CN117122603B - Pharmaceutical preparation and application thereof - Google Patents
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- CN117122603B CN117122603B CN202311156312.7A CN202311156312A CN117122603B CN 117122603 B CN117122603 B CN 117122603B CN 202311156312 A CN202311156312 A CN 202311156312A CN 117122603 B CN117122603 B CN 117122603B
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of medicines, and discloses a pharmaceutical preparation and application thereof. The components of the pharmaceutical preparation comprise pregnenolone 16 alpha-nitrile and pharmaceutically acceptable auxiliary materials or carriers. The invention provides a new application of a pharmaceutical preparation, which comprises pregnenolone 16 alpha-nitrile. The inventor researches find that the pharmaceutical preparation can be used for preparing medicines for improving peritoneal structure damage and hypofunction caused by long-term peritoneal dialysis; can be used for preparing medicines for improving the peritoneal ultrafiltration function reduction and glucose transport function reduction caused by long-term peritoneal dialysis; can be used for preparing medicines for reducing the mesenchymal transition of the peritoneal mesothelial cells caused by long-term peritoneal dialysis; can be used for preparing medicines for improving peritoneal metabolic disorder caused by long-term peritoneal dialysis.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical preparation and application thereof.
Background
Currently, chronic kidney disease (Chronic kidney disease, CKD) has a global prevalence of about 10% and is a common chronic disease that is a hazard to human health. The treatment modalities for patients with end-stage renal disease (End stage renal disease, ESRD) are mainly peritoneal dialysis (Peritoneal dialysis, PD) and hemodialysis. PD is widely used in clinic with the advantages of convenient operation, high economic benefit, better protection of residual kidney function and the like. However, as the age of peritoneal dialysis increases, the patient's peritoneal structure changes progressively and its function decreases progressively until ultrafiltration failure occurs. Once ultrafiltration failure occurs, this will directly lead to failure of peritoneal dialysis, and increased hospitalization and even mortality in PD patients.
However, there is currently a clinical lack of drugs for treating peritoneal structural damage and hypofunction caused by long-term peritoneal dialysis. Peritoneal dialysis solution contains high concentration glucose. It has been found that the mesenchymal transition (MMT) of the peritoneal mesothelial cells caused by the high concentration of glucose dialysate is an important cause of the damage and hypofunction of the peritoneal structure, that is, the polarization of the peritoneal mesothelial cells gradually disappears, the tight connection between cells is lost, the cells are transformed into mesenchymal cells which are myofibroblast-like, active and invasive, and the expression of the marker protein cadherin (E-cadherin) of the mesothelial cells is reduced, and the expression of the marker protein Vimentin (Vimentin), alpha smooth muscle actin (alpha-smooth muscle actin, alpha-SMA) and Fibronectin (FN) is increased. In addition, long term PD can also cause excessive inflammatory responses to peritoneal tissue, mesothelial cell damage and thickening of the subcutaneous tissue. As PD time increases, it also causes a decrease in the rate of peritoneal tissue solute transport and impaired ultrafiltration function. However, the MMT generation mechanism is not clear at present, and a method for preventing or improving peritoneal structure damage and hypofunction caused by long-term peritoneal dialysis is still to be further studied.
Pregnenolone 16 a-nitrile (PCN) is an agonist of Pregnenolone X receptor (Pregnane Xreceptor, PXR). PXR, one of the ligand-activated nuclear receptor superfamily members, plays a key role in endogenous and exogenous metabolism and metabolic homeostasis and produces important physiological and pathological effects. At present, the research on PXR is mainly focused on aspects of liver regeneration, inflammatory enteritis, kidney injury and the like, and the application of the PXR in peritoneal dialysis is lacking. Therefore, there is a need to develop a pharmaceutical preparation and its application, and provide a new use of the pharmaceutical preparation, thereby being used for preparing a medicament for improving peritoneal structural damage or functional decline caused by long-term peritoneal dialysis.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a pharmaceutical preparation and application thereof, and provides a new application of the pharmaceutical preparation, thereby being used for preparing medicines for improving peritoneal structural damage or functional decline caused by long-term peritoneal dialysis.
