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Clinics in Chest Medicine Mar 2017Most viral respiratory tract infections are caused by classic respiratory viruses, including influenza, respiratory syncytial virus, human metapneumovirus,... (Review)
Review
Most viral respiratory tract infections are caused by classic respiratory viruses, including influenza, respiratory syncytial virus, human metapneumovirus, parainfluenza, rhinovirus, and adenovirus, whereas other viruses, such as herpes simplex, cytomegalovirus, and measles virus, can opportunistically affect the respiratory tract. The M2 inhibitors, amantadine and rimantadine, were historically effective for the prevention and treatment of influenza A but all circulating strains are currently resistant to these drugs. Neuraminidase inhibitors are the sole approved class of antivirals to treat influenza. Ribavirin, especially when combined with intravenous antibody, reduces morbidity and mortality among immunosuppressed patients.
Topics: Antiviral Agents; Humans; Influenza, Human; Respiratory Syncytial Viruses; Respiratory Tract Infections
PubMed: 28159156
DOI: 10.1016/j.ccm.2016.11.008 -
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 -
Cancer Research Feb 2020Integrin β4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to...
Integrin β4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to target this cell population, with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumor-draining lymph node T cells. Two immunocompetent mouse models were utilized to assess the efficacy of these immunotherapies in targeting both CSCs and bulk tumor populations: 4T1 mammary tumors and SCC7 head and neck squamous carcinoma cell line. Immunologic targeting of ITGB4 utilizing either ITGB4-DC or ITGB4 BiAb-T cells significantly inhibited local tumor growth and metastases in both the 4T1 and SCC7 tumor models. Furthermore, the efficacy of both of these ITGB4-targeted immunotherapies was significantly enhanced by the addition of anti-PD-L1. Both ITGB4-targeted immunotherapies induced endogenous T-cell cytotoxicity directed at CSCs as well as non-CSCs, which expressed ITGB4, and immune plasma-mediated killing of CSCs. As a result, ITGB4-targeted immunotherapy reduced not only the number of ITGB4 CSCs in residual 4T1 and SCC7 tumors but also their tumor-initiating capacity in secondary mouse implants. In addition, treated mice demonstrated no apparent toxicity. The specificity of these treatments was demonstrated by the lack of effects observed using ITGB4 knockout 4T1 or ITGB4-negative CT26 colon carcinoma cells. Because ITGB4 is expressed by CSCs across a variety of tumor types, these results support immunologic targeting of ITGB4 as a promising therapeutic strategy. This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients.
Topics: Animals; Antibodies, Bispecific; B7-H1 Antigen; CD3 Complex; Cancer Vaccines; Carcinogenesis; Cell Line, Tumor; Dendritic Cells; Disease Models, Animal; Female; Gene Knockout Techniques; Humans; Immunotherapy, Adoptive; Integrin beta4; Lymph Nodes; Mice; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; T-Lymphocytes
PubMed: 31843981
DOI: 10.1158/0008-5472.CAN-19-1145 -
The Cochrane Database of Systematic... Nov 2014Influenza is an acute respiratory illness caused by influenza A and B viruses. Complications may occur, especially among children and the elderly. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Influenza is an acute respiratory illness caused by influenza A and B viruses. Complications may occur, especially among children and the elderly.
OBJECTIVES
To assess the effectiveness and safety of amantadine and rimantadine in preventing, treating and shortening the duration of influenza A in children and the elderly.
SEARCH METHODS
We searched CENTRAL (2014, Issue 9), MEDLINE (1966 to September week 4, 2014) and EMBASE (1980 to October 2014).
SELECTION CRITERIA
Randomised controlled trials (RCTs) or quasi-RCTs comparing amantadine and/or rimantadine with no intervention, placebo, other antivirals or different doses or schedules of amantadine or rimantadine in children and the elderly with influenza A.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the search results. We extracted and analysed data using the standard Cochrane methodology.
