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Arch Virol (2007)DOI 10.1007/s00705-007-0974-5Printed in the Netherlands Antiviral activity of arbidol against influenza A virus, respiratory syncytialvirus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo L. Shi, H. Xiong, J. He, H. Deng, Q. Li, Q. Zhong, W. Hou, L. Cheng, H. Xiao, and Z. Yang State Key Laboratory of Virology, Institute of Medical Virology, Wuhan University, Wuhan, P.R. China Received December 9, 2006; accepted March 18, 2007; published online May 14, 2007# Springer-Verlag 2007 fected with FLU-A (A=PR=8=34 H1N1). Our re- Arbidol, ethyl-6-bromo-4-[(dimethylamino)-meth- sults suggest that arbidol has the ability to elicit yl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-in- protective broad-spectrum antiviral activity against dole-3-carboxylate hydrochloride monohydrate, is a number of human pathogenic respiratory viruses.
an antiviral chemical agent. In this report, we stud-ied the antiviral activity of arbidol against a panelof human respiratory viruses, namely influenza A virus (FLU-A, A=PR=8=34 H1N1), respiratory syn- Viral respiratory infections are the most common cytial virus (RSV), human rhinovirus type 14 (HRV illnesses experienced by people of all ages. They 14), coxsackie virus B3 (CVB3) and adenovirus are also one of the major causes of morbidity and type 7 (AdV-7) in vitro in cell culture. Arbidol was mortality in elderly people and young children found to present potent inhibitory activity against throughout the world [19, 24, 29]. Of approximate- enveloped and non-enveloped RNA viruses, includ- ly 200 viral respiratory pathogens, the most impor- ing FLU-A, RSV, HRV 14 and CVB3 when added tant are influenza and respiratory syncytial viruses before, during, or after viral infection, with 50% (RSV). Other important human respiratory viruses inhibitory concentration (IC50) ranging from 2.7 include rhinoviruses, parainfluenza viruses, coxsack- to 13.8 mg=ml. However, arbidol showed selec- ie viruses, and adenoviruses [3]. Influenza A virus tive antiviral activity against AdV-7, a DNA virus, (FLU-A) is an enveloped single negative-strand only when added after infection (therapeutic index RNA virus, which is thought to be the cause of up- (TI) ¼ 5.5). Orally administered arbidol at 50 or wards of 500,000 deaths globally each year [31].
100 mg=kg=day beginning 24 h pre-virus exposure RSV is the most prevalent infectious agent of acute for 6 days significantly reduced mean pulmonary lower respiratory illness from infants to elderly virus yields and the rate of mortality in mice in- people [7, 30, 29]. Human rhinovirus (HRV), anon-enveloped single positive-strand RNA virus,is implicated in 50–80% of upper respiratory tract Author’s address: Zhanqiu Yang, State Key Laboratory of infections and has also been associated with lower Virology, Institute of Medical Virology, Wuhan University, respiratory tract disease in high-risk populations, 115 Dong-Hu Road, Wuhan 430071, P.R. China. e-mail:[email protected] such as patients with asthma or other airway in- flammation [9, 25]. Coxsackie B viruses are the ing serious sequelae. The utilization of ribavirin is etiological agents of a wide spectrum of human dis- limited due to its controversial efficacy and toxic- eases, including respiratory infection, aseptic menin- ity [32, 15]. Thus, the search for antiviral sub- gitis, and fatal myocarditis. Outbreaks of coxsackie stances that may elicit broad-spectrum protective B virus infection occur annually throughout the efficacy to a panel of respiratory virus pathogens world [26]. Adenovirus, a double-stranded DNA virus lacking an outer membrane, can cause numer- Arbidol, an anti-influenza therapeutic, was first ous diseases such as respiratory infections, cryptic developed in the Russian Research Chemical-Phar- enteric infection and gastroenteritis [34]. Evidence maceutical Institute. The chemical name of arbidol derived from numerous studies supports a crucial is ethyl-6-bromo-4-[(dimethylamino)-methyl]-5- role for respiratory viruses in acute otitis media hydroxy-1-methyl-2-[(phenylthio)methyl]-indole-3- (AOM) and acute exacerbation of asthma, which carboxylate hydrochloride monohydrate. Leneva are also serious health care problems for children et al. studied arbidol’s effect against influenza virus [33]. Several studies have indicated that RSV may and found that it showed a pronounced inhibitory be the principal virus leading to the development effect on influenza virus replication [16]. Fedyakina of AOM, followed by FLU-A and adenovirus [22].