In a first aspect the invention provides a pharmaceutical formulation.
Specifically, the components of the pharmaceutical preparation comprise pregnenolone 16 alpha-nitrile and pharmaceutically acceptable auxiliary materials or carriers.
Preferably, the pharmaceutically acceptable auxiliary materials or carriers are at least one of diluents, disintegrants, precipitation inhibitors, glidants, binders, dispersants, suspending agents, isotonic agents, thickeners, emulsifiers, preservatives and stabilizers.
Preferably, the administration form of the pharmaceutical preparation is any one of solution, emulsion, suspension, injection and transdermal preparation.
Preferably, the pregnenolone 16 alpha-nitrile is present in an effective concentration of 5-50nM.
In a second aspect, the invention provides the use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating damage to peritoneal structures caused by long-term peritoneal dialysis.
In a third aspect, the invention provides the use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating peritoneal hypofunction caused by prolonged peritoneal dialysis.
In a fourth aspect, the invention provides the use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating a decrease in peritoneal ultrafiltration caused by prolonged peritoneal dialysis.
In a fifth aspect, the invention provides the use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating a decrease in peritoneal glucose transport function caused by prolonged peritoneal dialysis.
In a sixth aspect, the invention provides the use of a pharmaceutical formulation for the manufacture of a medicament for reducing the mesenchymal transition of the peritoneal membrane to the peritoneal membrane caused by long-term peritoneal dialysis.
In a seventh aspect, the invention provides the use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating a peritoneal metabolic disorder caused by long-term peritoneal dialysis.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a new application of a pharmaceutical preparation, which comprises pregnenolone 16 alpha-nitrile. The inventor researches find that the pharmaceutical preparation can be used for preparing medicines for improving peritoneal structure damage and hypofunction caused by long-term peritoneal dialysis; can be used for preparing medicines for improving the peritoneal ultrafiltration function reduction and glucose transport function reduction caused by long-term peritoneal dialysis; can be used for preparing medicines for reducing the mesenchymal transition of the peritoneal mesothelial cells caused by long-term peritoneal dialysis; can be used for preparing medicines for improving peritoneal metabolic disorder caused by long-term peritoneal dialysis.
Drawings
FIG. 1 is a chart showing the results of Masson staining of peritoneal tissue of mice;
FIG. 2 is a graph showing analysis of glucose transport capacity of mice;
FIG. 3 is a diagram showing the analysis of MMT-related molecular expression of peritoneal mesothelial cells of mice;
FIG. 4 is an analysis chart of MMT-related molecular expression of rat peritoneal mesothelial cells cultured in vitro;
FIG. 5 is a graph showing analysis of peritoneal metabolism results in mice.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following examples do not limit the scope of the invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
Example 1
A pharmaceutical preparation.
The effective concentration of pregnenolone 16 alpha-nitrile in the prepared pharmaceutical preparation is 5-50nM, and the pharmaceutical preparation containing pregnenolone 16 alpha-nitrile is further prepared into injection.
Example 2
The specific operation steps of Western blot, real-time fluorescence quantitative PCR, masson staining and statistical analysis in the invention are as follows:
Western blot：
the total protein of the peritoneal tissue/cell is extracted from the tissue lysate, and the protein concentration is determined by the BCA method. 20. Mu.g protein samples were loaded, 6% or 10% polyacrylamide gel electrophoresis (SDS-PAGE), 300 mA.times.3 h wet transferred to PVDF membrane, 5% BSA blocking solution blocked for 1h at room temperature, TBST eluted and then primary antibodies, FN (Abcam), E-cadherin (Cell Signaling Technology), beta-actin (Cell Signaling Technology) and alpha-SMA (Abcam) were added and incubated overnight at 4 ℃. TBST was performed 3 times for 10min each, incubated with the corresponding secondary antibody for 1h at room temperature, and TBST was performed 3 times for 10min each. The antigen-antibody complex was visualized using Enhanced Chemiluminescence (ECL) and the protein bands were exposed using a omnipotent imaging system (ChemiD MP). And quantitatively analyzing the target band by adopting Image J software, and expressing the relative expression quantity of the target protein by using the gray value of the target band/the gray value of the beta-actin.
