Novel treatment method for viral hemorrhagic fever

Abstract

The present invention provides a novel method of treating viral hemorrhagic fever, including hemorrhagic fever with renal syndrome, which is treated or ameliorated by administering a neutrophil elastase inhibitor. When the neutrophil elastase inhibitor is used for treating hemorrhagic fever with renal syndrome, inflammatory response can be inhibited, endothelium and organ injury can be reduced, death rate can be reduced, and complications can be reduced.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a new treatment method for viral hemorrhagic fever. The viral hemorrhagic fever is treated or improved by administering a neutrophil elastase inhibitor, and the viral hemorrhagic fever includes hemorrhagic fever with renal syndrome (HFRS). Background Art

[0002] Hantavirus (HTNV) can cause epidemic hemorrhagic fever in humans who come into contact with infected mice or their excreta. These diseases mainly manifest as hemorrhagic fever with renal syndrome (HFRS) in Eurasia. The pathophysiological mechanism of this disease is still unclear, so there is an urgent need to explore specific candidate vaccines or targeted drugs.

[0003] Sivelestat is a neutrophil elastase inhibitor and can be used to treat diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There is no report in the prior art on the use of sivelestat for the treatment of viral hemorrhagic fever. The present invention has studied the efficacy of sivelestat in the treatment of viral hemorrhagic fever, especially hemorrhagic fever with renal syndrome. Summary of the Invention

[0004] In the first aspect of the present invention, there is provided the use of sivelestat or a salt thereof in the preparation of a drug for preventing or treating viral hemorrhagic fever.

[0005] Among them, the viral hemorrhagic fever is caused by hantavirus.

[0006] Among them, the viral hemorrhagic fever includes hemorrhagic fever with renal syndrome, epidemic nephropathy and hantavirus pulmonary syndrome.

[0007] Among them, the dosage of sivelestat or a salt thereof is 1 - 300 mg / kg / day.

[0008] Among them, the sivelestat or a salt thereof is sivelestat sodium.

[0009] In the second aspect of the present invention, there is provided the use of sivelestat or a salt thereof in the preparation of a drug for preventing or treating hemorrhagic fever with renal syndrome and its complications.

[0010] Among them, the complications are selected from one or more of acute pulmonary edema, acute renal failure, shock, acute pancreatitis, acute kidney injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, etc.

[0011] In the third aspect of the present invention, there is provided a pharmaceutical composition containing sivelestat or a salt thereof, and the pharmaceutical composition is used for preventing or treating viral hemorrhagic fever.

[0012] Among them, the viral hemorrhagic fever is caused by hantavirus.

[0013] Among them, the viral hemorrhagic fever includes hemorrhagic fever with renal syndrome, epidemic nephropathy, and hantavirus pulmonary syndrome.

[0014] Among them, the content of sivelestat or its salt is 1 - 500 mg.

[0015] When the sivelestat or its salt of the present invention is used in the treatment of hemorrhagic fever with renal syndrome, it can inhibit the inflammatory response, reduce the level of inflammatory factors, reduce endothelial and organ damage, reduce the 28-day mortality rate, reduce the usage rates of ECMO, mechanical ventilation, and continuous renal replacement therapy (CRRT). In addition, it also reduces the incidence of complications such as acute pulmonary edema, acute renal failure, acute pancreatitis, and shock. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1A It is the relationship curve of interleukin-1β and time for two groups of patients.

[0017] Figure 1B It is the relationship curve of interleukin-2 and time for two groups of patients.

[0018] Figure 1C It is the relationship curve of interleukin-6 and time for two groups of patients.

[0019] Figure 1D It is the relationship curve of interleukin-8 and time for two groups of patients.

[0020] Figure 1E It is the relationship curve of interleukin-10 and time for two groups of patients.

[0021] Figure 1F It is the relationship curve of serum interferon-α and time for two groups of patients.

[0022] Figure 1G It is the relationship curve of serum interferon-γ and time for two groups of patients.

[0023] Figure 1H It is the relationship curve of tumor necrosis factor and time for two groups of patients.

[0024] Figure 2 It is the correlation between neutrophils and time for two groups of patients.

[0025] Figure 3A It is the correlation between the vascular endothelial injury factor ICAM-1 and time for two groups of patients.