et al. reported that arbidol exerted a selective inhi- Serious efforts have been put into finding an ef- biting effect on the replication of highly pathogenic fective treatment or prevention of respiratory virus influenza A=H5N1 viruses in vitro [6]. Antiviral infections. However, there are no vaccines available effects of arbidol have also been reported for hepa- for preventing RSV at this time [29], and the pro- titis C virus and hepatitis B virus [2, 5]. With a duction of a vaccine to prevent HRV infection has view to evaluate the antiviral activity of arbidol, not been possible because there are over 100 immu- we investigate in this report arbidol’s effects against nologically non-cross-reactive HRV serotypes [8].
a number of human pathogenic respiratory viruses Influenza vaccines are available but induce immune in tissue culture cells and in BALB=c mice.
responses of limited duration, limited cross-strainprotection, and poor efficacy in frail older adults.
Control of these viruses infection remains a publichealth concern, and treatment by antiviral chemo- Arbidol was synthesized at Qianjiang Pharmaceutical Co.
To date, the M2 ion channel inhibitors, amanta- LTD, Hubei, China. Ribavirin, purchased from Qianjiang dine and rimantadine, have been widely used in Pharmaceutical Co. LTD, was used as positive control com- prophylaxis of influenza virus infections. However, pound in antiviral assays. Arbidol was initially dissolved indimethyl sulfoxide (DMSO) and was further diluted with they inhibit only type A viruses, and their utili- complete test medium. The final maximum DMSO concen- zation in clinic is further limited by the rapid tration was 0.05%, which showed no effect on cellular via- emergence of resistant virus mutants [12]. Two new bility or virus replication (data not shown). Therefore, 0.05% neuraminidase inhibitors, zanamivir and oseltami- DMSO was also added to all no-drug control samples. The vir, are effective in both prophylaxis and treatment efficacy of these preparations did not appear to change upon of influenza A and B viruses [11, 13]. The need for freezing and short-term storage (1 month at 4 C).
an inhaler device and the risk of bronchospasmslimits the use of zanamivir. Oseltamivir is being used although the gastrointestinal effects and emer- MDCK (Madin-Darby canine kidney) cells were purchased gence of resistant variants in some treated popula- from CDC of Wuhan City, Hubei, China. HEp-2 (human tions has limited the use of this drug [14]. Ribavirin laryngeal carcinoma) cells and HEL (human embryonic is the only antiviral drug approved by the FDA for lung) cells were maintained in our laboratory. All cell lineswere routinely grown in Dulbecco’s modified Eagle’s med- the treatment of RSV infection, but it is only rec- ium (DMEM; HyClone) supplemented with 10% heat- ommended for use as a small-particle aerosol by inactivated fetal calf serum, 0.1% L-glutamine, 100 U=ml RSV-infected children who are at high risk of hav- penicillin and 0.1 mg=ml streptomycin. The test medium used for the cytotoxic assay as well as for antiviral assays the therapeutic index (TI) for each compound was also deter- contained 2% of the appropriate serum.
FLU-A (A=PR=8=34 H1N1) was propagated in the allan- toic cavities of 10-day-old chicken eggs. After 72 h growth at 35 C and 12 h at 4 C, the allantoic fluid was harvested andcentrifuged at 5000 rpm for 15 min to remove cellular debris, and virus was titered by hemagglutination with guinea pigred blood cells. Sterile filtration was used for additional Serial two-fold dilutions of the test compound were dis- passages. The virus was passaged three times in embryo- solved in DMEM and incubated with cells for 24 h at 37 C nated eggs with a hemagglutination titer of 2560. RSV strain (for CVB3 and AdV-7) or at 35 C (for FLU-A, RSV, and Long, coxsackie virus B3 (CVB3), and adenovirus type 7 HRV 14) in 5% CO2 atmosphere. After removal of the com- strain (AdV-7) were maintained in our laboratory and prop- pound, the cells were washed twice with PBS and challenged agated in HEp-2 cells. HRV 14 was also maintained in our with 100 TCID50=0.1 ml of FLU-A, RSV, HRV 14, CVB3 or laboratory and was propagated in HEL cells. The viruses AdV-7, corresponding to a multiplicity of infection (MOI) of were stored in small aliquots at À80 C until use.
