Резюме
¹Заярнюк Н.Л., ²Собетов Б.Г., ¹Кричковська А.М., ¹Воробій М.В., ¹Федорова О.В., ³Загорій Г.В., ¹Новіков В.П. Нові терапевтичні можливості ін’єкційних пролонгів дисульфіраму.
Метою даної роботи було дослідити нові терапевтичні можливості ін’єкційного пролонгу дисульфіраму Тетлонг-250. За допомогою програми Pharma Expert було зпрогнозовано широкий спектр фармакологічної активності антиалкогольного лікарського засобу Тетлонг-250, а саме комбінації дисульфірам - димексид, що показує перспективність досліджень даного препарату при лікуванні інших захворювань, таких як атеросклероз тощо. Проведена монотерапія препаратом Тетлонг-250, пацієнта-добровольця з раком простати 4-ї стадії, яка дозволила значно покращити загальний стан та самопочуття хворого. Дані результати демонструють необхідність проведення широких, рандомізованих, плацебоконтрольованих досліджень для вирішення питання застосування ЛЗ в онкології при лікуванні різних захворювань.
Ключові слова: дисульфірам, пролонг (лікарський засіб пролонгованої дії), алкоголізм і наркоманія, онкологічні захворювання, рак передміхурової залози.

Резюме
Заярнюк Н.Л., Собетов Б.Г., Кричковская А.М., Воробий М.В., Федорова Е.В., Загорий Г.В., Новиков В.П. Новые терапевтические возможности инъекционных пролонгив дисульфирама.
Целью данной работы было исследовать новые терапевтические возможности инъекционного пролонга дисульфирама Тетлонг-250.
С помощью программы Pharma Expert был спрогнозирован широкий спектр фармакологической активности лекарственого средства Тетлонг-250, а именно комбинации дисульфирам - димексид, что показывает перспективность исследований данного препарата для лечении других заболеваний, таких как атеросклероз и т.д. Проведена монотерапия препаратом Тетлонг-250 пациента-добровольца с раком простаты 4-ой стадии, которая позволила значительно улучшить общее состояние и самочувствие больного. Данные результаты демонстрируют необходимость проведения широких рандомизированных плацебоконтролируемых исследований для решения вопроса применения его в онкологии при лечении различных заболеваний.
Ключевые слова: дисульфирам, пролонг (лекарственное средство пролонгированного действия), алкоголизму и наркомании, онкологические заболевания, рак предстательной железы.

Summary
Zayarnyuk N.L., Sobetov B.G., Krychkovska A.M., Vorobii M.V., Fedorova O.V., Zagoriy G.V., Novikov V.P. A new therapeutic possibility of disulfiram’s injection prolongs.
The aim of this study was to investigate new therapeutic possibilities of disulfiram’s injection prolong Tetlong-250. We predicted the wide range of pharmacological activity of drug Tetlong-250, namely the combination of disulfiram – dimethyl sulfoxide, by the program Pharma Expert. The results had showed the perspective for studies of this drug in the treatment of other diseases, such as atherosclerosis and others. The monotherapy, conducted by drug Tetlonh-250 on the patient-volunteers with IV stage of prostate cancer, showed that the general condition and health of the patient had significantly improved. These results demonstrate necessity in extensive, randomized, with using of placebo studies for solve the problem of its application in oncology to the treatment of various diseases.
Keywords: disulfiram, prolong (long-acting drug), alcoholism and drug addiction, cancer, prostate cancer.

Рецензент: д.фарм.н., проф. М.М. Слободянюк

УДК 615.214.032.014;541.64;542.91

¹Національний університет «Львівська політехніка» (Львів)

National University «Lviv Politechnic», Lviv, Ukraine

²Українська асоціація з проблем наркоманії та алкоголізма (Львів)

Украинская ассоциация по проблемам наркомании и алкоголизма (Львов)

Ukrainian Association of drug dependens and alcoholism, Lviv, Ukraine

3ПАТ «Фармацевтична компанія «Дарниця» (Київ)

3ПАТ «Фармацевтическая компания« Дарница »(Киев)

PJSC “Pharmaceutical company” Darnitsa”, Kyiv, Ukraine

nzayarnyuk@mail.ru, bsobetov@mail.ru, m.vorobiy@gmail.com, afedorova@polynet.lviv.ua, vnovikov@polynet.lviv.ua

Drug addiction and alcoholism are chronic diseases that are capable for relapse. Maintaining compliance is a major problem in the treatment of alcoholism and drug addiction that needs to be solved. One solution of the problem could be the use of long-acting dosage forms.

