CN117357508B - Application of ciliristat in preparation of medicine for treating primary cholangitis - Google Patents
Application of ciliristat in preparation of medicine for treating primary cholangitis Download PDFInfo
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- CN117357508B CN117357508B CN202311455177.6A CN202311455177A CN117357508B CN 117357508 B CN117357508 B CN 117357508B CN 202311455177 A CN202311455177 A CN 202311455177A CN 117357508 B CN117357508 B CN 117357508B
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- pbc
- medicine
- ciliristat
- ursodeoxycholic acid
- medicament
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- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000009120 supportive therapy Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Health & Medical Sciences (AREA)
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Abstract
The invention belongs to the field of medicines, and particularly relates to application of ciliristat in preparation of a medicine for treating primary cholangitis. The medicine contains cilomilast as the only active ingredient or one of the active ingredients, and when the medicine contains cilomilast as one of the active ingredients, the active ingredient also contains ursodeoxycholic acid. The invention also provides a medicine for treating primary cholangitis. The research of the invention discovers that the ciliristat cooperates with ursodeoxycholic acid to obviously slow down the liver inflammation level of PBC and enhance the treatment effect on PBC. The invention provides a new effective way for treating PBC and provides a theoretical basis for clinical treatment of PBC by combining cilirinotecan with ursodeoxycholic acid.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of ciliristat in preparation of a medicine for treating primary cholangitis.
Background
Primary cholangitis (Primary biliary cholangitis, PBC), known as "primary biliary cirrhosis", is a rare autoimmune liver disease. Currently, treatment regimens for PBC mainly include drug therapy and supportive therapy. Drug therapy is usually based on ursodeoxycholic acid (Ursodeoxycholic Acid, UDCA), which can reduce liver enzyme levels, alleviate cholestasis, and delay disease progression. However, there is a difference in the responses of different patients to UDCA, and about 20% -30% of patients respond poorly to UDCA, and may progress to end-stage liver disease. For patients who are intolerant to UDCA or ineffective in treatment, other drugs such as obeticholic acid (Ocaliva) and the like may be considered. For advanced disease, liver transplantation may need to be considered as a treatment option. The patient and doctor may together develop a personalized treatment plan to maximize disease control and improve quality of life. Treatment strategies may vary depending on the severity of the disease, the patient's medical history and health.
Clinicians are actively seeking new therapeutic options to improve the therapeutic effect of patients, but more effective targeted drugs based on autoimmune response have not yet been developed, and many biological agents have not been successful in clinical trials, such as Rituximab (Rituximab), abacavir (Abatacept), and Utebub (ustekinumab), etc. Thus, for PBCs, particularly those that do not respond well to UDCA treatment, it is urgent to explore new specific PBC-targeted therapies.
Ciliristat (SIVELESTAT) is a highly specific Neutrophil Elastase (NE) inhibitor that inhibits neutrophil extracellular trap (Neutrophil extracellular traps, NEs) formation by inhibiting NE activity, allowing the control of inflammatory responses in patients, which has been reported in acute lung injury therapeutic applications, but has not been reported in primary cholangitis therapy.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to find a new medicine and a medicine combination for treating the primary cholangitis, and the treatment effect of the primary cholangitis is enhanced. Solves the problem of differential response of different patients to ursodeoxycholic acid and lack of specific targeting drugs for autoimmune response, and improves the therapeutic effect of PBC patients by the drug combination.
The first aspect of the invention is to provide the use of ciliristat in the manufacture of a medicament for the treatment of primary cholangitis.
Further, the medicine contains ciliristat as the only active ingredient or one of the active ingredients.
Further, when the ciliristat is one of the active ingredients in the medicament, the active ingredient further includes ursodeoxycholic acid.
Still further, the cilvelestat and ursodeoxycholic acid are administered simultaneously or sequentially in any order.
Still further, the medicament further comprises a pharmaceutically acceptable carrier.
A second aspect of the present invention is to provide a medicament for treating primary cholangitis, the medicament comprising the sivelestat.
Further, in the medicine, the content of the ciliristat is 0.1-99 wt%.
Still further, the medicament further comprises ursodeoxycholic acid.
Further, the mass ratio of the cilomilast to the cilomilast is 1:1.
