Elsevier

Medical Hypotheses

Volume 77, Issue 6, December 2011, Pages 1054-1057
Medical Hypotheses

Triple combinations of neuraminidase inhibitors, statins and fibrates benefit the survival of patients with lethal avian influenza pandemic

https://doi.org/10.1016/j.mehy.2011.09.001Get rights and content

Abstract

The high mortality of highly pathogenic avian influenza A (H5N1) viruses infection in humans gives rise to considerable concern that it might someday cause another lethal pandemic. At present there is no other effective alternative besides the early and enough administration of neuraminidase inhibitors, which may be crucial for the patient management. However, its efficacy is sometimes limited because of the late administration in some patients especially the seriously ill ones and the continual occurrence of oseltamivir resistant A (H5N1) strains. The specific candidate vaccine are still under development and the practical value of passive immunization is hard to be widely applied because of the scarcity of convalescent human plasma, especially in the early stage of a serious and rapidly progressing pandemic. Statins and fibrates, both of which are used in clinical practice, have anti-inflammatory and immunomodulatory effects and other multiple biologic activities. So we hypothesized that the two immunomodulatory agents may exhibit synergistic effects when they were combined to neuraminidase inhibitors to treat the A (H5N1) viruses infections via inhibiting the production of either the early inflammatory mediators (e.g., many cytokine/chemokine) or the late mediator (e.g., High Mobility Group Box Protein 1), even showing the anti-viral activities with the prevention of the development of antiviral resistance. Therefore, the novel triple combinations may be an optimal management to confront the next lethal influenza pandemic on its very beginning.

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)

  • M.D. de Jong et al.

    Oseltamivir resistance during treatment of influenza A (H5N1) infection

    N Engl J Med

    (2005)
  • B. Zhou et al.

    Treatment with convalescent plasma for influenza A (H5N1) infection

    N Engl J Med

    (2007)
  • WHO. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. Available from:...
  • M.D. de Jong et al.

    Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia

    Nat Med

    (2006)
  • C. Simmons et al.

    Insights into inflammation and influenza

    N Engl J Med

    (2008)
  • M.C. Chan et al.

    Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells

    Respir Res

    (2005)
  • E. Abraham et al.

    HMG-1 as a mediator of acute lung inflammation

    J Immunol

    (2000)
  • H.C. Wang et al.

    HMG-1 as a late mediator of endotoxin lethality in mice

    Science

    (1999)
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