Application of propionic acid or salt thereof in preparation of medicine for treating intrahepatic cholestasis in gestation period

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to application of propionic acid or salt thereof in preparation of a medicine for treating intrahepatic cholestasis in a gestation period. Experimental verification shows that propionic acid or salt thereof can significantly reduce the content of TBA, ALT, AST and ALP in serum of rats in a gestational intrahepatic cholestasis (ICP) model group, so that the content of TBA, ALT, AST and ALP approaches the content of serum of rats in a blank control group; in addition, propionic acid or its salt can significantly increase the weight of placenta and fetus of a gestational intrahepatic cholestasis (ICP) model group rat and reduce the fetal death rate, indicating that propionic acid or its salt can effectively treat the gestational intrahepatic cholestasis.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine preparation, and particularly relates to application of propionic acid or a salt thereof in preparation of a medicine for treating intrahepatic cholestasis in pregnancy. BACKGROUND

[0002] Intrahepatic cholestasis of pregnancy (ICP) is a unique liver disease in pregnancy, which usually occurs in the middle and late stages of pregnancy. Its main pathological feature is cholestasis caused by bile acid metabolism disorder. In clinical practice, ICP patients often have abnormal elevation of serum total bile acid (TBA) levels, accompanied by abnormal liver function indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). It is a relatively common specific liver disease during pregnancy. ICP can cause significant physical discomfort to pregnant women, with persistent skin itching as the most typical manifestation, and symptoms usually worsen at night. Some patients may also experience jaundice. These symptoms not only severely interfere with the sleep quality of pregnant women and affect their daily life rhythm, but also may lead to negative emotions such as anxiety and depression in pregnant women, causing adverse effects on their physical and mental health during pregnancy. More importantly, the harm of ICP to the fetus cannot be ignored. Due to the adaptive changes in placental barrier function during pregnancy, high concentrations of bile acids accumulated in the body of patients can break through the placental barrier and enter the fetus, thereby increasing the risk of fetal complications, including fetal distress, fetal growth restriction, etc., and in severe cases, it may even lead to fetal death in utero, posing a significant threat to the life safety of the fetus, and also causing heavy psychological and physiological burden to the pregnant woman's family.

[0003] Therefore, it is of great significance to develop a medicine that can effectively treat intrahepatic cholestasis in pregnancy. SUMMARY

[0004] Based on this, the present application found that propionic acid or a salt thereof can significantly reduce the TBA, ALT, AST and ALP content in the serum of rats with intrahepatic cholestasis of pregnancy and the fetal death rate, and increase the placental and fetal weights, indicating that propionic acid or a salt thereof can effectively treat intrahepatic cholestasis of pregnancy, and can be applied in the medicine for treating intrahepatic cholestasis of pregnancy.

[0005] In order to achieve the above purpose, the present application can adopt the following technical solutions: The present application provides application of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in preparation of a medicine for treating intrahepatic cholestasis of pregnancy.

[0006] Preferably, in the above application, the propionic acid salt is sodium propionate and / or calcium propionate.

[0007] Preferably, in the above use, the pharmaceutical composition containing propionic acid or a salt thereof further comprises one or more combinations of ursodeoxycholic acid, S-adenosylmethionine or L-malic acid.

[0008] Preferably, in the above use, the dosage form of the drug comprises oral liquid, inhalant, tablet, powder, capsule or ointment.

[0009] Preferably, in the above use, the effective amount of propionic acid or a salt thereof is 8 mg / kg / d-12 mg / kg / d.

[0010] Preferably, in the above use, the duration of continuous administration of propionic acid or a salt thereof is ≥5 days.

[0011] Preferably, the above use comprises one or more combinations of the following uses: (a1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for reducing serum TBA content in a subject with intrahepatic cholestasis of pregnancy; (b1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for reducing serum ALT content in a subject with intrahepatic cholestasis of pregnancy; (c1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for reducing serum AST content in a subject with intrahepatic cholestasis of pregnancy; (d1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for reducing serum ALP content in a subject with intrahepatic cholestasis of pregnancy.