[0026] Figure 3B It is the correlation between the vascular endothelial injury factor VCAM-1 and time for two groups of patients.

[0027] Figure 4 It is the cumulative survival rate of two groups of patients. Detailed implementation manners

[0028] Glossary of terms

[0029] "Sivelestat" as described in the present invention has the following structure,

[0030]

[0031] The "sivelestat or its salt" may be a sodium salt, potassium salt, calcium salt, etc.; preferably, the salt is a sodium salt. As a specific implementation manner of the present invention, the sivelestat or its salt is sivelestat sodium salt, or described as sodium sivelestat, sodium sivel. Further, sodium sivelestat may also exist in the form of hydrates, such as monohydrate, dihydrate, trihydrate, tetrahydrate. In a preferred implementation manner of the present invention, the sodium sivelestat is sodium sivelestat tetrahydrate.

[0032] The "viral hemorrhagic fever" as described in the present invention is a group of acute infectious diseases mainly characterized by fever and bleeding caused by vector pathogenic microorganisms. There are various viruses that can cause human viral hemorrhagic fever, including viruses in the Flaviviridae family, encephalitis virus, Bunyaviridae family, yellow fever virus, dengue virus, hemorrhagic fever virus, severe fever with thrombocytopenia syndrome Bunyavirus, Filoviridae family, Arenaviridae family, Togaviridae family, etc.

[0033] The "Hantavirus" as described in the present invention is the name of the "family" of viruses, belonging to the order Bunyavirales. The Hantaviridae family includes multiple virus "genera" or "species", such as Hantaan virus, Dobrava virus, Puumala virus, Sin Nombre virus, Andes virus, etc. The viral hemorrhagic fever "caused by Hantavirus" includes hemorrhagic fever with renal syndrome (HFRS), epidemic nephropathy, and hantavirus pulmonary syndrome (HPS), etc.

[0034] The "hemorrhagic fever with renal syndrome" as described in the present invention is a viral hemorrhagic fever, also known as epidemic hemorrhagic fever, mainly caused by Hantavirus.

[0035] Dosage form and dose selection

[0036] The sivelestat or its salt of the present invention can be adaptively adjusted according to factors such as the body weight, gender, age of the administration object, such as a human, and whether there are other diseases, etc., and can be administered once, multiple times or continuously. Calculated based on the cumulative daily administration dose, the appropriate administration dose of sivelestat is 0.1 - 500 mg / kg / day, preferably 0.5 - 400 mg / kg / day, more preferably 0.5 - 300 mg / kg / day, further preferably the administration dose is 1 - 300 mg / kg / day, further preferably the administration dose is 1 - 200 mg / kg / day, further preferably the administration dose is 1 - 150 mg / kg / day. In the specific embodiments of the present invention, the daily administration dose of sivelestat or its salt can be 1.0 mg / kg / day, 2.0 mg / kg / day, 3.0 mg / kg / day, 4.0 mg / kg / day, 5.0 mg / kg / day, 6.0 mg / kg / day, 7.0 mg / kg / day, 8.0 mg / kg / day, 9.0 mg / kg / day, 10.0 mg / kg / day, 15.0 mg / kg / day, 20.0 mg / kg / day, 25.0 mg / kg / day, 30.0 mg / kg / day, 35.0 mg / kg / day, 40.0 mg / kg / day, 50.0 mg / kg / day, 60.0 mg / kg / day, 70.0 mg / kg / day, 80.0 mg / kg / day, 90.0 mg / kg / day, 100.0 mg / kg / day, 150.0 mg / kg / day, 200.0 mg / kg / day, 250.0 mg / kg / day, 300.0 mg / kg / day.

[0037] The "pharmaceutical composition containing sivelestat or its salt" described in the present invention, wherein the content of the sivelestat or its salt is 1 - 500 mg, including 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg, etc. The pharmaceutical composition can be arbitrarily prepared into a pharmaceutically acceptable preparation with a pharmaceutically acceptable excipient, including: oral solid preparations, oral liquid preparations, injections, solid preparations for inhalation, liquid preparations for inhalation, sustained-release preparations, etc. Preferred preparations are solid preparations for inhalation and freeze-dried preparations for injection.