Real-time fluorescent quantitative PCR (qPCR):
total RNA from peritoneal tissue/cells was extracted using total RNA extraction kit (Mabio) and the RNA concentration and purity was determined spectrophotometrically. 1. Mu.g of RNA was reverse transcribed into cDNA using a reverse transcription kit (Vazyme), and the change of the different genes was examined according to the following reaction system.
a. The reaction system: SYBR qPCR master mix 5 μL; primer mix 3. Mu.L; cDNA 2. Mu.L.
Qpcr thermal cycling parameters:
1.95℃，10min；
2.95℃，15min；
3.60℃，1min；
goto 2, 39 cycles.
Masson staining:
fixing the tissue for 48 hours by 4% paraformaldehyde, embedding the slices in paraffin, and dewaxing to water; washing with tap water and distilled water for 3 times in sequence; staining the core with hematoxylin semen for 5-10min, and washing with running water for 10min; using Masson ponceau acid reddening solution for 5-10min; immersing and washing for a moment by using 2% glacial acetic acid aqueous solution; differentiating the 1% phosphomolybdic acid aqueous solution for 3-5min; directly dyeing with aniline blue or light green liquor for 5min without washing; immersing and washing for a moment by using 0.2% glacial acetic acid aqueous solution; 95% alcohol, absolute alcohol, xylene transparent, neutral gum sealing.
Statistical analysis:
the analysis of experimental data is represented by mean value + -SEM, the comparison among multiple groups is performed by analysis of variance (ANOVA), and p <0.05 has statistical significance; p <0.05 is marked; p <0.01 is marked as x; p <0.001 is labeled as x.
Example 3
Example 1 effect of pharmaceutical formulation on peritoneal structure damage caused by high concentration glucose dialysate.
Grouping: male C57BL/6J mice weighing 25-27g were randomly divided into three groups: control group CTR, high-sugar model group HG and example 1 drug formulation treatment group hg+pcn. Control group: an equal volume of physiological saline is injected into the abdominal cavity once a day for 4 weeks; high sugar model group: 4.25% glucose dialysate (100 mL/kg) was intraperitoneally injected daily for 4 weeks; example 1 pharmaceutical formulation treatment group: 4.25% glucose dialysate (100 mL/kg) was injected intraperitoneally daily, while the example 1 pharmaceutical formulation (50 mg/kg) was injected intraperitoneally daily for a total of 4 weeks. Peritoneal tissue was left behind.
A in fig. 1 is a result of Masson staining after molding with the high sugar dialysate and treatment with the pharmaceutical formulation of example 1, and it can be seen from the result that the high sugar dialysate resulted in a significant thickening of the peritoneum compared to the control group, whereas the high sugar dialysate resulted in a significant inhibition of the thickening of the peritoneum after treatment with the pharmaceutical formulation of example 1. The results of the statistical map of Masson staining, B in fig. 1, are consistent with the analysis of a in fig. 1.
Example 4
Example 1 effect of pharmaceutical formulation on peritoneal ultrafiltration and solute transport functions caused by high concentration glucose dialysis solutions.
The grouping is the same as in example 3.
As can be seen from a in fig. 2, the pharmaceutical formulation of example 1 treatment can inhibit the reduction of peritoneal ultrafiltration in mice caused by the high sugar dialysate; as can be seen from B in fig. 2, the high sugar dialysate resulted in a decrease in glucose transport capacity in mice, whereas the example 1 pharmaceutical formulation treatment significantly improved the decrease in glucose transport capacity caused by the high sugar dialysate.
Example 5
Example 1 effect of pharmaceutical formulation on expression of mouse peritoneal mesothelial cell MMT-related molecules by high concentration glucose dialysis fluid.
The grouping is the same as in example 3.
