Radiosynovectomy is a method of treating inflammatory diseases of the joints with the help of isotopes. Radiosynovectomy - a method of treatment of inflammatory diseases of the joints with the help of isotopes Microsources for brachytherapy

Radionuclides l86 Re (7 'i/2 = 90.6 h) and l88 Re (Tc 2 \u003d 6.9 h), being P-emitters, as well as l53 Sm and ll7m Sn, they have lines of the y-spectrum convenient for recording with energies of 137 and 155 keV, respectively. As follows from Table. 5.2, obtaining IX6 Re is possible in medium-flow reactors by neutron irradiation of powder or metal targets from enriched rhenium-185. All this makes it quite affordable for medicine. At the same time, its transportation over long distances requires the development of high specific activities of the radionuclide, which creates difficulties in the subsequent production of the required dosed amounts of the drug in clinical conditions. After irradiation, powder targets are converted into rhenium acid by dissolving them in nitric acid or hydrogen peroxide. A 30% peroxide solution is used to open metal targets. Known preparations based on IS6 Re include its complex compound with sodium salt of 1-hydroxyethylidine diphosphonic acid (HEDP).

Unlike l86 Re, the radionuclide rhenium-188 is a generator product (3-decay of 18 w and is formed as a result of nuclear transformations:

For the production of the parent radionuclide W, metal powder targets are usually used, as well as tungsten oxide targets enriched in the isotope l86 W. Further, the dissolution of metal targets is carried out in a mixture (0.1 M NaOH and 30% H1O2), and tungsten oxide - in solution (0.1 M NaOH and 5% NaOCl).

Taking into account the fact that W is formed as a result of two successive reactions (u, y), its production is expedient only in reactors with a neutron flux of at least 5 10 m n/cm 2 s. The calculation of the value of specific activity W, made for such a chain of transformations, shows that at a flow of 510 14 n/cm 2, s and an irradiation time of 100 days, it will be about 1.5 Ci/g. On reactors with flow 2? 10 15 n/cm 2 s, a radionuclide yield of ~ 10 Ci/g is achieved in 43 hours of irradiation.

To separate l88 Re from the parent isotope and obtain it without

carrier, chromatographic W / "Re-generators are used, where aluminum oxide is used as the main sorbent. Figure 5.1 shows a diagram of a generator developed at Oak Ridge National Laboratory. The presented generator, in addition to the main column with aluminum oxide, has concentrating anion exchange columns with cation exchanger and anion exchanger.

The generator works as follows: by communication 1 syringe through GC column, filter 2, silver cation exchange column 5, anion exchange column 3, pass 20 ml of 0.155 M NaCl solution, filter and collect in a collector 9, equipped with an air filter 8. The chromatographic and ion exchange columns, as well as the l88 Re collector, are located in protective containers. Three-way valves 6 and 7 designed for washing and regeneration of the ion-exchange column. The output of rhenium-188 with a radiochemical purity of more than 99.0% is more than 90%. The content of impurities of the parent radionuclide l88 W in the eluate does not exceed 1 10%

from Re activity.

Rice. 5.1. Schematic, HH W/ m Re alternator:

1 - eluent supply; 2 - filter; 3 - anion exchange column; 4 - ion exchange column; 5 - cation exchange column with silver; 6 - three-way valve for waste; 7 - three-way valve for washing water and eluate; 8 - air filter; 9 - general collection

A simpler and more technological way to obtain a rhenium-188 generator with high radionuclide purity and volumetric activity of the target radionuclide was developed at the Institute of Nuclear Physics of the Academy of Sciences of the Republic of Uzbekistan. Here, to ensure high radionuclide purity of the target product, purification from foreign radionuclide impurities is carried out at a preliminary stage before charging the generator. For this purpose, an irradiated target made of metallic tungsten enriched in the IS6 W isotope up to 99.79% is dissolved in hydrogen peroxide. Acid solution of tungsten is alkalized to pH 10 ... 12 and purification from radionuclide impurities is carried out by passing the alkaline solution through a column of aluminum oxide, treated immediately before use with 0.01 ... 0.10 M alkali solution. The resulting alkaline solution of tungstate is collected, acidified with hydrochloric acid to pH 3...4, dosed and sent to charge the generators. The adsorption of polytungstate ions is carried out on columns 7 ... 10 cm high and 0.8 ... 1.2 cm in diameter, containing up to 5 g of AlO3 oxide, pre-treated with a 0.1 M HCl solution when heated for 5 ... 10 min. In the lower part of the column, in addition, a filter layer of H-form alumina is placed.

After 18 hours, the generators are washed with 30 ml of 0.9% NaCl solution with pH 3...4. The elution of rhenium-188 is carried out with the same solution, but with a volume of 10 ml. This provides a radiochemical yield of more than 75.5% and RCP of the drug 99.9%, pH 5.51. The content of inactive impurities Al, Fe, Cu is not more than 5 μg / ml, radionuclide impurities li4 Cs, i37 Cs, 60 Co, 65 Zn, " 0m Ag, | 40 Va - less than K) 5%, l88 W - less than 10 3% .

A similar generator (GREN-1) with an eluate activity of rhenium-188 up to 1 Ci was developed in 2006 at the IPPE. Medical collaborator - MRRC RAMS (Obninsk). The supplier of raw materials for the production of these generators is OJSC RIAR (Dimitrovograd). To date, the SM-3 reactor has worked out the l86 W irradiation mode, which achieves a specific activity of l88 W up to 8 Ci/g.

The main advantage of W/Re-generators is that they have a long shelf life and provide an opportunity to obtain eluate-sodium perrhenate, l88 Re with the required volumetric activity directly in clinics. Despite the higher energy of P-particles compared to 186 Re, the relatively short half-life of 188 Re makes it possible to reduce pain in the absence of bone marrow damage. This effect is noted in

For example, when using the drug Re-HEDP instead of a similar 186 188 RP based on Re. In addition, when generating Re

there is an opportunity to use commercially available "reagents" developed for diagnostic radiopharmaceuticals of technetium-99t, for example, the Re(V)-DMSA dimercaitosuccinic acid complex (the domestic analogue of Carbomec). Abroad and in Russia, studies are being carried out to obtain rhenium-labeled albumin microspheres.

The number of deaths from the bridge from the floor

Table 4. Cirrhosis of the liver depending on the data of the Central Republican Clinical Hospital)

□ Coma in men

□ Bleeding in men

E3 Coma in women

□ Bleeding in women

Thus, according to the analysis of state statistical reports, the incidence of cirrhosis of the liver was 0.4%, mortality 2.1%, Morbidity and mortality by sex almost did not differ. According to inpatient referrals in the gastroenterological department of the Central Republican Clinical Hospital over the past 10 years, the share of treated patients with liver cirrhosis accounts for 8.7%, of which 51.1% of cases have a stage of decompensation, 48.9% - compensation and subcompensation. As can be seen, half of the patients in the stage of compensation and subcompensation were treated in a hospital, but should receive home care under the supervision of a family doctor.

