CN111514300A - An artemisinin enhanced pharmaceutical composition for preventing or treating malaria - Google Patents

An artemisinin enhanced pharmaceutical composition for preventing or treating malaria Download PDF

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CN111514300A
CN111514300A CN202010365552.8A CN202010365552A CN111514300A CN 111514300 A CN111514300 A CN 111514300A CN 202010365552 A CN202010365552 A CN 202010365552A CN 111514300 A CN111514300 A CN 111514300A
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pfsetvs
artemisinin
pharmaceutical composition
pfemp1
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李玉洁
陈利娜
郑钟原
刘慧�
王茜
杨婷
瞿水清
杨源民
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Institute of Materia Medica of CAMS
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P33/06—Antimalarials
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention belongs to the field of biological medicine, and relates to an artemisinin enhanced pharmaceutical composition for preventing or treating malaria. Experiments prove that the excessive expression of PfEMP1 can enhance the antimalarial effect of DHA, so that the combined application of a reagent for promoting the expression of PfEMP1 and DHA has a synergistic effect on antimalarial aspect.

Description

An artemisinin enhanced pharmaceutical composition for preventing or treating malaria
Technical Field
The invention belongs to the field of biological medicines, relates to an artemisinin enhanced pharmaceutical composition for preventing or treating malaria, and particularly relates to application of dihydroartemisinin and a reagent for promoting expression of PfEMP1 in preparation of a pharmaceutical composition for treating malaria.
Background
Malaria is a significant infectious disease that seriously threatens human health and life safety, spreads epidemic in 91 countries and regions worldwide, and is one of the three public health problems in the world. According to the world malaria report issued by WHO 2017 in 11 months, about 2.16 million malaria cases and 44.5 million people die of severe malaria worldwide in 2016. High risk populations of malaria include infants, children under 5 years of age, pregnant women and immunocompromised people, with over two thirds of cases of malaria death occurring in children under 5 years of age. Although malaria mortality in children under 5 years of age worldwide decreased by 29% in 2010-2015, 1 child died of severe malaria every 2 minutes.
Plasmodium falciparum (Plasmodium falciparum) is the most pathogenic Plasmodium, and occurs in the infrared phase and the erythrocytic phase 2 developmental stages in humans, the erythrocytic phase being the major pathogenic stage, at which clinical symptoms of malaria occur, as well as acquired immune protection following natural infection. Malaria disease incidence or mortality is effectively reduced by killing or reducing the causative plasmodium in the erythrocytic stage, and therefore, basic research and vaccine development for malaria in the erythrocytic stage has been a research hotspot in the field of antimalarial research.
The previous researches suggest that artemisinin drugs can selectively kill plasmodium in the erythrocytic stage, and the effects of the artemisinin drugs are mainly to intervene the membrane system structure of the plasmodium, influence the functions of a surface membrane and mitochondria and block host erythrocytes to provide enough nutrition for the plasmodium, so that the purpose of antimalarial is achieved. The artemisinin medicine also has a killing effect on plasmodium gametophytes, can quickly kill early gametophytes, inhibit the gametophytes in each stage, and has an effect of interrupting the development process of immature gametophytes.
Dihydroartemisinin (DHA) has a rapid and efficient killing effect on plasmodium and can kill early plasmodium in erythrocytes, thereby preventing the plasmodium from developing to a more mature stage.
Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1, Plasmodium falciparum erythrocytemembranane protein 1) is a family of proteins with a relative molecular mass between 200000-400000, and the molecule comprises 1 amino-terminal segment (NTS), several Duffy binding-like Domains (DBL), several cysteine-rich spacers, 1 transmembrane region, 1C 2 domain and 1C-terminal segment. The PfEMP1 is encoded by var genes of plasmodium falciparum, 1 plasmodium falciparum chromosome genome has up to 60 var gene copies, but only 1 var gene is finally expressed in each growth cycle, the var genes can be divided into A, B, C3 large groups, and the numerous var genes cause high variation of PfEMP 1. Adhesion between erythrocytes of plasmodium falciparum and normal erythrocytes occurs, and a phenomenon called rosette (rosetting) is generated, which is an important reason for the blockage of capillaries of patients and further severe malaria (such as cerebral malaria), and PfEMP1 is involved in the formation of rosette as a ligand of plasmodium. PfEMP1 can bind to several proteins in blood and receptors on erythrocyte membranes, such as fibrinogen, albumin, blood group A and B antigens, heparan sulfate and complement receptor 1, so that intercellular adhesion occurs, and the NTS-DBL1 alpha fragment at the amino terminal of PfEMP1 plays a key role in the formation of "rosettes". Studies have shown that antibodies capable of disrupting "rosettes" are associated with severe malaria, and that antibodies raised against the NTS-DBL1 α fragment lack the ability to disrupt "rosettes" and are opsonic for parasitic red blood cells in patients with severe malaria.
