Combination Drugs of Hypoxanthine and Human Immunoglobulin

Abstract

A combined drug contains hypoxanthine and human immunoglobulin (HIg). HIg has a therapeutic effect on radiation injuries, and the combination of hypoxanthine and HIg can further enhance this therapeutic effect. The combination drug can be administered to patients undergoing radiotherapy and to those who accidentally have excessive irradiation.

Claims

1. A combined drug for the treatment of radiation injuries, characterized in that the combined drug contains hypoxanthine and human immunoglobulin (HIg) with the same or different specifications, that are administered simultaneously or separately; said HIg includes intravenous immunoglobulin (IVIg), intramuscular immunoglobulin and/or subcutaneous immunoglobulin (SCIg).

2. The combined drug according to claim 1, characterized in that the combined drug is a drug that restores the hematopoietic function of the body and/or improves immunity after radiation injuries.

3. The combined drug according to claim 1, characterized in that the combined drug is a drug that mitigates thymic atrophy, spleen atrophy, leukocytopenia, decreased lymphocyte ratio, increased neutrophil ratio and/or inflammation caused by radiation injuries.

4. The combined drug according to claim 1, characterized in that the combined drug is for male (including human and animals).

5. A pharmaceutical composition for treating radiation injuries, characterized in that the pharmaceutical composition is composed of hypoxanthine and HIg, and the mass ratio of hypoxanthine to human immunoglobulin (HIg) is 1:(1-11).

6. The pharmaceutical composition according to claim 5, characterized in that the mass ratio of hypoxanthine to HIg is 1:6.

7. Use of a combined drug according to claim 1 in the preparation of a medicament for alleviating radiation damage.

8. A combined drug for treating tumors, characterized in that the combined drug contains anti-tumor radiotherapy drugs, hypoxanthine and HIg with the same or different specifications, that are administered simultaneously or separately; said HIg includes intravenous immunoglobulin (IVIg), intramuscular immunoglobulin (IMIg) and/or subcutaneous immunoglobulin (SCIg).

9. The combined drug according to claim 8, characterized in that the combined drug is a drug that restores the hematopoietic function after radiotherapy; preferably, the combined drug is a drug that retards thymic atrophy, spleen atrophy, leukocytopenia, decreased lymphocyte ratio, increased neutrophil ratio and/or inflammation caused by radiotherapy.

10. The combined drug according to claim 8, characterized in that the combined drug is for male (including human and animals).

Description

DESCRIPTION OF FIGURES

[0031] FIG. 1: The appearance of the thymus.

[0032] FIG. 2: The appearance of the spleen.

[0033] FIG. 3: Leukocyte count in peripheral blood.

[0034] FIG. 4: Statistical analysis on lymphocyte ratio (LY %) and neutrophil ratio (NE %).

[0035] FIG. 5: The appearance of the large intestine in TAI group and hypoxanthine group.

[0036] FIG. 6: Levels of TNF-α and IL-6 in the small intestine of TAI group and hypoxanthine group. The ordinate mL represents the volume of PBS used to extract TNF-α and IL-6 from the small intestine, and the volume of PBS used for each unit weight of the small intestine is consistent.

[0037] FIG. 7: The appearance of the large intestine in IVIg group and IVIg+hypoxanthine group.

[0038] FIG. 8: Levels of TNF-α and IL-6 in the small intestine of IVIg group and IVIg+hypoxanthine group. The ordinate mL represents the volume of PBS used to extract TNF-α and IL-6 from the small intestine, and the volume of PBS used for each unit weight of the small intestine is consistent.

EXAMPLES

Exmple 1

Use of IVIg Combined with Hypoxanthine for the Treatment of Radiation Injuries

[0039] 1. Method

[0040] 1.1. Analysis of hematopoietic system injury by total body irradiation at 5Gy [0041] 24 male mice were divided into two groups: [0042] 1) IVIg group, 12 mice; [0043] 2) IVIg+hypoxanthine group, 12 mice;

[0044] IVIg was administrated to IVIg group within 5 min after total body irradiation, followed by injecting

[0045] IVIg twice a week for two weeks at a dose of 0.3 g/kg body weight. [0046] For IVIg+hypoxanthine group, hypoxanthine was intraperitoneally injected to mice within 30 min before total body irradiation, and then IVIg was administrated within 5 min after irradiation, followed by administrating IVIg twice a week for two weeks as well as intraperitoneally injecting hypoxanthine every two days. The dose of hypoxanthine was 50 mg/kg body weight; while the dose of IVIg was 0.3 g/kg body weight.

