阅读说明：本技术 一种钩藤在治疗急性药物性肝损伤中的应用 (Application of uncaria in treating acute drug-induced liver injury ) 是由 江盼 闫宇辉 王静怡 戴润民 于 2021-07-13 设计创作，主要内容包括：本发明公开了一种钩藤在治疗急性药物性肝损伤中的应用,涉及医药领域,所述钩藤通过降压、保护中枢神经系统以平肝熄风从而保护肝细胞。钩藤是治疗高血压病、脑血管性疾病、头痛、抽动症及小儿惊风等疾病的常用药物,还可用于三叉神经痛、面神经炎、颈椎病、痴呆、癫痫以及肿瘤等疾病的治疗,不仅具有高生物活性,且无明显的副作用,同时钩藤能够抑制外周血管收缩,使血管阻力降低,血压降低,同时有抗血小板聚集和抗血栓的作用,本发明通过钩藤具有明显的降压、镇静、镇痛等中枢抑制作用,起到平肝熄风,镇静解热功效,具有明显的保护肝细胞,减轻急性肝损伤的作用,显著改善部分肝损伤相关生理指标。(The invention discloses an application of uncaria in treating acute drug-induced liver injury, and relates to the field of medicines. The uncaria rhynchophylla is a common medicine for treating diseases such as hypertension, cerebrovascular diseases, headache, tic disorder, infantile convulsion and the like, can be used for treating diseases such as trigeminal neuralgia, facial neuritis, cervical spondylosis, dementia, epilepsy and tumors, has high biological activity and no obvious side effect, can inhibit peripheral vasoconstriction, reduces vascular resistance and blood pressure, and has the effects of resisting platelet aggregation and resisting thrombus.)

1. An application of uncaria in treating acute drug-induced liver injury is characterized in that: the uncaria protects liver cells by reducing blood pressure and protecting the central nervous system to calm the liver and stop the wind.

2. The use of an uncaria rhynchophylla according to claim 1 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the uncaria is used for preparing a pharmaceutical composition for treating acute drug-induced liver injury.

3. The use of an uncaria rhynchophylla according to claim 2 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the pharmaceutical composition comprises uncaria and a pharmaceutically acceptable carrier.

4. The use of an uncaria rhynchophylla according to claim 3 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the carrier is at least one of diluent, excipient, filler, adhesive, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier and lubricant.

5. The use of an uncaria rhynchophylla according to claim 2 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the pharmaceutical composition also comprises a synergistic medicament, wherein the synergistic medicament is a medicament for treating acute drug-induced liver injury by coordinating uncaria.

6. The use of an uncaria rhynchophylla according to claim 5, for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the synergistic medicine is rhizoma Gastrodiae, cornu Saigae Tataricae, folium Mori, Notoginseng radix, and carapax Trionycis.

7. The use of an uncaria rhynchophylla according to claim 6 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the preparation method of the synergistic medicament comprises the following steps: soaking rhizoma gastrodiae, cornu saigae tataricae, folium mori, pseudo-ginseng and turtle shell for 0.8-2 hours, and then mixing the rhizoma gastrodiae, the cornu saigae tataricae, the folium mori, the pseudo-ginseng and the turtle shell with water according to the weight part of 1: 10, putting the mixture into a container for decoction, filtering the mixture after the decoction is carried out for 1 to 4 hours, taking filter residues, mixing the filter residues with water again according to the weight ratio of 1: 10 putting the mixture into a container, decocting for 1-2 hours, repeatedly decocting for three times, and combining liquid medicines.

8. The use of an uncaria rhynchophylla according to claim 7 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the pharmaceutical composition is in the form of one of solution, suspension, granule, tablet, capsule, powder and emulsion.

9. The use of an uncaria rhynchophylla according to claim 1 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the acute drug-induced liver injury is APAP or LPS/GalN induced acute liver injury.

10. The use of an uncaria rhynchophylla according to claim 9 for treating acute drug-induced liver injury, wherein the uncaria rhynchophylla is characterized in that: the method for establishing the APAP-induced mouse acute liver injury model comprises the following steps: carrying out intraperitoneal injection on a mouse by using 500mg/kgAPAP, and obtaining a mouse acute drug-induced liver injury model after administration for 28 hours;

the method for establishing the LPS/GalN induced mouse acute liver injury model comprises the following steps: LPS2.5mg/kg and GalN0.3g/kg are injected into the abdominal cavity of the mouse, and the acute drug-induced liver injury model of the mouse is obtained 8 hours after administration.

Technical Field

The invention relates to the field of medicines, and in particular relates to application of uncaria in treatment of acute drug-induced liver injury.

