CN115400119A - Medical application of arteether maleate in treating non-alcoholic fatty liver disease - Google Patents
Medical application of arteether maleate in treating non-alcoholic fatty liver disease Download PDFInfo
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- CN115400119A CN115400119A CN202110579406.XA CN202110579406A CN115400119A CN 115400119 A CN115400119 A CN 115400119A CN 202110579406 A CN202110579406 A CN 202110579406A CN 115400119 A CN115400119 A CN 115400119A
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- Prior art keywords
- liver
- maleate
- arteether
- alcoholic fatty
- fatty liver
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Abstract
The invention provides medical application of arteether maleate in treating non-alcoholic fatty liver disease.
Description
Technical Field
The invention relates to the field of medicines, in particular to a new medical application of arteether maleate in treating non-alcoholic fatty liver disease.
Background
Non-alcoholic fatty liver disease (NAFLD) refers to a series of liver diseases caused by excessive accumulation of fat in liver cells of people who drink little or no alcohol. NAFLD includes simple Nonalcoholic fatty liver (NAFL) and Nonalcoholic steatohepatitis (NASH) that accompanies liver inflammation and fibrosis. NASH is an extremely developed form of NAFLD, and has a complex etiology, difficulty in diagnosis, prolonged course of disease and numerous complications, and has become an important cause of liver cirrhosis, hepatocellular carcinoma, and liver transplantation. Typical pathologies of NASH are liver cell macrovesicular steatosis, lobular inflammation with punctate necrosis, hepatocyte ballooning, etc. The clinical manifestations are liver lipopexia of people without alcoholism, steatosis accompanied by inflammation and hepatocyte damage, leading to progressive fibrosis of the liver, and the final progression of some patients is cirrhosis and liver cancer. At present, the treatment means aiming at NASH is very limited, and no drug approved for treating NASH is available at home and abroad. The clinical existing treatment strategies mainly comprise application of vitamin E and an insulin sensitizer, and weight reduction through diet control and physical exercise, but the clinical existing treatment strategies have the disadvantages of long-term application of adverse reactions, low compliance and difficulty in reversing the progress of hepatic fibrosis. Therefore, there is a wide clinical need to develop NASH therapeutic drugs having the effects of controlling liver inflammation and promoting liver repair.
Artemisinin is an antimalarial active ingredient extracted from herba Artemisiae Annuae (plant Artemisia annua L.), and is a rare sesquiterpene lactone containing peroxy group. It has not only excellent antimalarial effect but also good anti-inflammatory immunosuppressive activity. The artemisinin compound has immunosuppressive activity, but the application popularization and research of the artemisinin in the field of immune system disease treatment are limited by the problems of poor solubility, low oral bioavailability and the like of the existing artemisinin drugs (artemether, dihydroartemisinin, artesunate and the like).
Arteether Maleate (Aminoarteether Maleate, SM 934) has the following structural formula:
the arteether maleate is a novel water-soluble artemisinin derivative, and compared with the artemisinin drugs for resisting malaria, the arteannuin type drugs for resisting malaria have the advantages of good water solubility, high pharmaceutical property, convenient preparation, easy oral absorption, high bioavailability, strong immunosuppressive activity and good safety.
The arteether maleate has excellent in vivo and in vitro inhibitory activity, and can inhibit mitogen and allogeneic antigen induced mouse or human lymphocyte proliferation reaction by in vitro administration, and inhibit inflammation-related cytokine production; the in vivo administration has obvious improvement effect on tissue organ inflammation and pathological changes caused by various inducers: SM934 improves kidney fibrosis in animals with passive Heiman nephritis by inhibiting TGF-beta/SMAD signaling pathways; SM934 can reduce kidney pathological changes of lupus nephritis animals by up-regulating macrophage secretion anti-inflammatory factor IL-10 level; SM934 directly inhibits macrophage expression of Toll-like receptor, improves conjunctival inflammation of xerophthalmia animals, and maintains tear secretion.
At present, the application and report of arteether maleate for treating non-alcoholic fatty liver disease are not available.
