WO2009157886A1

WO2009157886A1 - Antitumoral, antioxidant and immunomodulatory composite agent

Info

Publication number: WO2009157886A1
Application number: PCT/UA2009/000007
Authority: WO
Inventors: Анатолий Ивановыч ТКАЧЭНКО; Самир Хади РАШЭД; Джордж Михаэль ДАХЕР
Original assignee: Tkachenko Anatolii Ivanovych; Rached Samir Hadi; Daher Georges Mikhael
Priority date: 2008-06-26
Filing date: 2009-02-23
Publication date: 2009-12-30
Also published as: UA38114U

Abstract

The invention relates to pharmacology and medicine and can be used in developing agents for treating immune and oncological diseases, in particular skin neoplasms in the form of melanomas. The inventive composite agent Samirin comprises tannic acid, potassium iodide and ascorbic acid taken with a weight ratio of 3:1:1. The treatment is carried out by the intravenous drop infusion of a Samirin physiological solution once per day by 1.8-2.5 mg per 1 kg of body weight for 15-20 days.

Description

COMPOSITION AGENT HAVING ANTITUMOR, ANTIOXIDANT AND IMMUNOMODULATING ACTION

The invention relates to pharmacology and medicine and can be used in the development of agents for the treatment of immune and oncological diseases, in particular skin neoplasms - melanoma.

The search for new adequate methods of therapeutic effect in oncology is an urgent task of modern medicine. In this regard, both new synthetic and natural therapeutic agents and new compositions of existing drugs are of great interest.

Malignant melanoma of the skin is an aggressive tumor; among all types of malignant skin tumors, 65% of deaths are caused by melanoma [Balch CM, Reintgen DS, Kirkwood JM. Сutapeusus melapoma, in De Vita VT Jr, Hellman S, Rosenberg SA (eds.): Sapser Ripsylls apd Ractis оf Opsologu (ed 5) Rhildelrhia, PA, Liripotstt-Ravep, 1997; R. 1947-94.]. The number of melanoma diseases is steadily increasing. The median survival is 4-6 months and is determined by such factors as the general condition of the patient and the localization and number of tumor foci [Tilgep W. Maligapt melapoma: Surprt theraputic soperts. Optology 1995; 18: 534-47.].

At an early stage of the natural development of melanoma, it is curable using the surgical approach, but with the onset of metastasis, it is almost always fatal in nature, at this stage radical surgical treatment is used only in rare cases, and radiation therapy is used only for palliative purposes. Therefore, at the present chemotherapy remains the main treatment for melanoma. Chemotherapeutic agents active against melanoma are Da-carbazine, platinum derivatives, various nitrosourea derivatives and tubulotoxins, such as vinblastine and taxanes [MF.Avril, S. Amdal, JJ. Grob et al. J CIm Review 2004; 22: 11 18-25].

However, the effectiveness of systemic therapy remains quite low, with a low response rate when using mono-modes. Polychemotherapy does not exceed the clinical effects of monochemotherapy, as evidenced by the publication of the results of a randomized ECOG trial [Chharmap PB, Einhorn LH, Meers ML, et al. Rhase III multiseriter rápomizd trial оf thе Dаrtmоuth regimep vеrsus dаsarbаzіpe іp ratіepts with metаstаtіс melapoma. Slip Opsol, 1999; 17: 2745-51.]. The currently used treatments for metastatic melanoma do not provide satisfactory immediate and long-term results.

The natural development of melanoma suggests a possible modulating role of the host immune system. Among the modulators of the biological response, cytokines, the following mechanisms of antitumor activity are possible: cytostatic effect; stimulation of differentiation of transformed cells; anti-angiogenic activity; immunomodulatory activity. The latter is associated with the induction of expression of the molecules of the main histocompatibility complex and some tumor-associated antigens, which enhances the recognition of tumor cells by the host immune system.

The leading role in the impossibility of recognizing tumor cells by the host’s immune system is played by a linear homopolymer of 2-8 bound N-acetylneurominic acid, called polysialic acid (PSA). It has been shown that tannic acid reacts with PSA, which leads to the precipitation of three moles of N-acetylneurominic acid with each mole of tannic acid [Rat. US6063770, IPC 1-7 A61K31 / 70; A61K31 / 35. Tappis acid comsitiops for forreptsapser / Falcop Juap (US); ATAJJE INC (US). - US19980063397 1998.04.21, Publication date 2000.05.16]. Thus, tannic acid allows the body's own immune system to reject malignancy in much the same way as an incompatible graft is rejected.

