infection with a lethal dose of virus. In the absence of circulating immunoglobulins, we observed no in vivo protection from the adduct. The type of conjugates described here may thus find application for both anti-influenza prophylaxis and therapy.
Topics: Mice; Animals; Humans; Zanamivir; Oseltamivir; Immunoglobulin Light Chains; Neuraminidase; Influenza, Human; Mice, Inbred BALB C
PubMed: 37352373
DOI: 10.1126/sciimmunol.adg9459 -
Enzyme and Microbial Technology Oct 2023Shikimate, a precursor to the antiviral drug oseltamivir (Tamiflu®), can influence aromatic metabolites and finds extensive use in antimicrobial, antitumor, and... (Review)
Review
Shikimate, a precursor to the antiviral drug oseltamivir (Tamiflu®), can influence aromatic metabolites and finds extensive use in antimicrobial, antitumor, and cardiovascular applications. Consequently, various strategies have been developed for chemical synthesis and plant extraction to enhance shikimate biosynthesis, potentially impacting environmental conditions, economic sustainability, and separation and purification processes. Microbial engineering has been developed as an environmentally friendly approach for shikimate biosynthesis. In this review, we provide a comprehensive summary of microbial strategies for shikimate biosynthesis. These strategies primarily include chassis construction, biochemical optimization, pathway remodelling, and global regulation. Furthermore, we discuss future perspectives on shikimate biosynthesis and emphasize the importance of utilizing advanced metabolic engineering tools to regulate microbial networks for constructing robust microbial cell factories.
Topics: Antiviral Agents; Metabolic Engineering; Microbial Consortia; Oseltamivir
PubMed: 37598506
DOI: 10.1016/j.enzmictec.2023.110306 -
Current Opinion in Pulmonary Medicine May 2020Influenza represents a significant treatment burden to critical care services. A variety of treatment strategies exist, with more and more therapeutic avenues opening up... (Review)
Review
PURPOSE OF REVIEW
Influenza represents a significant treatment burden to critical care services. A variety of treatment strategies exist, with more and more therapeutic avenues opening up as research progresses. We examined both pharmacological and supportive treatment strategies currently available to see how they might be applied in an ICU setting.
RECENT FINDINGS
Supportive care in Influenza centres around optimizing respiratory failure, particularly through well established and recognized ventilatory strategies. Noninvasive ventilation and high-flow nasal oxygen may have a limited role in selected patients under carefully monitored circumstances. Drug therapy exerts only a modest clinical effect and has been poorly studied in the critically ill, though there is some evidence to support the use of neuraminidase inhibitors (NAI) - particularly oseltamivir - as early as possible in this cohort. Newer agents have failed to demonstrate superiority over NAIs but may be useful options if the patient fails to respond or should resistant influenza strains emerge. Steroid therapy, in the absence of another indication, must be recommended against given the repeated trend towards increased mortality in this group.
SUMMARY
Influenza management is an evolving field of significant interest to any critical care provider. Currently, good respiratory supportive care and early enteral oseltamivir are the best supported treatment strategies. Further study in the intensive care setting will be needed before the use of novel agents can be recommended.
Topics: Adrenal Cortex Hormones; Amides; Antiviral Agents; Critical Care; Critical Illness; Dibenzothiepins; Enzyme Inhibitors; Humans; Influenza, Human; Morpholines; Neuraminidase; Oseltamivir; Pyrazines; Pyridines; Pyridones; Pyrimidines; Pyrroles; Respiration, Artificial; Triazines; Zanamivir
PubMed: 32068576
DOI: 10.1097/MCP.0000000000000667 -
Seminars in Respiratory and Critical... Dec 2021Influenza is an acute respiratory illness caused by the influenza A, B, and C viruses. It can occur in local outbreaks or seasonal epidemics, with possibility to spread... (Review)
Review
Influenza is an acute respiratory illness caused by the influenza A, B, and C viruses. It can occur in local outbreaks or seasonal epidemics, with possibility to spread worldwide in a pandemic when a novel strain with significant antigenic differences emerges. During the past years, several new drugs have become available, with different accessibility related to specific countries' approval. We have conducted a review of literature, analyzing the most recent data on efficacy and safety of drugs currently available to treat influenza, with a particular attention toward special populations. Efficacy and safety profile of neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, peramivir) and recently approved cap-dependent endonuclease inhibitor baloxavir marboxil are reported in literature, but still little information is available about special populations such as critically ill patients and patients with a history of chronic respiratory disease. Moreover, the emergence of strains with reduced or no susceptibility to current drugs is a matter of concern, suggesting the need of constant monitoring of viral variants.
Topics: Antiviral Agents; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Zanamivir
PubMed: 34918326
DOI: 10.1055/s-0041-1733830 -
Drug Discovery Today Aug 2020Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A... (Review)
Review
Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A substantial reduction in influenza-related deaths can be attributed to both vaccination and administration of oseltamivir (OS), which is approved for oral administration and inhibits viral neuraminidase (NA), a transmembrane protein. OS carboxylate (OSC), the active form of OS, is formed by the action of endogenous esterase, which targets NA and is shown to significantly reduce influenza-related deaths. However, the development of resistance in various viral variants, including H3N2 and H5N1, has raised concern about the effectiveness of OS. This comprehensive review covers a range of OS analogs shown to be effective against influenza virus, comparing different types of substituent group that contribute to the activity and bioavailability of these compounds.