Of the inpatients of the gastroenterological department over the past 10 years, 78 (52.3%) died of liver cirrhosis. At the same time, there were almost twice as many men as l<енщин, что по-видимому связано с факторами, влияющими на обострение заболевания, такими как тяжёлая физическая работа, приём алкоголя и др.

LIVER CIRRHOSIS: MORBIDITY, COMPLICATION AND MORTALITY

N. Tuul, Ch. Dolgorsuren, Ts. Damjin (Central University Hospital, Mongolia)

From state statistics of ill people 0.4% of them had liver cirrhosis and 2.1% - death occurrence. Consider-

ing illness and death occurrence there was no noticeable difference between genders.

In gastroenterology department of central clinic hospital over the past 10 years 8.7% of all patients had liver cirrhosis. 51.1% were in compensation and 48.9% in compensation and sub-compensation. These facts show that patients with compensation and sub-compensation show the need to be under supervision of family doctors.

In the last 10 years in gastroenterology department 78 people or 53.8% of all deceased patients had liver cirrhosis. Men had a twice higher occurrence of liver cirrhosis than women, which can be explained as men hav-

ing more physical load, usage of alcohol and other causing factors.

Literature

1.Maüp K.P. Hepatitis and the consequences of hepatitis. - Moscow, 1999 -S.313-375.

2. Maleev A. T. Clinical hepatology. - Sofia, 1989 -S.326-363.

3. Levitan B.N., Dedov A.V. 50 years of experience in the clinical study of liver cirrhosis. Russian journal of gastroenterology, hepatology, coloproctology. - 2002 - No. 1 - S.76-79.

4. Levitan B.N., Kolchina V.P. The problem of survival and causes of mortality in cirrhosis of the liver

based on long-term prospective follow-up. South Russian medical journal. -1999. -#2. -p.76-78.

5. Khazanov A.I. From half a century of experience of observing patients with cirrhosis of the liver. Russian journal of gastroenterology, hepatology, coloproctology. - 1999. - No. 2 - S.50-56.

6 Sleisenger and Fordtrans, Gastrointestinal and Liver disease. - 1998. - Vol.2. - P. 1284-1334.

O ONKHUUDAY P., GONCHIGSUREN D., ERDENECHIMEG S., TSEVELMAA L., TUUL N. -UDK 616.36-006.6:615.849.2

EXPERIENCE OF TRANSARTERIAL RADIONUCLIDE EMBOLIZATION OF RHENIUM-188 HDD LIPIODOL IN THE TREATMENT OF LIVER CANCER

P. Onkhuudai, D. Gonchigsuren, S. Erdeiechimeg, L. Tsevelmaa, I. Tuul. (Mongolian State Medical University, Rector - Prof., MD Ts. Lhagvasuren)

Summary. Our study covered a total of 18 patients, and all of them underwent a single treatment, and 8 - repeated treatment. Measurement of the size of the tumor on CT, as well as ultrasound diagnostics showed that the average size of the tumor was 7.4±4.0 cm, the level of AFP in the serum determining the activation process: in 4 patients it was more than 200 ng/ml, in 3 patients it was more than 100 ng / ml, in 6 - less than 100 ng / ml, and in 3 - the level was normal.

The average therapeutic dose administered to the patient was 4.4 GBq, and the average experimental dose was 210 MBq. Application of the highest dose, which was 7.4 GBq Re-188

JU 1lry<1о1 не оказало на больного какнх-лнбо побочных эффектов и дозиметрическая проверка демонстрирует безопасность данной терапии.

Serum AGR levels normalized in 4 patients, decreased in 5, remained unchanged in 5 and increased in 3. Tumor size in 3 patients decreased to 50%, in 4 to 1440%, in 6 the size remained stable, and in 3 - its progression was noted.

In 4 patients, death was noted after 2-4 months. The remaining 14 patients are under observation for 4-18 months.

In the majority of patients, the tumor size and clinical signs either remain unchanged, or the tumor has decreased in size, and there has been an improvement in clinical signs, indicating the effectiveness of this therapy.

One of the most common malignant tumors according to research is primary liver cancer. More than 1 million people die every year, and 315 thousand people fall ill again. In Mongolia, the incidence of liver cancer per 100,000 population is 39.2 cases. Along with this, over the past 10 years, the incidence of liver cirrhosis, viral hepatitis has not decreased, steadily remaining at the same level.

Treatment of malignant tumors of the liver is one of the most urgent problems of clinical oncology. The only method that allows to achieve long-term survival in a malignant neoplasm of the liver is surgical correction. However, by the time of diagnosis, radical removal of the tumor is possible only in 10% of cases. The remaining patients are subject to palliative care. Considering the results of systemic cytostatic therapy and arterial chemoembolization, it seems very relevant to study the possibilities of other effective methods of treatment.

Since the 1990s, a new method of treatment has begun to be introduced into clinical practice - transarterial radionuclide embolization of the feeding branch of the tumor. Radioactive isotopes 1-131, Y-90 (microspheres), Ho-166 and Re-186 were used as means of internal irradiation in combination with monoclonal antibodies.

Materials and methods

The radioactive isotope Re-188 is produced from the W-188 Generator, which is supplied by the Oak Ridge National Laboratory, USA, and the HDD chemical components (4-hexadecyl 1-2, 9, 9-tetramethyl-4, 7-diaza-l, 10-decanetiol ) Seoul National University of the Republic of Korea.

When the radioactive isotope Re-188 is combined with the chemical component of HDD, the compound Re-188 HDD is formed. The next step is the combination with Lipiodol, resulting in the formation of radiopharmaceutical Re-188 HDD Lipiodol. Radiopharmaceutical Re-188 HDD Lipiodol is stable for 4 hours. Before introducing into the feeding branches of the tumor, its radiochemical purity is checked by the chromatographic method.

Research methods used by us in our work:

1. The selection of patients was made on the basis of scores in accordance with the Child-Pugh and Karnovsky classifications. The patient was explained the purpose of those

rapia, about the expected side effects and in the presence of his consent to this therapy.

2. Before starting therapy, computed tomography (CT) scans were taken to measure the size and volume of the liver and tumor.

3. Using the Seldinger method, an "experimental" dose of the isotope 200MBq (5mCi) was injected into the feeding branches of the tumor under the control of an angiographic screen.

4. After the introduction of the "experimental" dose, a static scan of the liver and lungs was performed on gamma-cams in frontal and posterior projections. After lung, liver and tumor scintigraphy, the recorded data were entered into a specially designed Excel program (P. Zanzonica, 2000, New York), and dosimetry was performed, which calculated the maximum tolerated dose (MTD) and the amount of radioactive radiation affecting normal organs.

