Neuroexcitatory actions of Tamiflu and its carboxylate metabolite

Abstract

Oseltamivir (Tamiflu) is now being stockpiled by several governments as a first line treatment for an anticipated outbreak of avian influenza caused by H5N1. However, abnormal behaviors and death associated with the use of Tamiflu have developed into a major issue in Japan where Tamiflu is often prescribed for seasonal influenza. Thus, it is critical to determine neuropsychiatric effects of oseltamivir and to establish methods for safe administration. Using juvenile rats and rat hippocampal slices, we investigated whether oseltamivir has adverse effects on the central nervous system. Systemic injection of oseltamivir (50mg/kg i.p.) produced no change in behavior within 2h. However, prior injection of oseltamivir significantly altered the duration of loss of lightning reflex following ethanol injection (3.3g/kg, i.p.). Ethanol injection in the presence of oseltamivir also resulted in enhanced hypothermia. In the CA1 region of hippocampal slices, oseltamivir (100 microM) induced paired-pulse facilitation in population spikes without changes in excitatory postsynaptic potentials. Similarly, 3 microM oseltamivir carboxylate, the active metabolite of oseltamivir, facilitated neuronal firing, though the facilitation did not involve GABAergic disinhibition. Moreover, oseltamivir carboxylate produced further facilitation following administration of 60mM ethanol. These findings indicate that oseltamivir has effects on the central nervous system, especially when combined with other agents.

The mechanisms of sudden-onset type adverse reactions to oseltamivir

“…following non-sedating dose of ethanol injection in rats significantly altered the duration of loss of lightning reflex [59]. They also reported diminished behavioral activity and poor locomotion by measuring the number of arm entries in the Y-maze, representing a form of anxious or fearful behavior as manifest by altered exploration [60].…”

“…Ethanol injection in the presence of oseltamivir also resulted in enhanced hypothermia. [59]. Izumi et al also reported that combination of oseltamivir with other neurostimulants altered synaptic plasticity and this may contribute to behavioural changes associated with the drug [60].…”

“…Izumi et al also reported that combination of oseltamivir with other neurostimulants altered synaptic plasticity and this may contribute to behavioural changes associated with the drug [60]. They discussed that the neuraminidase, the enzyme targeted by OC, can modulate synaptic function and possibly alter propagation of signals based on the fact that many ion channels are glycosylated [59]. …”

“…These findings suggest that if the concentration of OC in the brain increased and affected the excitability of the excitatory and/or inhibitory neurons and affected neuroplasticity, oseltamivir may contribute to behavioural changes, especially to the delayed onset and prolonged type of psychiatric symptoms such as the case 8 in the case series [6]. However, the acute behavioural changes observed in the in vivo experiment by Izumi et al [59,60] may be induced rather by OT considering all other findings.…”

“…Intraduodenal oseltamivir (500-1000 mg/kg) provoked similar ventilatory arrest 72 to 218 minutes after injection, followed by cardiac arrest [59], while oseltamivir carboxylate (OC: 100-200 mg/kg i.v.) had no significant effect on ventilation and blood pressure.…”