Background

The drugs are transformed and metabolized by the liver, and if a patient uses certain drugs for a long time or in a large amount, the load of the liver is increased, and drug-induced liver injury is caused. The drug-induced liver injury is liver injury caused by drug itself or metabolite thereof or reduction of hypersensitivity or tolerance of special body to the drug in the drug using process, and can be clinically manifested as various acute and chronic liver diseases. Various drugs can cause drug-induced liver injury, such as anti-tumor chemotherapeutic drugs, antituberculosis drugs, antipyretic analgesics, immunosuppressants, hypoglycemic and hypolipidemic drugs, antibacterial, antifungal and antiviral drugs, and the like.

The acute drug-induced liver injury is characterized by acute drug-induced liver injury, the symptoms of the acute drug-induced liver injury are obvious, toxic lesions in cells, such as liver necrosis, liver cell steatosis and inflammatory reaction, can appear in patients during the attack of the liver, cholestatic liver injury can also appear in the patients, the main characteristics are cholestasis and liver cell necrosis, once diagnosis is confirmed or the patients are suspected to be related to the drugs, all suspected liver injury drugs are stopped, most of cases can recover after the drugs are stopped, the patients with acute poisoning can adopt measures such as gastric lavage, catharsis, activated carbon adsorption and the like to eliminate residual drugs in the stomach and intestine, and the in vivo drugs can be quickly removed by adopting methods such as hemodialysis, peritoneal dialysis, blood perfusion, plasma replacement and the like.

Liver damage can be manifested as hyperactivity of liver yang, convulsion, tremor, dizziness and dim eyesight during pathological changes, which are mainly the signs of pathological changes of liver meridian. The disease condition of liver-yang hyperactivity develops further, and the symptoms of dizziness, headache, numbness of limbs and the like, or sudden and sudden fall, obnubilation, facial distortion, stiff tongue and hemiplegia are even more common. In addition, the phenomenon of stirring of liver wind can also be seen in diseases such as epilepsy, neurosis, Meniere's syndrome, tetanus, etc. This phenomenon is also common in hypertension.

The uncaria is a common medicine for treating diseases such as hypertension, cerebrovascular diseases, headache, tic disorder, infantile convulsion and the like, can also be used for treating diseases such as trigeminal neuralgia, facial neuritis, cervical spondylosis, dementia, epilepsy, tumors and the like, and has definite clinical curative effect and high medicine safety. The uncaria has high biological activity and no obvious side effect, and simultaneously, the uncaria can inhibit the contraction of peripheral blood vessels, reduce the resistance of blood vessels and the blood pressure, and simultaneously has the functions of resisting platelet aggregation and thrombus.

The invention provides an application of uncaria in treating acute drug-induced liver injury, which is used for treating acute drug-induced liver injury by using uncaria.

Disclosure of Invention

The uncaria has obvious central inhibition effects of reducing blood pressure, calming, easing pain and the like, has the effects of calming the liver, calming the wind, calming and relieving heat, has obvious effects of protecting liver cells and relieving acute liver injury, and obviously improves related physiological indexes of partial liver injury so as to solve the defects in the technology.

In order to achieve the above purpose, the invention provides the following technical scheme: an application of ramulus Uncariae cum uncis in treating acute drug-induced liver injury is provided, wherein ramulus Uncariae cum uncis protects liver cells by lowering blood pressure, protecting central nervous system to calm liver and calming endogenous wind.

Preferably, the uncaria is used for preparing a pharmaceutical composition for treating acute drug-induced liver injury.

Preferably, the pharmaceutical composition comprises uncaria and a pharmaceutically acceptable carrier.

Preferably, the carrier is at least one of diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier and lubricant.

Preferably, the pharmaceutical composition further comprises a synergistic drug, wherein the synergistic drug is a drug for treating acute drug-induced liver injury by virtue of synergistic uncaria rhynchophylla.

Preferably, the synergistic medicine is gastrodia elata, antelope horn, mulberry leaf, pseudo-ginseng and turtle shell.

Preferably, the preparation method of the synergistic medicament comprises the following steps: soaking rhizoma gastrodiae, cornu saigae tataricae, folium mori, pseudo-ginseng and turtle shell for 0.8-2 hours, and then mixing the rhizoma gastrodiae, the cornu saigae tataricae, the folium mori, the pseudo-ginseng and the turtle shell with water according to the weight part of 1: 10, putting the mixture into a container for decoction, filtering the mixture after the decoction is carried out for 1 to 4 hours, taking filter residues, mixing the filter residues with water again according to the weight ratio of 1: 10 putting the mixture into a container, decocting for 1-2 hours, repeatedly decocting for three times, and combining liquid medicines.

Preferably, the pharmaceutical composition is in the form of one of a solution, a suspension, a granule, a tablet, a capsule, a powder, and an emulsion.