Topics: Animals; Antiviral Agents; Humans; Life Cycle Stages; Neuraminidase; Orthomyxoviridae; Orthomyxoviridae Infections; Oseltamivir
PubMed: 32554062
DOI: 10.1016/j.drudis.2020.06.004 -
The Annals of Pharmacotherapy Nov 2021Oseltamivir is frequently administered to critically ill patients with presumed influenza. It may modulate Na, K, and Ca channels to produce bradycardia.
BACKGROUND
Oseltamivir is frequently administered to critically ill patients with presumed influenza. It may modulate Na, K, and Ca channels to produce bradycardia.
OBJECTIVE
To evaluate the association between oseltamivir and bradycardia in critically ill patients and assess parameters associated with bradycardia.
METHODS
This was a retrospective audit of 203 critically ill adults with presumed influenza receiving at least 2 doses of oseltamivir. The primary outcome was the occurrence of bradycardia, defined as a heart rate (HR) ≤59 beats per minute (BPM) while receiving oseltamivir or a decrease of ≥20 BPM compared with the lowest HR before initiating oseltamivir.
RESULTS
A total of 88 (43.4%) patients manifested bradycardia, 59 with HR ≤59 BPM, 19 with HR decrease of ≥20 BPM, and 10 with both. The time from first dose to bradycardia was 51.4 ± 43 hours. In all, 48 (54.6%) patients received therapies for bradycardia, including increased inotropic/vasopressor dose, electrolyte replacement, electrocardiogram, discontinuation of other medications, cardiology consult, discontinuation of oseltamivir, and pacer placement. There were no significant differences between groups with bradycardia versus without in terms of demographics, laboratory values, hospital characteristics, or oseltamivir dosing. Multivariate logistic regression showed that bradycardia was associated with baseline HR, age, past medical history of neurological issues, and positive influenza status. Between hours 6 through 126, significant differences existed between groups in actual and lowest HR.
CONCLUSION AND RELEVANCE
Oseltamivir was associated with clinically relevant bradycardia in critically ill patients. Clinicians should closely monitor HR in critically ill patients receiving oseltamivir.
Topics: Adult; Antiviral Agents; Bradycardia; Critical Illness; Humans; Influenza, Human; Oseltamivir; Retrospective Studies
PubMed: 33615828
DOI: 10.1177/1060028020988919 -
Antiviral Therapy May 2021Oseltamivir is an orally administered antiviral medication that selectively inhibits the influenza neuraminidase enzymes that are essential for viral replication and it... (Review)
Review
Oseltamivir is an orally administered antiviral medication that selectively inhibits the influenza neuraminidase enzymes that are essential for viral replication and it is active against both influenza A and B viruses. Oseltamivir is indicated for therapy or post-exposure prevention of influenza A and B. Side effects are uncommon and include mild nausea, gastrointestinal upset, dizziness, and headache. Despite widespread use, oseltamivir has not been associated with clinically apparent liver injury; however, there is growing evidence of possible toxic liver involvement during oseltamivir therapy. To the best of our knowledge, this is the first reported case in Italy linking the development of acute hepatitis and oseltamivir therapy, in a patient suffering from influenza H1N1 infection. We also present a review of the literature on cases of oseltamivir hepatotoxicity, through the consultation of PubMed database, the bibliographical references of various articles and an extensive search using Google. In view of the analyzed results, we suggest that experts should carefully consider the need for inclusion of potential serious liver reactions be added to the oseltamivir product label.
Topics: Acute Disease; Antiviral Agents; Hepatitis; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir
PubMed: 35485329
DOI: 10.1177/13596535211041494 -
Expert Review of Clinical Pharmacology 2023Older adults are the most vulnerable population to the effects of influenza. These patients have age-related characteristics that make response to both infection and... (Review)
Review
INTRODUCTION
Older adults are the most vulnerable population to the effects of influenza. These patients have age-related characteristics that make response to both infection and therapeutics different than younger patients.
AREAS COVERED
Influenza vaccination and antiviral therapy are the foundational approaches to preventing and treating influenza in geriatric patients. Older adults should receive one of the three enhanced vaccines before influenza season beings. There are five antivirals used in influenza. Geriatric patients have been under-enrolled in antiviral studies but have been included in small numbers. Oseltamivir has the most abundant evidence, including in the hospital and long-term care (LTC) facilities, and the strongest evidence for reducing mortality and complications. Peramivir offers the shortest time for symptom alleviation, while baloxavir is best tolerated.
EXPERT OPINION
Oseltamivir has the most versatility in preventing and treating influenza in geriatric patients. Parenteral peramivir and zanamivir are second-line alternatives for complicated influenza when oseltamivir cannot be used. Single-dose peramivir and baloxavir are attractive alternatives to oseltamivir in uncomplicated influenza but will not increase in utilization until more evidence is available regarding mortality and complications, particularly in hospitalized and LTC patients. More studies, including comparative trials, are required to elucidate the role in therapy for each therapeutic in the geriatric population.
Topics: Humans; Aged; Influenza, Human; Oseltamivir; Antiviral Agents
PubMed: 37526068
DOI: 10.1080/17512433.2023.2243221