The combined effect of dihydroartemisinin and PfEMP1 protein in the treatment of malaria has not been seen to date.
Disclosure of Invention
The invention utilizes var gene overexpression insect strain 8D5, the insect strain is an insect strain with 3D7 insect strain PfSETvs gene knocked out, and the insect strain can be used as pfEMP1 overexpression insect strain. The invention utilizes the insect strain to detect the killing effect of DHA: after DHA treatment, the var gene overexpression strain IC50 is reduced compared with the wild type, which shows that the antimalarial effect of DHA can be enhanced by overexpression of pfEMP 1. Based on this, the object of the present invention is to provide a pharmaceutical composition for the treatment of malaria comprising an agent promoting the expression of PfEMP1, dihydroartemisinin.
In order to achieve the purpose, the invention adopts the following technical scheme:
according to one aspect of the invention, there is provided a pharmaceutical composition for the prevention or treatment of malaria comprising an agent that promotes the expression of PfEMP1, artemisinin or a derivative thereof.
Further, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier. The pharmaceutical composition of the invention is prepared by a conventional preparation process of an agent for promoting the expression of PfEMP1, artemisinin or a derivative thereof and a pharmaceutically acceptable carrier, which are used as active ingredients.
According to the present invention, the pharmaceutically acceptable carrier may be one or more of diluents, binders, disintegrants, stabilizers, sweeteners, flavoring agents, coloring agents, glidants, and lubricants.
Diluents, including but not limited to sucrose, mannitol, xylitol, acesulfame potassium, aspartame, dextrose, fructose, saccharin, sodium saccharin, sorbitol, and mixtures thereof may be used.
The diluent of the present invention may also have other functions, such as acting as a sweetener.
Binders include, but are not limited to, cellulose, alkyl celluloses such as methyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose, low substituted hydroxypropyl cellulose and hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose or mixtures thereof, pregelatinized corn starch, or polyvinylpyrrolidone. Microcrystalline cellulose may be used, for example microcrystalline cellulose available from Asahi Kasei under the trade name PH 301.
Disintegrants, including but not limited to crospovidone, sodium starch glycolate, starches such as corn starch and dry starch, croscarmellose sodium and cellulose products such as microcrystalline cellulose, ultra fine (microfine) cellulose, low substituted hydroxypropyl cellulose and the like may be used alone or in admixture.
Stabilizers, including but not limited to sodium tripolyphosphate, anhydrous sodium carbonate, glycine, citric acid, and the like, or mixtures thereof.
Sweetening agents, including, but not limited to, sugars such as fructose, glucose, sucrose, sugar alcohols such as mannitol, sorbitol, or mixtures thereof, and artificial sweeteners such as sodium saccharin, sodium cyclamate, and aspartame.
Flavoring agent refers to a substance or mixture thereof that can increase the taste of the mixture. Representative flavoring agents include, but are not limited to, orange flavor, banana flavor, lemon mint flavor, strawberry flavor, grape flavor, and cream flavor.
Flavoring agents include, but are not limited to, sodium chloride, glycine, citric acid, tartaric acid, and the like, and mixtures thereof.
Colorants include, but are not limited to, titanium dioxide pigments, lake pigments, and iron dioxide pigments.
Glidants include, but are not limited to, colloidal silicon dioxide, talc and surfactants, where surfactants are used alone or as a mixture with other glidants. Mixtures of colloidal silica and one or more surfactants may also be used.
Lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, magnesium oxide, sodium fumarate stearate, hydrogenated vegetable oils, sodium lauryl stearate, stearic acid, corn starch, colloidal silicon dioxide, talc, and mixtures thereof.
The pharmaceutical composition of the invention can be prepared into various dosage forms according to requirements. Including, but not limited to, tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for transdermal, mucosal, nasal, buccal, sublingual or oral use.
The route of administration of the pharmaceutical composition of the present invention is not limited as long as it can exert the desired therapeutic or prophylactic effect, and includes, but is not limited to, intravenous, intraperitoneal, intraocular, intraarterial, intrapulmonary, oral, intravesicular, intramuscular, intratracheal, subcutaneous, transdermal, transpleural, topical, inhalation, transmucosal, cutaneous, gastrointestinal, intraarticular, intraventricular, rectal, vaginal, intracranial, intraurethral, intrahepatic, intratumoral. In some cases, the administration may be systemic. In some cases topical administration.
