The low bioavailability of zanamivir may be the major reason why reduction of antibody rise was not observed in the systematic review of zanamivir.[9] However, if zanamivir is administered at a high dose or for an extended period, or if the patient is very susceptible, inhaled zanamivir might reach a concentration high enough to reduce the immune response. and cytokine induction and renal, metabolic, cardiac, and prolonged psychiatric disorders after oseltamivir use may be related to inhibition of the hosts 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. findings showing inhibitory effects on immune cells Peripheral T-lymphocytes from healthy adult whole blood were incubated with antigen presenting cells (APCs) pre-sensitized with influenza viruses and were tested for their proliferation ability with and without oseltamivir carboxylate. Proliferation of the T-lymphocytes was suppressed by 15% and 20% when incubated with 1?M and 10?M of oseltamivir carboxylate, respectively, compared with the control.[29] Concentration of oseltamivir carboxylate (OC) of 1 1?M is compatible with the human clinical concentration of OC.[29,30] The Pharmaceuticals and Medical Devices Agency (PMDA) and the Summary Basis of Approval (SBA) did not refer to any published paper for these findings.[29,30] No published papers with these data could be found. Mechanism for delayed onset type reactions Delayed onset and prolonged type of psychiatric and other neurological symptoms Psychiatric and nervous symptoms that occur in the very early phase of the treatment such as acute behavioural change and respiratory depression leading APR-246 to death may be due to the effects of unmetabolized oseltamivir phosphate (OP) on the central nervous system (CNS). If OP has affinity to NMDA receptors [31,54,55] and is used for an extended period of time, it may induce schizophrenic reactions in humans, as shown in the prophylaxis RCTs of oseltamivir,[9,43] by a mechanism similar to that of the sudden onset type reactions. The symptoms that occur in the late phase of treatment with prolonged duration, such as psychosis, confusion, and aggression, and are frequently observed in the prophylaxis trials (shown in the section Other adverse effects (pneumonia, wheezing, gastric bleeding, and others)) may also be due to the effects of oseltamivir carboxylate (OC) on CNS. Pain in the limbs [9] may also be induced by both the mechanisms. Izumi et?al. reported that systemic injection of oseltamivir (50?mg/kg i.p.) significantly altered the duration of loss of lightning reflex following ethanol injection in rats. Met Ethanol injection in the presence of oseltamivir also resulted in enhanced hypothermia.[56] Izumi et?al. also reported that combination of oseltamivir with other neurostimulants alter synaptic plasticity and this may contribute to behavioural changes associated with the drug.[57] As described in section Cardiac disorders: bradycardia and QT prolongation, QT prolongation is APR-246 closely related to the plasma concentration of oseltamivir carboxylate. Taking these into account, it may be possible that oseltamivir carboxylate directly alters the cell excitability of both neurons and heart muscles, although it is not known whether the alteration is derived from inhibition of the hosts endogenous neuraminidase or APR-246 from other mechanisms, including effects on other receptors or enzymes. Among receptors or enzymes that were tested by Lindeman et?al.,[58] those that showed apparent dose-related increase are listed in Table 2. Table 2. Activity of OP and OC against molecular targets of high relevance for mood, cognition and behaviour in binding or functional assay (data are extracted from Ref. [58]). findings showing.