[0012] Preferably, the above use comprises one or more combinations of the following uses: (a2) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for increasing placental weight in a subject with intrahepatic cholestasis of pregnancy; (b2) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for increasing fetal weight in a subject with intrahepatic cholestasis of pregnancy; (c2) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for reducing fetal mortality rate in a subject with intrahepatic cholestasis of pregnancy.

[0013] The beneficial effects of the present application include: The present application can be known through experiments that propionic acid or its salt can significantly reduce the serum TBA (total bile acid), ALT (alanine aminotransferase), AST (aspartate aminotransferase) and ALP (alkaline phosphatase) content of the ICP model group of rats, so as to approach the content of the serum of the blank control group of rats; in addition, propionic acid or its salt can significantly increase the placenta and fetus weight of the ICP model group of rats and reduce the fetal death rate, indicating that propionic acid or its salt can effectively treat intrahepatic cholestasis of pregnancy. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1 Grouping of SD rats and schematic diagram of treatment process of each group; Figure 2a TBA content of serum of each group of SD rats; Figure 2b ALT content of serum of each group of SD rats; Figure 2c AST content of serum of each group of SD rats; Figure 2d ALP content of serum of each group of SD rats; Figure 3a HE staining of liver of the Control group of SD rats; Figure 3b HE staining of liver of the ICP group of SD rats; Figure 3c HE staining of liver of the PA+ICP group of SD rats; Figure 4a Body weight change of each group of SD rats; Figure 4b Fetus and placenta of each group of SD rats; Figure 4c Fetus weight of each group of SD rats; Figure 4d Placenta weight of each group of SD rats; Figure 4e Fetus death rate of each group of SD rats. DETAILED DESCRIPTION

[0015] The examples are used to better illustrate the present application, but are not the only embodiments of the present application. Therefore, the skilled in the art can make non-essential improvements and adjustments to the embodiments according to the above description, which still belong to the protection scope of the present application.

[0016] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. Unless otherwise defined, all terms of art used herein have the same meaning as commonly understood by one of ordinary skill in the art in the field of the disclosure. As used herein, it is also to be understood that the use of "and / or" means that unless otherwise specifically stated, the phrase "and / or" includes all possible combinations of one or more of the associated items. As used herein, "and / or" can be interpreted as "and" or "or" depending on the situation.

[0017] The application provides a use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the preparation of a drug for treating intrahepatic cholestasis of pregnancy.

[0018] It should be noted that the application can be verified by experiments that propionic acid or a salt thereof can significantly reduce the contents of TBA (total bile acid), ALT (alanine aminotransferase), AST (aspartate aminotransferase) and ALP (alkaline phosphatase) in the serum of the ICP model group of rats, so as to approach the contents of the serum of the blank control group of rats; in addition, propionic acid or a salt thereof can significantly increase the placenta and fetal weight of the ICP model group of rats and reduce the fetal mortality rate, which indicates that propionic acid or a salt thereof can effectively treat intrahepatic cholestasis of pregnancy.

[0019] In some specific examples, in the above application, the propionic acid salt is sodium propionate and / or calcium propionate.

[0020] It should be noted that the propionic acid salt in the application is a propionic acid salt known in the art, such as sodium propionate or calcium propionate.

[0021] In some specific examples, in the above application, the pharmaceutical composition containing propionic acid or a salt thereof further comprises one or more combinations of ursodeoxycholic acid, S-adenosylmethionine or L-malic acid.

[0022] It should be noted that in the application, the propionic acid salt can be combined with other components having intrahepatic cholestasis of pregnancy treatment activity to form a composition, and then the composition is prepared into a drug, so as to improve the curative effect of the drug; wherein the components having intrahepatic cholestasis of pregnancy treatment activity are known in the art, such as ursodeoxycholic acid, S-adenosylmethionine or L-malic acid.

[0023] In some specific examples, in the above application, the dosage form of the drug includes oral liquid, inhalation, tablet, powder, capsule or ointment.