Protein expression of each group of FN, E-cadherein, alpha-SMA, type I collagen fibers (collagenIA 1, COL IA 1) and the like was detected by qPCR and Western blot.
As can be seen from A and B in FIG. 3, the effect of the pharmaceutical formulation of example 1 on the expression of FN, E-cadherein and alpha-SMA proteins in peritoneal tissues was examined by Western blot. High sugar dialysate treatment resulted in significant increases in FN and α -SMA protein levels in peritoneal tissue, while FN and α -SMA protein levels were significantly reduced following treatment with the pharmaceutical formulation of example 1. Meanwhile, the effect of the pharmaceutical formulation of example 1 on peritoneal tissue FN and COL1A1 mRNA expression was examined by qPCR. As can be seen from C in fig. 3, FN mRNA expression levels were elevated in peritoneal tissue of mice in the high-sugar group compared to the control group, and FN mRNA levels were significantly reduced after treatment with the pharmaceutical formulation of example 1. D in FIG. 3 shows that COL1A1 mRNA levels also were similarly variable. These results demonstrate that the pharmaceutical formulation of example 1 can improve peritoneal mesothelial MMT caused by the high sugar dialysate.
Example 6
Example 1 effect of pharmaceutical formulation on expression of rat peritoneal mesothelial cell MMT-related molecules by high concentration of glucose dialysate in vitro.
Rat peritoneal mesothelial cells are used in vitro, cells in logarithmic growth phase are selected and inoculated into a 6-well plate, pretreatment is carried out for 2 hours by using the pharmaceutical preparation of example 1 (the concentration of pregnenolone 16 alpha-nitrile is 5nM and 50 nM) respectively, treatment is carried out for 48 hours by using 138mM high sugar culture medium, and the expression of FN is detected by Western blot.
As can be seen from a and B in fig. 4, the high sugar group significantly up-regulated FN protein expression compared with the control group, and the low concentration of the pharmaceutical preparation of example 1 (5 nM) treatment can significantly reduce FN protein expression in peritoneal mesothelial cells, and the high concentration of the pharmaceutical preparation of example 1 (50 nM) treatment effect is more significant. These results demonstrate that the pharmaceutical formulation of example 1 dose-dependently ameliorates the high-sugar induced peritoneal mesothelial MMT.
Example 7
Example 1 effect of pharmaceutical formulation on peritoneal metabolism disorder in mice caused by high concentration glucose dialysis solution.
The grouping is the same as in example 3.
Non-targeted metabonomics detection of peritoneal tissue was performed using a UPLC Q-TOF platform. The metabolic differences of the three groups were analyzed using the supervised partial least squares-discriminant analysis (PLS-DA), and as a result, as shown in fig. 5, a significantly shifted higher sugar group compared to the control group, whereas the higher sugar group of the example 1 pharmaceutical formulation treatment group was closer to the control group. Pathway enrichment analysis of significantly altered metabolites from the hyperglycemic group and the treatment group of the pharmaceutical formulation of example 1, it was found that the pharmaceutical formulation of example 1 may ameliorate metabolic abnormalities in the mouse peritoneal tissue (e.g., B in fig. 5) by modulating the pathways of hyperglycemic peritoneal dialysis induced sulfur metabolism, alanine, aspartic acid and glutamic acid metabolism in the mouse peritoneal tissue. Thermal profiling of these significantly altered metabolites showed that the high sugar group had significantly increased abundance of the taurine, aspartic acid, glutamine, citric acid, etc. metabolites compared to the control group, and significantly decreased following treatment of the example 1 pharmaceutical formulation (e.g., C in fig. 5). These results demonstrate that the pharmaceutical formulation of example 1 ameliorates peritoneal metabolic disorders in mice caused by high sugar dialysis solutions.
The foregoing describes in detail preferred embodiments of the present invention. It should be understood that numerous modifications and variations can be made in accordance with the concepts of the invention by one of ordinary skill in the art without undue burden. Therefore, any modification, equivalent replacement, improvement or the like of the prior art through logic analysis, reasoning or limited experiments according to the present invention will be within the scope of protection defined by the claims.