Preferably, the acute drug-induced liver injury is APAP or LPS/GalN-induced acute liver injury.

Preferably, the method for establishing the APAP-induced mouse acute liver injury model comprises the following steps: carrying out intraperitoneal injection on a mouse by using 500mg/kgAPAP, and obtaining a mouse acute drug-induced liver injury model after administration for 28 hours;

the method for establishing the LPS/GalN induced mouse acute liver injury model comprises the following steps: LPS2.5mg/kg and GalN0.3g/kg are injected into the abdominal cavity of the mouse, and the acute drug-induced liver injury model of the mouse is obtained 8 hours after the administration.

In the technical scheme, the invention provides the following technical effects and advantages:

1. the clinical manifestations of the internal stirring of the liver wind are mainly related to the hyperfunction or imbalance of the central nervous system, the uncaria has obvious central inhibition effects of reducing blood pressure, calming, easing pain and the like, plays the roles of calming the liver wind, calming and relieving fever, has obvious effects of protecting liver cells and relieving acute liver injury, and obviously improves part of the relevant physiological indexes of the liver injury;

2. the gastrodia elata can calm liver yang, dispel wind and dredge collaterals and mainly treat liver wind stirring, the antelope horn can calm the liver and stop endogenous wind, clear the liver and improve eyesight, the mulberry leaves can disperse wind and heat, clear the lung and moisten dryness, calm the liver and improve eyesight, the panax notoginseng can reduce the degenerative necrosis of liver cells, reduce the collagen fiber among the liver cells, reduce the hepatic steatosis, reduce the infiltration of inflammatory cells and reduce the degenerative necrosis of the liver cells, and the turtle shell can soften hardness and dissipate stagnation and treat the deficient wind stirring, thereby playing a synergistic effect in the aspects of protecting liver cells and reducing acute drug-induced liver injury.

Detailed Description

The present invention will be described in further detail below in order to enable those skilled in the art to better understand the technical solution of the present invention.

The invention provides an application of uncaria in treating acute drug-induced liver injury, which protects liver cells by lowering blood pressure and protecting the central nervous system to calm the liver and stop the wind.

The uncaria is used for preparing a pharmaceutical composition for treating acute drug-induced liver injury.

The pharmaceutical composition comprises uncaria and a pharmaceutically acceptable carrier, wherein the carrier is an adsorption carrier.

The pharmaceutical composition also comprises a synergistic medicine, the synergistic medicine is a medicine for treating acute drug-induced liver injury by synergistic uncaria, the synergistic medicine is gastrodia elata, antelope horn, mulberry leaf, pseudo-ginseng and turtle shell, and the preparation method of the synergistic medicine comprises the following steps: soaking gastrodia elata, antelope horn, mulberry leaf, pseudo-ginseng and turtle shell for 2 hours, and then mixing the gastrodia elata, the antelope horn, the mulberry leaf, the pseudo-ginseng and the turtle shell with water according to the weight part of 1: 10, putting the mixture into a container for decoction, filtering the mixture after the decoction is carried out for 4 hours, taking filter residues, mixing the filter residues with water again according to the weight ratio of 1: 10 putting the mixture into a container, decocting for 2 hours, repeatedly decocting for three times, and combining liquid medicines.

The pharmaceutical composition is a solution.

The acute drug-induced liver injury is APAP or LPS/GalN-induced acute liver injury, and the establishment method of the APAP-induced mouse acute liver injury model comprises the following steps: carrying out intraperitoneal injection on a mouse by using 500mg/kgAPAP, and obtaining a mouse acute drug-induced liver injury model after administration for 28 hours; the method for establishing the LPS/GalN induced mouse acute liver injury model comprises the following steps: LPS2.5mg/kg and GalN0.3g/kg are injected into the abdominal cavity of the mouse, and the acute drug-induced liver injury model of the mouse is obtained 8 hours after the administration.

Example 1: APAP model

1.1, subject: 200 SPF Kunming mice weighing 18-22g were divided equally into four groups: blank group, APAP model group, uncaria medicament low dose (1mg/kg) + APAP model group, uncaria medicament high dose (10mg/kg) + APAP model group;

the blank group and the APAP model group were given saline;

constructing an APAP model of the mouse: injecting a mouse with 500mg/kg paracetamol (APAP) in an abdominal cavity, obtaining an optimal mouse drug-induced liver injury model after 28 hours, and confirming whether the model construction is successful or not through blood sampling detection.

