Masterlek Webpage article on arbidol
Arbidol – Treat influenza, not just its symptoms!
Medicine now has new possibilities for prevention and treatment of influenza and RSV.
The drug arbidol is well-known in Russia. It has already been used successfully for several years in the prevention and treatment of influenza and RSV. Recently, in research laboratories in England and in the U.S. which study the problem of influenza, new studies concerning arbidol have been completed. These studies included observations of the details of the mechanism of arbidol’s antiviral action, and have brought this drug into the narrow circle of etiotropic antiviral preparations. Irina Leneva (PhD Biology), senior research fellow at the Center of Chemical Medicines of the Chemical-Pharmaceutical Scientific Research Institute of Russia, has taken part in research on arbidol. Here she explains the research, and the findings associated with it.
--First, I would like to talk a little in general about the anti-influenza drugs currently available. Even though our arsenal of anti-influenza medications now includes drugs which work at practically every phase of the infection process, the WHO (World Health Organization) recommends etiotropic drugs, which have a direct effect on viral reproduction, for treatment and prophylaxis of influenza. At present there are two generations of these drugs in existence. The first is represented by rimantadine, well known to us, and also by its counterpart amantadine, used in Europe and the United States. These drugs are effective against only type A of the virus, and often cause side effects in patients who take them. In addition, resistance to these drugs builds quickly. The second group are the so-called neuraminidase inhibitors, zanamivir and oseltamivir. Zanamivir, which comes in the form of inhalers or nasal spray, may sometimes cause irritation of the nasal passages and bronchii, and oseltamivir can cause nausea and vomiting. Both of these drugs are effective against influenza types A and B. Unfortunately, these drugs are quite expensive – one course of treatment costs $50 to $80.
As you see, the selection of both domestic and imported antiviral medications for prevention and treatment of influenza is not very large, and none of the options are without problems. For this reason, the search for a new drug is urgent and necessary.
Q: But doesn’t the WHO recommend vaccination as the first line of defense against influenza?
A: Yes, this is true, but there are several reasons why it is also important to use antiviral medications. First, there is always the possibility that the vaccine of the next predicted strain of influenza will be off – that the specialists will miscalculate in determining its antigen makeup. Secondly, the vaccine does not provide 100% guarantee of immunity, and in such scenarios there is no alternative but antiviral medications. Thirdly, what concerns specialists the most is the threat of a mutation of a particularly pathogenic strain of influenza capable of causing a pandemic. The so-called bird flu is an example of this kind of situation. It takes a minimum of six months to create a vaccine against a new influenza strain. This is unallowable in such a dangerous situation.
Q: That is, we cannot get by with just one vaccine?
A: Of course, we cannot rely solely on just one remedy. Arbidol is one of the most interesting, promising and safe drugs with antiviral effect. As you know, it is widely and successfully used in Russia. This drug was created by the joint effort of scientists from Chemical-Pharmaceutical Scientific Research Institute (CPSRI) of Russia, the Scientific Research Institute of Medical Radiology RAMN in Obninsk, and the Leningrad-Pasteur Scientific Research Institute for epidemiology and microbiology. The high therapeutic effectiveness of arbidol lies in its multi-faceted action. It stimulates the body’s production of interferon, which helps fight against a variety of infections. As an immunomodulator, it regulates the workings of the immune system. And in addition to all of this, it has antioxidant and virus-specific targeting effects. The first three characteristics of arbidol have been studied relatively thoroughly, but so far we have not been able to understand the details of its virus-specific mechanisms. This is in spite of the fact that we have never had reason to doubt the existence of these mechanisms. Naturally, this gap in our studies has kept arbidol from being accepted in the international arena. In order for it to be accepted in western countries as an antiviral agent, it was necessary to conduct detailed studies of arbidol’s active mechanism; to determine its “target” – the specific viral structures on which it acts when a virus is introduced and multiplies in an organism. This kind of research is difficult; it requires huge financial backing and state-of-the-art equipment, and only a few laboratories in the world are equipped to handle it.
Since we could not physically conduct such research in Russia, RAMN fellow Robert G. Glushkov, the director of the Center for Chemical Medicines at the CPSRI, applied to Professor Alan Hay, the director of the WHO center for influenza studies, at the National Institute for Medical Research in London. This institution has a very high reputation as an international research center. It was here, in 1931, that the influenza virus was separated and identified; here in 1945-46, that the first anti-influenza vaccines were studied; and here where the mechanisms of amantadine and rimantadine were studied. We described the effectiveness of arbidol in a letter to Mr. Hay, and explained its potential against influenza and RSV. We proposed a study of the drug in London with the equipment and expertise of British researchers. Mr. Hay became interested in the project and helped procure a grant from the Velcom Trust organization, which sponsors scientific research in the best laboratories across the world.