0.1, 1.0, 1.0, 1.0, and 0.01, respectively. After 1 h incubationfor virus adsorption, the monolayers were rinsed twice withPBS and were further incubated with test medium until typi- cal CPE was visible (2-day incubation with FLU-A, HRV 14,CVB3 and AdV-7; 5-day incubation with RSV). The inhibi- Virus titration was performed by the limit dilution method, tion of the virus-induced CPE was scored by light micros- using a 96-well microtitre plate with 6 wells per dilution.
copy and measured by the MTT assay. Four untreated virus The virus titer was estimated from cytopathogenicity of cells controls and four uninfected, untreated cell controls were induced by viral infection and expressed as 50% tissue cul- included in all assays. The IC50s were determined as de- ture infectious doses=ml (TCID50=ml) [27].
scribed above. All data presented are results of experimentsperformed in triplicate.
The cytotoxicity and antiviral activity of the compound were determined using quantitative colorimetric MTT [(3-(4, 5- Viral suspensions containing 100 TCID50=0.1 ml of viruses dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide)] were incubated with an equal volume of medium with or assay [21, 23, 8, 18]. Briefly, MDCK, HEp-2, and HEL cells without the test compound for 1 h at 35 C (for FLU-A, RSV, were seeded at 2 Â 104 cells per well in 96-well plates and and HRV 14) or at 37 C (for CVB3 and AdV-7). One hun- grown at subconfluence. After removal of the growth med- dred microliters of mixed suspension was then added to ium, serial two-fold dilutions of the compound in 200 ml test subconfluent monolayers of cells. After an incubation time medium were added. At each concentration, four wells were of 1 h, the solutions containing both compound and viruses infected with 100 TCID50=0.1 ml of virus while four wells were removed; the cell monolayers were rinsed carefully were left uninfected for toxicity determination. Cells were with PBS and further incubated with 200 ml test medium.
fed with arbidol daily since its half-life in cultured cells is After incubation for 2 days (with FLU-A, HRV 14, CVB3 about 18 h [10]. Plates were incubated at 37 C (for CVB3 and AdV-7) or 5 days (with RSV), the virucidal effect was and AdV-7) or at 35 C (for FLU-A, RSV, and HRV 14) and determined using the MTT assay following the protocol the development of cytopathic effect (CPE) was monitored described above (Drug treatment before virus infection daily by light microscopy until the virus-infected, untreated cells showed CPE up to 80%. At this time point, the cul-ture medium was removed and 25 ml of the MTT solution(5 mg=ml in phosphate buffered saline, PBS) was added to each well. The plate was further incubated for 4 h to allow The experiment was carried out as stated above with the MTT formazan formation. After removal of supernatant, following difference: monolayers were challenged with 100 50 ml of DMSO was added for solubilization of formazan TCID50=0.1 ml viruses for 1 h. The cell sheets were washed crystals and these were homogenized on a microplate shaker with PBS and overlaid with different doses of the compound for 15 min. The optical densities (OD) were then read using a microplate spectrophotometer at double wavelengths of540 and 690 nm. Results were expressed as a percentage ofOD value of treated cell cultures with respect to untreated ones. All data were analyzed with SPSS 11.5, and the 50% Arbidol and ribavirin were each evaluated for the dose con- cytotoxic (CC50) and 50% inhibitory (IC50) concentrations of sidered lethally toxic to mice. The doses studied for each the agent for the different cell lines were determined. Thus, compound were 500, 250, 125, 62.5 and 31.3 mg=kg=day.
The mice (n ¼ 8) were treated with each compound by oral Table 1. Cytotoxicities of arbidol and ribavirin gavage for 6 days. The animal weights were determined priorto the first treatment and again 18 h after the final treatment.
