E-DRUG: Two review articles on mechanisms of adverse reactions to oseltamivir
-------------------------------------------------------------------------------------------------
Dear E-druggers
I would like to introduce our two recent papers on
the mechanisms of adverse reactions to oseltamivir.
One on the sudden-onset type reactions [1]
and the other is on the delayed-onset type reactions [2].
[1] Hama R, Bennett C. The mechanisms of sudden-onset type adverse reactions
to oseltamivir
Version of Record online: 30 JUN 2016. DOI: 10.1111/ane.12629
http://onlinelibrary.wiley.com/doi/10.1111/ane.12629/full
Abstract
Oseltamivir is contraindicated for people aged 10�19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden-onset type reactions to oseltamivir.
First, the importance of animal models and the concept of human equivalent dose (HED) is summarized. Second, the specific condition for oseltamivir use, influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described.
Finally, coherence of toxicokinetic and molecular level of evidence (channels, receptors and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death.
Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase-A (MAO-A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABAA, GABAB and NMDA and their related receptors/channels including Na+ and Ca2+ channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic), respectively.
[2] Hama R. The mechanisms of delayed-onset type adverse reactions to oseltamivir
Infect Dis (Lond). 2016 Sep;48(9):651-60.
doi: 10.1080/23744235.2016.1189592. Epub 2016 Jun http://www.ncbi.nlm.nih.gov/pubmed/27251370
(in the process for OpenAccess)
Abstract
Oseltamivir is recommended for the treatment and prophylaxis of influenza in persons at higher risk for influenza complications such as individuals with diabetes, neuropsychiatric illnesses, and respiratory, cardiac, renal, hepatic or haematological diseases. However, a recent Cochrane review reported that reduction of antibody production, renal disorders, hyperglycaemia, psychiatric disorders, and QT prolongation may be related to oseltamivir use.
The underlying mechanisms are reviewed. There is decisive evidence that administration of a clinically compatible dose of oseltamivir in mice challenged by a respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed symptom-relieving effects and inhibition of viral clearance. These effects were accompanied by decreased level of T cell surface sialoglycosphingolipid (ganglioside) GM1 that is regulated by the endogenous neuraminidase in response to viral challenge. Clinical and non-clinical evidence supports the view that the usual dose of oseltamivir suppresses pro-inflammatory cytokines such as interferon-gamma, interleukin-6, and tumour necrosis factor-alpha almost completely with partial suppression of viral shedding in human influenza virus infection experiment.
Animal toxicity tests support the clinical evidence with regard to renal and cardiac disorders (bradycardia and QT prolongation) and do not disprove the metabolic effect. Reduction of antibody production and cytokine induction and renal, metabolic, cardiac, and prolonged psychiatric disorders after oseltamivir use may be related to inhibition of the host's endogenous neuraminidase. While the usual clinical dose of zanamivir may not have this effect, a higher dose or prolonged administration of zanamivir and other neuraminidase inhibitors may induce similar delayed reactions, including reduction of the antibody and/or cytokine production.
The former is the basis of sudden death, abnormal behaviours leading to
accidental death etc. Note that very clear dose-response relationship in
mortality, impairment of sensory, cognitive, consciousness and respiratory
suppression. Also note the similarity of the findings in clinical cases
and animal toxicity studies. These strongly suggest the causality of
sudden onset-type reactions to unchanged oseltamivir but not
oseltamivir carboxylate and not zanamivir and other NIs.
On the other hand, the latter is the basis of various reactions such as
abnormalities in renal, metabolic, immune, cardiac, nervous (or nociceptive)
and psychiatric systems.
Moreover the latter is the basis of ineffectiveness
of neuraminidase inhibitors (NIs) for influenza infection in reducing
complications needing hospitalization. This is because NIs reduce symptoms
not by reducing viral load but by inhibiting hosts' endogenous neuraminidase
leading to reduction of immune and cytokine responses of the hosts.
Best regards
Rokuro
HAMA, Rokuro MD Chairperson "Med Check"
NPOJIP: Non-Profit Organization
Japan Institute of Pharmacovigilance
"HAMA, Rokuro " <gec00724@nifty.com>