Perfluorane returns
Soviet blood substitute will be produced again in Russia
Varvara Fufayeva, Vademecum No. 9-2016
Perfluorane blood substitute, which is planned to be used during the world's first head transplant operation, will be produced in Russia by the end of the year, and in the future – exported to other countries. The legendary drug "blue blood", created by Soviet biophysicists, decided to bring back to the market the founder and former owner of the Lenta retail chain, and now the CEO of Solopharm, Oleg Zherebtsov.
Perftoran received a registration certificate for the release and sale in Russia on April 27, 2016. The holder of the registration, according to the State Register of Medicines, was Grotex LLC, which owns the St. Petersburg pharmaceutical plant Solopharm. The head of the company, Oleg Zherebtsov, confirmed to Vademecum that he had acquired a patent for the drug, technological know-how and plans to establish its production at the facilities of his plant by the end of the year: "We will produce Perfluorane in completely different purity classes and with completely different technological solutions, but according to the old Soviet recipe."
Perfluorane is known on the market for its scandalous history of invention. It was created in the 1980s by biophysicist Felix Beloyartsev. The professor was promised a State prize and world recognition for the formula, which he did not wait for, having committed suicide. The fate of the invention itself was no less dramatic. For more than ten years, until the end of the 1990s, he left the market, experienced a change of patent holders, and then a surge and a sharp drop in sales. According to the DSM Group, sales of the drug in Russia in 2015 fell to 11.4 million rubles against 24.5 million rubles in 2014.
Until the end of 2015, the sales and development of Perfluorane in Russia were handled by JSC "NPF "Perftoran". In March 2015, the Federal Tax Service of Russia filed a lawsuit with the Arbitration Court of the Moscow Region demanding that the company be declared bankrupt, but the arbitration rejected it. Although a year before, negotiations were held on the sale of licenses and technologies owned by Perftoran to Oleg Zherebtsov's company Grotex.
"The company found itself in a situation that excludes the possibility of further production," says Zherebtsov. – Most of the premises were badly worn out, did not meet GMP standards. We bought a registration certificate, the right to manufacture, the necessary licenses and technological know-how." The drug was absent from the market for about six months, until the entrepreneur decided to resume its sales.
Representatives of JSC "NPF "Perftoran" Vademecum could not be contacted.
In the first year, Stallions plans to put on the market 50 thousand packs of the drug with a volume of 200 ml and expects to increase the production capacity tenfold in 5 years.
The cost of transferring Perfluorane production to Solopharm's facilities is estimated by Stallions at 56 million rubles – these funds will be used for pilot tests, start-up and tooling of production, purchase of new homogenizers and substances.
The selling price of the package is expected to be about 8 thousand rubles, and, consequently, by 2021, the sales volume of Perfluorane may reach 50 million euros.
Zherebtsov is aimed primarily at the hospital segment of the market and intends to supply the drug to the surgical departments of clinics in St. Petersburg, Moscow, as well as distribution companies in Rostov, in the South of Russia and in other regions. "These are sales to hospitals, and to cancer centers, and to centers for operations on the lungs and kidneys, liver, where rapid recovery of organs after surgery is required. The drug can be used almost immediately in oxygenators. Since it has good gas transport functions, its drop is 70 times smaller than an erythrocyte, which carries oxygen and, consequently, penetration into the farthest capillaries of the body is high," the entrepreneur praises the product reanimated by him. In the future, Solopharm expects to supply the hemopreparation to the foreign market. "We know that some states are already interested in this product," says Zherebtsov. – For example, the Ministry of Defense of Mexico registered Perfluorane in its country many years ago, and is now trying to achieve the GMP standard for the start of production."
Specialists perceive the repeated release of the drug to the market ambiguously. Emergency doctor Andrey Zvonov, who was in charge of the blood service of the MC CELT from 1994 to 2011, says that the blood substitute does not solve all the problems of large blood loss in emergency conditions: "There is always very little time to save a patient. Unfortunately, organofluorine does not solve this problem, and if it is possible to stop the patient's bleeding with a tourniquet or a pressure bandage, ensure his rest, give him oxygen to breathe and at least give him warm salted and slightly sweetened water, then it will be better than perfluorocarbons." At the same time, the heads of two departments of cardiac surgery of large Russian medical centers at once told Vademecum that they would willingly use blood substitutes during operations with artificial blood circulation.