5. Under the control of the angiographic screen, a therapeutic dose of the drug was administered.

6. The patient was transferred to the therapeutic department, and his general condition was monitored. To register the radiation of the therapeutic dose after 24 hours on gamma camsrs, the whole body was scanned in frontal and posterior projections. When the patient was discharged, he was given a consultation.

7. After 24 hours, a week, 2 months, and then every 3 months, prospective monitoring of the level of erythrocytes, leukocytes, platelets, biochemical parameters of the functional state of the liver, activity of the tumor process is carried out, and the size of the formations was monitored by measuring them during ultrasound scanning and CT of the liver.

Results and discussion

Our study covered a total of 18 (men - 9 and women - 9, mean age 55.5±8.5 years) patients. All patients underwent a single treatment, and 8 - repeated treatment. The patients suffered from cirrhosis of the liver. Analysis of viral markers revealed the presence of HbsAg - in 7 patients, HVC - in 7. In 2 out of 18, viral antigens were not detected. In the remaining 2 patients, the markers of viral hepatitis were not determined. When assessing the severity of cirrhosis according to the Child-Pugn classification, 6 patients were graded A, and 12 - B. According to the Karnovski classification, the general physical condition of the patients was estimated at 70-90 points.

Measurement of the size of the tumor on CT, as well as ultrasound diagnostics showed that the average tumor size was 7.4±4.0 cm, the level of AFP (alpha fetoprotein) in serum, which determines the process of tumor activation: in 4 patients it was more than 200 ns/ml , in 3 - more than 100 ng/ml, in 6 - less than 100 ng/ml. In the remaining five patients, the level of AFP markers was normal.

The average therapeutic dose of Re-188 HDD Lipiodol administered to the patient was 4.4 GBq, and the average "experimental" dose was 210 MBq. The liver was the dose-limiting organ in 17 patients and the lungs in 9 patients.

Application of the highest dose of radiopharmaceutical, which was equal to 7.4 GBq Re-188 HDD Lipiodol. did not have any side effects on the patient. Moreover, the radiation dose affecting such critical organs as the lungs and bone marrow was negligible, and to healthy liver cells, compared to the above-mentioned organs, it was insignificantly high.

In peripheral and biochemical blood tests after treatment after 24 hours, a week, and even after 2 and 4 months, no noticeable changes were found in the number of leukocytes, erythrocytes, platelets, as well as the level of bilirubin, which indicates the absence of a toxic effect on bone marrow and the patient's body. Along with this, the level of transaminases (AlAT and AST) had slight fluctuations in the long-term follow-up period.

Table 1.

Results of Re-188 HDD Lipiodol Therapy

Frequency of occurrence of symptoms

Side effects Subfebrile temperature Epigastric pain Nausea Dry mouth

AFP level Complete normalization Decrease Stable Increase

Tumor size Regression >50% Regression 14-40% Stable Progression

General Improve- Stable- Degrade-

condition elk elk

sick 6 8 4

Table 1 shows that after our therapy, l<алобы у 8 больных на субфебриль-ную температуру тела, незначительную боль - у

6, dry mouth in 4, and nausea in 2, which stopped the next day after therapy and the patients were discharged from the hospital.

Serum AFP levels normalized in 4 patients, decreased in 5, remained unchanged in 5, and increased in 3. Tumor size decreased to 50% in 3 patients, to 14-40% in 4, and remained stable in 6 , and 3 showed progression.

In 6 patients, an improvement in the general condition was noted, in 9 patients it was stable without significant changes, and in 3 patients it worsened. In the last 3 patients, the deterioration of the general physical condition according to the classification of Karnovsky and Child-Pugh developed into stage C, 3-8 months after therapy, a fatal outcome occurred. The remaining 14 patients were under dynamic observation for 4-18 months.

Studies show that the course of the disease and the results of therapy are greatly influenced by the size of the tumor and the state of compensation for cirrhosis of the liver.

The use of 1-131 Lipiodol, Y-90 (microspheres) with selective internal irradiation is effective, but is a rather expensive type of treatment. The use of Re-188 HDD Lipiodol is cheaper compared to the above isotopes, while it is possible to use a generator system. Thus, one W188/Rel88 generator can serve for 4-6 months, while it is possible to combine a radioactive isotope with a chemical component in a conventional "hot" laboratory. The radioactive isotope Re-188 has a minimum half-life of 17.1 hours, the p beam, which has a high energy, has a depressing effect on tumor cell growth, and the os-beam, which has 155 KeV energy, is optimal for performing scintigraphy on a gamma camera with the subsequent implementation of dosimetry (Internal Dosimetry).

Re-188 HDD Lipiodol is the radiopharmaceutical of choice for transarterial embolization in the treatment of liver cancer. The study showed that when using Re-188 HDD Lipiodol at a dose of 7.4 Gbq, minimal side effects are detected, and dosimetric testing demonstrates the safety of this therapy.

In most patients, the tumor size and clinical signs are either at a constant level, or there was an improvement in clinical signs and morphometric - a decrease in tumor size, which indicates the effectiveness of this therapy.

TRANS-ARTERIAL RE-188 HDD LIPIODOL TREATMENT OF HCC

P. Onkhuudai, D. Gonchigsuren, S. Erdenechimeg, L. Tsevelmaa, N. Tuul.

(The National Medical University of Mongolia)

Rhenium-188-Lipiodol is an available radioconjugate transarterial treatment ot'IICC. The right quantity of the radioconjugate can be delivered after "scout" dose dosimetry studies have been done, to spare normal liver and lung from excess radiation dose.

Over a period of eighteen months eighteen patients received at least one treatment of radioconjugate. Some patients were re-treated if there was no evidence of disease progression. Patients were followed for at least twelve weeks after therapy, until recovery from all toxicity. The clinical parameters evaluated included toxicity, response as determined by contrast-enhanced CT, palliation of symptoms, overall survival, performance status (Karnofsky) and hepatic function (Child's classification). Liver function tests, serum alpha-fetoprotein (AFP) levels and complete blood counts were done at each follow-up visit/

From the small number of patients studied, we have found this treatment to be safe with minimal side-effects, at the dose up to about 7.4 GBq of Re-188 Lipiodol. There were significant response from the treatment and the new therapeutic procedure should be subjected to further evaluation to determine its efficacy.

Literature

1. Parkin DM, Muir CS, Whelan SL, Gao YT/ Cancer icidence in five Continents. Vol 6, Lyon; International Agency for Research on Cancer. - 1999.

2. Tanaka K, Hirohata T, Koga S, et al. Treatment modalities of Hepatocellular carcinoma. cancer research. - 2000. - Vol.51. - P.2842-2847.

3. Onkhuudai P. Report of Liver Cancer in Mongolia. In mat;Consultants Meeting on Radionuclide Treatment of Liver Cancer. Shanghai, China, 1999. - P.06-10.