Claims (6)
1. Use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating damage to the peritoneal structure caused by long-term peritoneal dialysis, wherein the pharmaceutical formulation comprises pregnenolone 16 α -nitrile and a pharmaceutically acceptable adjuvant or carrier.
2. Use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating peritoneal hypofunction caused by prolonged peritoneal dialysis, wherein the pharmaceutical formulation comprises pregnenolone 16 α -nitrile and a pharmaceutically acceptable adjuvant or carrier.
3. The application of a pharmaceutical preparation in preparing a medicament for improving the peritoneal ultrafiltration function decline caused by long-term peritoneal dialysis is characterized in that the pharmaceutical preparation comprises pregnenolone 16 alpha-nitrile and pharmaceutically acceptable auxiliary materials or carriers.
4. Use of a pharmaceutical formulation for the manufacture of a medicament for ameliorating a decrease in peritoneal glucose transport function caused by long-term peritoneal dialysis, wherein the pharmaceutical formulation comprises pregnenolone 16 α -nitrile and a pharmaceutically acceptable adjuvant or carrier.
5. Use of a pharmaceutical formulation for the manufacture of a medicament for reducing the mesenchymal transition of the peritoneal membrane cells caused by long-term peritoneal dialysis, wherein the pharmaceutical formulation comprises pregnenolone 16 α -nitrile and a pharmaceutically acceptable adjuvant or carrier.
6. The application of a pharmaceutical preparation in preparing a medicament for improving peritoneal metabolic disorder caused by long-term peritoneal dialysis is characterized in that the pharmaceutical preparation comprises pregnenolone 16 alpha-nitrile and pharmaceutically acceptable auxiliary materials or carriers.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2817671A (en) * | 1956-03-20 | 1957-12-24 | Searle & Co | 16-cyano and 16-cyanoalkyl 3, 20-dioxy-genated pregnenes |
| CN1838930A (en) * | 2003-06-20 | 2006-09-27 | 病毒基因混和公司 | Compositions and methods for treating HIV |
| WO2006133194A2 (en) * | 2005-06-06 | 2006-12-14 | Vgx Pharmaceuticals, Inc | Methods for treating viral infection with oral or injectible drug solution |
| CN108309987A (en) * | 2018-02-07 | 2018-07-24 | 南京市儿童医院 | Applications of the PCN in preparing the drug for treating acute kidney injury associated disease |
| CN108309986A (en) * | 2018-02-07 | 2018-07-24 | 南京市儿童医院 | Applications of the PCN in preparing the drug for treating type 1 diabetes nephrosis associated disease |
-
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- 2023-09-07 CN CN202311156312.7A patent/CN117122603B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2817671A (en) * | 1956-03-20 | 1957-12-24 | Searle & Co | 16-cyano and 16-cyanoalkyl 3, 20-dioxy-genated pregnenes |
| CN1838930A (en) * | 2003-06-20 | 2006-09-27 | 病毒基因混和公司 | Compositions and methods for treating HIV |
| WO2006133194A2 (en) * | 2005-06-06 | 2006-12-14 | Vgx Pharmaceuticals, Inc | Methods for treating viral infection with oral or injectible drug solution |
| CN108309987A (en) * | 2018-02-07 | 2018-07-24 | 南京市儿童医院 | Applications of the PCN in preparing the drug for treating acute kidney injury associated disease |
| CN108309986A (en) * | 2018-02-07 | 2018-07-24 | 南京市儿童医院 | Applications of the PCN in preparing the drug for treating type 1 diabetes nephrosis associated disease |
Non-Patent Citations (2)
| Title |
|---|
| Deficiency of PXR decreases atherosclerosis in apoE-deficient mice;Yipeng Sui等;《Journal of Lipid Research》;第52卷;1652-1659 * |
| Pregnane X receptor activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling;Wen-hua Ming等;《Acta Pharmacologica Sinica》;第44卷;2075-2090 * |
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