Current status of antihistamine drugs repurposing for infectious diseases

ABSTRACT

Objectives The principal objectives of this review were to gather information on the potential role of antihistamines as anti-infective agents and to identify the gaps in research that have impaired their applicability in human health. Methods The literature search was carried using MEDLINE, PubMed and Google Scholar and included all articles in English from January 1990 to May 2022. Results The literature search identified 12 antihistamines with activity against different pathogens. Eight molecules were second-generation antihistamines with an intrinsically lower tendency to cross the blood brain barrier, thereby with fewer side effects. Only five antihistamines had in vivo evaluations in rodents, while one study utilized a wax moth model to determine astemizole's anti-Cryptococcus sp. activity when combined with fluconazole. In vitro studies showed that clemastine was active against Plasmodium, Leishmania, and Trypanosoma, while terfenadine suppressed Candida spp. and Staphylococcus aureus growth. In vitro assays found that SARS-coV-2 was inhibited by doxepin, azelastine, desloratadine, and clemastine. Different antihistamines inhibited the Ebola virus (diphenhydramine, chlorcyclizine), Hepatitis C virus (chlorcyclizine), and Influenza virus (carbinoxamine, chlorpheniramine). Generally, in vitro activity (IC50) of antihistamines was in the low to sub-µM range, except for Staphylococcus epidermidis (loratadine MIC=50 µM) and SARS-coV-2 (desloratadine 70% inhibition at 20 µM). Conclusion Many antihistamine drugs show potential to progress to clinical trials based on in vitro data and the availability of toxicological and pharmacological data. However, the eventual need to use high antihistamine doses to achieve efficacy could be an additional problem. The overall lack of systematic preclinical trials has hampered the advancement of repurposed antihistamines for off-label evaluation. The low interest of pharmaceutical companies has to be counterbalanced through collaborations between research groups, granting agencies, and the government to support the needed clinical trials.