" Tamiflu " .Stop mutation

How to invent a cure for flu
Even now against influenza mortality in the world reaches 2 million people a year - more than AIDS.If we recall the major flu epidemic, it becomes clear why many generations of pharmacists felt obliged to creating a cure for flu.

chapter from the book «Great medications: In the struggle for life»

And only in the late twentieth century, there was a medicine based on the active ingredient oseltamivir, which could effectively counter the constantly mutating flu virus.A pinch of this powder is still worth several times more expensive than gold.

history of the drug, known today the world under the name of "Tamiflu", launched October 14, 1992.On this day Bishofberger Norbert was a member of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy in Los Angeles.As head of the department of research and development by Gilead small biotechnology company, based in Foster City, California, Bishofberger was always looking for ideas for new projects.

Between lectures, he walked into the

lobby, where different research groups have placed their stands with the results not yet published studies.Among the many reports of his attention was drawn to the stand with the results of experiments carried out on animals.Scientists from Monash University in Parkville (Australia) have discovered a molecule capable of stopping the proliferation of influenza virus in mice.The British pharmaceutical giant - the company Glaxo Wellcome intended to modify the substance and release it on the market under the brand name GG 167. Bishofberger was impressed with the results of the Australians, but there was some detail in the report, which had eluded him time, and that gave him no peace.

Bishofberger well imagine how big the potential of an effective drug against influenza market.

just sick of about 100 million people in the United States, Japan and Western Europe, the flu each year.According to statistics, deaths flu is not inferior to AIDS, and at the same time every 20 years in the world breaks new, especially dangerous form of flu.

flu doctors for centuries was not too tough.Annual vaccination is often not given the desired effect if the vaccine strains did not coincide with the epidemic.The existing drugs that are considered to be running - amantadine and rimantadine - had quite serious side effects and can withstand only one of the two types of influenza virus.In addition, viruses have gained resistance to these medications for several days.

flu doctors for centuries was not too tough.Annual vaccination is often not given the desired effect if the vaccine strains did not coincide with the epidemic.

Another complex issue, which had to decide pharmacists in search of drugs - namely the identification of influenza virus, whose symptoms are similar to the symptoms of colds.It is for this reason that in many cases the drugs that people take at elevated temperature, fever, general aches and pains, were not influenza.Various powders, drops, pills only eliminates the symptoms of the flu or joined a secondary infection.But these were not the means acting on the virus itself.And because all of these states, and similar symptoms often develop at the same time, even for physicians is difficult to distinguish the flu from the common cold, upper respiratory tract inflammation and bronchitis.

But the attempts of scientists to find an effective remedy for influenza remained unsuccessful: they simply did not know how to work on very variable virus.The fact is that the human immune system fights penetrated into the body of viruses and microbes with the help of special cells, destroying them.At first contact with the microorganism in their education takes time, but the repeated attacks of the same pathogen the person becomes immune to it, because the body already "knows" this stranger, and has the information needed to develop appropriate immune cells.But with the influenza virus that it did not work - the surface of the influenza virus mutated year-on-year, and the human immune system simply could not recognize the changed virus.For pharmacists and researchers it was the most serious problem.

In 1983, Australian researchers were able to create three-dimensional model of one of the molecules of the influenza virus - neuraminidase.They followed that year by year the surface of the molecule changes, but there is one unchangeable site - a deep crevice on the surface of the molecule, which just passed the dissolution of sialic acid, which was part of the virus replication process.This site and found the Achilles heel of the virus.

molecule, which was found by Australian scientists, was just able to close this gap and thereby prevent further propagation of the virus.This molecule was composed of the drug, which Australians tested in mice and the results are presented at the conference.

Bishofberger As a result, once again returning to the experiences of Australian pharmacists concluded that GG 167 molecule could be the first effective anti-influenza agent.And finally he realized what had been bugging him: because the structure of the molecule GG 167 did not allow it to penetrate the mouse from the stomach into the bloodstream, the drug may not be effective if it is taken orally.It had to be administered by inhalation.Bishofbergera is not happy: if you give the patient a choice between drugs that need or swallow, or breathe, people will choose the former.He decided that it should be his aim - to create something that could be swallowed.So, after a short period of time after the conference at the headquarters of Gilead in Foster City, California, gathered a group of ten scientists, who began work on the creation of anti-influenza drug.

to such a molecule could be a remedy, it must satisfy a number of requirements: to have enough power to act, but at the same time placed in a small pill;be selective to block only the neuraminidase of the virus and does not affect other molecules with similar chemical structure;do not dissolve in the body too quickly;be safe.

Once the programmers have created a model most suitable molecule, chemists in the laboratory started its synthesis.Thus, more than 600 substances have been tested.Only 50 of them it was decided to test animals.By the end of 1995, it came to light a molecule consisting of 44 atoms, which satisfies all the requirements.It was called GS 4071.

the end of 1995 was born molecule consisting of 44 atoms, which satisfies all the requirements.

After three years of testing on mice and ferrets molecule started to work as required by it.It was advanced, in fact, the new molecule, which gave the name of GS 4104. Undoubtedly, for patients with influenza in mice and ferrets, it was a great piece of news.But no scientist could not vouch for how to behave influenza molecule in the human body.The cost of creating a new drug substance development from beginning to release it on the market were assessed by the pharmaceutical company Gilead in the amount of 0.5 billion to 1 billion Swiss francs.However, about 2/3 of the cost is usually laid on the clinical trials of a new drug in humans.major funding needed for further work with the GS 4104 material.Gilead company needed a financial partner.