Disclosure of Invention
The invention combines high fat diet with carbon tetrachloride (CCl) 4 ) The research of the induced non-alcoholic steatohepatitis model of the mouse finds that arteether maleate can obviously inhibit liver lobular inflammation, liver cell vacuole-like lesion and liver fibrosis; reducing the levels of glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, total bilirubin and triglyceride in serum; reversing immune cell abnormal response and macrophage phenotype transformation caused by liver lipid accumulation, inducing the liver to enter the damage and repair, thereby playing a role in treating NASH and being developed into a medicament for treating non-alcoholic fatty liver disease.
Accordingly, in one aspect, the present invention provides the use of arteether maleate in the manufacture of a medicament for the treatment or co-treatment of non-alcoholic fatty liver disease.
The research of the invention proves that arteether maleate can effectively inhibit liver lobular inflammation, hepatocyte vacuole-like lesion and hepatic fibrosis, promote liver tissue damage repair, and can be used for preparing medicines for treating or assisting in treating non-alcoholic fatty liver diseases.
Therefore, in another aspect, the invention provides the use of arteether maleate in preparing a medicament for inhibiting liver lobular inflammation, hepatocyte vacuolar lesion and liver fibrosis, and promoting liver tissue damage repair.
Preferably, in the above-mentioned application, the drug may be in the form of tablet, capsule, granule, oral liquid, or intravenous or intramuscular injection, but is not limited thereto.
In yet another aspect, the invention provides a method of treating or adjunctively treating non-alcoholic fatty liver disease, the method comprising providing to a subject in need thereof a therapeutically effective amount of arteether maleate.
In yet another aspect, the invention provides a method of inhibiting lobular inflammation, hepatocellular vacuolar pathology, and liver fibrosis, promoting repair of liver tissue damage, comprising providing to a subject in need thereof a therapeutically effective amount of arteether maleate.
In still another aspect, the present invention provides a pharmaceutical composition for the treatment or adjuvant treatment of non-alcoholic fatty liver disease, comprising arteether maleate as an active ingredient.
In still another aspect, the present invention provides a pharmaceutical composition for inhibiting liver lobular inflammation, hepatocellular vacuole-like lesion, and hepatic fibrosis, and promoting liver tissue damage repair, comprising arteether maleate as an active ingredient.
In some embodiments of the above uses, methods or pharmaceutical compositions, the non-alcoholic fatty liver disease may comprise non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
As used herein, the term "therapeutically effective amount" means that amount which has a therapeutic effect and is useful in the prevention or treatment of the particular disease, disorder, or condition described herein. For example, a "therapeutically effective amount" may refer to the amount required to provide a therapeutic or desired effect in the subject being treated. As will be appreciated by those skilled in the art, a therapeutically effective amount will vary with the route of administration, the use of excipients, and the possibility of co-administration with other therapies.
The experimental research results in a non-alcoholic steatohepatitis mouse animal model induced by high-fat diet combined with carbon tetrachloride prove that the compound can effectively improve liver lobular inflammation, liver cell vacuole-like lesion and hepatic fibrosis, reduce the collagen deposition of liver tissues, reduce the levels of serum glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, total bilirubin and triglyceride of an experimental mouse, inhibit the expression of genes related to hepatic fibrosis, up-regulate the level of matrix metalloproteinase of the liver and promote the differentiation of liver macrophages to repair phenotype. Pharmacodynamic and pharmacological studies prove that arteether maleate can be used as a medicament for treating and assisting in treating the non-alcoholic fatty liver disease and has good clinical application prospect.
The present invention has been described in detail hereinabove, but the above embodiments are merely illustrative in nature and are not intended to limit the present invention. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary or the following examples.
Unless expressly stated otherwise, a numerical range throughout this specification includes any sub-range therein and any numerical value incremented by the smallest sub-unit within a given value. Unless expressly stated otherwise, numerical values throughout this specification represent approximate measures or limitations to the extent that they include minor deviations from the given values, as well as embodiments having values about the mentioned as well as having the precise values mentioned. Other than in the operating examples provided at the end of the detailed description, all numbers expressing quantities or conditions of parameters (e.g., quantities or conditions) used in the specification (including the appended claims) are to be understood as being modified in all instances by the term "about" whether or not "about" actually appears before the number. "about" means that the numerical value so stated is allowed to be somewhat imprecise (with some approach to exactness in that value; about or reasonably close to that value; approximately). As used herein, "about" refers to at least variations that can be produced by ordinary methods of measuring and using such parameters, provided that the imprecision provided by "about" is not otherwise understood in the art with this ordinary meaning. For example, "about" can include variations of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5%.