They were observed for death daily for 21 days.
Specific-pathogen-free female BALB=c mice, 5–7 weeks old (17–19 g), obtained from Animal Center of Wuhan Univer- Mean Æ S.D. values are shown from three independent sity, were used in all experiments. Mice were anesthetized by aether (Shanghai Chemicals Inc, China) and infected intra- CC50 is the cytotoxic concentration required to reduce the nasally with 50 ml viral suspension containing approximately 105 TCID50 of influenza A virus. The mice were divided intofive groups; and arbidol at a dose of 25, 50, or 100 mg=kg=day, tectable alterations. Arbidol exhibited cytotoxicity ribavirin at a dose of 68 mg=kg=day or a placebo was orally against MDCK, HEL, and HEp-2 cells, with CC50 administered to the mice three times daily (at 8-h intervals) of 69.4, 72.5, and 85.4 mg=ml, respectively. Thus, for 6 days beginning 24 h pre-virus exposure. The placebo the maximal concentration of 16 mg=ml of arbidol controls received 0.5% methylcellulose solution instead ofthe drug. In the survival rate study (n ¼ 10) the mice were was adopted in the mode of action study to ensure observed for mortality daily for 21 days after infection. The that its antiviral effect was not due to cytotoxicity.
protection was estimated by the reduction of the rate of mor-tality and prolongation of mean day to death (MDD). In thelung virus yield study (n ¼ 8), the mice were sacrificed by cervical dislocation on the 5th day after viral exposure. The body weights of the mice were recorded daily until the ani-mals were killed. The lungs were harvested, weighed, and Cells were treated with arbidol or ribavirin prior to subsequently homogenized to $10% (w=v) suspensions in viral infection as described in Materials and Meth- test medium. The homogenates were frozen and thawed ods. As seen in Table 2, arbidol showed significant twice to release the virus and centrifuged at 3000 rpm for10 min. Virus titration was determined as described above.
inhibitory activity against FLU-A and RSV, with The lung index was expressed as the ratio of mean lung IC50s of 2.7 and 8.7 mg=ml, resulting in TIs of weights to mean body weights was also determined [28].
25.7 and 9.8, respectively. Infected MDCK cellstreated with arbidol at concentrations up to 4 mg=ml did not show any visible CPE in comparisonwith the virus-control wells, which showed typical The data were analyzed by SPSS 11.5 software. Differencesin mean day to death, mean body weights, lung virus yields CPE. In contrast, ribavirin could not inhibit FLU-A and lung indexes compared with the control values were or RSV replication in this assay. Arbidol showed evaluated by Student’s t-test. The log rank test was used relatively weaker activity against HRV 14 and to evaluate differences in the survival rates of the mice. A CVB3, with IC50s being greater than that for P value of < 0.05 was considered statistically significant.
FLU-A, resulting in lower TIs of 5.4 and 6.7. Itis interesting to note that arbidol lacked inhibitory activity against AdV-7, a non-enveloped, double-stranded DNA virus.
The cytotoxicities of arbidol and ribavirin forMDCK, HEL, and HEp-2 cells were evaluated.
To investigate the direct inactivating effect of arbi- The results are summarized in Table 1. Subcon- dol, viruses were treated for 1 h with concentra- fluent monolayers treated with arbidol at concen- tions of arbidol ranging from 1 to 16 mg=ml. As trations of 1–16 mg=ml did not show any visible shown in Table 2, arbidol was virucidal with FLU- changes in cell morphology or cell density, whereas A, RSV, HRV 14, and CVB3, with IC50s of 4.3, 32 mg=ml of arbidol caused microscopically de- 10.4, 13.8, and 13.1 mg=ml, respectively. Concen- Table 2. Antiviral activity of arbidol against different viruses a Mean Æ S.D. values are shown from three independent experiments.
NR: IC50 not reached.