[0038] The following examples are used to further elaborate the concept of the present invention and should not be construed as any limitation to the present invention. The drugs, reagents, etc. used in the present invention are all commercially available.

[0039] Example 1

[0040] The research subjects were children diagnosed with hemorrhagic fever with renal syndrome (HFRS) and hospitalized in a children's hospital. Patients who received neutrophil elastase inhibitor (sivelestat sodium) infusion during hospitalization were assigned to the sivelestat group, while those who did not receive the infusion were assigned to the control group.

[0041] Demographic data and laboratory indicators (blood routine, coagulation, arterial blood gas, renal function, C-reactive protein, procalcitonin) were obtained from the electronic medical record system within 8 hours after admission. At the same time, important indicators of relevant items were extracted, including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), D-dimer, von Willebrand factor (vWF), platelet count (PLT), lactate (Lac), Scr, neutrophil count, inflammatory factors, and biomarkers of vascular endothelial injury (including intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). Treatment measures were collected, including CRRT, mechanical ventilation, ECMO, and 28-day clinical outcomes.

[0042] The primary endpoint was set as 28-day mortality, and the secondary endpoints were set as ECMO, mechanical ventilation, CRRT use and complications, and duration of renal failure.

[0043] Data analysis was performed using SPSS software (version 21.0). Continuous variables in the normal distribution were expressed as mean ± standard deviation. Independent sample t-tests were used for between-group analysis. Categorical variables were analyzed using chi-square tests and Fisher's exact probability tests. Spearman correlation tests were used to evaluate the correlation between continuous variables in the two groups. Kaplan-Meier survival curves and Log-Rank tests were used to evaluate the differences in cumulative survival rates between the two groups. A P value < 0.05 was considered statistically significant.

[0044] A total of 132 children were included. Among them, there were 33 males and 26 females in the sivelestat group; 34 males and 39 females in the control group. All patients lived in rural areas, and 34 in the sivelestat group and 51 in the control group had a history of exposure. There were no statistically significant differences in gender, age, history of exposure, body mass index, and disease severity between the two groups (P > 0.05).

[0045] There were no significant differences in the coagulation indicators of the patients between the two groups, including PT, APTT, Fib, D-dimer, vWF, PLT, and Scr, the inflammatory response markers, including C-reactive protein, procalcitonin, and lactate concentration, and blood cell analysis and count (P > 0.05). (1) Dynamic characteristics of inflammatory cytokines in the two groups of patients

[0046] There was no significant difference in interleukin-1β levels between the two groups at the time of admission. However, the level of interleukin-1β in the sivelestat group was significantly decreased at 24 h (12 ± 3.1 vs. 15.6 ± 5.9), 48 h (9.5 ± 4.3 vs. 18.5 ± 5.6), and 72 h (8.5 ± 3.2 vs. 12.6 ± 3) (P < 0.05; Figure 1A ). The level of interleukin-2 between the two groups increased at 24 h (12.6 ± 3 vs. 14.5 ± 2), and continued to decline at 48 h (7.9 ± 2.5 vs. 11 ± 3.5) and 72 h (5.6 ± 2 vs. 7.6 ± 3.1), and these data were statistically significant (P < 0.05; Figure 1B ). The level of interleukin-6 in the sivelestat group was significantly lower than that in the control group at 24 h (12.4 ± 4.8 vs. 17.8 ± 4.5), 48 h (8.9 ± 3.2 vs. 16.3 ± 3.5), and 72 h (5.5 ± 2.5 vs. 14.6 ± 6.5) (P < 0.05; Figure 1C ). Compared with the control group, the levels of interleukin-8 (P < 0.05; Figure 1D ) in the sivelestat group at 48 h (28.5 ± 3 vs. 34.5 ± 3.5) and 72 h (21.3 ± 4.5 vs. 31.5 ± 5.6), and interleukin-10 (P < 0.05; Figure 1E ) at 24 h (18.1 ± 2.5 vs. 22.3 ± 4.6), 48 h (12.5 ± 3.2 vs. 18.4 ± 3.5), and 72 h (9.5 ± 2.4 vs. 17.1 ± 3.1) were significantly decreased.