Zherebtsov successfully chose the moment to restart Perfluorane – Italian surgeon Sergio Canavero plans to use the drug during the planned December 2017 head transplant on the donor body of Russian programmer Valery Spiridonov, suffering from spinal muscular atrophy.
The drug will have to help the surgeon and his colleagues cope with the large-scale blood loss that will inevitably occur during the operation.
In an interview with Vademecum, Spiridonov confirmed that a team of surgeons is already actively using the blood substitute Perfluorane, conducting experiments on head transplants on animals, and noted that "the drug fulfills its task."
The preparation for the operation is widely covered in the Russian and international media, which will help to make a good advertisement for the Perfluorane.
What are blood substitutes?
Blood substitutes are sterile fluids that replace blood and plasma, which are used for large blood losses in order to restore the volume of circulating blood.
World hematology has been developing blood substitutes for more than a hundred years. At the beginning of the XIX century, the basis of this direction was the transfusion of human donor blood, then salt solutions appeared, replenishing the volume of blood, but not carrying oxygen. Finally, in the middle of the twentieth century, the development of a whole range of drugs began to replace individual components of blood (erythrocytes, platelets, plasma), and then hemopreparations with gas transport function, transferring oxygen to blood vessels and capillaries narrowed after injury or surgery.
Blood substitutes have been considered very promising products since the beginning of their history. The developers believed that hemopreparations have a number of advantages over donor blood – they are suitable for all recipients, regardless of the group and Rh factor, neutralize the risks of transmission of hepatitis C virus or AIDS to the patient, can be stored for a long time.
Blood substitutes with a gas transport function, to which Perfluorane belongs, are focused on situations of large–scale blood loss - extensive interventions of cardiovascular surgery, traumatology, orthopedics, as well as extreme, catastrophic and military medicine.
Another target audience of the drug is Jehovah's Witnesses, to whom religious postulates do not recommend transfusion of donor blood, so in some cases blood substitutes are the only alternative for them. "Surgeons and anesthesiologists themselves often insist on using a blood substitute. These drugs do not contain any blood fractions, so most believers agree to use this drug in their treatment," confirms Mikhail Panichev, a member of the committee for communication with hospitals for Jehovah's Witnesses. According to him, in Russia in 2015, the denomination numbered 175615 "proclaimers". The number of adherents of the creed in the world is estimated at about 8 million people.
However, despite the potentially large-scale market, these drugs have not been widely distributed. Suffice it to note that the FDA has not yet issued any permits for the sale of blood substitutes in the United States. If Solopharm does not abandon its plans, then Perfluorane will become the only drug of this type allowed in Russia. Blood substitutes developed since the 1980s are still not welcomed by all anesthesiologists and transfusiologists.
Who invented and marketed the blood substitute Perfluorane?
In Russian transfusiology, the topic of blood substitutes first sounded in the 1970s, when Soviet scientists received information that their colleagues around the world were researching drugs based on perfluorocarbon emulsions. The political leadership of the country hoped that the creation of such a drug would raise the stakes of the Soviet state in the technology race with the West, and instructed the USSR Academy of Sciences to deal with the issue. Another motive for activating the development of Perfluorane is considered to be the beginning of the war in Afghanistan. Research in this direction was simultaneously started by the Moscow and Leningrad Institutes of Hematology and Blood Transfusion, and then the Institute of Biophysics of the USSR Academy of Sciences, headed by the famous Soviet hematologist Heinrich Ivanitsky. The practical work on perfluorocarbon emulsions was led by Professor Felix Beloyartsev, head of the Laboratory of Medical Biophysics of the Institute.