Drawings
Figure 1 is a graph showing the results of an experiment with SM934 inhibiting levels of inflammatory factors produced by palmitic acid induced RAW264.7 macrophages in vitro (= P <0.05, = P <0.001, compared to palmitic acid stimulated control cells).
Figure 2 is a graph showing the results of experiments with SM934 inhibiting palmitic acid induced Huh7 cell lipid accumulation in vitro (= P <0.05, = P <0.01, = P <0.001, compared to palmitic acid stimulated control cells).
Figure 3 is a representative cell photograph showing the results of an experiment in which SM934 inhibits transforming growth factor- β 1-induced hepatic stellate cell migration in vitro.
Figure 4 is a graph showing the results of experiments with SM934 inhibiting transforming growth factor- β 1-induced hepatic stellate cell migration in vitro (= P <0.05, = P <0.001, compared to transforming growth factor- β 1-stimulated control cells).
Figure 5 is a representative photograph showing that SM934 gastric lavage significantly reduces liver tissue lobular inflammation and hepatocyte vacuolar lesions in mice model NASH.
Figure 6 is a representative photograph showing that SM934 intragastric administration significantly reduced collagen deposition in liver tissue of mice model NASH.
Figure 7 is a representative photograph showing that SM934 intragastric administration significantly reduced liver tissue fibrogenesis in NASH model mice.
FIG. 8 is a graph showing the results of an experiment in which administration of SM934 by gavage significantly reduced the proportion of inflammatory macrophages in the liver of mice model NASH, increasing the proportion of reparative macrophages.
Detailed Description
Hereinafter, the present invention will be described in detail by examples. However, the examples provided herein are for illustrative purposes only and are not intended to limit the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Experimental examples
Example 1 inhibition of free fatty acid-induced macrophage inflammatory factor production by arteether maleate
1. Main experimental materials and sources
(1) Cell: the mouse macrophage cell line RAW264.7 was purchased from ATCC, usa.
(2) The main experimental drugs:
specific methods for the preparation of arteether maleate (SM 934) may be found in applicant's previous patent (ZL 93112454.9) and published article j.med.chem,2000,43.
White crystals. Melting point: 139-141 deg.C
Elemental analysis (C) 21 H 33 NO 9 )：
Calculated values: C56.87H 7.50N 3.16
Measured value: C56.84H 7.59N 3.10
(3) Reagent:
DMEM high-glucose medium was purchased from GibcoBRL company; sodium palmitate was purchased from Shanghai Michelin Biochemical technology, inc.; (fatty acid free) Bovine Serum Albumin (BSA) was purchased from Sigma-Aldrich; TNF-alpha and IL-6ELISA kits were purchased from BD, USA.
2. Experimental methods
24-well culture plates were inoculated with RAW264.7 cells (5X 10) 5 Cell/well), in DMEM medium containing 2% BSA (no fatty acids) and 1% penicillin-streptomycin based on 37 ℃,5% 2 And (3) performing conditioned culture, then adding sodium palmitate with the final concentration of 200 mu M and SM934 with different concentrations, collecting cell supernatants after culturing for 24 hours, and detecting the contents of TNF-alpha and IL-6 in the supernatants by an ELISA method.
3. Results of the experiment
Figure 1 is a graph showing the results of an experiment with SM934 inhibiting levels of inflammatory factors produced by palmitic acid induced RAW264.7 macrophages in vitro (= P <0.05, = P <0.001, compared to palmitic acid stimulated control cells). As shown in fig. 1, under lipid overload conditions, macrophages secrete a large amount of inflammatory factors, and the results show that SM934 significantly inhibits free fatty acid-induced macrophage secretion of inflammatory factors TNF- α and IL-6.