[0024] It should be noted that propionic acid or its salt can be prepared into different dosage forms such as oral liquid, inhalant, tablet, powder, capsule or ointment in combination with different excipients; the above dosage forms can be selected according to the condition of the subject; in addition, the excipients of the above different dosage forms are well known to those skilled in the art, and the preparation methods of different dosage forms are also well known to those skilled in the art, for example, the preparation of tablets will mainly use diluents (such as starch, dextrin, sucrose or glucose, etc.), absorbents (calcium sulfate, calcium hydrogen phosphate or light magnesium oxide, etc.), binders (povidone, syrup or hydroxypropyl methyl cellulose, etc.), wetting agents (water, etc.) or disintegrating agents (dry starch, sodium hydroxymethyl starch or cross-linked povidone, etc.); for example, the preparation of oral liquid will mainly use solubilizers, suspending agents, emulsifiers or colorants, etc.

[0025] In some specific examples, in the above application, the effective amount of propionic acid or its salt is 8 mg / kg / d-12 mg / kg / d.

[0026] It should be noted that when propionic acid or its salt is used to treat intrahepatic cholestasis of pregnancy in the present application, the effective amount can be 8 mg / kg / d-12 mg / kg / d, for example, 9 mg / kg / d, 10 mg / kg / d or 11 mg / kg / d, etc.

[0027] In some specific examples, in the above application, the duration of continuous administration of propionic acid or its salt is ≥5 days.

[0028] It should be noted that when propionic acid or its salt is used to treat intrahepatic cholestasis of pregnancy in the present application, the duration of continuous administration can be ≥5 days, that is, the effect can be achieved by continuous administration for 5 days.

[0029] In some specific examples, the above application includes one or a combination of the following applications: (a1) the use of propionic acid or its salt or a pharmaceutical composition containing propionic acid or its salt in the preparation of a drug for reducing the serum TBA content of a subject with intrahepatic cholestasis of pregnancy; (b1) the use of propionic acid or its salt or a pharmaceutical composition containing propionic acid or its salt in the preparation of a drug for reducing the serum ALT content of a subject with intrahepatic cholestasis of pregnancy; (c1) the use of propionic acid or its salt or a pharmaceutical composition containing propionic acid or its salt in the preparation of a drug for reducing the serum AST content of a subject with intrahepatic cholestasis of pregnancy; (d1) the use of propionic acid or its salt or a pharmaceutical composition containing propionic acid or its salt in the preparation of a drug for reducing the serum ALP content of a subject with intrahepatic cholestasis of pregnancy.

[0030] It should be noted that, through verification, this invention shows that propionic acid or its salts significantly improve liver injury indicators in ICP rats, restoring TBA and ALP to normal levels (with no statistical difference compared to the Control group). Although ALT and AST were not fully restored, they were significantly reduced (by 35.4% and 20.0%, respectively). Specifically, after administration of propionic acid or its salts, TBA in ICP rats decreased by 3.39 times, ALT by 1.55 times, AST by 1.25 times, and ALP by 2.24 times. The therapeutic efficacy was ranked as follows: TBA (↓70.5%) > ALP (↓55.4%) > ALT (↓35.4%) > AST (↓20.0%).

[0031] In some specific examples, the above applications include one or more combinations of the following applications: (a2) Use of propionic acid or its salts or pharmaceutical compositions containing propionic acid or its salts in the preparation of a medicament for increasing placental weight in subjects with intrahepatic cholestasis of pregnancy; (b2) Use of propionic acid or its salts or pharmaceutical compositions containing propionic acid or its salts in the preparation of a medicament for increasing the fetal weight in a subject with intrahepatic cholestasis of pregnancy; (c2) Use of propionic acid or its salts or pharmaceutical compositions containing propionic acid or its salts in the preparation of a medicament for reducing fetal death rate in subjects with intrahepatic cholestasis of pregnancy.

[0032] It should be noted that, through verification, this invention shows that intervention with propionic acid or its salts (PA+ICP) can significantly increase placental and fetal weight in ICP rats and reduce fetal mortality in ICP rats.

[0033] To better understand the present invention, specific examples are provided below to further illustrate the content of the present invention, but the content of the present invention is not limited to the examples below.

[0034] In the following examples, 17β-estradiol (Estradiol) was purchased from Sigma-Aldrich (catalog number E8875), and sodium propionate (PA) was purchased from Xi'an Youlanda Biotechnology Co., Ltd.

[0035] In the following examples, SPF-grade SD rats (female, 8-10 weeks old, 250g-300g) were obtained from the Experimental Animal Center of Chongqing Medical University (License No.: SCXK (Yu) 2023-0001); housing conditions: constant temperature (22±2℃), 12h light-dark cycle, free access to food and water.

