LAUSR

We read with interest the discussion by Andrews et al. on the mechanisms of nausea and vomiting accompanied coronavirus disease 2019 (COVID‐19). Andrews et al. hypothesized that the access of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative pathogen of COVID‐19, via neuroinvasion along vagal afferent nerves to the nucleus of the solitary tract and the area postrema, which can express angiotensin‐converting enzyme 2 receptor, the entry receptor of SARS‐CoV‐2, could be implicated in nausea and vomiting accompanied COVID‐19. Therefore, they proposed that combination of a 5‐HT3 receptor antagonist and a neurokinin receptor antagonist, which would inhibit the activation/sensitization of vagal afferents and nucleus of the solitary tract/area postrema, may be effective to relieve nausea and vomiting in patients with COVID‐19. Based on the pathophysiology of nausea and vomiting in patients with COVID‐19 hypothesized by Andrews et al., we believe that prochlorperazine could also be effective. Prochlorperazine is a broad‐spectrum antiemetic where it antagonizes D2‐dopaminergic, histaminergic (H1 and H2), and cholinergic (muscarinic) receptors within the chemoreceptor trigger zone located in the area postrema and, at high doses, the alpha‐adrenergic receptors (alpha‐1 and alpha‐2) within the nucleus of the solitary tract. In addition, prochlorperazine also produces vagal blockade in the gastrointestinal tract by antagonizing D2‐dopaminergic receptors. Most importantly, prochlorperazine possesses antiviral activity. It has been previously shown in two cell‐based screening studies that prochlorperazine possesses anti‐hepatitis C virus activity though the antiviral mechanism was unknown. Later, prochlorperazine has been reported in an in vitro study to inhibit the cellular entry of the hepatitis C virus by increasing the fluidity of lipid raft membrane, leading to decreased packing of cholesterol‐rich microdomains. Prochlorperazine also exhibits antiviral activity against dengue virus serotype 2 via blockade of the entry of dengue virus through clathrin‐mediated endocytosis. It was then confirmed in another cell‐based screening study during the Ebola virus disease outbreak, which demonstrated the potential for prochlorperazine to inhibit the entry of the Ebola virus‐like particle into SNB19 cells. Upon binding of S glycoprotein of SARS‐CoV‐2 to the angiotensin‐converting enzyme 2 (ACE2) receptor, the ACE2/virus complex enters the host cell through clathrin‐mediated endocytosis. However, the cellular entry process of SARS‐ CoV‐2 is cholesterol dependent where proper localization and assembly of SARS‐CoV‐2 with ACE2 in lipid rafts are required. With the potential of prochlorperazine to block clathrin‐mediated endocytosis and to disrupt the fluidity of lipid raft membrane, prochlorperazine may be able to inhibit also the cellular entry of SARS‐CoV‐2. Specifically, inhibition of viral entry into enteroendocrine cells via ACE2 may lead to reduced stimulation of these cells to release neuroactive agents to activate vagal afferents. Besides, there may also be reduced sensitization of the nucleus of the solitary tract/area postrema with inhibition of the entry of SARS‐CoV‐2 into brainstems via ACE2. Therefore, prochlorperazine may worth a trial to relieve nausea and vomiting in patients with COVID‐19, and we await observational studies that evaluate the clinical outcomes among patients who receive prochlorperazine to relieve nausea/vomiting accompanied COVID‐19 to inform if the in vitro antiviral activity of prochlorperazine is of clinical relevance.