An important component of the pathogenesis of cancer is oxidative damage to DNA, in which reactive oxygen species act as cellular destructors [Laviapo A., Mguid M.M., Preziosa L, Fappelli F.R. Ohidative strss apd wastipg ip sapper. Surr Opin CHn Nutr Metab Sage, 2007, 10 (4): 449-456]. Gallic acid (tannic acid monomer) is known to be a highly effective inhibitor of reactive oxygen species. In the presence of an iodide ion, a cascade of redox reactions that occur in a tumor is accompanied by the formation of molecular iodine, which is involved in the doubling of halogen fragments in tannic acid. According to published data, a mixture of tannic acid and potassium iodide in a molar ratio of 1: 1 inhibits the formation of free radicals to a greater extent compared to the same amount of tannic acid itself [Khap NS, Ahmad A., Nadi SM Apti-oxidapt, pro-oxidaproporesis Of tashiiс asid its its bpdiпg to DNA. Scheme Viol Ipterast. 2000, Mage 15; 125 (3): 177-189].

However, despite the presence of the antitumor and antioxidant activity of tannic acid, the high toxicity is a limiting factor for its use [Tourifto S., Lizarraga D., Carréas A. at all. Highlight gallouletted tannin frothiops fr witсh hazel (Namamelis virgipiapa) bark: elastroopserparasit, ip vitro apidokhidaptivtiv, apdeffeptsport ski. Chem Res Tohisol. 2008 Mage; 21 (3): 696-704]. The combined use of tannic acid and potassium iodide can reduce its toxic effects. Our experimental data indicate that the combined administration of tannic acid and potassium iodide in a molar ratio of 1: 2.5-3.5 does not have a toxic effect. It is known that ascorbic acid, due to the presence of a dienol group in its molecule, has a pronounced reducing effect. This promotes the regeneration of normal body cells and their replacement of cells destroyed during the tumor process and explains the fact that ascorbic acid has antitumor activity [Henson D. E., Block G., Levin M. Ascorbic acid: biological functions and effect on oncological diseases / Journal Institute of Oncological Diseases J. Nath, 1991: 83 (8): 547-53.].

The objective of the invention is to develop a composite agent that would have antitumor, antioxidant and immunomodulatory activity.

The problem is solved in that it is proposed a composite tool Samirin containing tannic acid, potassium iodide and ascorbic acid in a weight ratio of 3: 1: 1. The treatment is carried out with a solution of Samirin in saline, by intravenous drip once a day at a dose of 1.8 - 2.5 mg / kg of body weight for 15-20 days.

The technical result is the expansion of the arsenal of purposefully acting, low-toxic agents, which can improve the effectiveness of cancer treatment.

As raw materials for the production of Samirin, tannic acid is used, which contains mainly hydrolyzable tannins - polygalo-yl derivatives of glucose, manufactured by VAG Chermis (Germany). The series of tannic acid used was compared with a working standard sample of tannic acid (CAS Ipdex 1401-55-4) Sigma-Aldrich (USA).

IR spectrum used tannic acid, measured in KBr tablet comprises the absorption band at 3400 cm ^" '(stretching vibrations of the OH groups), 1700 ^cm"' (stretching vibrations of the C = O-gpypp galoilnyh fragments), 1615 cm ^"1 (stretching vibrations C = C bonds of aromatic fragments), 1200 cm ^"1 (vibrations of COC bonds). The general appearance of the spectra is consistent with that cited in the literature [Gaudreult R, vapde vep TG, Whithead MA. Molesular model poly (ethylene oxide) model compounds; 1,3,6-tri-O-galloul-beta-d-glucose-ad corilaggi. J MoI Model. 2002, Vol.8, N 3, P. 73-80] and coincides with the spectrum of the working standard sample ..

HPLC analysis of tannic acid series was carried out using a chromatography-mass spectroscopic system including an Agilept 1100 Series (USA) high-performance liquid chromatograph equipped with a single-matrix detector, Agilept LC \ MSD SL 1956B mass-selective detector, and a detector laser light scattering ELSD 2000ES. For the used series of tannic acid and its working standard sample, identical chromatograms were obtained. For tannic acid, in accordance with the data of [The Merck Idex, 13th ed; 2001; R. 1615-1616], the accepted value of the average molecular weight of 1700 carbon units.

To obtain Samirin, a mixture of tannic acid, potassium iodide and ascorbic acid is prepared in a ratio of 3: 1: 1 parts by weight. Weighed portions of 180 mg of the composite mixture are lyophilized, Packed in sterile vials and hermetically sealed.

Treatment of patients with melanoma is carried out as follows: the contents of one vial of Samirin is dissolved in 200 ml of physiological saline and injected intravenously. Once a day at a dose of 1.8 - 2.5 mg / kg body weight. The course of treatment is 15-20 intravenous infusions. In the presence of positive dynamics, the treatment is repeated until an expressive effect is obtained.

