CN117122603A - Pharmaceutical preparation and application thereof - Google Patents
Pharmaceutical preparation and application thereof Download PDFInfo
- Publication number
- CN117122603A CN117122603A CN202311156312.7A CN202311156312A CN117122603A CN 117122603 A CN117122603 A CN 117122603A CN 202311156312 A CN202311156312 A CN 202311156312A CN 117122603 A CN117122603 A CN 117122603A
- Authority
- CN
- China
- Prior art keywords
- peritoneal
- pharmaceutical formulation
- caused
- long
- peritoneal dialysis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 21
- 238000000502 dialysis Methods 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 25
- 230000007774 longterm Effects 0.000 claims abstract description 21
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 claims abstract description 12
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 claims abstract description 12
- 229960000249 pregnenolone Drugs 0.000 claims abstract description 12
- 230000006378 damage Effects 0.000 claims abstract description 10
- 230000006377 glucose transport Effects 0.000 claims abstract description 7
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 7
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 6
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 230000007704 transition Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 41
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 230000006870 function Effects 0.000 claims description 8
- 230000007423 decrease Effects 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000002035 prolonged effect Effects 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000002270 dispersing agent Substances 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 239000007951 isotonicity adjuster Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000002562 thickening agent Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 210000004927 skin cell Anatomy 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 12
- 210000003245 peritoneal mesothelial cell Anatomy 0.000 abstract description 10
- 239000000969 carrier Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 210000001519 tissue Anatomy 0.000 description 15
- 238000011282 treatment Methods 0.000 description 15
- 102000016359 Fibronectins Human genes 0.000 description 13
- 108010067306 Fibronectins Proteins 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 208000020832 chronic kidney disease Diseases 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 238000003753 real-time PCR Methods 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 239000000385 dialysis solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 102000007469 Actins Human genes 0.000 description 4
- 108010085238 Actins Proteins 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 102000000905 Cadherin Human genes 0.000 description 3
- 108050007957 Cadherin Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 239000006180 TBST buffer Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000000523 end stage renal failure Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000008719 thickening Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 206010069568 Ultrafiltration failure Diseases 0.000 description 2
- 102100035071 Vimentin Human genes 0.000 description 2
- 108010065472 Vimentin Proteins 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000001378 electrochemiluminescence detection Methods 0.000 description 2
- 208000028208 end stage renal disease Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000008717 functional decline Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000003345 hyperglycaemic effect Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 210000005033 mesothelial cell Anatomy 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 210000004303 peritoneum Anatomy 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 238000010802 RNA extraction kit Methods 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000010201 enrichment analysis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- -1 glidants Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 208000037806 kidney injury Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000010239 partial least squares discriminant analysis Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 238000005382 thermal cycling Methods 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
- XOSXWYQMOYSSKB-LDKJGXKFSA-L water blue Chemical compound CC1=CC(/C(\C(C=C2)=CC=C2NC(C=C2)=CC=C2S([O-])(=O)=O)=C(\C=C2)/C=C/C\2=N\C(C=C2)=CC=C2S([O-])(=O)=O)=CC(S(O)(=O)=O)=C1N.[Na+].[Na+] XOSXWYQMOYSSKB-LDKJGXKFSA-L 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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
Landscapes
- 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 (10)
1. A pharmaceutical formulation, wherein the pharmaceutical formulation comprises pregnenolone 16 α -nitrile and a pharmaceutically acceptable adjuvant or carrier.
2. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable adjuvant or carrier is at least one of a diluent, a disintegrant, a precipitation inhibitor, a glidant, a binder, a dispersing agent, a suspending agent, an isotonic agent, a thickening agent, an emulsifier, a preservative, a stabilizer.
3. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is administered in any one of a solution, emulsion, suspension, injection, transdermal formulation.
4. The pharmaceutical formulation of claim 1, wherein the effective concentration of pregnenolone 16 a-nitrile is 5-50nM.
5. Use of a pharmaceutical formulation according to any one of claims 1-4 for the manufacture of a medicament for improving the damage to peritoneal structures caused by long-term peritoneal dialysis.
6. Use of a pharmaceutical formulation according to any one of claims 1-4 for the preparation of a medicament for improving peritoneal hypofunction caused by long-term peritoneal dialysis.
7. Use of a pharmaceutical formulation according to any one of claims 1-4 for the manufacture of a medicament for ameliorating a decrease in peritoneal ultrafiltration function caused by prolonged peritoneal dialysis.
8. Use of a pharmaceutical formulation according to any one of claims 1-4 for the manufacture of a medicament for improving the reduction of peritoneal glucose transport function caused by long-term peritoneal dialysis.
9. Use of a pharmaceutical formulation according to any one of claims 1-4 for the preparation of a medicament for reducing the mesenchymal transition of peritoneal skin cells caused by long-term peritoneal dialysis.