IC50 is the inhibitory concentration required to reduce viral replication by 50%.
trations of arbidol >8 mg=ml completely abolished the biological activity of FLU-A virus. Arbidol in- Oral gavage treatment with arbidol and ribavirin for hibited the CPE of FLU-A on MDCK cells, RSV on 6 days indicated the approximate 50% lethal dose HEp-2 cells, HRV 14 on HEL cells, and CVB3 on HEp-2 cells, with TIs of 16.1, 8.2, 5.3, and 6.5, 50) of rivavirin to be 213 mg=kg=day, whereas approximately 314 mg=kg=day (Table 3). It shouldbe noted that no obvious weight loss was seen at dosages below the LD50 dose. No attempt was madeto determine the cause of death in the mice in this Subconfluent cells were infected with the various viruses and then incubated with the drugs as de-scribed in Materials and Methods. Arbidol wasbroadly inhibitory for the five viruses when added after infection. The rank order of virus sensitivityto arbidol was CVB3, RSV, FLU-A, HRV 14, By Day 3, after viral exposure, clinical signs of mu- and AdV-7. The IC50 values ranged from 9.5 to rine influenza pneumonia were observed in some mice, especially in the placebo controls. Changes Table 3. Comparison of toxicity of oral gavage treatmenta with arbidol and ribavirin in mice a Treated by oral gavage for 6 days beginning 24 h pre-virus infection.
b Mean day to death of mice dying prior to day 21.
c Difference between weight prior to start of treatment and weight 18 h after end of therapy.
d Determined by line of regression.
Table 4. Effect of oral treatment with arbidol in mouseinfluenza model a Mean day to death of mice dying prior to day 21.
b The placebo controls received 0.5% methylcellulose solu-tion instead of the drug.
ÃP<0:05 vs. placebo-treated controls; ÃÃP<0:01 vs. pla- Fig. 1. Effects of orally administered arbidol on weight loss in influenza-virus-infected mice (5–7 weeks old). Micewere infected with influenza virus A=PR=8=34 as describedin Materials and Methods. Mice were treated with an oral in behavior, such as tendencies to huddle, dimin- dose of arbidol of 25 (&), 50 (~), or 100 () mg=kg=day or ished vitality, and ruffled fur were also observed.
with 0.5% methylcellulose solution as a control () for 6 Parameters for determining the protective efficacy days beginning 24 h before infection. ÃP < 0:05 vs. place-bo-treated controls (Student’s t-test) of arbidol against influenza virus A=PR=8=34-in-fected mice included prevention of death through21 days and lessening of lung virus titer and lung in the 25, 50, and 100 mg=kg=day arbidol-treated groups were 1.97, 1.44, and 0.7 g (P<0:05), re- Most of the mice infected with influenza virus spectively, while the maximum mean weight loss A=PR=8=34 died within 21 days if they were in the placebo-control group was 2.89 g. Addition- treated with only placebo (Survival rate ¼ 20%) ally, the i.n. infection with FLU-A virus led to an (Table 4). Orally administered arbidol prevented increase in mean lung weight, which was detectable influenza-virus-induced death in a dose-dependent on day 5 after viral exposure (Table 5). However, manner. For the groups treated with arbidol at a lung weights of mice treated with arbidol at 50 and dose of 50 or 25 mg=kg=day, the survival rates were70 and 50%, respectively. In this experiment, Table 5. Effect of oral treatmenta with arbidol on lung virus 100 mg=kg=day of arbidol demonstrated relatively greater effect to the mice than 68 mg=kg=day of ri- bavirin, approximately one-third of the LD50 doseof each compound, in terms of the better survival rate and the higher length of MDD (P <0:05).
Oral administration of arbidol beginning 24 h pre-virus infection significantly decreased the virus titers of mice lung homogenates. In the groups treat- ed with arbidol at 25, 50, or 100 mg=kg=day, the mean virus yields were reduced to 3.2, 2.4 and 2.0 (P<0:01) Log10 TCID50=lung, respectively, whereas the yields in placebo controls were 4.9 Treated by oral gavage for 6 days beginning 24 h pre-virus 10 TCID50=lung (Table 5). Based on the de- celerated loss of the body weight, the beneficial ef- infection.
b Mean Æ S.D. values are obtained from a single represen- fects of arbidol treatment at 50 and 100 mg=kg=day were noticeable as early as on day 3 post challenge ÃP<0:05 vs. placebo-treated controls; ÃÃP<0:01 vs. pla- (Fig. 1). At day 5, the maximum mean weight loss 50 or 100 mg=kg=day 24 h before infection withinfluenza virus A=PR=8=34 for 6 days significantlyreduced mean pulmonary virus yields in mice andthe rate of mortality. Our results suggest that arbi-dol, a potent non-specific, broad-spectrum antiviralagent, should deserve our attention in future [3].