The dosage of the pharmaceutical composition of the present invention is not limited as long as the desired therapeutic effect or prophylactic effect is obtained, and can be appropriately determined depending on the symptoms, sex, age, and the like. The dose of the therapeutic agent or prophylactic agent of the present invention can be determined using, for example, the therapeutic effect or prophylactic effect on a disease as an index.
The pharmaceutical composition is used for treating malaria by combining two agents, namely artemisinin or derivatives thereof, of which the effective ingredients promote the expression of PfEMP 1. The agent that promotes expression of PfEMP1, artemisinin or a derivative thereof, may be formulated and used separately or a combination therapy may be achieved by administering the agent that promotes expression of PfEMP1, artemisinin or a derivative thereof in a single formulation. Other combinations are also contemplated by combination therapy, for example, an agent that promotes expression of PfEMP1, artemisinin or a derivative thereof may be formulated and administered along with a separate formulation comprising a third agent. Although the two active ingredients may be administered simultaneously in a combination therapy, this need not be the case. For example, the administration of the first active ingredient may be minutes, hours, days or weeks before the administration of the second active ingredient. Thus, the two active ingredients may be administered within minutes of each other, or 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, longer intervals are possible. Although in some cases both active principles for combined therapy may be present in the body of the patient, this need not be the case.
The pharmaceutical composition of the present invention is administered to the subject for a period of about 1 week to about 2 weeks. The administration may be intermittent or continuous during the treatment period.
The pharmaceutical composition of the invention may be administered with food at any time of day, not at any time of day, after a night on an empty stomach (e.g. breakfast).
The pharmaceutical composition of the invention may be administered once a day, twice a day, three times a day, four times a day, five times a day or six times a day.
According to another aspect of the invention, there is provided the use of PfEMP1 in the manufacture of a medicament for enhancing the antimalarial effect of artemisinin or its derivatives.
Further, the medicament is the pharmaceutical composition as described above.
According to a further aspect of the invention there is provided the use of artemisinin or a derivative thereof in the preparation of a pharmaceutical composition as hereinbefore described.
According to a further aspect of the invention, there is provided the use of PfEMP1 and artemisinin or a derivative thereof in the manufacture of a medicament for the prevention or treatment of malaria.
Further, the medicament is the pharmaceutical composition as described above.
According to a further aspect of the invention there is provided a medicament for enhancing the antimalarial effect of artemisinin or a derivative thereof, comprising an agent which promotes the expression of PfEMP 1.
According to a further aspect of the invention there is provided a method of preventing or treating malaria comprising administering to a subject in need thereof an agent that promotes expression of PfEMP1 and artemisinin or a derivative thereof.
The artemisinin derivative comprises artesunate, artemether, arteether and dihydroartemisinin. In a particular embodiment of the invention, the artemisinin derivative is dihydroartemisinin.
The reagent for promoting expression of PfEMP1 comprises a PfEMP1 gene, a PfEMP1 overexpression vector, a PfEMP1 protein, a promoting miRNA, a promoting transcription regulatory factor, a promoting targeting small molecule compound and a reagent for inhibiting methylation of a var gene promoter.
Further, the agent that inhibits methylation of the var gene promoter includes an agent that inhibits histone lysine methylase.
Preferably, the histone lysine methylase is PfSETvs.
The agent inhibiting PfSETvs includes an agent inhibiting PfSETvs gene mRNA, and an agent inhibiting PfSETvs protein. The agent for inhibiting PfSETvs gene mRNA comprises an agent for inhibiting mRNA stability and an agent for inhibiting mRNA translation activity. The agent for inhibiting the PfSETvs protein comprises an agent for inhibiting the stability of the PfSETvs protein, an agent for inhibiting the activity of the PfSETvs protein and an agent for inhibiting the function of the PfSETvs protein.
Further, the agent that inhibits the PfSETvs gene mRNA includes a double-stranded ribonucleic acid for the PfSETvs gene mRNA; agents that inhibit the function of PfSETvs protein include antibodies that inhibit the function of TMED2 protein. The antibody may be a polyclonal antibody, or a monoclonal antibody.
