by Marina MALYGINA, journalist

The Irkutsk company Farmasynthesis, one of the ten leading pharmaceutical enterprises of Russia, in December 2012 began a serial production of the innovational preparation Perchlozon, which, according to national and foreign phthisiotherapeutists, can achieve a breakthrough in the treatment of tuberculosis. Nowadays it is the only preparation in the world, which is capable to suppress strains, resistant to this widely spread infectious disease. The first lot of anti-tubercular preparation have already been delivered to the country's hospitals. This year it is planned to arrange its industrial production in the volume necessary to meet the requirements of medical institutions of the appropriate profile.

A history of Perchlozon creation (derived from the chemical formula perchlorate thiosemicarbazon) is a convincing example of the fruitful cooperation of national scientists and representatives of high-tech business. It began in the 1980s at the Irkutsk Institute of Chemistry named after A. Favorsky, the USSR Academy of Sciences (Siberian Branch); from the very first days of its foundation (1957), specialists were engaged in fundamental studies plus applied works, including creation of medicines. Probably, the interest of Siberian specialists in pharmaceutical preparations is connected with the fact that the Institute's first director was a corresponding

member of the USSR AS Mikhail Shostakovsky--the creator of the famous antiseptic balsam Vinilin (it is still widely used by physicians and is on trial as a component for different cosmetic and medical products). For over half a century, Shostakovsky's followers received more than 1,700 patents and author's certificates for invention of medicinal substances, 8 preparations have been already produced.

Among them Perchlozon occupies a special place. It is intended for the treatment of tuberculosis (a disease, caused, as a rule, by Mycobacterium tuberculosis, a microbacterium, opened in 1882 by the German physician, the 1905 Nobel Prize winner, Robert Koch), which still remains one of the major infectious causes of mortality. Around 1.7 mln men throughout the world are affected by a pathogenic organism of this ineradicable disease. Over 9 mln go down with its active forms annually, more than 3 mln die. Fortunately, according to the data of the World Health Organization, the mortality level in the world from this perfidious disease has been lowering since 1990. But this improvement of statistics takes place at the expense of developed and rich countries: 3-7 men per 100,000 of the population "catch" the infection in the USA and EU states annually, while in Russia the figure is 82. This can be explained by the low range of prophylactic examination of our residents, absence of social support of patients, considerable wear and tear of the material and technical base of anti-tubercular institutions, insufficient number of qualified medical personnel. Russia holds the 13th place after Myanma and Vietnam in the world "rating" by spreading of infection. According to the statistics of Rospotrebnadzor, approximately 117-120 thous. people are registered annually, 10 percent of those infected for the first time have drug resistant forms. The most unfavorable situation is in the Far-Eastern Region and Siberian Federal District.

The Irkutsk region is not an exception. According to the data of the Regional Ministry of Health, the rate of spreading of infection by tuberculosis micobacteria in the region exceeds that of average Russian almost twice. Every year here are registered from 3 to 3.5 thous. carriers of Koch's bacillus, around 1,000 men die, the majority of them--able-bodied population. However, we cannot ignore the fact that there are correctional institutions in the region, which present favorable soil for the development of the infection.

The control over the disease is made more difficult due to the fact that Mycobacterium tuberculosis in the process of evolution works out mechanisms of protection against once effective drugs. It is not accidental that phthisiotherapeutists widely use the term "tuberculosis with multiple medicinal resistance". It is just resistance (resistance of the organism to one preparation) that has

become one of the main factors limiting treatment for "white plague". There is only one way out--to work out and put into practice innovational methods of saving patients.

A lot of laboratories in the world have been working for 40 years in this direction, registering an enormous number of substances, possessing anti-tubercula characteristics. However, created on the basis of old methods, they destroyed only the laboratory Mycobacterium and became completely impotent against stable bacteria living in man's organism. It must be admitted that forecasts were rather depressing before creation of Perchlozon.

The preparation was carving its way to the patient for more than 25 years--the time, which passed since the chemists from Irkutsk devised a molecular formula of a new substance, which then transformed into a medicine. In early 1980s, working in close cooperation with the Leningrad Research Institute of Tuberculosis (today St. Petersburg Research Institute of Phthisiopulmonology), Siberian scientists created more than 100 compounds, which had gone through screening (selection, sorting), and received author's certificates and patents for a part of them.