The results show that SM934 has a remarkable inhibiting effect on the generation of inflammatory factors by macrophages caused by lipid overload.
Example 2 inhibition of free fatty acid-induced steatosis in hepatocytes by arteether maleate
1. Main experimental materials and sources
(1) Cell: the human hepatoma cell line Huh7, purchased from ATCC, usa.
(2) The main experimental drugs:
artemether maleate (SM 934)
(3) Reagent:
DMEM high-glucose medium was purchased from GibcoBRL company; sodium palmitate was purchased from Shanghai Michelin Biochemical technology, inc.; (fatty acid free) Bovine Serum Albumin (BSA) was purchased from Sigma-Aldrich; the triglyceride detection kit is purchased from Nanjing technology Ltd.
2. Experimental methods
12-well culture plates were inoculated with Huh7 cells (3X 10) 5 Per well) in DMEM containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37 ℃,5% CO 2 Conditioned for 12 hours, then added to a final concentration of sodium palmitate of 1mM and various concentrations of SM934, the supernatant was discarded and washed once with PBS. Mu.l of triton X-100 (1% triton X-100 in 50mM Tris) was added per well and cells were lysed by three freeze-thaw cycles. The content of triglyceride in the cell lysate was determined by GPO-PAP colorimetry.
3. Results of the experiment
Palmitic acid has strong lipotoxicity and the ability to induce lipid production, and is therefore commonly used as an inducer for hepatic steatosis models. Figure 2 is a graph showing the results of experiments with SM934 inhibiting palmitic acid induced Huh7 cell lipid accumulation in vitro (= P <0.05, = P <0.01, = P <0.001, compared to palmitic acid stimulated control cells). As shown in fig. 2, palmitic acid at a concentration of 1mM was able to cause significant fat accumulation in Huh7 cells, and SM934 was able to reduce palmitic-induced hepatocyte fat accumulation concentration-dependently, in a concentration range that did not produce non-specific cytotoxicity.
The above results indicate that SM934 can significantly inhibit free fatty acid-induced lipid production in parenchymal liver cells, and reduce the occurrence of hepatic steatosis.
Example 3 inhibition of transforming growth factor induced hepatic stellate cell fibrosis by arteether maleate
1. Main experimental materials and sources
(1) Cell: the human hepatic stellate cell line LX-2 was purchased from ATCC, USA.
(2) The main experimental drugs:
arteether maleate (SM 934)
(3) Reagent:
DMEM high-glucose medium was purchased from GibcoBRL; recombinant human transforming growth factor-beta 1 (TGF-. Beta.1) was purchased from R & D systems; mitomycin C was purchased from Sigma-Aldrich.
2. Experimental methods
6-well plate-seeded LX-2 cells (5X 10) 5 Per well) in DMEM containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37 ℃,5% CO 2 The serum-free culture was continued for 8 hours after overnight conditioned culture. Three horizontal lines were drawn with a 1ml tip horizontally perpendicular to the plate bottom and washed 3 times with PBS. Mitomycin C (1. Mu.g/ml) inhibited cell division by treatment for 1 hour. Then adding TGF-beta 1 (10 ng/ml) and SM934 with different concentrations to co-culture the cells, observing the width of the scratch under a microscope at time points of 0 hour, 12 hours and 24 hours respectively, analyzing the area of the scratch area by using Image J software after photographing and recording, and calculating the migration rate of the cells to reflect the degree of fibrosis change of hepatic stellate cells.
3. Results of the experiment
Hepatic stellate cells are the major cell type involved in liver fibrosis. TGF-beta 1 is a key factor for activating hepatic stellate cells, and the activated stellate cells have the characteristics of proliferation and chemotaxis and can be converted into fibroblasts. FIG. 3 is a representative cell photograph showing the results of an experiment in which SM934 inhibits transforming growth factor- β 1-induced hepatic stellate cell migration in vitro; figure 4 is a graph showing the results of experiments with SM934 inhibiting transforming growth factor- β 1-induced hepatic stellate cell migration in vitro (= P <0.05, = P <0.001, compared to transforming growth factor- β 1-stimulated control cells). As shown in figures 3 and 4, TGF-beta 1 can induce hepatic stellate cells to migrate and generate fibrosis characteristics, and SM934 can obviously inhibit the activation and migration of the hepatic stellate cells in a concentration-dependent manner after being acted in vitro for 12 hours and 24 hours.
