Table II.

Oral antiseptics against other coronaviruses: in-vivo and in-vitro studies

Study	Study type	Test product	Methods	Results
Eggers et al. [6]	In vitro	PVP-I 4% PVP-I 7.5% PVP-I 1%	Vero E6 cells were infected with MERS-CoV and HCoV-EMC/2012. The test solutions and viruses were incubated at RTa for 15, 30 and 60 s.	All products achieved 99.99% virucidal activity at 15 s of contact. Reduction in viral titres (TCID50/mL) ≥4.00.
Mukherjee et at. [27]	In vivo	ARMS-I™: cetylpyridinium chloride 0.1%	Randomized, double-blinded, placebo-controlled pilot clinical trial. Healthy adults (18–45 years) were randomized into ARMS-I™ or placebo group (50 subjects each). 94 individuals completed the study. The drug was sprayed intra-orally (3× daily) for 75 days. PCR analysis was performed on the oral and nasal swabs collected from individuals with URIs (upper respiratory infections) to determine whether ARMS-I™ decreases the detection of respiratory viruses (influenza B, coronavirus, or rhinovirus (OC43)).	Relative decrease (55%) in URIs. PCR analysis showed the presence of influenza B, coronavirus or rhinovirus (OC43) in three participants; all in the placebo group. Fever was reported only in the placebo group. ARMS-I significantly reduced the frequency and severity of cough and sore throat, and duration of cough (P ≤ 0.019 for all comparisons). ARMS-I was safe, well tolerated, had high acceptability and high adherence to medication use. Medical visits occurred only in the placebo group. Absenteeism did not differ between the two groups. Prior influenza vaccination had no effect on study outcome.
Eggers et al. [28]	In vitro	PVP-I 0.23%	PVP-I was tested against Klebsiella pneumoniae and Streptococcus pneumoniae according to bactericidal quantitative suspension test EN13727. PVP-I was tested against SARS-CoV and MERS-CoV, rotavirus strain Wa and influenza virus A subtype H1N1 according to virucidal quantitative suspension test EN14476. The test solutions and virus were incubated at RTa for 15 s for SARS-CoV and MERS-CoV, 15 and 30 s for influenza, and 15, 30, 60 and 120 s for rotavirus.	All bacterial counts were reduced by a log10 reduction factor between >×5.20 and >×5.47 copies/mL (reduction in bacterial count of ≥99.999%) after 15 s of contact time. All viral titres were reduced by between 4.40 and 6.00 TCID50/mL (reduction in viral titres of ≥99.99%) after 15 s of contact time.
Kariwa et al. [29]	In vitro	Isodine solution®: PVP-I 1% Isodine Scrub®: PVP-I 1% Isodine Palm®: PVP-I 0.25% Isodine Gargle®: PVP-I 0.47% Isodine Nodo Fresh®: PVP-I 0.23%	Hanoi strain of SARS-CoV in Vero E6 cells. The exposure of the virus to PVP-I products was performed at RTa for 60 s.	Treatment of SARS-CoV for 60 s with Isodine Scrub, Isodine Palm, and Isodine Nodo Fresh strongly reduced the virus infectivity from 1.17×106 TCID50/mL to below the detection limit, <40 to <160. Treatment of SARS-CoV for 60 s with Isodine and Isodine Gargle did not completely eliminate the virus infectivity: 8.1×10−5 and 1.6×10−4 TCID50/mL, respectively.
Meyers et al. [30]	In vitro	Neti Pot, nasal rinse: sodium bicarbonate (700 mg), sodium chloride (2300) mg Johnson's Baby Shampoo, nasal rinse: water, cocamidopropyl betaine, decyl glucoside, sodium cocoyl isethionate, lauryl glucoside, PEG-80, sorbitan laurate, glycerin Peroxide Sore Mouth, oral rinse: H2O2 1.5% Orajel Antiseptic Rinse, oral rinse: H2O2 1.5%, menthol 0.1% H2O2 1.5%, oral rinse Crest Pro-Health, oral rinse: cetylpyridium chloride 0.07% Listerine Antiseptic, Listerine Ultra, Equate, Antiseptic Mouthwash, oral rinses: eucalyptol 0.092%, menthol 0.042%, methyl salicylate 0.06%, thymol 0.064%. Betadine 5%, oral rinse: PVP-I 5%	Virus (HCoV-229e) and product were mixed thoroughly and incubated for 30 s, 1 min, or 2 min at RTa. Reductions in titres were measured by using the tissue culture infectious dose 50 (TCID50) assay in Huh7 cells.	Neti Pot had no effect on the infectivity of the virus at any incubation time tested. With contact times of 1 and 2 min, the 1% baby shampoo solution inactivated >99% and ≥99.9% of the virus, respectively. The three products with H2O2 as their active ingredient demonstrated that reduction of infectious virus ranged from lower than a log10 reduction factor of x1 to x2 or <90%–99% at 30 s, 1 min or 2 min of contact. Crest Pro-Health decreased infectious virus by a log10 reduction factor of x3 (at 30 s or 2 min of contact), to ×4 (at 1 min of contact), or 99.9% to >99.99%. Listerine Antiseptic decreased infectious virus levels by a log10 reduction factor of ×4, or >99.99% at 30 s, 1 min or 2 min of contact. Listerine-like mouthwashes/gargles decreased infectious virus titres by >99% at 30 s, 1 min or 2 min of contact. Betadine 5% decreased infectious virus levels by a log10 reduction factor of >×4 (at 30 s of contact) or >99.99% (at 1 min or 2 min of contact).
Shen et al. [31]	In vitro and in vivo	Lycorine Emetine Phenazopyridine Mycophenolic acid Mycophenolate mofetil Pyrvinium pamoate Monensin sodium (cetylpyridinium chloride)	A search for effective inhibitory agents was carried out by high-throughput screening (HTS) of a 2000-compound library of approved drugs and pharmacologically active compounds using the established genetically engineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43-ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro (HCoV-OC43, HCoV-NL63, MERS-CoV, MHV-A59). Broad-spectrum anti-CoV activity was evaluated in vitro and in vivo in an experimental infection mouse model. Dose–response curves for seven broad-spectrum inhibitors of four types of CoVs in vitro. BHK-21, Vero E6, LLC-MK2, or DBT cells were infected with HCoV-OC43-WT, MERS-CoV, HCoV-NL63, or MHV-A59 at an MOI of 0.01, respectively, and treated for 72 h with eight doses (0.1, 0.25, 0.5, 1, 2, 5, 10, or 20 μM) of each product.	56 results from the HTS data were examined and 36 compounds were validated in vitro using wild-type HCoV-OC43. Seven compounds inhibited the replication of all CoVs with EC50 values of <5 μM: lycorine, emetine, phenazopyridine, mycophenolic acid, mycophenolate mofetil, pyrvinium pamoate, and monensin sodium. Emetine blocked MERS-CoV entry according to pseudovirus entry assays, and liquorine protected BALB/c mice against HCoV-OC43-induced lethality by lowering the viral load in the central nervous system.

PVP-I, povidone-iodine.

^aRoom temperature: 22 ± 2°C.