Triple combinations of neuraminidase inhibitors, statins and fibrates benefit the survival of patients with lethal avian influenza pandemic
Section snippets
Background
In April 2009, a novel H1N1 influenza A virus (the 2009 H1N1 virus) emerged in Mexico and caused the first influenza pandemic of the 21st century. Since then, nearly all countries in the world had reported the cases, and the World Health Organization (WHO) had received reports of 18,449 deaths among laboratory confirmed cases as of 1 August 2010 [1]. Although the overall mortality of cases is less than 0.5%, it has been reported that many previously healthy patients with the 2009 H1N1 virus
Inflammatory response to severe influenza infection
Up to now, the worldwide mortality of highly pathogenic avian influenza H5N1 viral infection in humans is nearly 60% [7]. In serious patients, high viral burdens in the respiratory tract and hypercytokinemia or sometimes called a “cytokine storm” which was released by virally infected cells proportionally, were both associated with the poor clinical outcome [8]. Inflammatory cells such as macrophages, neutrophils, activated lymphocytes infiltrate pulmonary tissues and, together with direct
Possible mechanisms of statins and fibrates for influenza infection
It is now accepted that both excessive viral replication and overwhelming inflammatory responses contribute to the poor prognosis in human influenza A (H5N1) infections [8], [9]. Yet corticosteroid therapy is not recommended routinely in the management of influenza A (H5N1) disease [4]. Glucocorticoids suppress the transcription of multiple inflammatory genes through binding to glucocorticoid response elements (GREs) in glucocorticoid-responsive genes by glucocorticoid receptors (GR)
Presentation of the hypothesis
As suggested above, the complex relationship among the host immune conditions, the high-level viral burden, and the clinical outcome may be critical over the course of influenza A (H5N1) virus infections [3], [8], as well the rational alternatives and timing of administration of immunomodulatory drugs that target the host immune responses. As an immunomodulator, statins can activate both PPARα and PPARγ which are mediated by cyclooxygenase (COX)-2-dependent increases in 15-deoxy-Δ12,14
Preliminary test of the hypothesis
To show whether the triple combinations of neuraminidase inhibitors, statins, and fibrates can provide additional benefits, we used a murine model infected by influenza A (H5N1) virus to test the hypothesis. Our preliminary research indicated that the triple combinations of oseltamivir, simvastatin, and fenofibrate exhibited synergistic effects on inhibiting the mice body weight loss in 5 days and delay the death time in 2 days, as shown in Figs. 1 and 2, respectively. Here, our own work suggests
Implications of the hypothesis
No one can predict when and where the next influenza pandemic will occur, especially the lethal avian influenza A (H5N1) infection. Our preliminary results support the development of the triple combinations as a viable and potentially effective alternative to improve the survival of a future lethal influenza pandemic during the early stage. Further investigations should be conducted to enhance our knowledge of the mechanisms by which this synergistic action occurs when the two immunomodulatory
Conflict of interest
We declare that we have no any conflict of interest.
Acknowledgment
This project supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China (Grant No. 2009ZX10004-016).
References (36)
Mechanisms and resistance in glucocorticoid control of inflammation
J Steroid Biochem Mol Biol
(2010)- et al.
Practical strategies for targeting NF-kappaB and NADPH oxidase may improve survival during lethal influenza epidemics
Med Hypotheses
(2010) - et al.
Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1
J Biol Chem
(1999) - et al.
PPARalpha agonist fenofibrate protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress and MAPK activity
Biochem Biophys Res Commun
(2010) Confronting an influenza pandemic with inexpensive generic agents: can it be done?
Lancet Infect Dis
(2008)- et al.
Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial)
Am J Cardiol
(2005) - Pandemic (H1N1) 2009 – Update 112. Geneva: World Health Organization 2010. Available from:...
- et al.
Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection
N Engl J Med
(2010) - et al.
Pathogenesis of emerging avian influenza viruses in mammals and the host innate immune response
Immunol Rev
(2008) - et al.
Update on avian influenza A (H5N1) virus infection in humans
N Engl J Med
(2008)
Oseltamivir resistance during treatment of influenza A (H5N1) infection
N Engl J Med
Treatment with convalescent plasma for influenza A (H5N1) infection
N Engl J Med
Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia
Nat Med
Insights into inflammation and influenza
N Engl J Med
Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells
Respir Res
HMG-1 as a mediator of acute lung inflammation
J Immunol
HMG-1 as a late mediator of endotoxin lethality in mice
Science
Cited by (15)
Modulation of sterol biosynthesis regulates viral replication and cytokine production in influenza A virus infected human alveolar epithelial cells
2015, Antiviral ResearchCitation Excerpt :IFN treatment reduced sterol metabolism and protects against cytomegalovirus infection in mouse macrophages through down regulation of geranylgeraniol (Blanc et al., 2011). Interference on sterol metabolic pathway by drugs such as statins have shown both positive and negative effects on pneumonia and influenza infection in human and animal studies (An et al., 2011; Belser et al., 2013; Vandermeer et al., 2012). One major difference between low pathogenic and HPAI influenza virus is the increased release of cytokine and chemokine that occurs with the lethal infections (Chan et al., 2005; Cheung et al., 2002; Loo and Gale, 2007).
Antiviral combinations for severe influenza
2014, The Lancet Infectious DiseasesCitation Excerpt :The use of widely available, low cost drugs with immunomodulatory activity has been promoted as a possible treatment strategy,114 but so far no prospective randomised controlled trials of such agents have been completed in patients with severe influenza illness. In mice infected with avian H5N1 virus, simvastatin given with oseltamivir did not improve the efficacy of oseltamivir monotherapy,131 whereas a preliminary study reported some disease-modifying effects with a triple regimen of osetltamivir, simvastatin, and fenofibrate compared with oseltamivir alone.132 Observational studies from the 2009 pandemic did not find improved outcomes in severely ill patients given neuraminidase inhibitors and various immunomodulatory therapies including macrolides and statins.133
Damage-Associated Molecular Patterns in Human Diseases: Volume 3: Antigen-Related Disorders
2023, Damage-Associated Molecular Patterns in Human Diseases: Volume 3: Antigen-Related DisordersADVERSE EFFECTS OF OSELTAMIVIR IN THE TREATMENT OF AH1N VIRUS INFECTIONS IN PEDIATRIC POPULATIONS
2020, Encyclopedia of Virology: New Research: Volume 6: (6 Volume Set)