The results show that SM934 can inhibit the activation and migration processes of hepatic stellate cells and block the transformation of the hepatic stellate cells into fibroblasts.
Example 4 therapeutic Effect of arteether maleate on high fat diet in combination with carbon tetrachloride-induced non-alcoholic steatohepatitis in mice
1. Main experimental materials and sources
(1) Animals: SPF grade C57BL/6N mice, male, 5-6 weeks old, were provided by the Beijing Wintolite laboratory animal technology, inc., and the certification code was 20200611Abzz0619000123.
(2) The main experimental drugs:
arteether maleate (SM 934); pioglitazone was purchased from Sigma-Aldrich.
(3) Reagent:
high fat Diet (60% kcal) was purchased from readech Diet company; carbon tetrachloride was purchased from national chemical group, chemical reagents, ltd; the total bilirubin determination kit, the alanine aminotransferase detection kit, the aspartate aminotransferase detection kit and the triglyceride determination kit are purchased from Shanghai date and trade company Limited; percoll cell isolates were purchased from GE Healthcare; collagenase type IV was purchased from Sigma-Aldrich; flow cytometry detection of mouse fluorescent antibodies was purchased from BD, usa.
2. Experimental methods
(1) Experimental grouping: each group of 8 mice was divided into: normal control group (fed with common feed), model control group (fed with high-fat feed), pioglitazone control group (10 mg/kg), and SM934 treatment group (1, 3, 10 mg/kg), except the normal control group, each experimental group was gavaged daily at 0.2 ml/mouse from the initial day of the experiment.
(2) Model construction: the mice were fed high-fat for 14 weeks, and were injected intraperitoneally with 50. Mu.l CCl 2 times a week for the last 4 weeks, except for the normal control group 4 Solution (3.5%), normal group was intraperitoneally injected 2 times a week with 50 μ l olive oil.
(3) Index detection:
1) The treatment end carries out eyeball picking and blood taking on the mouse, separates serum, and detects the levels of glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, total bilirubin and triglyceride;
2) Separating mouse liver tissue at the treatment end point, and performing H & E staining and pathological analysis;
3) Performing collagen immunohistochemical staining and area quantitative analysis on mouse liver tissues;
4) Performing immunohistochemical staining and area quantitative analysis on alpha-smooth muscle actin (alpha-SMA) on mouse liver tissues;
5) Separating mouse liver infiltrating immune cells, and analyzing the phenotypic characteristics of the immune cells by flow cytometry.
3. Results of the experiment
(1) SM934 is administered by intragastric administration, and the serum biochemical indexes of the NASH model mouse are obviously improved.
Serum biochemical indexes of each group of mice are measured at an experimental end point, and the levels of glutamic-pyruvic transaminase (AST), glutamic-oxalacetic transaminase (ALT), total Bilirubin (TBIL) and Triglyceride (TG) related to liver injury degree are obviously reduced after SM934 administration (Table 1);
TABLE 1 Experimental end-Point serum Biochemical index levels for various groups of mice
* P value <0.05, P value <0.01, P value <0.001, compared to model control group.
(2) SM934 is administered by intragastric administration, and can significantly reduce liver tissue lobular inflammation and hepatocyte vacuolar lesion of mice in NASH model.
Fig. 5 is a representative photograph showing that administration of SM934 by gavage significantly reduced liver tissue lobular inflammation and hepatocyte vacuolar lesions in mice model NASH. As shown in FIG. 5, H & E staining was performed on the liver of mice isolated at the end point of the experiment, and the results showed that the liver of mice model NASH exhibited hepatokaryon shrinkage, disorganization, increased cytoplasmic and nuclear gaps, partial infiltration of inflammatory cells, formation of a large number of local necrotic foci, and vacuolar lesions of hepatocytes. The SM934 intragastric administration obviously improves liver lobular inflammation and liver cell vacuole-like lesion, and reduces the formation of liver tissue necrotic foci.