Q: How was this research conducted?
A: Working in the WHO influenza center, I first had to identify the specific viral “target” which arbidol affects. In order to understand the essence of the research, it is necessary to understand how a virus reproduces. This process has early and late stages. First, the virus is absorbed (that is, attaches itself) to the outer surface of the cell; only after attachment can it enter the cell. The forms it takes at this point are called “endosomes,” similar to small bubbles which are separated from the actual cell membrane. The low pH (that is, relatively acidic condition) within the endosomes induces conformational (structural) changes of the virus protein hemagglutinin HA, which are situated on the surface of the virus. It so happens that this protein is one of the main antigens of the influenza virus, along with neuraminidase. As you may remember, neuraminidase is another antigen whose action is blocked by the group of drugs called neuraminidase inhibitors.
The conformational changes of HA allow the virus to fuse with the endosome membrane, and the genome within the virus, which has the encoding for the formation of new virus, is set free. At this moment begins what is called the later stage of viral reproduction, where the genome processes viral genetic information and begins to replicate the virus.
The research showed that arbidol works in the first stage of this process, preventing the fusion of the virus with the endosome membrane. Further, we needed to know how arbidol accomplishes this. Studies on this process were conducted using mutations of the virus which were resistant to arbidol. It turned out that arbidol’s “target” is the hemagglutinin of the influenza virus.
Q: Strange – doesn’t the presence of viral mutations resistant to arbidol suggest that this medication will not be effective against them?
A: This is the flip side of the effectiveness of any antiviral drug. It shows that the majority of the virus is killed, with only a few remnants surviving. The existence of mutations resistant to the drug is actually the criteria by which we prove antiviral action.
At first, we were unable to produce these resistant viruses. But when we infected cell culture with the virus in successive stages, finally after the fifth succession we produced this result. As a comparison, in the case of rimantadine, resistant viruses arise relatively quickly, after 2 to 3 successive stages, while with neuraminidase inhibitors they appear only after 17 successions. This means that the probability of influenza viruses naturally resistant to arbidol occurring in circulation among humans is very low. Moreover, viruses resistant to rimantadine frequently occur not only in the laboratory, but in patient populations.
Thus, the production in the laboratory of viruses resistant to arbidol proves conclusively its direct antiviral effect. And these results were produced under the strictest international experimental standards.
Q: Describe how you studied arbidol’s effectiveness against the avian flu virus.
A: The avian influenza virus H5N1 first appeared among humans in 1997 in Hong Kong, where out of 18 ill with the disease, six people died. The following year, in the same location, a new strain, H9N2, surfaced, and at the end of 2003 and start of 2004, an outbreak occurred simultaneously in several Asian countries, again associated with H5N1. In this outbreak also, there were several fatalities – the fatality rate for avian influenza is quite high.
Prior to these outbreaks, scientists thought that avian flu was not dangerous to humans. But Robert Webster, the department director of virology and molecular biology at St. Jude Children’s Medical Center in Memphis, Tennessee, that the source of avian flu might also be a threat to humans. He developed a theory under which avian flu could be transmitted to humans. Most scientists had thought that humans could get influenza viruses only from pigs. Specifically, it was supposed that the “flu” which had earlier carried off millions of human lives had been caused by a pig influenza virus.
Robert Webster had worked in Hong Kong at the time of the outbreak, and in his laboratory was a sample of the avian flu from that region. This is a striking coincidence, since very few laboratories in the world had this dangerous virus – but it happens I was fortunate enough to be working at this time with Professor Webster. When I told him about arbidol, he was interested in it and proposed a study of its effectiveness against avian influenza. After the first experiments it became clear that arbidol inhibits a wide group of avian influenza viruses, which confirms the high potential of this drug.
Q: Will arbidol receive international acclaim?
A: This is a tough question. As we all know, the registration system for drugs in the West and in the U.S. is very stringent, and very bureaucratic. There is a known precedent; the WHO has already accepted another of our antiviral preparations. This was rimantadine, and this was still in the Soviet era. Rimantadine has an interesting history. Americans discovered it, but for some reason they abandoned research on it. Around the same time they introduced amantadine, which has an analogous antiviral action.
Then the USSR began to study, make and use rimantadine. The drug became popular, and was used widely in clinical practice. After some time, the WHO recognized it as an effective medicine for the prevention and treatment of influenza. This happened all because the Soviet Union provided the training ground for experimenting with the drug. (Interestingly, even the Americans now recognize rimantadine’s advantages compared to amantidine.)
The situation now with arbidol is quite similar. The use of arbidol now in Russia is on a par with that of rimantadine, and research proving its antiviral effect is being conducted at the highest levels. It is difficult to predict the development of future events. This much, however, is clear: we have awakened interest in arbidol, and this drug is already known in the West.