In 1996, Gilead has started to negotiate a license agreement for the development of GS 4104 with several major companies, among which was a group of companies Roche (F. Hoffman-La Roche), with headquarters in Basel.Under the new corporate strategy, Roche aims were ambitious enough - over the next ten years to take a leading position in the market of antiviral drugs.

proposed anti-influenza drug for investments correspond to this strategy is the best.Nine months after the start of negotiations on 30 September 1996 by Roche and Gilead announced an agreement: Roche has received a license for the production of GS 4104, and Gilead - immediate payment of $ 10 million guarantee receipt of $ 40 million after reaching the interim results, as well as guaranteeobtaining a share of profit in case of success.

By this time, the main competitor in the race to become the first in the fight against influenza - a company Glaxo Wellcome - has already begun to study its drug GG 167 in humans.And if you want to catch up with rival Roche, it was necessary as soon as possible to produce a sufficient amount of GS 4104 and start their studies.It is easy enough on paper appeared, GS 4104 material was extremely difficult to manufacture.The process of obtaining the substance of the final product comprised 12 stages.

issue price and the complexity of the process at this stage were not important.The main was the speed of its receipt.The problem was that for clinical trials GS 4104 required a kilogram of substance, and to enter the market - tons.Chemists Gilead feedstock used Quinic acid is obtained as a byproduct from the extraction quinine cinchona bark.However, it became clear that the world does not reach as quinic acid to adjust the production of sufficient quantities of GS 4104. But that's not all.Cinchona supplied from Central Africa, a region characterized by political instability, that at any moment could lead to supply disruptions.Under these conditions, to pharmaceutical scientists have developed a new method of producing substances using shikimic acid.Although her face was significantly higher price, a new raw material in its action it was effective.Moreover, the conversion process of raw materials into a finished product GS 4104 held only 11 instead of 12 steps.In addition, it was found that the necessary amount of shikimic acid can be at the most favorable terms available from China.Subsequently, to produce it was possible to use genetically modified bacteria.Thus it eliminates the problem of dependence on suppliers.

In September 1999, just before the onset of the influenza season, "Tamiflu" were allowed to be used in Switzerland.

In November 1996, Roche began preparations for conducting clinical trials GS 4104. In ferrets and mice worked substance.A further object of the experiments was to become a man.Usually, all three phases of human studies take seven years.However, given that Glaxo Wellcome company significantly ahead of Roche, and has completed the second phase of clinical trials, the company went to take the plunge and planned introduction of GS 4104 for the year 2000.Thus, clinical studies and obtain permission to enter the market, which usually takes about 12 months, was three years old.

research scientists managed to cope with this task.The main component of the current medications, oseltamivir phosphate, competitively and selectively inhibits the action of neuraminidase - an enzyme that promotes the growth and penetration into healthy cells viral agents.

In June 1998, were collected and analyzed data for research on humans.The drug has shown real effectiveness: in patients receiving GS 4104, the disease receded within 36 hours after the start - by 1.5 days earlier than in patients receiving placebo (although the placebo effect also has not been canceled).So all FDA requirements have been met.And in May 1999, the company Roche has applied to the FDA for a license to influenza drug GS 4104.

have drug usually two names: a generic (nonproprietary) name, derived from the name of the active substance, and commercial (corporate) name bywhich the product comes on the market.The World Health Organization as the nonproprietary name approved GS 4104 "oseltamivir".As the same trade name in 1999 settled on "Tamiflu".

In September 1999, just before the onset of the influenza season, "Tamiflu" were allowed to be used in Switzerland.Four weeks later, the license has been obtained in the USA.Almost seven years have passed since Norbert Bishofberger of company Gilead Sciences has started the establishment of anti-flu drug - a relatively short time, considering that usually the process takes from 10 to 15 years.As expected Bishofberger, the need for new drug was enormous.Only during the influenza season, from December 1999 to March of 2000, revenue from sales of "Tamiflu" amounted to 100 million Swiss francs.

If we talk about the main competitor of Roche, Glaxo Wellcome and then withdrew its drug to market.However, its inhaled drug "Relenza" less demand.In the first season of influenza, "Tamiflu" has won 70% of the market.People turned out really prefer to swallow pills and not to use inhalers.Bishofberger was right.

«Tamiflu" is now considered the world's only drug capable of destroying most severe influenza viruses A and B.

Since then, the "Tamiflu" is still the leader on the market of anti-influenza drugs.Since its registration in 1999 at the present time have been treated about 95 million patients, including about 30 million children for whom the virus is particularly dangerous.And the annual sales of the drug exceeded $ 1 billion. This figure does not include the cost of 10.65 million "Tamiflu" packages, which, since 2006, Roche donated by WHO to send the drug to the need of the country (according to the WHO's discretion).

But at the same time the volume of drugs produced at full capacity in the United States and Switzerland (in these countries focused its production) enough for the treatment of patients is not always the case.When in 2009 it became clear that developing a pandemic influenza A / H1N1, and not all in need receive a cure for this virus, Roche company donated licenses to manufacture generic "Tamiflu" to several manufacturers in China, India and some other developing countries.

On the Russian market, "Tamiflu" has officially come from Switzerland.In Russia, according to the rights granted Roche manufacturing company in 2011, is its final (packaging) production stage.

patent for the production of "Tamiflu" for European producers to expire in 2016, from US - in 2017.And it is likely that many countries, and Russia in particular, will launch its own production of oseltamivir.It is not known how these drugs will be referred to in different countries, but, according to the company F. Hoffman - La Roche, in the foreseeable future in the pharmaceutical industry is unlikely to emerge something new and more effective than oseltamivir.Is this true, time will tell.But in fact the "Tamiflu" is now considered the world's only drug capable of destroying most severe influenza viruses A and B.

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