Still further, the medicament further comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier comprises a conventional diluent (such as at least one of water for injection, microcrystalline cellulose and the like), a filler (such as at least one of mannitol, sucrose, lactose, polyethylene glycol, tween 80, sorbitol, menthol, liquid paraffin, vaseline, stearic acid, glyceryl monostearate, lanolin, mineral oil, DMSO and the like), a binder (such as at least one of carbomer, acacia, starch, cellulose, gelatin, polyvinylpyrrolidone, polyacrylamide and the like), a disintegrant (such as at least one of sodium carboxymethyl starch, croscarmellose sodium, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and the like), a lubricant (such as at least one of talcum powder, magnesium stearate, calcium stearate, solid polyethylene glycol, lecithin, silicon dioxide, micro-powder silica gel and the like), a wetting agent (such as at least one of propylene glycol, glycerol, ethanol and the like), a stabilizer (such as at least one of disodium edetate, sodium thiosulfate, sodium metabisulfite, sodium sulfite, sodium bisulphite, ethanolamine, sodium acetate, nicotinamide, vitamin C and the like), an osmotic pressure regulator (such as sodium chloride, glucose and the like), a pH regulator (such as at least one of triethanolamine, sodium benzoate and the like), and the like. The auxiliary materials can be commonly used dosage, and are mixed with the cilvelslat and the ursodeoxycholic acid according to commonly used proportion, and after the dosage of the cilvelslat and the ursodeoxycholic acid is determined, the proportion among the medicinal auxiliary materials can be properly regulated according to the requirement.
Further, the dosage form of the medicine is granule, tablet, capsule, pill, dripping pill, oral liquid preparation, gastric lavage or injection administration.
The invention has the following beneficial effects:
According to the invention, the first time the cilomilast can be used for relieving PBC by inhibiting NETs formation, the further discovery that the cilomilast can be used for remarkably relieving PBC liver inflammation level by cooperating with ursodeoxycholic acid, and the treatment effect on PBC is enhanced. The invention provides a new effective way for treating PBC and provides a theoretical basis for clinical treatment of PBC by combining cilirinotecan with ursodeoxycholic acid.
Drawings
FIG. 1 is a schematic flow chart of a 2OA-BSA combined with Poly I: C to construct a PBC mouse model.
Fig. 2 is a graph showing the therapeutic effect of cilirinotecan in combination with ursodeoxycholic acid in PBC model mice, wherein:
a is a histogram of the level of a PBC specific antibody AMA-M2 in serum of a PBC model mouse after drug treatment;
B is a histogram of ALP level in serum of PBC model mice after drug treatment measured by ELISA method;
C is a histogram of inflammatory factors IFN-gamma and TNF-alpha in serum of PBC model mice after drug treatment;
d is a liver tissue HE staining chart of the PBC model mouse after drug treatment;
e is a PBC model mouse liver tissue NETs immunofluorescence staining chart after drug treatment.
Detailed Description
The present invention will now be described in detail with reference to the drawings and specific examples, which should not be construed as limiting the invention. Unless otherwise indicated, the technical means used in the following examples are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise indicated.
Example 1: verification that combination of ciliristat and ursodeoxycholic acid can enhance therapeutic effect of PBC
1 Experimental method
(1) PBC mouse model construction
As shown in FIG. 1, a PBC mouse model was constructed using 2OA-BSA in combination with PolyI:C.
Female C57BL/6J mice (6 per group) were used 6-8 weeks old.
10Mg of 2OA-BSA was dissolved in 5mLPBS, and the solution was subjected to ultrasonic emulsification under ice bath conditions with 5mL of Complete Freund's Adjuvan (CFA) containing 1mg/mL of Mycobacterium tuberculosis H37Ra strain. The same procedure was used to prepare emulsifiers for 2OA-BSA and incomplete Freund's adjuvant (incomplete Freund' sadjuvant, IFA).
On day 1, PBC model mice were intraperitoneally injected with 100. Mu.L of an emulsion of 2OA-BSA and complete Freund's adjuvant. On days 1 and 3, PBC model mice were intraperitoneally injected with 100. Mu.L pertussis toxin (1. Mu.g/mL). On day 15, PBC-molded mice were intraperitoneally injected with 100. Mu.l of an emulsion of 2OA-BSA and incomplete Freund's adjuvant. Meanwhile, poly I: C (5 mg/kg) was intraperitoneally injected every three days from day 1.