A. V. Korzhuev, E. V. Shevchenko, and N. A. Khlopenko -UDK 577.352:1022

MEMBRANE THEORY IN BIOPHYSICS IN HISTORICAL DEVELOPMENT AS AN EXAMPLE OF THE STRUGGLE OF IDEAS IN SCIENTIFIC KNOWLEDGE

A.B. Korzhuev, E.V. Shevchenko, I. A. Khlopenko.

(Irkutsk State Medical University, Rector - Academician of the MTA and the Academy of Sciences of the Higher School of Medicine, Prof. A.A. Mayboroda, Department of Medical and Biological Physics, Head - Prof. E.V. Shevchenko)

Summary. The article provides a scientific and historical outline of the development of the membrane theory in biophysics - from the beginning of the 20th century to its third quarter.

The issues of the formation and development of the membrane theory since the end of the 19th century, when the idea that the emergence of bioelectric potentials is due to ion transport through the surface separating the internal contents of the cell from the external environment, were strengthened in the scientific world. Quantitative assessments were carried out according to the Nernst formula, indicating that the potential difference between the membrane surfaces in a cell at rest is directly proportional to the temperature and the natural logarithm of the ratio of the internal and external concentrations of ions.

In 1902, Bernstein published his first article on the membrane theory - this year is considered in the history of science to be the year of its birth. The weak point of the membrane hypothesis at this point was the complete lack of data on which ion is responsible for the resting potential. In 1905 in Berlin, an employee of Nernst Geber discovers that all salts containing potassium (for example, KCl, KN03, etc.) have a similar effect on the muscle. The area of ​​the muscle, on which the solution of such a salt acts, is acquired

retaet negative potential in relation to other parts of the muscle.

Bernstein immediately appreciates the significance of Geber's work - after all, the membrane theory explained these results very simply: one had only to assume

live that K is the ion that creates the potential. All salts containing potassium, dissociating in solution, increase the external concentration of potassium ions. - while the concentration ratio O / C? falls, and the area affected by the salt acquires a lower potential than other participants.

However, the facts themselves say little about anything: for example, Herman, almost forty years before Bernstein, observing the effect of temperature on a muscle, saw that when the area remote from the cut was heated, the potential increased. These facts had no interpretation at that time and therefore were half-forgotten. The influence of potassium salts on the potential was described ten years before Geber in Biedermann's book on electrobiology, and this was also ignored. Only theory gives meaning to experimental facts, allows us to separate

The owners of the patent RU 2567728:

SUBSTANCE: group of inventions relates to a radiopharmaceutical preparation for the treatment of bone tissues of the skeleton and a method for producing this radiopharmaceutical (RP), which can be used for radionuclide treatment in oncology, namely the treatment of bone lesions of the skeleton. The method is as follows: a sterile solution is obtained, consisting of a ligand, a reducing agent and an antioxidant, into which non-radioactive rhenium is then introduced in the form of sodium perrhenate (NaReO 4), the resulting solution is neutralized, filtered, frozen and freeze-dried, followed by the introduction of a solution of radioactive rhenium-188 (188 Re) (Na 188 ReO 4) with the reaction of complex formation of 188 Re with the ligand. EFFECT: group of inventions makes it possible to carry out pain syndrome therapy in case of bone metastases. 2 n. p. f-ly, 3 ill., 4 tab.

The invention relates to a method for producing a sterile solution consisting of a monopotassium salt of 1-hydroxyethylidene diphosphonic acid dihydrate, a reducing agent and an antioxidant, into which non-radioactive rhenium is then introduced in the form of sodium perrhenate (NaReO 4 ). The resulting solution is neutralized, filtered, frozen and freeze-dried, followed by the introduction of a solution of radioactive rhenium-188 (188 Re) (Na 188 ReO 4) with the reaction of complex formation of 188 Re with the ligand. EFFECT: invention makes it possible to obtain a sterile radiopharmaceutical (RP), the preparation time of which is reduced to 30-60 minutes due to the simplification of the technological cycle to one stage.

The invention also relates to a radiopharmaceutical for the treatment of bone lesions of the skeleton.

A known method for producing diphosphonate labeled with 188 Re . The method of obtaining a labeled diphosphonate is carried out as follows: 15 mg of sodium salt of 1-hydroxyethylidene diphosphonic acid (Na 2 HEDP), 4.5 mg of stannous chloride (SnCl 2 ·H 2 O) and 4.0 mg of gentisic acid are mixed in a vial. The resulting mixture is dissolved in an appropriate amount of distilled water, frozen and freeze-dried. To the dried mixture is added 1.0 ml of a solution containing 0.01-0.1 mg of inactive ammonium perrhenate (NH 4 ReO 4). The mixture is then heated in a boiling water bath for 15 minutes. After that, the mixture is cooled to room temperature and adjusted to pH 5-6 by adding 1 ml of 0.3 M sodium acetate solution. The binding of 188 Re to the ligand (Na 2 HEDP) is 95.2-95.6%. The stability of the complex compound 188 Re-(Na 2 HEDP) is maintained for 2 hours. In subsequent periods, the complex is destroyed and the amount of 188 Re bound to the ligand after 3 hours is about 94%, after 24 hours - about 93%.

The disadvantage of this method is the difficulty of obtaining the drug in clinical conditions and its relatively low stability.

A known method for producing diphosphonate labeled with 188 Re applicable in the laboratory. The method consists in the fact that in a mixture of reagents consisting of 2-20 mg (0.01-0.15 M) sodium salt of 1-hydroxyethylidene diphosphonic acid (Na 2 HEDP), 2.5 mg (0.0005-0.02 M) tin chloride (SnCl 2 H 2 O) and 0.5-5 mg (3 10 -3 3.5 10 -2 M) of gentisic acid, add a perrhenate solution (l86 Re or 188 Re) containing stable rhenium with a concentration of 5 10 -6 -2 10 - 3 M. The resulting mixture is heated and kept at 80-100°C for 10-30 minutes. Then it is cooled and the pH of the solution is adjusted to 5.0-6.0. Radiochemical impurities of perrhenate and rhenium dioxide in the preparation did not exceed 1.5%.

The disadvantage of this method is the difficulty of obtaining the drug in a clinical setting.

The prototype of the proposed technical solution is a method consisting in the fact that at the first stage a sterile solution is prepared containing a mixture of radioactive sodium perrhenate (Na 188 ReO 4) with a volume activity of 148 to 2960 MBq / ml and non-radioactive sodium perrhenate (NaReO 4) with a concentration of 10 -4 -10 -3 mol/l. At the second stage, the prepared solution is added to a lyophilized mixture of reagents, which includes a ligand (1-hydroxyethylidene diphosphonic acid), a reducing agent (SnCl 2 ·H 2 O) and an antioxidant (ascorbic acid). Next, the mixture is heated and maintained at 90 - 100°C for 15-30 minutes. In the third stage, the mixture is cooled and neutralized to a pH of no more than 7. As a result, a sterile injectable radiopharmaceutical is obtained.

The disadvantage of this method is the technological complexity, which leads to an increase in the duration of its preparation in clinical conditions. The complexity is due to the presence of three stages of obtaining a radiopharmaceutical. To prepare it in a clinic, it is necessary to have three bottles with sterile reagents: one bottle with a lyophilized mixture containing a ligand, a reducing agent and an antioxidant; vial with stable rhenium in the form of sodium perrhenate and a third vial with a solution to neutralize the radiopharmaceutical. The implementation of the method requires control and adjustment of the pH of the resulting solution, which imposes additional difficulties, since in order to adjust the pH of the product, it is necessary to have a sterile solution of pharmaceutical quality, it is necessary to use additional equipment and control the product after adjusting the acidity, as well as to carry out all these manipulations under aseptic conditions. In addition, a greater number of operations in the preparation of radiopharmaceuticals in a medical institution will require additional measures to ensure radiation safety and their implementation.

The availability of a sterile reagent kit containing three vials significantly increases the cost of the final product and the time of its preparation, which leads to an undesirable increase in the radiation exposure of the clinic staff. Thus, the proposed method for obtaining a radiopharmaceutical is inconvenient for practical use.

The technical result of the invention is the simplification of the method for obtaining a radiopharmaceutical due to the effect obtained by combining non-radioactive (NaReO 4) and radioactive (Na 188 ReO 4) rhenium with a lyophilizate in one stage. At the same time, it seems possible to reduce the preparation time of a sterile radiopharmaceutical to 30-60 minutes by simplifying the technological cycle to one stage.

The essence of the invention lies in the fact that in a method involving the preparation of a sterile solution consisting of a monopotassium salt of 1-hydroxyethylidene diphosphonic acid dihydrate, a reducing agent and an antioxidant, non-radioactive rhenium is introduced in the form of sodium perrhenate (NaReO 4). The resulting solution is neutralized, filtered, frozen and freeze-dried, followed by the introduction of a solution of radioactive rhenium-188 (Na 188 ReO 4). Then heated until the manifestation of the reaction of formation of the complex compound 188 Re with the ligand. After cooling, the resulting radiopharmaceutical is suitable for use in the clinic.

Thus, according to the proposed method, a radiopharmaceutical suitable for the treatment of bone lesions of the skeleton, prepared in one stage in a clinical setting, was obtained.

The given examples illustrate the implementation of the method.

In a flask with a round bottom and two necks with a capacity of 250 ml, equipped with a dropping funnel and a magnetic stirrer, put 10 ml of a 20% solution of monopotassium salt of 1-hydroxyethylidene diphosphonic acid (COEDP - ligand) (2 g, 8.16 10 -3 mol), add 100 ml of water, add 1.12 g (5.91·10 -3 mol) of stannous chloride (SnCl 2) - reducing agent and stir until it is completely dissolved. 0.7 g (3.97·10 -3 mol) of ascorbic acid (antioxidant) is added to the resulting solution and stirred until complete dissolution. Then add 0.0365 g (1.335·10 -3 mol) of sodium perrhenate (NaReO 4) and stir for 20 minutes. The resulting mixture was neutralized with 0.1 M sodium hydroxide (NaOH) to pH 3.0. The solution is brought to a total volume of 150 ml, stirred for 10 minutes and subjected to sterilizing filtration. The resulting solution is packaged in vials for injection with a capacity of 10 cm 3 for 1.5 ml. The contents of the vials are frozen at liquid nitrogen temperature and placed in a sublimator chamber cooled to -20°C. A pressure of 0.1-0.2 mm Hg is created in the chamber. using a vacuum pump. Under these conditions, freeze-drying is carried out for 23 hours, the chamber temperature is raised to +20°C and drying is carried out for 1 hour. 5 ml of a solution of radioactive rhenium-188 (Na 188 ReO 4) is injected into the contents of the vial, stirred until the contents of the vial are completely dissolved, heated in a boiling water bath to 95-100 ° C and incubated for 30 minutes to carry out

reactions of formation of a complex compound 188 Re with a ligand, cooled to room temperature. After cooling, the radiopharmaceutical solution is ready for injection.

In a flask with a round bottom and two necks with a capacity of 250 ml, equipped with a dropping funnel and a magnetic stirrer, put 10 ml of a 20% solution of monopotassium salt of 1-hydroxyethylidene diphosphonic acid (COEDP - ligand) (2 g, 8.16 10 -3 mol), add 100 ml of water, add 1.12 g (5.91·10 -3 mol) of stannous chloride (SnCl 2) - (reducing agent) and stir until it is completely dissolved. 0.7 g (3.97·10 -3 mol) of ascorbic acid (antioxidant) is added to the resulting solution and stirred until complete dissolution. Then add 0.0365 g (1.335·10 -3 mol) of sodium perrhenate (NaReO 4) and stir for 20 minutes. The resulting mixture was titrated with 0.1 M sodium hydroxide (NaOH) to pH 3.0. The solution is brought to a total volume of 150 ml, stirred for 10 minutes and filtered through a filter with a pore size of 0.22 μm. The resulting solution is packaged in vials for injection with a capacity of 10 cm 3 for 1.5 ml. The contents of the vials are frozen at liquid nitrogen temperature and placed in a sublimator chamber cooled to -20°C. A pressure of 0.1-0.2 mm Hg is created in the chamber. Art. using a vacuum pump. Under these conditions, freeze-drying is carried out for 23 hours, the chamber temperature is raised to +20°C and drying is carried out for 1 hour. 5 ml of a solution of radioactive rhenium-188 (Na 188 Re04) is injected into the contents of the vial, stirred until the contents of the vial are completely dissolved, heated in a boiling water bath to 95-100 ° C and kept for 60 minutes to carry out the reaction of formation of the complex compound 188 Re with ligand, cooled to room temperature. After cooling, the radiopharmaceutical solution is ready for injection.

Confirmation of the technical result

As a result of combining non-radioactive and radioactive rhenium-188, a new technical result was obtained in the present invention. It consists in simplifying the method of obtaining the radiopharmaceutical "Phosforen, 188 Re", which consists in obtaining radiopharmaceuticals in one stage instead of three, as was done according to the prototype. At the same time, the stage of neutralization of the finished radiopharmaceutical was excluded. The proposed solution makes it possible to reduce the time of its preparation in a medical institution and, thereby, makes it possible to significantly reduce the dose load on medical personnel during the receipt of a labeled drug.

Clinical studies of the radiopharmaceutical "Phosphoren, 188 Re", prepared from a lyophilized composition of reagents with the introduced radioactive rhenium-188 (Na 188 ReO 4), were carried out in research centers:

Department of radiosurgical treatment with open radionuclides, MRRC MZRF, Obninsk,

Department of Nuclear and Radiation Medicine of the Federal State Budgetary Institution "Russian Scientific Center for Radiology" of the Ministry of Health of the Russian Federation, Moscow.

The clinical study was conducted in accordance with the principles of the Declaration of Helsinki on the conduct of biomedical research involving humans, in accordance with local requirements and the Rules for Conducting Quality Clinical Trials, and in accordance with current regulatory requirements, namely: FEDERAL AGENCY FOR TECHNICAL REGULATION AND METROLOGY NATIONAL STANDARD RUSSIAN FEDERATION, GOST R 52379-2005 GOOD CLINICAL PRACTICE, Moscow 2005; RUSSIAN FEDERATION FEDERAL LAW ON THE CIRCULATION OF DRUGS, N61-FZ, April 12, 2010; Decree of the Government of the Russian Federation of September 13, 2010 N 714 "On Approval of the Model Rules for Compulsory Life and Health Insurance of a Patient Participating in Clinical Trials of a Medicinal Product".

The main (primary) goal of the study was to compare the effectiveness of palliative therapy of pain syndrome in bone metastases of the radiopharmaceutical "Phosphoren, 188 Re" and "Strontium chloride, 89 Sr" by assessing the degree of analgesic effect. Additional (secondary) objectives of the study were to compare the safety and tolerability of Phosphorene, 188 Re and Strontium chloride, 89 Sr radiopharmaceuticals based on the assessment of adverse events in response to the drug administration and the degree of hemotoxicity in terms of thrombocytopenia and leukopenia.

The study was conducted among patients suffering from malignant neoplasms, in whom bone metastases were detected during clinical, radiological and/or scintigraphic examination, accompanied by severe pain syndrome, and/or progression of bone metastases was observed against the background of previous treatment.

57 patients were recruited to participate in the study. Of these, according to the selection criteria, 50 patients were included: 30 with the use of the radiopharmaceutical "Phosforen, 188 Re" (experiment) and 20 with the use of the reference drug "Strontium chloride, 89 Sr" (control).

In both groups, patients had a fairly pronounced pain syndrome, determined by the scale of the intensity of bone pain.

Each of the therapeutic radiopharmaceuticals was administered once intravenously, subject to the rules of radiation safety.

The average therapeutic dose of Phosphoren, 188 Re was 3120 MBq (80.4 mCi). However, in patients with excess or underweight, the recommended dose was determined at the rate of 44.0 MBq/kg body weight. Therefore, there was a dose deviation depending on the body weight of the patients. The drug "89 Sr chloride" was administered intravenously, in accordance with the recommended therapeutic dose of 150 MBq (4.0 mCi).

The average and specific dose for the drug "Phosphoren, 188 Re" is shown in table 1.

After the administration of the drug, the patient's condition was monitored, during which adverse events were registered and, if necessary, their correction. Blood samples were taken weekly for laboratory testing.

All patients underwent:

1. A blood test with the determination of the following parameters: the number of leukocytes, platelets, platelet concentrations, followed by an assessment of hematological toxicity according to the CTC-NCIC criteria.

2. Biochemical analysis of blood parameters (creatinine, urea, electrolytes, ALT, ACT, bilirubin).

3. Evaluation of the dynamics and intensity of bone pain.

During the study, all concomitant therapy was accounted for. Therapy aimed at reducing pain associated with bone metastases was evaluated separately. A separate account was made of opiate and non-opiate analgesics. Particular attention was paid to accounting for the use of opiate analgesics, which is reflected in table 2.

As can be seen from the data in Table 2, the frequency of taking opiate analgesics did not differ in the studied groups of patients.

The effect of treatment in patients with prostate, breast and thyroid cancer was evaluated 1, 3 and 6 months after the injection. For other groups, this period was limited to 3 months. This was due to the fact that in the three diseases mentioned above, progression is mainly due to bone metastases and the main problem is that there may be bone pain and decreased activity for a long time. In other tumors (lung cancer, stomach cancer, etc.) in such periods as 6 or more months after injection, extraskeletal lesions begin to play the most significant role, which usually determines the deterioration in the general condition of patients during this period.

The result of treatment was evaluated in each clinical case for each patient individually. The evaluation was carried out both according to the criterion of treatment effectively, ineffectively, and using a 5-point scale for evaluating the effectiveness.

Despite the greater therapeutic effect in the main group (the effect was better by 12%), no statistically significant differences were found (p=0.089, Spearman's test), which demonstrates a similar treatment efficacy of both study drugs in the groups as a whole.

On the other hand, when analyzing the clinical effect of pain relief by assessing the distribution of patients according to the degree (points) of reduction on the scale for assessing the dynamics of bone pain, a significant advantage of therapy in the main group was revealed in the number of patients in whom the pain syndrome decreased by 3 points (Fig. 1)

Differences in the number of patients in whom the pain syndrome did not decrease or decreased by 1 and 2 points were not significant (p>0.08 - Spearman's test). On the other hand, the main number of patients who had a decrease in pain by 3 points (47%) was significantly higher in the main group (47%) compared with the control (18%). This difference turned out to be significant (p<0,02 - тест Спирмена).

The overall result of the effectiveness of treatment with both drugs is shown in Fig. 2. In the main group, the positive result of therapy was 90%, in the control group 77%. In general, the drug "Phosphoren, 188 Re" showed a significantly better result compared to the control (p=0.012, McNemar's test).

The initial level of blood parameters that were evaluated to analyze the tolerability of therapy is presented in table 3.

As can be seen from Table 3, the initial level of blood parameters did not differ in patients of the main and control groups (p>0.09).

The results of the assessment of hematotoxicity in points, obtained by the CTC - NCIC scale, are presented in table 14 in Fig. 3.

The average levels of hematotoxicity did not differ in patients of both groups (p>0.5). None of the groups showed 4 - the most severe degree of hematotoxicity. At the same time, the number of patients with grade 2 hematotoxicity was significantly higher in the control group (29% and 10%, respectively, p<0,05, тест Спирмена). Число больных с остальными степенями токсичности в группе пациентов, получавших препарат «Фосфорен, 188 Re», по сравнению с группой больных, получавших препарат «Стронция хлорид, 89 Sr» - не отличалось, (р=0,367, тест Спирмена).

The results of the clinical study indicate that both drugs "Phosphoren, 188 Re" and "Strontium chloride, 89 Sr" demonstrate similar efficacy in the treatment of pain associated with bone metastasis of malignant neoplasms of various localization.

However, the drug "Phosphoren, 188 Re" showed significantly greater therapeutic activity.

At the same time, it was found that Phosphoren, 188 Re demonstrates a better safety profile both in terms of tolerability and the number of serious adverse events compared to the reference drug Strontium chloride, 89 Sr. Thus, according to the results of the study, the radiopharmaceutical

Information sources

1. Lin W.Y., Hsieh J.F., Lin C.P., Hsieh V.T., Ting G., Wang S.J., Knapp F.F. Effect of reaction conditions on preparations of rhenium-188 hydroxyethylidene diphosphonate complexes, Nucl. Med. Biol., 1999, V. 26 P. 455-459.