[0047] After admission, the serum interferon-α levels of the patients in both groups continued to decline. It should be noted that the serum interferon-α levels in the sivelestat group were significantly lower than those in the control group at 24 h (7.7 ± 5.6 vs. 13.5 ± 3.5), 48 h (5.8 ± 3.5 vs. 9.8 ± 4.4), and 72 h (4.5 ± 2.8 vs. 8.5 ± 3.1) (P < 0.05; Figure 1F ). At 48 h (27.4 ± 11.5 vs. 38.5 ± 11) and 72 h (15.6 ± 5.9 vs. 26.9 ± 15.7), the serum interferon-γ levels in the sivelestat group were significantly lower than those in the control group (P < 0.05; Figure 1G ). The tumor necrosis factor levels in the sivelestat group at 48 h (28.9 ± 10.5 vs. 47.4 ± 12.8) and 72 h (11.5 ± 5.9 vs. 24.2 ± 12.6) were significantly lower than those in the control group (P < 0.05; Figure 1H ).

[0048] (2) Correlation between neutrophils and time in the two groups of patients

[0049] Compared with the control group, the neutrophil count in the sivelestat group was significantly decreased at 24 h (16 ± 4.5 vs. 21 ± 4.5), 48 h (13 ± 4.5 vs. 18 ± 4.7), and 72 h (8 ± 6 vs. 13 ± 3.5) (p < 0.05; Figure 2 )

[0050] (3) Time correlation of vascular endothelial injury in the two groups of patients

[0051] There was no significant difference in the level of ICAM-1 between the two groups within 24 h after admission (P > 0.05; Figure 3A ) Compared with the control group, the level of ICAM-1 in the sivelestat group was significantly decreased at 48 h (553 ± 122 vs. 784 ± 187) and 72 h (452 ± 130 vs. 623 ± 85) (P < 0.05; Figure 3A ) The level of VCAM-1 in the sivelestat group showed a continuous downward trend and was significantly lower than that in the control group at 24 h (1760 ± 289 vs. 2180 ± 445), 48 h (1450 ± 441 vs. 1890 ± 267), and 72 h (1149 ± 33 vs. 1500 ± 396) (P < 0.05; Figure 3B )

[0052] (4) The primary and secondary endpoints of the two groups of patients

[0053] The primary endpoint of this study was the 28-day mortality rate. Kaplan-Meier curve analysis showed that there was a significant difference in the cumulative survival rate between the sivelestat group and the control group (P = 0.041, Figure 4 ) In the secondary endpoints, the utilization rates of ECMO and CRRT in the sivelestat group decreased. In addition, the incidence of complications such as acute pulmonary edema, acute renal failure, and acute pancreatitis also showed a significant statistical decrease (P < 0.041; Table 1).

[0054] Table 1 Secondary endpoints and complications

[0055]

Claims

1. Use of sivelestat or its salt in preparing a medicament for preventing or treating viral hemorrhagic fever.

2. The use according to claim 1, wherein the viral hemorrhagic fever is caused by Hantavirus.

3. The use according to claim 1, wherein the viral hemorrhagic fever is hemorrhagic fever with renal syndrome, epidemic nephropathy and Hantavirus pulmonary syndrome.

4. The use according to claim 1, wherein the dosage of sivelestat or its salt is 1-300 mg / kg / day.

5. The use according to claim 1, wherein the sivelestat or its salt is sivelestat sodium.

6. Use of sivelestat or its salt in preparing a medicament for preventing or treating hemorrhagic fever with renal syndrome and its complications.

7. The use according to claim 6, wherein the complication is selected from one or more of acute pulmonary edema, acute renal failure, shock, acute pancreatitis, acute kidney injury, acute respiratory distress syndrome, and systemic inflammatory response syndrome.

8. A pharmaceutical composition containing sivelestat or a salt thereof, wherein the pharmaceutical composition is used for preventing or treating viral hemorrhagic fever.

9. The pharmaceutical composition according to claim 8, wherein the viral hemorrhagic fever is hemorrhagic fever with renal syndrome, epidemic nephropathy and Hantavirus pulmonary syndrome.

10. The pharmaceutical composition according to claim 8, wherein the content of sivelestat or its salt is 1-500 mg.

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