The double-stranded ribonucleic acid directed against the PfSETvs gene mRNA may be siRNA. To ensure that the PfSETvs gene can be efficiently knocked out or silenced, siRNA-specific fragments were designed based on the mRNA sequence of the PfSETvs gene. The design of siRNA was accomplished by an in-line tool according to published general design principles (Elbashir et al 2001, Schwarz et al 2003, Khvorovaet al 2003, Reynolds et al 2004, Hsieh et al 2004, Ui-Tei et al 2004) which was: the siraseelection program of Whitehead Institute (BingbingYuan et al 2004, http:// jura. wi. mit. edu/bioc/siraext /) and BLOCK-iTTMRNAi Designer of INVITROGEN (runner of the 2004 Frost & Sullivan Excellence in research Award, https:// rnaidesigner. invitrogen. com/sirna /). In order to further improve the effectiveness of siRNA fragments, the advantages of two on-line design tools are combined to design siRNA fragments for screening. Finally, the siRNA sequences are filtered through a homology alignment (NCBI BLAST) to improve the specificity of the siRNA fragments and reduce off-target effects of RNAi interference.
The term "treating" refers to reducing or alleviating a symptom in a subject, preventing the worsening or progression of a symptom, or preventing the progression of a disease. The improvement, worsening, recovery or progression of symptoms for a given subject can be determined by subjective or objective measures commonly employed by those skilled in the art. Thus, effective treatment should include treatment of existing disease, control of disease by slowing or stopping the progression of disease, prevention of disease, reduction in the number or severity of symptoms, or a combination thereof. Using one or more statistically significant criteria, therapeutic efficacy can be demonstrated in controlled studies.
The term "preventing" means that an agent is administered to prevent a disease before the disease is not present.
The invention has the advantages and beneficial effects that:
the pharmaceutical composition has simple components, low toxicity and definite curative effect, and accords with the modern medical research theory. The two effective components in the pharmaceutical composition have obvious synergistic effect in preventing and treating malaria.
Drawings
FIG. 1 shows a graph of the results of IC50 detection of DHA antimalarial.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description is made with reference to the accompanying drawings and the detailed description.
Example 1 Effect of pfEMP1 expression on antimalarial Effect of DHA
1. Material
The plasmodium falciparum international standard strain 3D7 is presented by professor of the key laboratory Chengxiang army of the education department of zoonosis of the zoonosis research institute of Jilin university, and the laboratory carries out subculture and breed conservation.
An insect strain obtained by knocking out PfSETvs gene from International Standard strain 3D7 of Plasmodium falciparum is named as 8D5 and is given by Shang land laboratory of Shanghai Pasteur research institute of Chinese academy of sciences (the construction process of the insect strain is disclosed in the documents of PfSETvs methylation of custom H3K36 expression genes in Plasmodiumfalciparum, Nature.2013Jul 11; 499(7457):223-7), and the strain is subcultured in the laboratory. And a research group succeeded in finding a key factor PfSETvs controlling the silencing of var gene. PfSETvs, a homologous protein of drosophila ASH1, is a histone lysine methylase. Researchers have demonstrated that PfSETvs can produce a specific class of histone modification H3K36me3 in the promoter region of the var gene, thereby inhibiting transcription of the var gene family. The research proves the mediation effect of histone modification H3K36me3 on gene silencing in eukaryote for the first time; in the research, a transgenic plasmodium falciparum strain 8D5 which can express all PfEMP1 proteins and is generated by knocking out PfSETvs genes can be used as a pfEMP1 overexpression insect strain. The insect strain is used for detecting the killing effect of DHA.
2. Step (ii) of
2.1 insect Strain culture
Established methods according to Trager and Jensen (see literature: Trager W, Jensen J B. Humamaliana parasites in continuous culture [ J)]J Parasitol, 1976, 2005, 91(3):484), using 0.5% AlbumaxII instead of human serum, 1L complete medium was prepared: 1640 powder 1 bag, albumax II 5g, L-glutamine 0.3g, glucose 2g, Hepes 5.98g, hypoxanthine 0.025g, gentamicin 0.2 g; dissolving the reagent in 1L of triple distilled water, stirring uniformly, adding 2.56g of sodium bicarbonate, mixing uniformly, filtering the culture medium by a sterilizing filter, and subpackaging for use. Adjusting the volume ratio to 2% by using human O-type blood erythrocytes; place the petri dish in a three-gas incubator (5% CO environment)2，5％O2，90％N2Humidity 95%, temperature 37 ℃ C.).