10. Use of a pharmaceutical formulation according to any one of claims 1-4 for the preparation of a medicament for ameliorating a peritoneal metabolic disorder caused by long-term peritoneal dialysis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311156312.7A CN117122603B (en) | 2023-09-07 | 2023-09-07 | Pharmaceutical preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311156312.7A CN117122603B (en) | 2023-09-07 | 2023-09-07 | Pharmaceutical preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117122603A true CN117122603A (en) | 2023-11-28 |
| CN117122603B CN117122603B (en) | 2024-03-19 |
Family
ID=88850782
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311156312.7A Active CN117122603B (en) | 2023-09-07 | 2023-09-07 | Pharmaceutical preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117122603B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118436652A (en) * | 2024-04-18 | 2024-08-06 | 南方医科大学顺德医院(佛山市顺德区第一人民医院) | Roflumilast pharmaceutical preparation and application thereof |
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 |
-
2023
- 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 |
|---|
| WEN-HUA MING等: "Pregnane X receptor activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling", 《ACTA PHARMACOLOGICA SINICA》, vol. 44, pages 2075 - 2090 * |
| YIPENG SUI等: "Deficiency of PXR decreases atherosclerosis in apoE-deficient mice", 《JOURNAL OF LIPID RESEARCH》, vol. 52, pages 1652 - 1659 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118436652A (en) * | 2024-04-18 | 2024-08-06 | 南方医科大学顺德医院(佛山市顺德区第一人民医院) | Roflumilast pharmaceutical preparation and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117122603B (en) | 2024-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhou et al. | Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis | |
| CN117122603B (en) | Pharmaceutical preparation and application thereof | |
| Xiao et al. | Emodin alleviates cardiac fibrosis by suppressing activation of cardiac fibroblasts via upregulating metastasis associated protein 3 | |
| Grote Beverborg et al. | Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy | |
| Sekiguchi et al. | Rapamycin inhibits transforming growth factor β‐induced peritoneal angiogenesis by blocking the secondary hypoxic response | |
| Zhou et al. | SGLT-2 inhibitors reduce glucose absorption from peritoneal dialysis solution by suppressing the activity of SGLT-2 | |
| Li et al. | Low molecular weight heparin (LMWH) improves peritoneal function and inhibits peritoneal fibrosis possibly through suppression of HIF-1α, VEGF and TGF-β1 | |
| Liu et al. | STF-083010, an inhibitor of XBP1 splicing, attenuates acute renal failure in rats by suppressing endoplasmic reticulum stress-induced apoptosis and inflammation | |
| Du et al. | Pentamethylquercetin protects against cardiac remodeling via activation of Sestrin2 | |
| Wong et al. | Semicarbazide-sensitive amine oxidase (SSAO) inhibition ameliorates kidney fibrosis in a unilateral ureteral obstruction murine model | |
| Chen et al. | In vivo renal arginine release is impaired throughout development of chronic kidney disease | |
| Zhang et al. | lncRNA TUG1 regulates hyperuricemia-induced renal fibrosis in a rat model: TUG1/miR-140-3p/CtsD axis in renal fibrosis | |
| Lu et al. | Exosomes from tubular epithelial cells undergoing epithelial‐to‐mesenchymal transition promote renal fibrosis by M1 macrophage activation | |
| Liu et al. | ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1–7)–Mas Receptor Axis | |
| Zhang et al. | Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury | |
| Zhong et al. | Berberine inhibits NLRP3 inflammasome activation by regulating mTOR/mtROS axis to alleviate diabetic cardiomyopathy | |
| Yoshimine et al. | Hepatocyte growth factor ameliorates methylglyoxal-induced peritoneal inflammation and fibrosis in mouse model | |
| Chen et al. | Qinzhu Liangxue inhibits IL-6-induced hyperproliferation and inflammation in HaCaT cells by regulating METTL14/SOCS3/STAT3 axis | |
| Chen et al. | Damage of uremic myocardium by p-cresyl sulfate and the ameliorative effect of Klotho by regulating SIRT6 ubiquitination | |
| Min et al. | Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis | |
| Wang et al. | Inhibition of Xanthine Oxidase Protects against Sepsis‐Induced Acute Kidney Injury by Ameliorating Renal Hypoxia | |
| An et al. | Angiotensin II type-2 receptor attenuates liver fibrosis progression by suppressing IRE1α-XBP1 pathway | |
| Duan et al. | [Retracted] Sulodexide Prevents Peritoneal Fibrosis by Downregulating the Expression of TGF‐β1 and Its Signaling Pathway Molecules | |
| WO2022059694A1 (en) | Composition for improving renal function | |
| Zoccali | Asymmetric dimethylarginine in end-stage renal disease patients: a biomarker modifiable by calcium blockade and angiotensin II antagonism? |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |