CN111888355A

CN111888355A - Application of arbidol hydrochloride in preparing medicament for treating sepsis diseases

Info

Publication number: CN111888355A
Application number: CN202010856964.1A
Authority: CN
Inventors: 周红刚; 李霄鹤; 李海龙; 张亮; 李建; 伦东超
Original assignee: Tianjin Jikun Pharmaceutical Technology Co ltd; Nankai University
Current assignee: Tianjin Jikun Pharmaceutical Technology Co ltd; Nankai University
Priority date: 2020-08-24
Filing date: 2020-08-24
Publication date: 2020-11-06

Abstract

The invention provides application of arbidol hydrochloride in preparing a medicament for treating sepsis diseases, wherein the structure of arbidol hydrochloride is shown as the following formula (I):

research shows that arbidol hydrochloride has good efficacy on sepsis, has no adverse reaction, and has good application prospect in the aspect of treating, relieving or improving sepsis diseases.

Description

Application of arbidol hydrochloride in preparing medicament for treating sepsis diseases

Technical Field

The invention relates to the field of medicinal chemistry, in particular to application of arbidol hydrochloride in preparing a medicament for treating sepsis diseases.

Background

Sepsis is a highly heterogeneous syndrome caused by a host's dysregulated response to infection, which disrupts the normal functions of the immune, respiratory, cardiovascular, renal, and central nervous systems, affecting coagulation, temperature control, and metabolic homeostasis. Exacerbations are severe sepsis (organ dysfunction) and septic shock (refractory hypotension). The acute deterioration of the disease condition of the patient in the epidemic situation is closely related to the outbreak of the inflammation storm in the body, and the inflammation storm is an important reason for the death of the patient. The cytokine storm was closely related to the 2019 coronavirus (COVID-19). Viral sepsis caused by SARS-COV-2 is characterized by a typical pathophysiological process of sepsis, namely an early cytokine storm and a subsequent immunosuppressive phase.

Until now, no anti-sepsis medicine with definite curative effect and high safety exists, the existing treatment schemes mainly comprise liquid resuscitation, etiological treatment, antibiotic treatment, vasoactive medicine treatment, anticoagulant treatment and the like, which are main measures for treating sepsis at home and abroad, but the measures cannot well relieve inflammatory response of patients with sepsis and improve prognosis. Therefore, the molecular mechanism of sepsis needs to be deeply analyzed, a link or a target for reversing the occurrence of sepsis is found, and the research of a medicine with exact curative effect and high safety has important significance.

Arbidol hydrochloride (Arbidol hydrochloride) has special effect on eliminating A, B type influenza virus, and can prevent virus from contacting and permeating into cells, and eliminate the combination of lipid membrane virus and cell membrane. Has effects in interfering and inducing the immune function of liquid cell and the phagocytic function of macrophage, improving the resistance of tissue to virus infection, and reducing the complications related to virus infection and the attack frequency of chronic malignant bacteria diseases. Prevent the combination of virus cell wall and normal cell, and resist influenza A virus and influenza B virus. Inducing the synthesis of interferon, and improving immune response, macrophage and phagocytosis. Improving the ability of the body to resist virus infection. Is currently used in clinical trials for new coronaviruses.

Disclosure of Invention

Aiming at the problems, the invention provides application of arbidol hydrochloride in preparing a medicament for treating sepsis diseases, wherein the structure of arbidol hydrochloride is shown as the following formula (I):

in the application, the dosage of the arbidol hydrochloride is 10 mg/kg-500 mg/kg.

The invention also provides a medicament for treating sepsis diseases, which comprises arbidol hydrochloride, pharmaceutically acceptable salts, esters, hydrates and auxiliary materials of arbidol hydrochloride.

In the above drugs, the pharmaceutically acceptable salts of arbidol hydrochloride include organic salts and inorganic salts.

In the above drugs, the organic salt includes methanesulfonate, formate, acetate, trifluoroacetate, maleate, tartrate, succinate, fumarate, citrate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, lactate and benzoate; the inorganic salts include hydrochloride, hydrobromide, sulfate and phosphate salts.

In the above medicines, the dosage form of the medicine is selected from tablets, capsules, pills, suppositories, aerosols, oral liquid preparations, granules, powders, injections, syrups, medicated liquors, tinctures, lotions, films or combinations thereof.

In the above drugs, the administration mode of the drug includes oral administration, injection, implantation, external application, spraying, inhalation or a combination thereof.

The research of the invention shows that arbidol hydrochloride has good efficacy on sepsis, has no adverse reaction, and has good application prospect in the aspect of treating, relieving or improving sepsis diseases.

Drawings

FIG. 1 is a graph showing the change in body weight of mice in each group.

Fig. 2 is a survival curve for each group of mice.

