Method for treating immunodeficiency by intravenous administration of sodium aminodihydrophthalazinedione

Abstract

The present invention relates to the field of healthcare. What is described is a method for treating immunodeficiency which includes intravenously administering 0.5-40.0 mg / kg body weight per day of sodium aminodihydrophthalazinedione. The invention enhances the effectiveness of parenteral therapy for immunodeficiency.

Description

[0001] A method for treating immunodeficiency by intravenous administration of sodium aminodihydrophthalazinedione

[0002] The present invention relates to the field of healthcare. More specifically, the invention relates to a method for treating immunodeficiency conditions by intravenous administration of effective amounts of sodium aminodihydrophthalazinedione.

[0003] Immunodeficiency (immunodeficiency state, IS) is a condition characterized by decreased activity or the body's inability to effectively carry out cellular and / or humoral immune responses. ICD-10 disease code D84.9 defines immunizations as D84.9. IM may have various origins and are often subdivided into physiological, primary (congenital), due to a genetic defect that impairs the functioning of immune system cells, and secondary, developing under the influence of various physical or biological factors. Depending on the predominant impairment of immune system cells, immunizations are conventionally subdivided into those associated with predominant damage to cellular immunity, humoral immunity, and those combined with damage to both cellular and humoral immunity.

[0004] Sodium aminodihydrophthalazinedione is the active ingredient in medications used to treat immunodeficiency conditions in adults and adolescents aged 12 years and older. Tamerit® instructions for use, Russian Medicines Register: https: / / www.rlsnet.ru / druqs / tamerit-84753. The drug's mechanism of action is related to its ability to regulate the functional and metabolic activity of innate and adaptive immune cells (monocytes, macrophages, neutrophils, and natural killers). Sodium aminodihydrophthalazinedione normalizes the phagocytic activity of monocytes / macrophages, the bactericidal activity of neutrophils, and the cytotoxic activity of natural killers.By restoring the reduced activity of innate and adaptive immune cells, the drug increases the body's resistance to bacterial, viral, and fungal infections, promotes faster elimination of pathogens, and reduces the frequency, severity, and duration of infections. Furthermore, sodium aminodihydrophthalazinedione normalizes antibody production, increases the functional activity (affinity) of antibodies, and indirectly regulates the production of endogenous interferons (IFNα, IFNγ) by producer cells. The effects of sodium aminodihydrophthalazinedione are associated, among other things, with its ability to inhibit excessive synthesis of tumor necrosis factor-α, interleukin-1, interleukin-6, and other proinflammatory cytokines by hyperactivated macrophages, the levels of which determine the severity of inflammatory reactions, and to reduce the production of reactive oxygen species by hyperactivated macrophages, thereby reducing oxidative stress.

[0005] As an immunomodulatory and anti-inflammatory agent, sodium aminodihydrophthalazinedione is used in combination therapy with other immunomodulators and anti-inflammatory drugs used to treat gastric ulcer and duodenal ulcer; viral hepatitis; chronic recurrent diseases caused by the herpes virus; diseases caused by the human papilloma virus; infectious and inflammatory urogenital diseases such as chlamydial and trichomonas urethritis, chlamydial prostatitis, acute and chronic salpingo-oophoritis, endometritis; purulent-inflammatory diseases of the pelvic organs; postoperative rehabilitation of patients with uterine fibroids; postoperative complications in women of reproductive age; postoperative purulent-septic complications and their prevention; chronic recurrent furunculosis and erysipelas;sthenic conditions, neurotic and somatoform disorders, decreased physical performance; mental, behavioral and post-withdrawal disorders in alcohol and drug addiction; inflammatory diseases of the mucous membrane of the mouth and throat, periodontal diseases; acute and chronic infectious and inflammatory diseases of the gastrointestinal tract, accompanied by intoxication and / or diarrhea; chronic urogenital infections, including during immunorehabilitation measures in the interrelapse period in order to maintain clinical remission. Instructions for use of Tamerit®, the register of medicines of Russia. https: / / www. rlsnet. ru / druas / tament-84753.;

[0006] The use of sodium aminodihydrophthalazinedione in the form of lyophilized powder for the preparation of solutions for intramuscular administration (Instructions for use of Tamerit®, Russian Register of Medicines https: / / www.rlsnet.ru / druos / tamerit-84753), as well as powder for the preparation of solutions for intramuscular administration (Instructions for use of Galavit®, Russian Register of Medicines https: / / www.rlsnet.ru / druqs / qalavit-691) are known from the prior art. According to the above instructions, effective amounts of sodium aminodihydrophthalazinedione administered parenterally to patients in the form of intramuscular solutions range from 50 to 200 mg per day per person, depending on the cause (disease) that caused the immunodeficiency, and can be administered once or in a course of up to 25 injections.