1.2, after the model is successfully constructed, the mice are treated by gastric lavage, the abdominal cavities of the mice are sampled after 48 hours, serum is separated, and the levels of aspartate Aminotransferase (AST) and alanine Aminotransferase (ALT) in the serum are measured by adopting a kit, wherein the data are shown in a table 1:

the data in table 1 show that the AST and ALT levels of the APAP model group are obviously higher than those of the blank group, which indicates that the model is successfully made, compared with the APAP model group, the AST and ALT levels of the uncaria medicament low-dose + APAP model group and the uncaria medicament high-dose + APAP model group are lower than those of the APAP model group, which indicates that the AST and ALT levels can be reduced after the treatment of uncaria, particularly the high-dose uncaria medicament has obvious reduction level, and indicates that the uncaria can effectively prevent and treat APAP-induced acute drug-induced liver injury.

1.3, immediately performing laparotomy on each mouse, taking a piece of liver tissue at the same part, fixing the liver tissue with 10% formalin solution, performing paraffin-embedded sectioning, observing the pathological condition of the liver tissue of each group of mice under a microscope by using an HE staining method, and dividing the degree of liver injury into 4 grades:

level 0: the liver tissue structure is normal, and no obvious degeneration, necrosis and inflammatory cell infiltration exist;

level 1: the liver lobule structure is normal, and obvious turbid swelling, balloon-like or fatty degeneration and scattered point-like necrosis can be seen;

and 2, stage: the liver lobule has unclear structure, and obvious focal necrosis accompanied by inflammatory cell infiltration can be seen;

and 3, level: the liver lobule has unclear structure, obvious sheet necrosis and inflammatory cell infiltration.

The data are shown in table 2:

as can be seen from the data in Table 2, the APAP model group shows obvious pathological changes, which indicates that the model is successfully prepared, and the uncaria medicament can obviously improve the liver cell pathological changes, the cell degeneration necrosis and the like from pathological sections, and the improvement is obvious along with the increase of the administration dosage, which indicates that the uncaria medicament has an obvious effect of protecting liver cells.

Example 2: LPS/GalN model

2.1, subject: 200 SPF Kunming mice weighing 18-22g were divided equally into four groups: blank group, LPS/GalN model group, uncaria drug low dose (1mg/kg) + LPS/GalN model group, uncaria drug high dose (10mg/kg) + LPS/GalN model group;

the blank group and LPS/GalN model group were given physiological saline;

constructing a mouse LPS/GalN model: LPS2.5mg/kg and GalN0.3g/kg are injected into the abdominal cavity of the mouse, and the acute drug-induced liver injury model of the mouse is obtained 8 hours after the administration.

2.2, after the model is successfully constructed, the mice are treated by gastric lavage, the abdominal cavities of the mice are sampled after 48 hours, serum is separated, and the levels of aspartate Aminotransferase (AST) and alanine Aminotransferase (ALT) in the serum are measured by adopting a kit, wherein the data are shown in a table 3:

the data in the table 3 show that the AST and ALT levels of the LPS/GalN model group are obviously higher than those of the blank group, which indicates that the modeling is successful, and compared with the LPS/GalN model group, the low-dose uncaria rhynchophylla drug, the LPS/GalN model group and the high-dose uncaria rhynchophylla drug, the AST and ALT levels of the LPS/GalN model group are lower than those of the LPS/GalN model group, which indicates that the uncaria rhynchophylla can effectively prevent and treat acute drug-induced liver injury induced by LPS/GalN.

2.3, immediately performing laparotomy on each mouse, taking a piece of liver tissue at the same part, fixing the liver tissue with 10% formalin solution, performing paraffin-embedded sectioning, observing the pathological condition of the liver tissue of each group of mice under a microscope by using an HE staining method, and dividing the degree of liver injury into 4 grades:

level 0: the liver tissue structure is normal, and no obvious degeneration, necrosis and inflammatory cell infiltration exist;

level 1: the liver lobule structure is normal, and obvious turbid swelling, balloon-like or fatty degeneration and scattered point-like necrosis can be seen;

and 2, stage: the liver lobule has unclear structure, and obvious focal necrosis accompanied by inflammatory cell infiltration can be seen;

and 3, level: the liver lobule has unclear structure, obvious sheet necrosis and inflammatory cell infiltration.

The data are shown in table 4:

as can be seen from the data in Table 4, the LPS/GalN model group shows obvious pathological changes, which indicates that the model is successfully prepared, and the uncaria medicament can improve the steatosis and the necrosis of liver cells from pathological sections, which indicates that the uncaria medicament has obvious effect of protecting the liver cells.

While certain exemplary embodiments of the present invention have been described above by way of illustration only, it will be apparent to those of ordinary skill in the art that the described embodiments may be modified in various different ways without departing from the spirit and scope of the invention. Accordingly, the foregoing description is illustrative in nature and is not to be construed as limiting the scope of the invention as claimed.