MAIN RESULTS
We identified 12 studies (2494 participants: 1586 children and 908 elderly) comparing amantadine and rimantadine with placebo, paracetamol (one trial: 69 children) or zanamivir (two trials: 545 elderly) to treat influenza A.Amantadine was effective in preventing influenza A in children (773 participants, risk ratio (RR) 0.11; 95% confidence interval (CI) 0.04 to 0.30). The assumed risk of influenza A in the control group was 10 per 100. The corresponding risk in the rimantadine group was one per 100 (95% CI 0 to 3). Nevertheless, the quality of the evidence was low and the safety of the drug was not well established.For treatment, rimantadine was beneficial in abating fever on day three of treatment in children: one selected study with low risk of bias, moderate evidence quality and 69 participants (RR 0.36; 95% CI 0.14 to 0.91). The assumed risk was 38 per 100. The corresponding risk in the rimantadine group was 14 per 100 (95% CI 5 to 34).Rimantadine did not show any prophylactic effect in the elderly. The quality of evidence was very low: 103 participants (RR 0.45; 95% CI 0.14 to 1.41). The assumed risk was 17 per 100. The corresponding risk in the rimantadine group was 7 per 100 (95% CI 2 to 23).There was no evidence of adverse effects caused by treatment with amantadine or rimantadine.We found no studies assessing amantadine in the elderly.
AUTHORS' CONCLUSIONS
The quality of the evidence combined with a lack of knowledge about the safety of amantadine and the limited benefits of rimantadine, do not indicate that amantadine and rimantadine compared to control (placebo or paracetamol) could be useful in preventing, treating and shortening the duration of influenza A in children and the elderly.
Topics: Adolescent; Aged; Amantadine; Antiviral Agents; Child; Humans; Influenza A Virus, H1N1 Subtype; Influenza A virus; Influenza, Human; Randomized Controlled Trials as Topic; Rimantadine; Sex Factors; Young Adult
PubMed: 25415374
DOI: 10.1002/14651858.CD002745.pub4 -
GMS Infectious Diseases 2017Influenza is a serious and frequently underestimated, but vaccine preventable disease. The adamantane derivates rimantadine and amantadine and the neuraminidase... (Review)
Review
Influenza is a serious and frequently underestimated, but vaccine preventable disease. The adamantane derivates rimantadine and amantadine and the neuraminidase inhibitors zanamivir and oseltamivir are the only antiviral drugs currently approved in Europe for therapy and prophylaxis of influenza infections. Resistance to these drugs occurs due to mutations within the therapeutic target proteins M2 ion channel protein and viral neuraminidase. An unexpected occurrence of oseltamivir-resistant seasonal A(H1N1) viruses was detected in winter 2007/2008. The prevalence of these viruses increased rapidly and nearby all viruses circulating during the following seasons were resistant to oseltamivir. The A(H1N1)pdm09 viruses replaced the former seasonal A(H1N1) subtype during the 2009-2010 influenza season. Fortunately, resistance to neuraminidase inhibitors was detected in A(H1N1)pdm09, A(H3N2) and influenza B viruses only sporadically and was treatment related mostly. Comprehensive analyses of circulating viruses showed a high prevalence of A(H3N2) influenza viruses that are resistant to adamantane derivates since 2004/2005 and a progressive trend in the prevalence of resistant viruses up to 100% in following seasons. The M2 ion channel protein of A(H1N1)pdm09 viruses is associated with the Eurasian avian-like swine lineage and thus show "natural" resistance to adamantane derivates. Therefore, only neuraminidase inhibitors are recommended for influenza treatment today. This manuscript summarizes the occurrence and spread of antiviral resistant influenza viruses and highlights the importance for developing and/or approving new antiviral compounds.