[0007] Studies of the immunotropic activity of pharmacological drugs on mammalian biomodels are conducted in accordance with the Methodological Recommendations for the Study of the Immunotropic Activity of Pharmacological Drugs, for example, Protocol M3 RF No. 10 dated 10.12.1998, or other similar protocols. According to the Guidelines for Conducting Preclinical Studies of Drugs, Part 1, Moscow 2012, edited by A.N. Mironov, the dose conversion factor (mg / kg) from humans to the equivalent dose for mammals is 3.2 for rabbits, 5.9 for rats, and 11.8 for mice (Appendix 3, p. 22), which yields a dose range of 0.5–40.0 mg / kg for a group of mammals consisting of humans, rabbits, rats, and mice, equivalent to human doses of 50–200 mg / kg per day for a human body weight of approximately 60 kg.

[0008] The inventors have discovered that intravenous administration of sodium aminodihydrophthalazinedione has a significant advantage over intramuscular administration, as it has a better efficacy profile in the treatment of immunodeficiency conditions in mammals.

[0009] The present invention relates to a method for treating immunodeficiency, comprising intravenous administration of an effective amount of sodium aminodihydrophthalazinedione to a mammal in need thereof.

[0010] The technical result of the present invention is to increase the effectiveness of parenteral therapy for immunodeficiency using sodium aminodihydrophthalazinedione solutions, achieved by replacing intramuscular administration of sodium aminodihydrophthalazinedione with intravenous administration. The term "immunodeficiency" refers to a condition characterized by decreased activity or the inability of the body to effectively carry out cellular and / or humoral immune responses.

[0011] Sodium aminodihydrophthalazinedione, chemical name 5-amino-1, 2,3,4-tetrahydrophthalazine-1,4-dione sodium salt, has the molecular formula CbHb ag 3Og and the structural formula:

[0012] The pharmaceutical substance sodium aminodihydrophthalazinedione is available as a powder or lyophilized powder. https: / / www.rlsnet.ru / druqs / tamerit-84753; https: / / www.rlsnet.ru / druqs / qalavit-691.

[0013] Intravenous administration of sodium aminodihydrophthalazinedione according to the present invention is carried out in the form of a solution prepared by dissolving the powder or lyophilisate of sodium aminodihydrophthalazinedione powder in a solvent selected from the group consisting of water for injection and a 0.9% by weight solution of sodium chloride in water, immediately prior to administration to a mammal in need thereof. The resulting solution of sodium aminodihydrophthalazinedione is administered intravenously to the mammal in need thereof.

[0014] The term "water for injection" refers to water produced in accordance with the requirements of the pharmacopoeial article FS.2.2.0019.15 "Water for injection".

[0015] A solution of 0.9% sodium chloride by weight in water is an isotonic solution, also known as "saline".

[0016] The term "intravenous administration" refers to the intravenous administration of a solution of the present invention to a mammal as a bolus or infusion.

[0017] According to the present invention, the treatment of immunodeficiency by the method of the present invention can be useful in the treatment of gastric ulcer and duodenal ulcer; viral hepatitis; chronic recurrent diseases caused by the herpes virus; diseases caused by the human papilloma virus; infectious and inflammatory urogenital diseases such as urethritis of chlamydial and trichomonas etiology, chlamydial prostatitis, acute and chronic salpingo-oophoritis, endometritis; purulent-inflammatory diseases of the pelvic organs; postoperative rehabilitation of patients with uterine fibroids; complications of the postoperative period in women of reproductive age; postoperative purulent-septic complications and their prevention; chronic recurrent furunculosis and erysipelas; sthenic conditions, neurotic and somatoform disorders, decreased physical performance; mental, behavioral and post-withdrawal disorders in alcohol and drug addiction;inflammatory diseases of the mucous membrane of the oral cavity and throat, periodontal diseases; acute and chronic infectious and inflammatory diseases of the gastrointestinal tract, accompanied by intoxication and / or diarrhea; chronic urogenital infections, including during immunorehabilitation measures in the interrelapse period in order to maintain clinical remission.

[0018] The mammals according to the present invention are selected from the group consisting of a rabbit, a mouse, a rat and a human.

[0019] An effective amount of sodium aminodihydrophthalazinedione for the treatment of immunodeficiency states is known from the prior art and, depending on the type of mammal (mouse, rat, rabbit, human) and the nature of the disease, can be 0.5 - 40.0 mg / kg of the mammal's body weight per day.

[0020] The following examples are illustrative and are not intended to limit the scope of the invention.

[0021] Example 1.

[0022] Comparative efficacy of aminodihydrophthalazinedione sodium (AN) with intravenous and intramuscular administration for the treatment of immunodeficiency caused by impaired cellular and humoral immunity.

[0023] A study of the comparative efficacy of AN administered intravenously and intramuscularly was conducted on a biomodel of cyclophosphamide-induced immunodeficiency in Wistar rats. Cyclophosphamide causes disturbances in both cellular and humoral immunity. Temple L et al. Fundam Appl Toxicol. 1993, 21(4):412-9. Winkelstein A. Blood. 1973, 41(2):273-84.