(2) Treatment with cilirisetron alone or in combination with cilirisetron and ursodeoxycholic acid
The PBC mouse model with successful modeling was treated according to the following grouping scheme:
Control group: lavage of 100 μl of PBS + intraperitoneal injection of 100 μl of PBS;
sivelestat single drug treatment group: lavage 100 μl PBS+intraperitoneal injection of 100 μl ciliristat (50 mg/kg);
Ursodeoxycholic acid single drug treatment group: lavage 100. Mu.L UDCA (50 mg/kg) +intraperitoneal injection 100. Mu. LPBS;
combination treatment group: lavage 100 μl UDCA (50 mg/kg) +intraperitoneal injection of 100 μl cilomilast (50 mg/kg);
The single medicine and the combined treatment are all treated for 1 week.
(3) Detection index
Levels of the PBC specific antibody AMA-M2
At the end of the experiment, the peripheral blood of the mice is obtained by adopting an eyeball blood taking method, and after standing at room temperature for 30min, the serum of the mice is obtained by centrifugation at 4,000rpm multiplied by 15min, and the mice are placed in a refrigerator at 4 ℃ for standby. AMA-M2 antibody levels in mouse serum were detected by ELISA according to the ELISA kit instructions. Briefly, mouse serum was diluted 1:100, and diluted serum samples were incubated in ELISA plates coated with AMA-M2 antibodies, followed by biotin antibodies, streptavidin HRP and TMB substrates. The absorbance of each well was measured at 450nm using a spectrophotometer. Using the standard curve and absorbance values, the concentration of AMA-M2 antibodies in the mouse serum was calculated.
B. Cholestasis level
The ALP concentration in the serum of mice was measured by ELISA, reflecting the level of mouse gall sediment. The specific detection method is the same as that described above.
C. Inflammation level
ELISA was used to measure IFN-gamma and TNF-alpha concentrations in mouse serum, reflecting the inflammatory levels in mice. The specific detection method is the same as that described above.
D. inflammation of the mouse sink region
At the end of the experiment, mouse liver tissue specimens were dissected and immediately placed in 4% paraformaldehyde for tissue fixation. After tissue fixation, the tissue is subjected to specimen dehydration, paraffin embedding and sectioning. The tissue sections were stained with each of the hemaloxylin and Eosin sequentially, and after staining, excess dye was removed and the tissue was dried. After the tissue was dried, the mice were sealed with neutral resin and examined under an optical microscope for infiltration of inflammatory cells in the sink region of the liver tissue to evaluate the level of inflammation in the sink region of the mice.
E. Formation of NETs in mouse liver
At the end of the experiment, mouse liver tissue specimens were dissected, immediately fixed in liquid nitrogen, and then sectioned. The tissue sections were mounted on slides, fixed with methanol, subjected to antigen retrieval and antigen blocking, and incubated overnight at 4℃with 1:200CitH3 primary antibody and 1:200MPO primary antibody. Washing the primary antibody, adding a specific fluorescent labeled secondary antibody combined with the primary antibody, dying the core by DAPI, and sealing the chip. The mouse liver sections were observed under a fluorescence microscope to evaluate the level of NETs formation in the mouse liver.
2 Experimental results
The results showed that the combination treatment group significantly reduced PBC specific antibody AMA-M2 levels (fig. 2A), inflammation levels (fig. 2B) and cholestasis levels (fig. 2C) in the PBC murine model compared to the single drug treatment group. Observation of inflammation in liver tissue of PBC mice by HE staining showed that the combination treatment group reduced inflammation in the sink zone of the mice more significantly (fig. 2D), and that the combination treatment group also significantly reduced the formation of NETs in the liver of the mice compared to the single drug treatment group (fig. 2E).
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following claims be interpreted as including the preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (4)
1. The application of the ciliristat in preparing a medicament for treating primary cholangitis is characterized in that the ciliristat in the medicament is taken as the only active ingredient or one of the active ingredients.
2. The use according to claim 1, wherein when cilexetil is one of the active ingredients in the medicament, the active ingredient further comprises ursodeoxycholic acid.
3. The use of claim 2, wherein the medicament further comprises a pharmaceutically acceptable carrier.
4. The use according to claim 3, wherein in the medicament, the ursodeoxycholic acid is in the form of granules, tablets, capsules, pills or oral liquid, and the sivelestat is in the form of injection administration.
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