2. Piprs D.W. Preparation of rhenium phosphonate therapeutic agents for bone cancer without purification. US Patent No. 5021235 (1991).

3. Basmanov V.V., Kolesnik O.V. Method for obtaining a radiotherapeutic drug. Auth. certificate No. 2164420 (2001).

4. Report on clinical trials to establish the effectiveness of the generator therapeutic radiopharmaceutical with rhenium-188 for patients with a certain disease under the state contract dated 19.06.2012 No. 12411.0810200.13.B15 R&D “Clinical studies of the generator therapeutic radiopharmaceutical with rhenium-188. Organization of Pilot Production” code “Isotope 4.1”.

1. A method for producing a radiopharmaceutical for the treatment of bone lesions of the skeleton, including obtaining a sterile solution consisting of a ligand, a reducing agent and an antioxidant, characterized in that non-radioactive rhenium is introduced into the solution in the form of sodium perrhenate (NaReO 4), the resulting solution is neutralized, filtered, frozen and freeze-dried, followed by the introduction of a solution of radioactive rhenium-188 (Na 188 ReO 4) and carry out the reaction of complexation 188 Re with the ligand.

2. Radiopharmaceutical preparation for the treatment of bone lesions of the skeleton, obtained by the method according to p. 1.

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This is the second event in a series of seminars organized by JSC "SSC RF - IPPE" and dedicated to the most promising radioactive isotopes for nuclear medicine.

The purpose of such seminars, the participants of which are not only researchers and manufacturers of medical devices and preparations, but also their consumers - practicing doctors in the field of nuclear medicine, is to show how promising the isotope under consideration is and how much the drugs based on it will be in demand in clinical practice.

This seminar was attended by leading experts in this field - manufacturers of raw materials, developers and manufacturers of medical devices, developers of radiopharmaceuticals and practicing radiologists from leading institutions in Russia:

• FGBU SSC FMBC im. A.I. Burnazyan FMBA of Russia,
• FSUE "FC PROYAM" FMBA of Russia,
• JSC "SSC RIAR",
• JSC "NIFHI named after L.Ya. Karpov",
• JSC "Science and Innovations",
• JSC "V/O" Izotop ",
• FSUE "PA "Mayak"
• FGBU "VNIIIMT" of Roszdravnadzor,
• MRRC named after A.F. Tsyba - branch of the Federal State Budgetary Institution "NMITs" of the Ministry of Health of the Russian Federation,
• IATE NRNU MEPhI,
• Federal State Budgetary Institution National Medical Research Center of Oncology named after N.N. Blokhin of the Ministry of Health of Russia.

The purpose of the seminar was: review of radiopharmaceutical drugs (RPMs) with rhenium-188, the state of their registration and development of new RPs for radionuclide therapy (RNT) of various diseases.

The seminar discussed the production of the parent isotope tungsten-188 and generators of rhenium-188 based on it, the development of cold kits for the synthesis of RFLP, the state of affairs with preclinical trials, the pharmaceutical development of new RFLP based on rhenium-188 and the possibility of their clinical application, the results of marketing research domestic market for a rhenium-188 generator.

All messages aroused great interest of the listeners.

It was noted that nuclear medicine today is a strategic area of ​​healthcare, it is an area of ​​state interest and state priorities, its development will radically improve the quality of medical care for a huge number of patients who need therapy for oncological and other diseases.

A significant place in this is given to preparations with rhenium-188, which are currently being actively developed all over the world.

In Russia, clinical trials of RFLP for radionuclide therapy of metastatic skeletal lesions have been developed and conducted:

• Zoleren, 188 Re, is intended for the palliative treatment of bone metastases, the treatment of rheumatoid arthritis and other non-cancer diseases of the joints;
• Phosphorene, 188 Re, is intended for the palliative therapy of bone lesions of the skeleton.

Clinical trials of domestic RFLP based on rhenium-188 are underway:

• Sinoren, 188 Re - RFLP based on tin dioxide suspension for radionuclide therapy of rheumatic diseases; the results of studying the therapeutic effect of the radiopharmaceutical "Sinoren, 188 Re" in animals with acute aseptic synovitis clearly demonstrate an increase in the proportion of the supporting function of the affected limb in animals;
• Geparen, 188 Re - RFLP based on albumin microspheres 5-10 μm in size with rhenium-188 for the treatment of resistant synovitis.

New areas of application will find preparations based on rhenium-188 in metastases of solid tumors, in skin cancer and keloids, in the treatment of medullary cancer of the thyroid gland, breast, prostate, in the treatment of patients with multiple bone metastases.

At the end of the seminar, a round table discussion of the listened reports was held, where it was noted that work with rhenium-188 had already begun in the USSR, and only now Russian specialists have developed a number of radiopharmaceuticals based on it and conducted clinical trials.

There are still a number of popular drugs in development.

In general, the participants noted that the development and testing of RFLP is at a decent level, but it is necessary to separately note the weak synergy with direct users (doctors) of existing developments, which, of course, requires more active involvement of the Ministry of Health of the Russian Federation.

In particular, it is necessary to inform and train radiologists to work with rhenium generators and radiopharmaceuticals based on it.

The lack of trained medical personnel for the synthesis of RFLP in medical institutions and the lack of awareness of radiologists about the possibilities of RFLP based on rhenium-188 create problems in promoting their use.

To do this, you can use the resources of the trading house JSC "V / O" Izotop "and the Ministry of Health of Russia.

The participants of the seminar noted that RFLP based on rhenium-188 must take its rightful place in radionuclide therapy, and the rhenium-188 generator can be as widely used in the treatment of various oncological and non-oncological diseases as the technetium-99m generator was once received in diagnostics.

Suicides in cancer patients are most often from insurmountable pain, when available painkillers, other than narcotic ones, do not help. However, it turns out that there is an alternative remedy - radionuclide therapy.

In Russia, 2.3 million cancer patients are officially registered. At least 200 thousand cases of newly diagnosed cancer are recorded per year. And in more than 60% of patients, this is already the third or fourth stage, accompanied by severe pain.

Targeted diagnostics

The standard scheme for suppressing pain in cancer metastases is various drugs with an analgesic effect. First, something from the group of non-steroidal anti-inflammatory drugs, then more serious, and ultimately the patient goes on narcotic drugs.

Are there no other methods? There are, but they are little known to the general public. Meanwhile, radionuclide therapy is developing very intensively in the world, including in Russia. ZAO Pharm-Synthesis is completing clinical trials of an original radiopharmaceutical for the treatment of skeletal metastases. One injection - and in most patients there is a significant reduction in pain for up to six months. Someone completely refuses analgesics, someone significantly reduces doses, and in many cases even regression of metastases is observed, that is, the quality improves and life expectancy increases.