[0036] Example 1 According to the embodiments of the present invention Figure 1 The flowchart shown illustrates the grouping and treatment of rats, as detailed below: (1) A number of SD female rats and a number of male rats are mated; (2) At 13.5 days of pregnancy (13.5D), the female rats are grouped, with 8 rats in each group, and the groups include: a Control group, an ICP model group, and a PA treatment group (PA+ICP); wherein the rats in the Control group are subcutaneously injected with propylene glycol solvent (1 mL / kg / d) every day, and are simultaneously given distilled water 0.3 mL by gavage every day for 5 days; the rats in the ICP model group are subcutaneously injected with estrogen (5 mg / kg / d, the estrogen is dissolved in propylene glycol to configure 1 mg / mL, and the injection is according to the actual weight of the rats, assuming that the rats weigh 300 g, 1.5 mL of liquid needs to be injected every day), for 5 days; the rats in the PA treatment group are subcutaneously injected with estrogen (5 mg / kg / d), and are simultaneously given sodium propionate (10 mg / kg / d, the sodium propionate is dissolved in distilled water to configure 10 mg / mL of liquid, and the gavage is according to the actual weight of the rats, assuming that the rats weigh 300 g, 0.3 mL of liquid needs to be gavaged every day), for 5 days; meanwhile, the body weight changes of the rats in each group are monitored; (3) At 18 days of pregnancy (18D), the rats in each group are anesthetized by carbon dioxide inhalation and then the cervical vertebrae are dislocated; (4) The samples are collected, and the details are as follows: Heart blood is collected in a coagulation tube, centrifuged at 3000 rpm for 15 min, and then stored frozen, and the serum is measured on the instrument later to avoid repeated freezing of the serum; The middle part of the left lobe of the liver tissue is taken and fixed with paraformaldehyde (for pathology), and then H&E staining is performed later; Fetal rats and placenta: the number of surviving fetal rats is counted, and the body weight of the fetal rats and the weight of the placenta are measured.

[0037] (5) Detection of related indexes 1) Detection of serum indexes The contents of TBA (total bile acid), ALT (alanine aminotransferase), AST (aspartate aminotransferase), and ALP (alkaline phosphatase) in the serum of the rats in each group are detected (determined using a Beckman Coulter AU5821 chemical analyzer (Shizuoka, Japan)), and the average value of each group is taken, and the results are shown in Figures 2a to 2d , and the data statistics table is shown in Table 1 below.

[0038] Table 1 Contents of TBA, ALT, AST, and ALP in the serum of rats in each group

[0039] From Figures 2a to 2d and the data in Table 1 above, it can be seen that: The TBA content of the ICP group (36.50 ± 3.96 μmol / L) was significantly higher than that of the Control group (10.15 ± 4.29 μmol / L) by 3.60 times (calculated: 36.50 / 10.15 = 3.60), indicating that the liver injury model was successfully established (p < 0.05); For the changes in the serum TBA content of the rats in each group: The serum TBA content of the PA+ICP group (10.78 ± 2.01 μmol / L) was significantly lower than that of the ICP group by 70.5% (calculated: (36.50-10.78) / 36.50 x 100%), and returned to the normal level (vs Control group p > 0.05); For the changes in the serum ALT content of the rats in each group: The serum ALT content of the ICP group (64.00 ± 14.67 U / L) was significantly higher than that of the Control group (46.50 ± 7.68 U / L) by 37.6% (calculated: (64.00-46.50) / 46.50 x 100%) (p < 0.05), and was decreased by 35.4% (calculated: (64.00-41.33) / 64.00 x 100%) after PA treatment (PA+ICP group) For the changes in the serum AST content of the rats in each group: The serum AST content of the ICP group (139.33 ± 27.07 U / L) was significantly higher than that of the Control group (93.33 ± 18.06 U / L) by 49.3% (calculated: (139.33-93.33) / 93.33 x 100%), and was decreased by 20.0% (calculated: (139.33-111.50) / 139.33 x 100%) after PA treatment (PA+ICP group) (111.50 ± 35.22 U / L), indicating that the treatment was effective in reducing AST; For the changes in the serum ALP content of the rats in each group: The serum ALP content of the ICP group (187.67 ± 33.77 U / L) was significantly higher than that of the Control group (86.67 ± 11.91 U / L) by 116.5% (calculated: (187.67-86.67) / 86.67 x 100%), and was significantly decreased by 55.4% (calculated: (187.67-83.67) / 187.67 x 100%) after PA treatment (PA+ICP group) (83.67 ± 21.88 U / L), returning to the normal level; From the above data, it can be seen that all liver injury indicators (TBA / ALT / AST / ALP) of the ICP group of rats were significantly increased (p<0.05), confirming that the model was reliable. In addition, sodium propionate treatment (PA+ICP group) can significantly improve liver injury indicators. Specifically, the TBA and ALP contents returned to normal levels (no statistical difference with the Control group), although the ALT and AST contents were not completely restored, they were significantly reduced (by 35.4% and 20.0%, respectively). That is, from the above statistics, the rat TBA decreased by 3.39 times, ALT decreased by 1.55 times, AST decreased by 1.25 times, and ALP decreased by 2.24 times. The order of the intensity of the therapeutic effect is: TBA (70.5%) > ALP (55.4%) > ALT (35.4%) > AST (20.0%), indicating that sodium propionate treatment has the most significant improvement effect on cholestasis indicators (TBA / ALP).