FIG. 3 is a graph showing the serum release levels of inflammatory factors in each group of mice. (. p <0.05, i.e. statistically significant differences)

FIG. 4 shows HE staining of heart, liver, spleen, lung and kidney tissues of various groups of mice.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

The invention provides an application of arbidol hydrochloride in preparing a medicament for treating sepsis diseases, wherein the structure of arbidol hydrochloride is shown as the following formula (I):

example 1

Effect of arbidol hydrochloride on mouse sepsis induced by fecal diluent

Preparation of sepsis animal model: c57BL/6J (5-6 weeks old) wild-type mice were taken, and a 10% stool dilution (physiological saline as a solvent) in mass fraction of 1mL/100g (body weight) was given to the mice intraperitoneally on the first day and weighed and recorded.

Grouping condition: injecting normal saline with the same volume into the abdominal cavity of a control group; the model group is molded according to the method and is injected into the abdominal cavity with corresponding solvent physiological saline on the 1 st day; the arbidol hydrochloride treatment group administered 200mg/kg of arbidol hydrochloride to mice by gavage on the day of molding and 24 hours later, with the corresponding solvent physiological saline as a control. The body weight of the mice was recorded once a day, the death time of the mice was recorded, and the serum inflammatory factors of each group were measured after 48 hours.

Mouse weight change record: mouse body weights were recorded daily. The body weight of the mice was counted. The mice were observed for 48 hours of body weight change.

And (3) survival rate statistics: mice were observed every 12 hours for mortality

ELISA for serum TNF- α and IL-6 levels: taking 100 mul serum from blood samples of 3 groups of mice, adding 100 mul detection antibody into the serum, reacting for 60min at 37 ℃, adding 100 mul biotin-labeled secondary antibody, reacting for 60min at 37 ℃, washing the plate for 5 times, adding TMB color developing solution into the serum, incubating for 15min at 37 ℃, adding stop solution into the serum, measuring the OD value within 5min after adding, and calculating the concentration of the corresponding sample according to a standard curve equation.

Pathological staining is carried out on tissue sections of heart, liver, spleen, lung and kidney: mouse tissues are fixed by paraformaldehyde, dehydrated conventionally, embedded in paraffin, sliced, subjected to HE staining and sealed by neutral gum, and then HE staining image data are acquired by using an upright microscope.

As shown in fig. 1 to 4, it can be seen from fig. 1 that the body weight of the mice increases after the arbidol hydrochloride treatment, while the body weight of the mice in the model group continuously decreases, which indicates that the health status of the mice can be improved after the arbidol hydrochloride treatment. As can be seen from fig. 2, arbidol hydrochloride can prolong the survival time of the mice compared with the mice of the model group; as can be seen from FIG. 3, arbidol hydrochloride significantly reduced the expression levels of TNF- α and IL-6 in the serum of mice compared to the mice of the model group, and p was <0.05, i.e., there was a statistically significant difference. As can be seen from FIG. 4, HE staining observation and statistical analysis show that the infiltration of inflammatory cells of kidney, liver and lung tissues of mice in the arbidol hydrochloride treatment group is obviously lower than that of the inflammatory cells in the model group, the vacuole degeneration of the epithelial part of the renal tubule is obviously protected, the structure of the liver tissue is more complete, the arrangement of cardiac muscle cells is more orderly, and the spleen tissue has no obvious change. The arbidol hydrochloride is shown to be capable of effectively relieving the mouse sepsis induced by the excrement diluent.

In conclusion, the arbidol hydrochloride has good efficacy on sepsis, has no adverse reaction, can improve mouse sepsis induced by the excrement diluent, and has good application prospect in the aspect of treating, relieving or improving sepsis diseases.

The present invention is not limited to the above embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. The application of arbidol hydrochloride in preparing the medicament for treating the sepsis diseases is disclosed, wherein the structure of the arbidol hydrochloride is shown as the following formula (I):

2. use according to claim 1, characterized in that: the dosage of the arbidol hydrochloride is 10 mg/kg-500 mg/kg.

3. A medicament for the treatment of sepsis disease, comprising: comprises arbidol hydrochloride, pharmaceutically acceptable salts, esters, hydrates and auxiliary materials of arbidol hydrochloride.

4. The medicament of claim 3, wherein: the pharmaceutically acceptable salt of arbidol hydrochloride comprises organic salt and inorganic salt.

5. The medicament of claim 4, wherein: the organic salts include mesylate, formate, acetate, trifluoroacetate, maleate, tartrate, succinate, fumarate, citrate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, lactate, and benzoate; the inorganic salts include hydrochloride, hydrobromide, sulfate and phosphate salts.

6. The medicament of claim 3, wherein: granule, powder, injection, syrup, medicated wine, tincture, distillate, pellicle, or their combination.

7. The medicament of claim 3, wherein: the administration mode of the medicament comprises oral administration, injection, implantation, external application, spraying, inhalation or the combination of the oral administration, the injection, the implantation, the external application and the spraying.