Disulfiram is the most common sensitizing agent, which creates a chemical barrier and prevents drinking of alcohol. Over 50 years, he officially registered in almost all countries, as a specific antialcohol drug.

In EU countries introduced special programs that aim to estimate the importance of disulfiram in the treatment of addiction. The data show that disulfiram may be effective treatment for cocaine or opiate dependence in patients with / or without alcohol dependence.

Recently, the interest is increasing for the possibility of using disulfiram to treat patients with cancer. The first clinical trials associated with the interaction of carcinogens with disulfiram were conducted in the 70's of last century. Studies, which were carried out on Wistar rats in 1979 at the University of Tennessee center for the health sciences, had shown that the introduction disulfiram in the diet significantly inhibits the formation of bladder cancer. Since 2000, conducted a large number of biochemical, histological, biological, genetic, preclinical and clinical studies that have shown that disulfiram slows or stops the growth of cancer cells. Mechanism of action disulfiram cancerous tumor is the subject of much current research. In the international press has information on the results of studies that have shown the feasibility of using disulfiram in combination with other therapeutic agents in the treatment of diseases such as prostate cancer, breast cancer, glioblastoma (brain cancer) and others.

Perspective is the use of the long-acting dosage forms of disulfiram as implants and injections which containing about 3200 mg of drug substance on annual treatment in rehabilitation programs.

The scholars of our Department technology of biologically active compounds, pharmaceutical and biotechnology in National University "Lviv Polytechnic" engaged in solving the problems of develop new drugs, with prolonged action, based on the new and famous active substances.

The aim of this study was to investigate new therapeutic possibilities of disulfiram’s injection prolongs.

We had chosen the object of study injecting prolong of disulfiram - Tetlonh-250, which was developed at the Lviv State Medical Institute (now Lviv National Medical University by Danilo Galician). We checked its toxicity and safety by using the program Pharma Expert.

Mono-therapy patient-volunteer with the 4^th stage prostate cancer that has spread  in the pelvic bones, testes, lymph nodes by using the drug "Tetlonh-250" is conducted by us in conjunction with the Ukrainian Association of drug dependes and alcoholism from 2010 to present. Disease proceeded with constant severe pain in the lower half of the body. Patient lost 15 kg over a period of illness. There were severe depression, suicidal thoughts, insomnia. Following the recommendations of oncologists, who observed the patient, he was offered the following treatments: emergency chemical or surgical castration, radiation or chemotherapy, hormone therapy. Since the doctors prognosis were after 1-3 months to be expected fatal. The patient refused from conventional treatment that was offered to him by oncologists. The patient refused from conventional treatment that was offered to him by oncologists. However, he consented to experimental treatment, under which he has got intramuscular DSF injection of 1 ml 1-2 times a month. General data of blood and urine, and special characteristics improved significantly as of January 2013. Prostate specific antigen (PSA) decreased with 697 ng / ml to 12.6 ng / ml at a norm of PSA 4 ng / ml. Sleep is recovered without the use of medication. Regular sex resumed 1-2 times a week. The patient gained 15 kg in weight. Overall improved quality of life.

We predicted the wide range of pharmacological activity of drug Tetlonh-250, namely the combination of disulfiram – dimethyl sulfoxide, by the program Pharma Expert. The results had showed the perspective for studies of this drug in the treatment of other diseases, such as atherosclerosis and others. The monotherapy, conducted by drug Tetlonh-250 on the patient-volunteers with IV stage of prostate cancer, showed that the general condition and health of the patient had significantly improved. These results demonstrate necessity in extensive, randomized, with placebo studies for solve the problem of its application in oncology to the treatment of various diseases.