[0047] 1.2. Analysis of intestinal injury by 12 Gy of local abdominal irradiation 44 male mice were divided into 4 groups:

[0048] 1) TAI group, 10 mice;

[0049] 2) hypoxanthine group, 10 mice;

[0050] 3) IVIg group, 12 mice;

[0051] 4) IVIg+hypoxanthine group, 12 mice; [0052] TAI group received only local abdominal irradiation. [0053] Hypoxanthine was orally administered to the mice in hypoxanthine group 30 min before irradiation, followed by gavage through mouth every two days. The dose of hypoxanthine for each gavage was 50 mg/kg body weight.

[0054] IVIg was intravenously injected into the mice in IVIg group within 5 min after irradiation, followed by injection twice a week for two weeks at a dose of 0.3 g/kg body weight.

[0055] Hypoxanthine was orally administrated to the mice in IVIg+hypoxanthine group 30 min before irradiation, and then IVIg was injected within 5 min after irradiation, followed by injecting IVIg twice a week for two weeks as well as gavaging hypoxanthine through mouth every two days. The dose of hypoxanthine was 50 mg/kg body weight; while the dose of IVIg was 0.3 g/kg body weight.

[0056] Then, blood was collected from mice to determine the number of leukocytes, lymphocytes and neutrophils. Spleen, thymus and large intestine were taken for observation, and the levels of IL-6 and TNF-α in small intestine were further detected.

[0057] 2. Results

[0058] It is shown that total body irradiation can cause the following abnormalities in mice: atrophy of thymus and spleen, decrease in hematopoietic function, and subsequent reduction of white blood cells. As shown in FIGS. 1-3, the volumes of thymus and spleen as well as leukocyte numbers were significantly increased in the IVIg+hypoxanthine group compared with IVIg group. The results indicated that the combination of IVIg and hypoxanthine could restore the size of thymus and spleen more obviously in mice compared with IVIg alone, and further lead to the recovery of the hematopoietic function in irradiated mice.

[0059] Radiation could cause a decrease in the level of lymphocytes and an increase in the level of neutrophils in the peripheral blood of mice. Compared with IVIg group, the ratio of lymphocyte is higher in IVIg+hypoxanthine group, while the ratio of neutrophils is lower (FIG. 4), indicating that the combination of IVIg and hypoxanthine could improve the immune function in irradiated mice. Local abdominal radiation can induce intestinal inflammation in mice, such as shortening of the large intestine and elevation of inflammatory factors TNFα and IL-6 in the small intestine (Li et al., Gut commensal derived-valeric acid protects against radiation injuries, Gut Microbes, 2020, 11: 789-806). Hypoxanthine alone (hypoxanthine group) could not improve the above symptoms, that is no difference in the length of the large intestine and the inflammatory factors TNFa and IL-6 in the small intestine was found between hypoxanthine group and TAI group (FIGS. 5 and 6), indicating that oral administration of hypoxanthine alone could not inhibit radiation-induced inflammation.

[0060] Although IVIg may alleviate the aforementioned changes to some extent, the length of the large intestine in IVIg+hypoxanthine group was longer than that in IVIg group, and the levels of inflammatory cytokines TNFα and IL-6 in the small intestine were also lower than that in IVIg group (FIGS. 7 and 8). This suggested that compared with the single use of IVIg, the combination of IVIg and hypoxanthine could further inhibit the radiation-induced inflammation.

[0061] In summary, the combination drug of the present invention can be used to restore the hematopoietic function of the body after irradiation, and can relieve the atrophy of thymus and spleen, leukocytopenia and/or inflammation caused by irradiation; and the combination drug has overcome the disadvantage that IVIg alone cannot effectively treat male animals.