In the early 80s, a unique hemopreparation was obtained. For his heavenly color, he received the name "blue blood" in the Soviet and then international scientific community. The inventor of Perfluorane Felix Beloyartsev was promised a State prize and indispensable international recognition. In 1984, the Pharmaceutical Committee of the USSR Ministry of Health authorized the first, and a year later – the second phase of clinical trials of Perfluorane, during which material was collected on the use of the drug in 234 patients in 19 nosological directions. But in 1985, the blood substitute was suddenly banned, Professor Beloyartsev was removed from the head of the laboratory and scientific work in general. Searches took place at the inventor's dacha, after one of which the scientist committed suicide, according to the official version, hanged himself.
The head of Beloyartsev, Henrikh Ivanitsky, described these events in an interview with the Kommersant newspaper in 1998 as follows: "Then there was a struggle for power at a high level: posts in the presidium of the Academy of Sciences, positions in the Central Committee were divided... The struggle was serious, and the following hierarchical levels, of course, were involved in this struggle. We in this story – those who worked on Perfluorane – turned out to be the third echelon, which did not seek to join any groups. So the Perfluorane turned out to be an occasion to put us in our place and demonstrate "who is the boss here". The commissions of the Ministry of Health and the Presidium of the Academy of Sciences showered... Beloyartsev could not stand the psychological pressure… The KGB has developed a whole system of how to bring a person to suicide. Yes, he had violations of instructions, a difficult family situation, but he was sure that he was engaged in the most important state business, and he was reduced to the level of a criminal. There were rumors about medical experiments on humans. In the end, he was removed from office and accused of "abuse of office" and "violation of reporting on alcohol consumption." Beloyartsev was ready for the State Prize, but received the status of a potential criminal. It was incredibly stressful, and he broke down – he hanged himself at his dacha after the investigators left. The onslaught of the KGB was very strong. He just couldn't stand it."
By the 90s, the passions around the ban of Perfluorane and the death of its creator subsided, but then perestroika began and, as Ivanitsky later explained in his memoirs, the Institute of Biophysics did not have the resources to resume work on the drug and put it into circulation. So Perfluorane dropped out of the pharmaceutical and medical field for 11 years.
In the mid-1990s Ivanitsky and his colleagues created JSC "NPF "Perftoran" on the basis of the academic institute. In February 1996, Perfluorane emulsion was registered in the Russian Federation and allowed for medical use and industrial production in containers of 100 and 200 milliliters. The indications for use then included acute and chronic hypovolemia, microcirculation and peripheral circulation disorders, purulent-septic condition, cerebral circulation disorders, fatty embolism and preliminary preparation of donors. In numerous interviews, Ivanitsky stated that, finally, after the tragic events and trials, Perfluorane has found a new life. And in fact, in the following years, the affairs of his company went uphill. In his memoirs, one of the employees of the NPF "Perftoran" Sergey Vorobyov said that in 1999 the release of the drug was blessed by Patriarch Alexy II of Moscow and All Russia. And in 2002, a group of Perfluorane creators was awarded the "Vocation" prize, its leader Felix Beloyartsev – posthumously.
Sales of the drug grew: according to SPARK-Interfax, in 1999 the revenue of NPF "Perftoran" was 2.2 million rubles, and by 2007 it reached 34.5 million rubles.
The commercial success of the blood substitute was also favored by the transition of transfusiology to a new paradigm – from component hemotherapy to drug transfusiology, one of the apologists of which was the head of the Department of Clinical Transfusiology of the First Honey, Aligeydar Rahimov. "Blood preparations are stored much longer, they are easier to transport, monitor the effectiveness and so on. It is obvious that over time, medicine will gradually switch to the use of drugs in clinical practice that make it possible to fill in the missing link of the patient's peripheral blood to the necessary extent," explains the emergence of the trend, Professor Rahimov.
The decline in Perfluorane sales began during the last crisis: the manufacturer's revenue, according to SPARK-Interfax, by 2014 fell from peak values by more than two times – to 13.7 million rubles. However, until recently, the drug remained in demand both in the hospital and in the retail segment: according to DSM Group, the total volume of public purchases of Perfluorane in the period from 2010 to 2015 amounted to 82.2 million rubles against 55.4 million rubles in pharmacy chains.