Література

1. Пат. № 25842 С2 Україна. МПК А61К 31/145. Протиалкогольний засіб для ін’єкцій / Собетов Б.Г., Зіменковський Б.С., Фільц О.О., Собетова В.Б., Кузьмінов Б.П.; заявник та патентовл. Собетов Б.Г. - № 95073554; заявл.28.07.1995; опубл. 26.02.1999.
2. Пат. № 98560 Україна, МПК А61К 31/45; А61Р 25/32, А61Р 25/36. Спосіб одержання протиалкогольного та протинаркотичного засобу для інєкцій «Налтетлонг / Собетов Б.Г., Новіков В.П., Шияненко О.Є., Заярнюк Н.Л., Гасс В.Б., Гасс Р.С., Бабій С.В.; заявники та патентовл. Собетов Б.Г., Новіков В.П., Шияненко О.Є., Заярнюк Н.Л., Гасс В.Б., Гасс Р.С., Бабій С.В. - № a 2010 15938; заявл. 30.12.2010; опубл. 25.05.2012, Бюл. № 10.
3. Собетов Б.Г. Ін’єкційний пролонг дисульфіраму «Тетлонг-250» – місце в терапії та реабілітації наркотично залежних пацієнтів / Б.Г. Собєтов, О.О. Фільц, О.Р. Березюк [та ін.] // Укр. вісник психоневрології. – 2002. – Т.10, вип.2. – С. 196-197.
4. Carroll K.M. One year follow up of disulfiram and psychotherapy for cocaine – alcohol users: sustained effects of treatment / K.M.Carroll, S.A. Nich, E. Ball // Addiction. – 1999. – Vol. 92. – P. 713-727.
5. Charles C. Inhibition of N-n-Butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder cancer in rats by administration of disulfiram in the diet / C. Charles, J. Irving, J. Arvil [et al.] // American Association for Cancer Research. – 1979. – Vol. 39. - P. 3040-3043.
6. Disulfiram, a сlinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity / Di Chen, Qiuzhi Cindy Cui, Huanjie Yang [et al.] // American Association for Cancer Research. - 2006. - Vol. 66. – Р. 10425-10433.
7. Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies/ Concetta Conticello, Daniela Martinetti, Luana Adamo [et al.] // International Journal of Cancer. – 2012. - Vol. 131. – P. 2197–2203.
8. Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth / Jianqing Lin, Michael C. Haffner, Yonggang Zhang [et al.] // The Prostate. – 2011. - № 71. – P. 333-343.
9. Liu P. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells / P. Liu, S. Brown, T. Goktug [et al.] // British Journal of Cancer. – 2012. - № 107. – P. 1488–1497.
10. Mutchler J. Pharmacology of disulfiram. Pharmacology of disulfiram· An update: Klinische pharmakologie von disulfiram eine actuelle ubers/cht / J. Mutchler, A. Diehl, F. Kiefer // Fortschritte der Neurologie Psychiatrie - 2008. - Vol. 76, № 4. - P. 225-231.
11. Petrakis I.L. Disulfiram treatment for cocaine dependence in methadone – maintained opioids addicts / I.L. Petrakis, R.M. Carroll, S.A. Nich // Addiction. – 2000. – Vol. 95. – P. 219-228.
12. Rosin M.P. Assessment of the use of the Salmonella mutagenesis assay to determine the influence of antioxidants on arcinogen-induced mutagenesis / Miriam P. Rosin, H. F. Stich // Int. J. Cancer. – 1979. - Vol. 23. – P. 722-727
13. Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer/ M.T. Schweizer, J. Lin, A. Blackford [et al.] // Prostate Cancer and Prostatic Disease. – 2013. - № 16. – P. 357–361.
14. The status of disulfiram: a half of a century later / J. Suh, H. Pettinati, K. Kampman [et al.] // Journal of Clinical Psychopharmacology. - 2006. - Vol. 26, № 3. - P. 290-302.
15. Triscott J. Disulfiram, a drug widely used to control alcoholism, suppresses self-renewal of glioblastoma and overrides resistance to temozolomide / Joanna Triscott, Cathy Lee, Kaiji Hu [et al.] // Oncotarget. - 2012. - Vol.3, № 10. – Р. 1112-1123.
16. Wilkins J.N. Traditional pharmacotherapy of alcohol dependence / J.N. Wilkins // Journal of Clinical Psychiatry. – 2006. – Vol. 67, № 14. - P. 14-22.
17. Zagoriy G. Development of THE optimal composition and THE technology OF NEW combined injectable drug with prolonged action based on disulfiram and naltrexone / G. Zagoriy, N. Zayarnyuk, B. Sobetov [et al.] // RJPBCS. – 2013. - Vol. 4(2). – P. 221-227.
18. Zhang H. Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vivo and in vitro / Haijun Zhang, Di Chen, Jonathan Ringler [et al.] // American Association for Cancer Research. - 2010. - Vol. 70. – Р. 3996-4004.