The "predecessor" of Perchlozon--a substance, which turned out to be least toxic for man and most aggressive to tuberculosis,--was synthesized in 1986 at the laboratory of Galina Skvortsova, Dr. Sc. (Chem.). Then it was studied in the course of 2-3 years under supervision of Gennady Dolgushin, Cand. Sc. (Chem.) and Svetlana Amosova, Dr. Sc. (Chem.), and only in 1989 received author's certificate for it.

In 1990, there started preclinical trials of Perchlozon on mice and rats at the Research Institute of Phthisiopulmonology within the framework of RAS program "Fundamental Sciences--to Medicine". But the time which set in the country brought drastic reduction of financing of the scientific-technical complex and postponed the process for a long time. The further promotion of the preparation--its trials at the clinic--was out of the question. "The path of creation of the drug is very long--out of hundreds of active molecules, which the chemist gets in his retorts, only one or two have a chance to reach the chemist's," confessed in an interview to the local newspaper Valery Stankevich, Dr. Sc. (Chem.), deputy director for scientific work of the Irkutsk Institute of Chemistry named after A. Favorsky. According to him, this process takes at least 7-10 years and costs from 300 mln to 1 bln dollars.

This unique invention of Siberian scientists could possibly remain unnoticed like other innovational works of a number of national research institutes. But the events of 2004 played a decisive role. "That year,"--recollect Director of the Irkutsk Institute of Chemistry named after A. Favorsky, Acad. Boris Trofimov, and his deputy Andrei Ivanov, Dr. Sc. (Chem.), who delivered a report on this subject at a meeting of the Presidium of the Irkutsk Academic Center (RAS Siberian Branch) in March of 2013,--"the exposition 'Innovations: Economics, Social Sphere, Science and Education' was held within the framework of celebration of Days of Science at the Sibexpotsentr. Our Institute presented its works, including Perchlozon. The young pharmaceutical company Farmasyntez, set up in Irkutsk by a businessman of Indian origin Vikram Puniya, got interested in it." Registered in 1997, the company by that time was already producing dozens of designations of traditional, time tested preparations, including anti-tubercular drugs (every second tablet of such drug was made there). It was possible to proceed in the same direction by increasing the quantity of the range of drugs. But President of the company Vikram Puniya and his colleagues Director General Olga Turchaninova and Director for science and innovational activities Alexander Gushchin did not seek easy life. Guided by strict business logic, they decided to invest the company's money into realization of a rather risky but promising innovational project.

In 2005, the partners--Irkutsk Institute of Chemistry named after A. Favorsky, St. Petersburg Research Institute of Phthisiopulmonology and OAO Farmasyntez concluded a tripartite agreement for further systematic studies of the anti-tubercular preparation. Business took upon itself financing of the final preclinical phase and, what is more important, assigned funds for carrying out of very expensive and money- and time-consuming clinical trials, working out of technologies and creation of a pharmacopoeia article on the given preparation.

In 2006, the Research Institute of Phthisiopulmonology completed the basic preclinical studies in compliance with the GLP (Good Laboratory Practice) standard*, which allowed to examine the drug thoroughly at the hospital. So, the Irkutsk Institute of Chemistry made pilot series of the substance (30 kg) with account for all requirements to the production of sterile products and handed it over to Farmasyntez. Made in 2009, at the company's plant, the new preparation reached patients with a pulmonary form of tuberculosis in specialized clinics of the country: State Research Center of Prophylactic Medicine of the RF Ministry of Health, Institute of Immunology (FMBA of Russia), St. Petersburg

* GLP standard--a system of norms, rules and instructions intended to guarantee coordination and authenticity of the results of laboratory trials. As a national standard of the RF, the system functions from March 1, 2010.-Ed.

Research Institute of Phthisiopulmonology, Novosibirsk Research Institute of Tuberculosis and Regional Anti-Tubercular Clinic in Orel.