[0040] 2) Histopathological injury score The liver tissue was stained with H&E and observed under an optical microscope (400x) for inflammatory factors, with the following specific steps: 2-1) Tissue fixation: remove the target tissue and immediately immerse it in pre-cooled (4°C) 4% paraformaldehyde phosphate buffer (pH 7.4); to ensure adequate fixation, the ratio of tissue volume to fixing solution volume should not be less than 1:10; fix in a 4°C refrigerator for 24 hours; after fixation is complete, rinse the tissue with phosphate buffered saline (PBS) 3 times, 10 minutes each time, to completely remove residual fixing solution; 2-2) Dehydration and transparency: dehydrate the tissue with a series of gradient ethanol, with the following specific process: 70% ethanol (4 hours) → 80% ethanol (2 hours) → 90% ethanol (2 hours) → 95% ethanol (1 hour) → 100% ethanol I (1 hour) → 100% ethanol II (1 hour); then, transfer the tissue to the transparency agent xylene for transparency treatment: xylene I (15 minutes) → xylene II (15 minutes), until the tissue appears transparent; 2-3) Paraffin embedding and sectioning: immerse the transparent tissue in 60°C melted paraffin (Paraffin) for 3 times, 1 hour each time; then use a paraffin embedding machine to embed the tissue block in a mold and cool and solidify; use a paraffin sectioning machine to continuously section the embedded tissue block, with a thickness of 5 pm; flatten the sections in warm water at 45°C, then use a glass slide to lift them, and place them in a 60°C oven overnight to dry, so that the sections are tightly attached; 2-4) H&E staining Dewaxing and Hydrating: The paraffin sections were sequentially immersed in xylene I (15 minutes), xylene II (15 minutes) to remove paraffin. Then gradient ethanol hydration: 100% ethanol (5 minutes)→95% ethanol (5 minutes)→80% ethanol (5 minutes)→70% ethanol (5 minutes), and finally immersed in distilled water for 2 minutes; hematoxylin staining: the sections were immersed in Harris hematoxylin staining solution for 8 minutes; differentiation and bluing: the sections were washed with running water for 5 minutes to remove the floating color; then placed in 1% hydrochloric acid ethanol solution (70% ethanol) for several seconds, immediately washed with running water for 15 minutes again, so that the cell nucleus showed clear blue color; eosin re-staining: the sections were immersed in 0.5% eosin Y aqueous solution (or alcohol-soluble eosin) for 3 minutes; dehydration and transparency: after re-staining, the sections were quickly dehydrated with gradient ethanol: 70% ethanol (30 seconds)→80% ethanol (30 seconds)→95% ethanol (1 minute)→100% ethanol I (2 minutes)→100% ethanol II (2 minutes); finally transferred into xylene I and xylene II for 2 minutes respectively; mounting: the sections were taken out from xylene, the excess liquid was absorbed with filter paper, and an appropriate amount of neutral gum was added, then covered with a cover glass for mounting; 2-5) After the mounting agent was completely solidified, the Nikon Eclipse E100 upright optical microscope was used to observe the tissue structure of the sections at 400 times magnification and collect images.