Experts attribute the decline in popularity and commercial success of the drug to the identification of numerous side effects, including hyperemia, hyperthermia, tachycardia, hypotension, headache, pain behind the sternum and in the lumbar region, difficulty breathing, allergic reactions. Evgeny Zhiburt, Chief transfusiologist at the Pirogov National Medical and Surgical Center, notes that multicenter, randomized controlled clinical trials have not been conducted for Perfluorane. Sergey Vorobyov, who left the academic laboratory and the company in the late 90s, indirectly points to the same problem in his memoirs: "In 1997, JSC NPF Perftoran acquired commercial structures that have nothing to do with pharmaceuticals and medicine. For a number of reasons related to fundamental disagreements with the new owners of the company, who curtailed all research work aimed at creating promising, safe perfluorocarbon drugs, the author of these lines was forced to leave first from the NPF "Perftoran" in 1997, and then from ITEB RAS in 1999."
According to SPARK-Interfax, during the period described by Vorobyov, the company's board of directors included five entrepreneurs: Natalia Galushkina, Yuri Dzitovetsky, Igor and Elena Maslennikov, Alexey Stashkov. It was not possible to contact any of the participants of the events of that time Vademecum at the time of signing the number.
But the head of Solopharm Oleg Zherebtsov saw commercial prospects in Soviet developments. "There was a culture of donation in the Soviet Union. And now there is not enough clean and proven donor blood in Russia. Due to the large number of viruses identified over the past 15 years, we see that in many cases blood is unsuitable, financial compensation for it is a penny, and much more costs are required for quality control than the cost of the blood itself," the entrepreneur says. What other blood substitutes have tried to enter the Russian market?The fate of other blood substitutes who have tried to enter the Russian market in the last five years has been unenviable. In the early 2000s, Evgeny Selivanov, Director of the Russian Research Institute of Hematology and Transfusiology, corresponding member of the Russian Academy of Medical Sciences, created the drug Gelenpol. The blood substitute passed clinical trials, flashed in the hands of transfusiologists at scientific conferences and went for revision to the Obninsk Science City, where it was taken up by the research and production company Medbiopharm, which was going to invest $ 6 million in the construction of the Gelenpol plant.
The main investor of the project was the General director of the NPC "Medbiopharm" Rahimjan Rosiev, who took Academician of the Russian Academy of Medical Sciences Anatoly Tsyba, the father of the current Deputy Minister of Industry and Trade Sergey Tsyba, as a partner in LLC "Gelenpol". Now LLC "Gelenpol" does not exist, and the drug of the same name has not been registered. Rahimjan Rosiev declined to comment on the Vademecum story of a decade ago.
Another drug of this series – Hemopur – was trying to bring the infamous entrepreneur Sergey Pugachev to the Russian and world market, but this hemopreparation also left the market last year.
Despite all the apparent failures, the head of the Department of Clinical Transfusiology of the First Honey, Aligeydar Rahimov, believes that blood substitutes still have a future: "The fundamental difference between such drugs and blood components is that any hemopreparation has an active substance that can be measured. In the component, as in living tissue, this parameter is, firstly, dynamic, and secondly, poly-composite, and many different molecules exhibit biological activity during transfusion. Thirdly, any component is unique, since it is obtained from a separate blood donor, while bioactivity in the preparation is standardized as much as possible and the entire period of suitability is constant and predictable."
A similar point of view on blood substitutes is shared by scientists of Tomsk State University, who are now engaged in the removal of a component for the manufacture of modified hemoglobin with a gas transport function. Vyacheslav Butikov, one of the project participants, told Vademecum that the basis of the drug will be the biomass of annelids, but he did not talk about the commercial component of the initiative.
Evgeny Zhiburt, the chief transfusiologist of the N.I. Pirogov NMHC, disagrees with these experts. He doubts that blood substitutes will be in demand in the market, noting that the situation with blood substitution in the industry is improving. In July 2012, a new federal law "On Blood Donation and its components" was adopted, providing for annual monetary compensation to honorary donors. In 2016, it amounted to 12373 rubles.According to the Ministry of Health, for 6 months of 2013, the total number of donors increased by 3% compared to the same period in 2012.
Portal "Eternal youth" http://vechnayamolodost.ru
19.05.2016