In our study, enveloped viruses were found to be more sensitive to arbidol than non-envelopedviruses. The results of pre-treatment assay and viru-cidal assay showed that arbidol exhibited signifi-cant inhibitory activity against FLU-A and RSV,two enveloped viruses, while it showed weak ac-tivity or no activity against HRV 14, CVB3, or Fig. 2. Effect of oral administration of arbidol on preven- AdV-7, three non-enveloped viruses. These results, tion of lung index increase in influenza-virus-infected mice.
taken together, are in agreement with previous Mice were infected with influenza virus A=PR=8=34 at 105 studies that showed that the mechanism of arbidol TCID50=mouse, and the lung index was determined as de-scribed in Materials and Methods. Mice were treated with action against influenza viruses is connected to in- an oral dose of arbidol of 25, 50, or 100 mg=kg=day or with hibition of the process of membrane fusion [17, 1].
0.5% methylcellulose solution as a control for 6 days be- In addition, Boriskin et al. reported recently that the ginning 24 h before infection. ÃÃP < 0:01 compared to the antiviral activity of arbidol towards hepatitis C results for placebo-treated controls (Student’s t-test) virus is due to a direct effect of arbidol on virus-cell membrane interactions [2]. However, the exact 100 mg=kg=day remained relatively normal com- antiviral mechanism of arbidol is an interesting pared to the placebo controls (P< 0:01) (Table 5).
Therefore, arbidol treatment at 25, 50, or 100 mg= Based on its chemical structure, which contains kg=day dramatically prevented lung index increases a carboxylic acid ester moiety, arbidol may be a compared to the placebo controls (P< 0:01) (Fig. 2).
substrate for hydrolysis in vivo, leading to the intra- These results suggest that arbidol may be effective cellular accumulation [2]. The fact that arbidol dis- for prevention of influenza virus infection.
played prophylactic activity when administered24 h before infection might indicate a prerequisitefor arbidol accumulation in intracellular compart- ments before antiviral activity is observed. Clearly, We have demonstrated the broad-spectrum antiviral additional studies of arbidol and various chemical activity of arbidol in vitro. First, we used a simple and rapid staining method (MTT assay) to identify It has been reported that the nucleoside ana- the mode of action of arbidol against a series of res- logue ribavirin inhibits both DNA and RNA viruses piratory viruses. Arbidol was found to present anti- [20, 29], and in our study, ribavirin inhibited the viral activity against enveloped and non-enveloped replication of some RNA viruses, FLU-A and RSV RNA viruses, namely FLU-A, RSV, HRV 14, and (data not shown), but not the DNA virus, AdV-7.
CVB3 when added before, during, or after infec- Besides, ribavirin could not inhibit RSV when tion. Besides, arbidol showed weak activity against added before infection but could inhibit RSV repli- AdV-7, a DNA virus when added after infection.
cation when added after infection [18]. In contrast, The high in vitro inhibitory activity obtained for cells pretreated with arbidol were resistant to sub- arbidol against influenza virus in these studies and sequent infection with FLU-A, RSV, HRV 14, and others [16, 17] was reflected in the in vivo (BALB=c CVB3. In addition, arbidol showed an inhibi- mice) studies where significant anti-FLU-A activity tory effect against AdV-7 when added after infec- was also observed. Orally administered arbidol at tion. In our experiment, 100 mg=kg=day of arbidol demonstrated a relatively greater effect in mice 9. Gern JE, Busse WW (1999) Association of rhinovirus than 68 mg=kg=day of ribavirin, approximately infections with asthma. Clin Microbiol Rev 12: 9–18 10. Guskova TA, Leneva IA, Fedyakina IT, Chistyakov VV, one-third of the LD50 dose of each compound, in Glushkov RG (1999) Arbidol kinetics and its effect on terms of the better survival rate and longer MDD influenza A virus replication in MDCK cell culture.
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