PubMed: 30671326
DOI: 10.3205/id000030 -
Ugeskrift For Laeger Jun 2022Viroporins are ion channels found in many viruses, where they contribute to virus life cycle and thereby pathogenesis. Viroporin targeting is a known, yet largely... (Review)
Review
Viroporins are ion channels found in many viruses, where they contribute to virus life cycle and thereby pathogenesis. Viroporin targeting is a known, yet largely unexplored, therapeutic strategy so far only used in Influenza A with the drugs amantadine and rimantadine. In this review, we seek to utilize the inhibition by amantadine of the viroporin Protein E in SARS-CoV-2 in an attempt to treat COVID-19 in its early stages. We are executing a double-blinded placebo-controlled trial based on promising in vivo and in vitro work as a stepping-stone for establishing a therapeutic antiviral regime: blocking of viroporins.
Topics: Amantadine; Antiviral Agents; Humans; SARS-CoV-2; Viroporin Proteins; COVID-19 Drug Treatment
PubMed: 35703076
DOI: No ID Found -
Viruses Sep 2015Influenza is a major cause of severe respiratory infections leading to excessive hospitalizations and deaths globally; annual epidemics, pandemics, and sporadic/endemic... (Review)
Review
Influenza is a major cause of severe respiratory infections leading to excessive hospitalizations and deaths globally; annual epidemics, pandemics, and sporadic/endemic avian virus infections occur as a result of rapid, continuous evolution of influenza viruses. Emergence of antiviral resistance is of great clinical and public health concern. Currently available antiviral treatments include four neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, laninamivir), M2-inibitors (amantadine, rimantadine), and a polymerase inhibitor (favipiravir). In this review, we focus on resistance issues related to the use of neuraminidase inhibitors (NAIs). Data on primary resistance, as well as secondary resistance related to NAI exposure will be presented. Their clinical implications, detection, and novel therapeutic options undergoing clinical trials are discussed.
Topics: Antiviral Agents; Drug Resistance, Viral; Humans; Influenza, Human; Neuraminidase; Orthomyxoviridae; Viral Proteins
PubMed: 26389935
DOI: 10.3390/v7092850 -
Drugs in R&D Sep 2021Several adamantanes have established actions against coronaviruses. Amantadine, rimantadine, bananins and the structurally related memantine are effective against human... (Review)
Review
Several adamantanes have established actions against coronaviruses. Amantadine, rimantadine, bananins and the structurally related memantine are effective against human respiratory coronavirus HCoV-OC43, bovine coronavirus and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and a spiroadamantane amine is effective against the coronavirus strain 229E. Molecular docking studies suggest that amantadine may block the viral E protein channel, leading to impaired viral propagation. Additionally, amantadine analogues may inhibit entry of the virus into the host cell by increasing the pH of the endosomes and thus inhibiting the action of host cell proteases such as Cathepsin L. High-throughput drug screen gene expression analysis identified compounds able to down-regulate Cathepsin L expression where the fifth most potent agent of 466 candidates was amantadine. Amantadine inhibits severe acute respiratory syndrome coronavirus 2 replication in vitro but does not inhibit the binding of the spike protein to ACE2. Adamantanes also may act against coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via antagonism of glutamate (NMDA) and the α-7 subtype of the nicotinic acetylcholine receptor located on bronchial and alveolar epithelial cells. As an NMDA receptor antagonist, memantine has the potential to inhibit entry of SARS-CoV-2 into these cell populations. Amantadine and memantine are widely employed for the treatment of neurodegenerative diseases and a pathophysiologic link between the antiviral and anti-Parkinson actions of amantadine has been entertained. Case reports involving 23 patients with reverse transcription polymerase chain reaction-confirmed coronavirus disease 2019 (COVID-19) and a range of co-morbidities including type 2 diabetes mellitus, Parkinson's disease, multiple sclerosis and severe cognitive impairment reveal significant potential benefits of amantadine and memantine for the prevention and/or treatment of coronavirus disease 2019 and its neurological complications.
Topics: Adamantane; Antiviral Agents; COVID-19; Drug Repositioning; Humans; Nervous System Diseases; COVID-19 Drug Treatment
PubMed: 34152583
DOI: 10.1007/s40268-021-00351-6