In the course of 2010-2012, the preparation got 108 patients with tuberculosis. According to the RF chief phthisiotherapeutist Pyotr Yablonsky, who summed up the results of clinical trials in March of 2013, the treatment results of volunteers using Perchlozon were by 30-40 percent better than without it. "It does not possess mutagenic activity and is less toxic than isoniasid and streptomycin. Its activity in relation to tuberculosis strain No. 3714 is 200 times higher than that of isoniasid, and 400

times higher than that of streptomicin,"--emphasized Yablonsky. Besides, the preparation turned to be effective in acute cases, when the tuberculosis bacterium is resistant to a majority of traditionally used preparations. "It is really a powerful instrument in the hands of phthisiotherapeutists,"--concluded the leading specialist in this sphere. In November of 2012, the RF Ministry of Health issued a registration certificate for Perchlozon and included it in the tuberculosis treatment standard.

While experiments in clinics were still in progress, the laboratories of applied chemistry of the Irkutsk Institute under supervision of Valery Stankevich were working on pilot regulations for production of the preparation, as a result of which there appeared a complete technology for its synthesis in industrial scales.

Besides, the work group continued its efforts to make it better. The laboratory of chalcogen-organic* compounds headed by professor Svetlana Amosova tried to improve the molecular formula of Perchlozon--strived to lower toxicity without lowering bioactivity. In addition, medical workers recommended to make it watersoluble, i.e. fit for intramuscular injections (liquid solution is better assimilated). The chemists coped with this task successfully too: in 2011-2012 they found an ecologically pure method of getting the preparation in water under the room temperature, i.e. in the simplest technological process. Moreover, its purity, according to the creators, even exceeds requirements of pharmacopoeia.

Farmasyntez built a plant for Perchlozon production in Irkutsk. "It is a rare event,--says professor Stankevich,--not all big companies have their own chemicopharmaceutical plant.--Usually companies, producing preparations, make pills, injections, while substances for them are made at pharmaceutical giants, such as in Usolye (Usolye Chemico-Pharmaceutical Industrial Complex). But as there are practically no such plants in our country (only 5-7 percent of all drugs are produced using substances prepared in Russia), that is why Farmasyntez had to create in its holding a separate production--now it makes ready products from its own raw materials."

This year the entrepreneurs plan to supply consumers with 20-30 thous. packages of Perchlozon. The patient needs only 1 for treatment. And it will cost, according to preliminary estimates, 1,200 dollars (36 thous. rubles). By comparison with the standards of the World Health Organization, the course treatment of tuberculosis (first symptoms) will cost 8-10 thous. dollars, though physicians do not guarantee complete recovery.

* Chalcogens--chemical elements of the 16th group of Mendeleev's Periodic Table.--Ed.

By the late 2013, the company intends to increase production volumes to cover the requirements of all specialized hospitals of the country. By that time the company plans to complete construction of one more production site--a chemico-pharmaceutical plant in Bratsk, where it will produce active substances, for Perchlozon as well.

And then the total sale volume can make up not less than 10 mln dollars annually (this figure is comparable with the annual turnover of the company). According to Vikram Puniya, by 2015 Russia's sales will approximately make up 20-25 percent. The "surplus" will be delivered to the world market--to China, India and the Republic of South Africa.

By the way, the preparation is well known abroad: in December 2012, within the framework of the World Conference "Against Tuberculosis and Lung Diseases" (Kuala Lumpur, Malaysia), the medical adviser of OAO Farmasyntez Sergei Koren made a report about new perspectives in the treatment of tuberculosis using Perchlozon, which attracted attention of international experts in the sphere of phthisiotherapeutics. Perhaps, for the first time in over 40 years the medical community could get acquainted with the anti-tubercular preparation, which had been registered and was ready to be used in clinics.

One more fact of its recognition. In April of this year the International Forum IPhEB & CPhI Russia held in St. Petersburg attracted more than 300 leading figures of national and world pharmaceutics and biotechnologies. The last work of Farmasyntez and its partners was granted a prize for contribution into creation of Russian innovational products. Assessing the capacity of Perchlozon to cure tuberculosis with multiple medicinal resistance, which is a kind of invention of last years, the professionals emphasized its another capacity--possibility of its use for people with HIV-infection, as the preparation does not have a negative effect on the immune system of man.

Illustrations from Internet-sources