[0024] In the first series of experiments, control animals received a daily intraperitoneal injection of saline solution for 14 days, and additionally on the 11th day they received 2x10 intraperitoneal 8sheep erythrocytes. In the experimental groups, immunodeficiency was induced by daily intraperitoneal administration of 3 mg / kg cyclophosphamide (Sigma-Aldrich) in phosphate buffer for 14 days, and on the 11th day, rats additionally received intraperitoneal 2x10 8 sheep erythrocytes. Additionally, the experimental groups were administered saline solution intravenously (Saline), AN intravenously (AN IV) or intramuscularly (AN IM) on the day of ram erythrocyte administration as indicated in Table 1. In all groups, serum antibody titers (hemagglutinins) were determined on the 18th day. The results are presented in Table 1 as the mean ± standard deviation (n=5) of hemagglutinin titers in the groups. The hemagglutinin titer in the control was taken as 100%.

[0025] Table 1. Comparison of the effects of intravenous and intramuscular administration of sodium aminodihydrophthalazinedione on antibody formation in a rat immunodeficiency model.

[0026] ■^Statistically significant difference from control (p<0.05); Statistically significant difference from saline intravenously (p<0.05); Statistically significant difference from AN intramuscularly (p<0.05). One-way ANOVA with Tukey's post-hoc test for multiple comparisons.

[0027] Table 1 shows that cyclophosphamide causes significant humoral immunodeficiency, reducing antibody production compared to controls. Administration of sodium aminodihydrophthalazinedione (AN) increases antibody production in conditions of immunodeficiency associated with impaired humoral response at all studied doses when administered intravenously and only at high doses when administered intramuscularly. Moreover, the effects of intravenous administration of sodium aminodihydrophthalazinedione (AN IV) are statistically significantly superior to the effects of intramuscular administration of AN (AN IM) across the entire range of AN's effective doses.

[0028] In the second series of experiments, the effects of intravenous and intramuscular administration of sodium aminodihydrophthalazinedione on the cellular component of immunity under conditions of immunodeficiency were studied with a single intraperitoneal administration of cyclophosphamide at a dose of 40 mg / kg. Wistar rats were administered aminodihydrophthalazinedione sodium intravenously (AN IV) or intramuscularly (AN IM) at the doses indicated in Table 2 or saline solution (Si) on the day of cyclophosphamide administration and on the following two days. There were 5 animals in each group. On the 3rd day after cyclophosphamide administration, the number of lymphocytes in the rats' blood was measured. The results are presented in Table 2 as the mean ± standard error of the percentage of the number of lymphocytes in the blood, where the number of lymphocytes in intact rats is taken as 100%.

[0029] Table 2. Comparison of the effects of intravenous and intramuscular administration of sodium aminodihydrophthalazinedione on blood lymphocyte levels in a rat immunodeficiency model.

[0030] ■^Statistically significant difference from control (p<0.05); Statistically significant difference from saline intravenously (p<0.05); Statistically significant difference from AN intramuscularly (p<0.05). One-way ANOVA with Tukey's post-hoc test for multiple comparisons.

[0031] Table 2 shows that cyclophosphamide causes significant cellular immunodeficiency, resulting in lymphopenia compared to the control. Administration of sodium aminodihydrophthalazinedione (AN) increases lymphocyte counts in conditions of immunodeficiency associated with impaired cellular immunity at all doses studied when administered intravenously and only at high doses when administered intramuscularly. The effects of intravenous administration of sodium aminodihydrophthalazinedione (IV AN) are statistically significantly superior to those of intramuscular administration of AN (IM AN) across the entire range of AN's effective doses.

[0032] In general, replacing intramuscular administration of aminodihydrophthalazinedione sodium with intravenous administration of the same amount of aminodihydrophthalazinedione sodium leads to increased effectiveness of parenteral therapy for immunodeficiency conditions.

Claims

Formula A method for treating immunodeficiency caused by: gastric ulcer and duodenal ulcer, viral hepatitis; chronic recurrent diseases caused by the herpes virus, human papillomavirus, infectious and inflammatory urogenital diseases - urethritis of chlamydial and trichomonas etiology, chlamydial prostatitis, acute and chronic salpingo-oophoritis, endometritis, purulent-inflammatory diseases of the pelvic organs, postoperative rehabilitation of patients with uterine fibroids, complications of the postoperative period in women of reproductive age, postoperative purulent-septic complications, chronic recurrent furunculosis and erysipelas, sthenic condition, neurotic and somatoform disorders, decreased physical performance, mental, behavioral and post-withdrawal disorders in alcohol and drug addiction, inflammatory diseases of the mucous membrane of the mouth and throat, periodontal diseases,acute and chronic infectious and inflammatory diseases of the gastrointestinal tract, accompanied by intoxication and / or diarrhea, chronic urogenital infections, including intravenous administration of 0.5-40.0 mg / kg of body weight per day of amino dihydrophthalic azinedione sodium.