References

1. Sobetov, BG. Zimenkovsky, BS. Filz, OO. 26/02/1999. Antialcoholic means for injections. Patent of Ukraine No. 25842.
2. Sobetov, BG. Novіkov, VP. Shiyanenko, OY. 05/25/2012. Method of production of anti-alcoholic and anti-narcotic agent for injections “Naltetlong”. Patent of Ukraine No.98560.
3. Sobetov, B. Filz, O. (2002), “In'iektsijnyj prolonh dysul'firamu «Tetlonh-250» – mistse v terapii ta reabilitatsii narkotychno zalezhnykh patsiientiv”[ Injection prolong of disulfiram "TETLONG-250"– place in the treatment and rehabilitation of drug-dependent patients], Ukrainian J, psychoneurology, vol.10(2), pp.196-197.
4. Carroll, K.M. Nich, S.A. Ball, E. (1999), “One year follow up of disulfiram and psychotherapy for cocaine – alcohol users: sustained effects of treatment”, Addiction, vol.92, pp. 713 – 727.
5. Charles, C. Irving, J. Arvil, J. Tice (1979,) “Inhibition of N-n-Butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder cancer in rats by administration of disulfiram in the diet”,  American Association for Cancer Research, vol.39, pp. 3040-3043.
6. Chen Di. Qiuzhi Cindy Cui, Huanjie Yang. (2006), “Disulfiram, a сlinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity”, American Association for Cancer Research, N66, pp. 10425-10433.
7. Conticello, C. Martinetti, D. Adamo, L. (2012), “ Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies”, International Journal of Cancer, vol.131, pp. 2197–2203.
8. Lin Jianqing. Haffner, M. (2011) “Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth” TheProstate. N71, pp.333-343.
9. Liu, P. Brown, S. Goktug T. ⁽2012) “Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells”, British Journal of Cancer, N107, pp. 1488–1497.
10. Mutchler, J. Diehl, A. Kiefer, F. (2008), “Pharmacology of disulfiram. Pharmacology of disulfiram· An update: Klinische pharmakologie von disulfiram eine actuelle ubers/cht”, Fortschritte der Neurologie Psychiatrie, vol.76, N4, pp. 225 - 231.
11. Petrakis, I.  Carroll, R. Nich S. (2000), “Disulfiram treatment for cocaine dependence in methadone – maintained opioids addicts”, Addiction, vol.95, pp. 219 – 228.
12. Rosin, M.P. (1979). “Assessment of the use of the Salmonella mutagenesis assay to determine the influence of antioxidants on arcinogen-induced mutagenesis”, Int. J. Cancer, vol.23, pp. 722-727.
13. Schweizer, M. (2013), “Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer”, Prostate Cancer and Prostatic Diseas, N16, pp.357–361.
14. Suh ,J. Pettinati, H. Kampman, K. (2006), “The status of disulfiram: a half of a century later”, Journal of Clinical Psychopharmacology, vol26, N3. pp. 290 – 302.
15. Triscott, J. Lee, C. Hu, K. (2012), “Disulfiram, a drug widely used to control alcoholism, suppresses self-renewal of glioblastoma and overrides resistance to temozolomide”, Oncotarget, vol.3, N10, pp. 1112-1123.
16. Wilkins, J. (2006) “Traditional pharmacotherapy of alcohol dependence”, J. Clin. Psychiatry, 67(14), pp. 14-22.
17. Zagoriy, G. Zayarnyuk, N. Sobetov, B. (2013), “Development of THE optimal composition and THE technology OF NEW combined injectable drug with prolonged action based on disulfiram and naltrexone”, RJPBCS, 4(2), pp. 221-227.
18. Zhang, H. Chen, D. Ringler, J. (2010), “Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vivo and in vitro”, American Association for Cancer Research, N70. pp. 3996-4004.