For many years, strontium-89 and samarium-153 isotopes were used in the radionuclide therapy of skeletal metastases, which, in addition to the tumor, had a negative effect on the entire body.

But now we are talking about a new generation of drugs. The isotope on the basis of which it was created has low toxicity, and the carrier that delivers it to the body goes exactly to the target - the tumor. The goal in English is "target", therefore such targeted drugs are called targeted.

"Earlier, doctors could not even think that it was possible to achieve a highly specific accumulation of a therapeutic radiopharmaceutical drug in a tumor, to act directly on it, minimally irradiating other organs. Our drug is concentrated locally - in a metastasis, which means that the irradiation comes from within the foci themselves. And healthy organs and tissues are protected from it,” explains Lev Voloznev, head of the radiopharmaceuticals department at Pharm-Sintez CJSC. “The prerequisite for synthesizing a therapeutic drug was another development — a radiopharmaceutical for diagnosing skeletal metastases, which is already used in medical institutions in Russia. The carrier is zoledronic acid and the isotope is technetium-99m.

Diagnostics is carried out in gamma cameras, which register isotope radiation (displayed on the monitor screen as a glow) and form tomographic images. Since the drug accumulates in the metastasis, if there is a glow in the skeleton, then there is a metastasis.

The perfect couple

“Then we asked ourselves the question: why not add some more serious, beta-emitting isotope to zoledronic acid in order to have a therapeutic effect?” Lev Voloznev continues. “Of course, the radiation exposure will increase. But the most important thing is that the absorbed dose remains as in metastasis. This is what we have achieved with the complex of zoledronic acid and rhenium-188."

Rhenium-188 is one of the most powerful beta-emitting radionuclides. The flow of beta-particles intensively affects tumor tissue, pathological cells that destroy bone, cells that stimulate pathological bone formation, as well as nerve endings. The short half-life of the isotope (17 hours) allows you to quickly achieve a clinical effect, and the bone marrow does not have time to suffer. As a result, according to the developers, a "perfect couple" was obtained: zoledronic acid labeled with technetium-99m - diagnostics, zoledronic acid with rhenium-188 - therapy. Next year Pharm-Sintez is planning to bring its new drug for the treatment of skeletal metastases to the market.

The "ideal couple" strategy underlies the modern direction of medicine - theranostics ("theranostics", English, from "therapy" - "treatment", "diagnostics" - "diagnosis"), that is, the creation of drugs for the diagnosis and treatment of diseases based on one molecular platform. If zoledronic acid with technetium-99m has accumulated in the metastasis and registered the spread of the tumor, then zoledronic acid with rhenium-188 is prescribed, which will have a therapeutic effect.

In the field of diagnostics and therapy of neuroendocrine tumors, Pharm-Sintez also has its own developments. The strategy is the same: the carrier is a peptide molecule that binds to receptors on the surface of the tumor, and various isotopes are attached to it. Indium-111 is for single photon emission tomography, gallium-68 is for positron emission tomography, and lutetium-177 is for radionuclide therapy.

“Identification of the disease in the early stages is an important task,” explains Lev Voloznev. “Actually, therefore, the main vector of the use of radiopharmaceuticals goes into the field of diagnostic areas. We are trying to change this a little, in addition to drugs for diagnosing tumors using single-photon emission and positron emission tomography we create those that diagnose and then treat."

“The uniqueness and prospects of the rhenium-188 isotope became one of the reasons for organizing the first International Congress on Rhenium-188 (1WCRe, Coimbatore, India) this autumn,” adds Lev Voloznev. “Of course, we will make presentations there. managed to be at the level of world developments in this direction - they know us, we are invited."

At the leading international conference International Conference on Radiopharmaceutical Therapy (ICRT-2013) in Manila (Philippines) in 2013, the report of Pharm-sintez CJSC researchers (Tatyana Kochetova, MD Sergey Shiryaev, led by MD. Valery Krylova) on the topic of clinical studies of zoledronic acid with rhenium-188 was recognized as the best scientific work. This year, new development data were presented at the international conference on radionuclide therapy ICRT-2015 on May 4 in Innsbruck (Austria).

Costs for two treatments for skeletal metastasis (per patient)

According to CJSC Pharm-Sintez.

Relief Technology

Developing an original drug is a rather expensive business, unlike the production of generics - copies of a drug already created by someone, which is what many are doing today. In addition, such developments are considered venture: if 5% of them achieve results, this is considered high efficiency. According to Lev Voloznev, pharmaceutical companies spend 10-20% or more of their proceeds on research and development.

In the current economic situation, the domestic developer has additional problems - the share of the imported component in the form of equipment, consumables, and more is too high. Some types of research have to be ordered abroad, because our scientific laboratories, for one reason or another, cannot perform them.

“We are invited to the State Duma, the Ministry of Industry and Trade, the Government of the Russian Federation, where we are jointly trying to find solutions,” says Anna Nazarenko, Chairman of the Board of Directors of CJSC Pharm-sintez. “But you need to understand that we will not get results tomorrow. These are quite serious and long-term programs. And we hope that thanks to them, a powerful, adequate modern system of providing medical and diagnostic care will be created in Russia. True, in order to build such a system, as experts say, it is not enough to create a drug. A lot depends on the availability of specialists in the field of nuclear medicine and the equipping of clinics with serious technological equipment.

According to expert data, up to 3 thousand people annually need radionuclide diagnostics of neuroendocrine tumors, and about 100 underwent the necessary studies last year. N. N. Blokhin: nowhere else. Radionuclide therapy of metastatic lesions of the skeleton is needed annually by 14 thousand patients, and no more than 300 receive it.

Innovative products of CJSC "Pharm-sintez", which are currently undergoing various stages of clinical trials, can change the situation. In fact, clinics will receive not just medicine, but technology. Thus, a drug for the treatment of skeletal metastases is synthesized directly in the radionuclide therapy department and used on an outpatient basis, without the use of "hot" wards. Rhenium-188 is obtained from a generator the size of a two-liter jar, which is quite simple and easy to use. The isotope can be obtained every three days with a generator life of up to three months. Thus, one generator will enable 70 patients to live without pain for half a year.

The question now is different: will ordinary clinics be able to install the necessary equipment? Unfortunately, there is no answer to it yet. As well as to another question - about the separate financing of radionuclide therapy for metastatic lesions of the skeleton and, in general, nuclear medicine. Especially now, when the state has transferred financial responsibilities to insurers. In any case, according to Sergei Kalashnikov, Chairman of the Russian State Duma Health Committee, the national oncology program should be broader than just resolving issues of equipping clinics with new equipment and providing patients with medicines.

Anna Podpalnaya

Tomographic images of the patient after the administration of zoledronic acid labeled with rhenium-188, made during clinical studies at the MRRC named after. F.I. Tsyba. Glowing foci - metastases in which a radiopharmaceutical drug accumulates