[0041] The results are shown in Figures 3a to 3c Figure 6, the HE results show that the production of inflammatory factors is inhibited after PA treatment (red arrows indicate inflammatory factors).

[0042] 3) Fetal rat related index test The body weight changes (average value) of rats in each group are shown in Figure 4a The results show that the total amount of rats in the Control group gradually increased with the gestational days, while the body weight of rats in the ICP model group significantly decreased after subcutaneous injection of estrogen, and the PA+ICP group can significantly improve the condition of body weight reduction of rats in the ICP model group.

[0043] In addition, the total number of fetal rats (including dead fetuses and fetal rats and fetuses that are not obviously separated (the subsequent calculation will be artificially separated and counted)) of rats in each group is shown in Table 2.

[0044] Table 2 Total number of fetal rats of rats in each group

[0045] In addition, 8 fetal rats and placentas were randomly taken from each group, and the results are shown in Figure 4bAs shown, the results indicated that the fetuses in the ICP group were smaller than those in the Control group, and in one group, no fetuses even formed. The fetal condition in the PA+ICP group was significantly better than that in the ICP group, and the fetal volumes in the Control group were relatively similar, indicating that sodium propionate had a therapeutic effect.

[0046] In addition, the average weights of fetuses and placentas, as well as the fetal mortality rate, were recorded for each group of rats. The results are as follows: Figure 4c , 4d As shown in 4e, the statistical data is listed in Table 3 below.

[0047] Table 3. Weight of fetus and placenta and fetal mortality rate in each group of rats.

[0048] Depend on Figures 4c to 4e And from the data in Table 3 above, we can see that: Sodium propionate intervention (PA+ICP) significantly increased placental and fetal weight in ICP model rats. The placental weight of the PA+ICP group was slightly higher than that of the Control group, while the fetal weight of the PA+ICP group was slightly lower than that of the Control group, but much higher than that of the ICP group. In addition, the fetal mortality rate of the PA+ICP group was much lower than that of the ICP group, indicating that sodium propionate can improve fetal and placental weight and fetal mortality rate in ICP rats.

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for the treatment of intrahepatic cholestasis of pregnancy.

2. Use according to claim 1, characterized in that, The propionic acid salt is sodium propionate and / or calcium propionate.

3. Use according to claim 1 or 2, characterized in that, The pharmaceutical composition containing propionic acid or a salt thereof also includes one or more combinations of ursodeoxycholic acid, S-adenosylmethionine or L-malic acid.

4. Use according to claim 1 or 2, characterized in that, The dosage form of the medicament includes oral liquid, inhalant, tablet, powder, capsule or ointment.

5. Use according to claim 1 or 2, characterized in that, The effective amount of propionic acid or a salt thereof is 8 mg / kg / d to 12 mg / kg / d.

6. Use according to claim 5, characterized in that, The duration of the administration of propionic acid or a salt thereof is ≥ 5 days.

7. Use according to claim 1, 2 or 6, characterized in that, The use includes one or more combinations of the following uses: (a1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for reducing serum TBA levels in a subject with intrahepatic cholestasis of pregnancy; (b1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for reducing serum ALT levels in a subject with intrahepatic cholestasis of pregnancy; (c1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for reducing serum AST levels in a subject with intrahepatic cholestasis of pregnancy; (d1) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for reducing serum ALP levels in a subject with intrahepatic cholestasis of pregnancy.

8. Use according to claim 1, 2 or 6, characterized in that, The use includes one or more combinations of the following uses: (a2) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for increasing placental weight in a subject with intrahepatic cholestasis of pregnancy; (b2) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for increasing fetal weight in a subject with intrahepatic cholestasis of pregnancy; (c2) Use of propionic acid or a salt thereof or a pharmaceutical composition containing propionic acid or a salt thereof in the manufacture of a medicament for reducing fetal death rate in a subject with intrahepatic cholestasis of pregnancy.

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