Keywords
1. Oseltamivir Hypothermia
2. Antiviral Drug Side Effects
3. Influenza Treatment
4. Nicotinic Acetylcholine Receptor
5. Dopamine D2 Receptor
Since the introduction of oseltamivir (commercially known as Tamiflu), it has been widely recognized for its efficacy in ameliorating the symptoms of influenza. However, as with many pharmaceutical agents, the discovery of unintended side effects is not uncommon. In a recent study published in Yakugaku Zasshi, the Journal of the Pharmaceutical Society of Japan, researchers have shed light on an intriguing and concerning side effect of the anti-influenza drug: hypothermia. This meticulous study, spanning over 12 years, aimed to dissect the pharmacological mechanisms underlying oseltamivir’s ability to induce a drop in body temperature independent of its antiviral activity.
The study, which was conducted by esteemed researchers including Ono Hideki from the Laboratory of Clinical Pharmacy and Pharmacology at Musashino University, provided insights that could have significant implications for the clinical use of oseltamivir. Reports of adverse events associated with the hypothermic effects of oseltamivir in patients led the team to explore its effects on normal mice, providing a controlled environment to examine oseltamivir’s pharmacodynamics without the influence of the influenza virus.
In a series of carefully designed experiments, the researchers found that oseltamivir induces a dose-dependent hypothermic response by impairing nicotinic cholinergic transmission at sympathetic ganglia, which in turn dampens the sympathetic nervous system’s modulation of brown adipose tissue (BAT). BAT is well known for its role in thermogenesis, the process by which the body generates heat. By impeding the normal functions of BAT, oseltamivir inadvertently brings about a reduction in body temperature.
Digging deeper into the molecular level, the study pinpointed the ion channels of nicotinic acetylcholine receptors (nAChRs) as the target of oseltamivir. Patch clamp experiments on cells expressing the human α3β4 nicotinic receptor confirmed oseltamivir’s inhibitory action on these ion channels. Interestingly, the research highlighted that oseltamivir carboxylate, the metabolized form of oseltamivir which actively inhibits the influenza virus neuraminidase, did not produce hypothermia or suppress ion channel activity, suggesting a distinct mechanism of action for the parent drug.
The effects of hypothermia were further validated through intracerebroventricular administration of oseltamivir in animal models. Importantly, the study revealed that this drop in temperature could be stymied by a dopamine D2 receptor antagonist, suggesting a role for dopaminergic pathways in this side effect profile. The D2 receptor subtype, belonging to the dopamine receptor family, has been implicated in thermoregulation, and the findings from this study contribute to our understanding of how pharmacological interventions can influence these processes.
The observations from this comprehensive study have far-reaching implications in the medical community. They serve as a reminder that drug effects can extend beyond their primary mechanisms and that side effects can emerge from interactions with complex physiological systems. The hypothermic action of oseltamivir stresses the importance of monitoring patients for adverse thermal responses, particularly in populations that may be more susceptible, such as the elderly or those with underlying health conditions.
Healthcare professionals need to be aware of the potential for oseltamivir-induced hypothermia and should counsel patients accordingly when prescribing the drug for influenza treatment. It also raises the question of whether alternative therapies or additional drugs, such as amantadine, which was also discussed in the study in comparison with oseltamivir, may be worth considering in certain scenarios.
Moreover, this study delineates the vital role played by preclinical research in understanding the intricacies of drug action. As oseltamivir continues to be a cornerstone in the arsenal against influenza, ongoing research and vigilance are required to ensure its safe and effective use.
Reflecting on these findings, it is important to recognize the merits of scientific inquiry and its impact on clinical practice. The conclusions drawn from the study not only call for heightened attention to adverse side effects but also spur further investigation into the pharmacology of antiviral medications.
References
1. Ono Hideki et al. Yakugaku Zasshi, Journal of the Pharmaceutical Society of Japan, “Hypothermic Action of Oseltamivir Not Dependent on Its Anti-influenza Virus Action”, 2019. DOI: 10.1248/yakushi.18-00191
2. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol. 2013;30(12):2725-2729. DOI: 10.1093/molbev/mst197.
3. Jackson S, Van Hoek ML. Oseltamivir, other antiviral drugs, and the risk of influenza-associated adverse events in patients with laboratory-confirmed influenza. J Infect Dis. 2013;207(3):487-494. DOI: 10.1093/infdis/jis702.
4. Jefferson T, et al. Oseltamivir for influenza in adults and children: Systematic review of clinical study reports and summary of regulatory comments. BMJ. 2014;348:g2545. DOI: 10.1136/bmj.g2545.
5. Davanço MG, et al. Influence of oseltamivir and Amantadine on murine central nervous system. Pharmacol Biochem Behav. 2005;81(3):688-692. DOI: 10.1016/j.pbb.2005.04.018.
Given the pertinence of the research on oseltamivir’s hypothermic effects, further exploration into alternative treatment options with fewer systemic impacts should be encouraged. The overall safety profiles of drugs, both old and new, must continually be analyzed through postmarketing surveillance and targeted research initiatives. As our understanding of pharmacodynamics evolves, so too should our strategies for managing and mitigating the risks associated with these powerful therapeutic tools.