(3) SM934 is administered by intragastric administration, and the deposition of the collagen in the liver tissue of the mice of the NASH model is obviously reduced.
Figure 6 is a representative photograph showing that SM934 intragastric administration significantly reduced collagen deposition in liver tissue of mice model NASH. As shown in fig. 6, the liver of the mice isolated at the end point of the experiment was Masson trichrome stained (Masson trichmatic staining), and the results showed that the tissue of liver fibers (blue collagen fibers) of the mice model NASH proliferated through the central leaflet and extended to the parahepatic lobe, the collagen fibers extended and attached to and surrounded the entire leaflet and surrounded the central vein, leaflet structural damage, portal vein fibrosis and pseudoleaflet formation. SM934 intragastric administration significantly inhibited proliferation of fibrous tissue within the liver parenchyma and formation of hepatic collagen fibers.
(4) SM934 is administered by intragastric administration, and liver tissue fibrogenesis of mice of the NASH model is remarkably reduced.
Figure 7 is a representative photograph showing that SM934 intragastric administration significantly reduced liver tissue fibrogenesis in NASH model mice. As shown in fig. 7, the liver of the mice isolated at the end point of the experiment was subjected to α -SMA specific histochemical staining, and the results showed that the mice with NASH model have increased formation of α -SMA positive myofibroblasts and increased activation of hepatic stellate cells. The expression level of the alpha-SMA in the liver of the NASH mouse is detected by an immunohistochemical staining method, and the SM934 gastric perfusion administration obviously reduces the expression of the alpha-SMA and inhibits the activation of hepatic stellate cells and the formation of myofibroblasts of the NASH mouse.
(5) SM934 is administered by intragastric administration, which significantly reduces the proportion of inflammatory macrophages in the liver of mice in the NASH model and increases the proportion of reparative macrophages.
FIG. 8 is a graph showing the results of an experiment in which administration of SM934 by gavage significantly reduced the proportion of inflammatory macrophages in the liver of mice model NASH, increasing the proportion of reparative macrophages. As shown in fig. 8, the end-point of the experiment was analyzed for flow cytometry phenotyping by density gradient centrifugation to isolate mouse liver-infiltrated immune cells. The results showed that the liver of the NASH model mouse infiltrated a large number of inflammatory macrophages (CD 45) + CD11b + F4/80 low Ly6C + ) The administration of SM934 by intragastric administration significantly reduced the proportion of inflammatory macrophages, while increasing the number of reparative macrophages (CD 45) + CD11b + F4/80 + Ly6C low ) The ratio of (a) to (b).
The results show that the administration of SM934 through gastric lavage can obviously inhibit liver lobular inflammation, liver cell vacuolation-like lesion and liver fibrosis in the liver of a mouse model NASH; reducing the levels of glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, total bilirubin and triglyceride in serum; the abnormal response of immune cells and the phenotype transformation of macrophages caused by liver lipid accumulation are reversed, and the liver is induced to enter the damage and repair, so that the NASH treatment effect is exerted, and the NASH can be developed into a treatment medicament for non-alcoholic fatty liver diseases.
Claims (7)
1. Use of arteether maleate in the manufacture of a medicament for the treatment or co-treatment of non-alcoholic fatty liver disease.
2. The use of claim 1, wherein the non-alcoholic fatty liver disease comprises non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
3. The application of arteether maleate in preparing medicine for inhibiting liver lobular inflammation, hepatocyte vacuole-like lesion and hepatic fibrosis and promoting liver tissue injury repair is provided.
4. The use according to any one of claims 1-3, wherein the medicament is a tablet, capsule, granule, oral liquid formulation, or intravenous or intramuscular injection.
5. A pharmaceutical composition for the treatment or co-treatment of non-alcoholic fatty liver disease comprising arteether maleate as active ingredient.
6. The pharmaceutical composition of claim 5, wherein the non-alcoholic fatty liver disease comprises non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
7. A pharmaceutical composition for inhibiting liver lobular inflammation, hepatocellular vacuole-like lesion, and hepatic fibrosis, and promoting liver tissue damage repair, comprising arteether maleate as an active ingredient.
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