SUBSTITUTE SHEET (RULE 26) In most clinical studies, dacarbazine serves as a benchmark for comparing the efficacy and toxicity of new drugs for treating melanoma. The use of dacarbazine in the first line of chemotherapy allows obtaining objective answers in 11-25% of cases, with a median survival of 4.5 to 6 months [Luce JK, Thurman WG, Sega FM et al. Dasarbazipe-based chemoteru for metastastis melapota: Thirtuar exreriveps. J Exp CIm Sapseg Res 2000; 19: 21-34.].

A comparative assessment of the effectiveness and toxicity of Samirin and Dacarbazine in patients with metastatic melanoma, including both metastases and without metastases to the brain, was performed. Along with assessing the frequency of objective responses to therapy, indicators such as quality of life, tolerance of therapy, and overall survival were studied in a comparative aspect.

The developed method was tested on 30 patients. The study included patients aged 18 to 75 years with a histologically confirmed diagnosis of skin melanoma. None of the patients had previously received chemotherapy. All patients received informed consent to participate in the study. Treatment continued until disease progression or development of side effects requiring cessation of therapy.

Dacarbazine at a dose of 250 mg / m ^" was prescribed as an infusion, lasting 60 minutes, 1 time per day for consecutive 5 days every 4 weeks, respectively, on days 1-5 and 29-33. Repeated courses were carried out only on that patients who have not been registered progression of the disease.

The frequency of objective responses in the group of patients receiving Samirin was 95%, while using Dacarbazine - 23%. Objective responses have been reported with metastases of skin melanoma of various localization.

With metastases to the skin and peripheral lymph nodes in the Samirin group, complete and partial regression of tumor foci was recorded in 54.5%, when using dacarbazine - in 8.3% of cases; with metastases of multi-organ localization - in 52.6 and 19.9% of cases, respectively.

Thus, the use of the developed product Samirin gives a more noticeable effect in patients with metastases to the skin and lymph nodes and metastases of multi-organ localization. Samirin has a positive effect on life expectancy and improves overall health (reduces painful symptoms, general weakness, dizziness, improves motor activity). An expressive positive effect was not achieved in patients with a tumor spreading to the visceral organs, bones and brain.

The course of induction therapy was fully carried out in 95% of patients in the Samirin group and 77% of patients in the Dakarbazin group. The reasons why the induction course of therapy was not completed were the progression of the disease and the development of side effects. The most common side effects were hematologic complications. In patients receiving Samirin, neutropenia was not registered, thrombocytopenia was recorded in 9% of cases. In patients receiving dacarbazine, neutropenia was recorded in 14% of cases, thrombocytopenia was recorded in 57% of patients.

An assessment of the toxic effects of Samirin showed that its use causes minimal changes in the patient’s well-being, which do not affect his normal activity and vital activity. Laboratory parameters of patients receiving Samirin are practically unchanged and do not require correction. While all anticancer drugs used in chemotherapy exhibit extremely high toxicity, which leads to damage not only to organs that carry the tumor, but also to organs and systems that are not covered by the pathological process, the immune system is particularly depressed [Translatorova N.I. Antitumor chemotherapy / Ed. Medicine: Moscow. - 1996. - 166s]. Samirin has a pronounced immunomodulatory effect, which is very important in the treatment of advanced stages of the tumor process, in which secondary immunodeficiency already occurs (table 1).

Table 1

Changes in the content of immunocompetent cells in the blood during treatment with Samirin

Analysis of the data shows that all patients have a pronounced secondary immunodeficiency. This is evidenced by a decrease in T- and, to a lesser extent, B-lymphocytes and their subpolar composition. After the course of treatment with Samirin, all patients showed a positive dynamics in the quantitative indicators of immunocompetent cells and a significant increase in the number of helper lymphocytes, which was reflected in the growth of the immunoregulatory index.

One of the most common pathologies that causes persistent leukopemia and restricts the use of chemotherapy is a lesion of the white blood cell. Studies have shown that treatment with the composite tool Samirin does not affect the white blood cell count (table 2). table 2

The practical results of the use of the composite tool Samirin

Thus, the developed composite tool Samirin selectively affects the tumor process and does not adversely affect organs and systems, which allows it to be used at all stages of the development of the tumor process.

SUBSTITUTE SHEET (RULE 26)

Claims

Claim

1. A composite agent having an antioxidant, immunomodulating and antitumor effect, which contains tannic acid, characterized in that it further comprises potassium iodide and ascorbic acid.

2. The tool according to claim 1, characterized in that tannic acid, potassium iodide and ascorbic acid are taken in a weight ratio of 3: 1: 1.

3. A method for the treatment of tumor skin formations using the tool according to claim 2.

4. The method according to p. 3, characterized in that the treatment is carried out with a solution of a composite agent in physiological saline intravenously once a day at a dose of 1.8 - 2.5 mg / kg body weight for 15-20 days

SUBSTITUTE SHEET (RULE 26)