2.2 synchronization
According to the research of oryzanol and the like (see the literature: oryzanol, Liyujie, Chuaibu, and the like. the influence research of dihydroartemisinin on the permeability of erythrocyte membranes of in-vitro plasmodium infected human), 5 percent D-sorbitol solution can be used for better selecting plasmodium to realize synchronization. And (5) observing by coating a thin blood film, and performing ring period synchronization operation when the infection rate of the insect strains is 5-10% and the ring period accounts for the majority (> 60%). Mixing culture medium and red blood cells in culture dish, 1900r min-1Centrifuge at room temperature for 2min and discard the supernatant. Adding 8mL of 5% D-sorbitol solution preheated at 37 deg.C, mixing, incubating at 37 deg.C for 10min, 1900 r.min-1Centrifuging at room temperature for 2min, and removingAnd (5) clearing. Adding complete culture medium with proper volume, regulating the volume ratio to be 2% by using fresh human O-type blood red cells, and placing the mixture into a three-atmosphere incubator to continue constant-temperature culture.
2.3 grouping and dosing
Continuously carrying out 3 times of synchronization treatment and then carrying out medicine adding treatment. Dihydroartemisinin is prepared with dimethyl sulfoxide (DMSO) to give 1 μmol/L-1Storing the stock solution (DMSO concentration is less than or equal to 0.1%), keeping at-20 deg.C in dark, and diluting to the required concentration before adding medicine. Adding medicine after 6h of the last synchronization, changing the culture medium every 48h, and repeating 4 holes in each group.
2.4 IC50 calculation
The method comprises the following steps: adding drug to plasmodium falciparum (4-8 hours after plasmodium infects red blood cells), culturing for about 72 hours (until plasmodium is in trophozoite stage), lightly discarding 100 μ l of supernatant, adding 100 μ l/pore lysis solution (containing fluorescent dye SybrGreen1), and mixing well. Incubating for 1.5-2h at room temperature in a dark place, and detecting Ex (485 nm) by a multifunctional microplate reader; em 525 nm. Calculating the growth inhibition rate: percentage inhibition growth ═ 1- (A)well–Aneg/Apos–Aneg) X 100) and IC50 values were counted using a non-linear regression analysis method.
The results are shown in fig. 1, and after DHA treatment, IC50 of the 8D5 insect strain was reduced compared with that of the 3D7 insect strain, indicating that over-expression of pfEMP1 can enhance the antimalarial effect of DHA.

Claims (10)

1. An artemisinin-based enhanced pharmaceutical composition for the prevention or treatment of malaria comprising an agent that promotes expression of PfEMP1, artemisinin or a derivative thereof.
2. The pharmaceutical composition of claim 1, wherein the artemisinin derivative comprises artesunate, artemether, arteether, dihydroartemisinin; preferably, the artemisinin derivative is dihydroartemisinin.
3. The pharmaceutical composition of claim 1 or 2, wherein the agent that promotes the expression of PfEMP1 comprises a PfEMP1 gene, a PfEMP1 overexpression vector, a PfEMP1 protein, an enhancer miRNA, an enhancer transcriptional regulator, or an enhancer targeting small molecule compound, an agent that inhibits the methylation of the var gene promoter.
4. The pharmaceutical composition of claim 3, wherein the agent that inhibits methylation of the var gene promoter comprises an agent that inhibits histone lysine methylase; preferably, the histone lysine methylase is PfSETvs.
5. The pharmaceutical composition of claim 4, wherein the agent that inhibits PfSETvs comprises an agent that inhibits PfSETvs gene mRNA, an agent that inhibits PfSETvs protein.
6. The pharmaceutical composition of claim 5, wherein the agent that inhibits PfSETvs gene mRNA comprises an agent that inhibits mRNA stability, an agent that inhibits mRNA translation activity; the agent for inhibiting the PfSETvs protein comprises an agent for inhibiting the stability of the PfSETvs protein, an agent for inhibiting the activity of the PfSETvs protein and an agent for inhibiting the function of the PfSETvs protein.
7. The pharmaceutical composition of claim 6, wherein the agent that inhibits PfSETvs gene mRNA comprises a double-stranded ribonucleic acid directed against PfSETvs gene mRNA; agents that inhibit the function of PfSETvs protein include antibodies that inhibit the function of TMED2 protein; preferably, the double-stranded ribonucleic acid aiming at PfSETvs gene mRNA comprises siRNA and shRNA.
Use of PfEMP1 in the manufacture of a medicament for enhancing the antimalarial effect of artemisinin or derivatives thereof; preferably, the medicament is a pharmaceutical composition according to any one of claims 1 to 7, the artemisinin derivative comprises artesunate, artemether, arteether, dihydroartemisinin; more preferably, the artemisinin derivative is dihydroartemisinin.
9. Use of artemisinin or a derivative thereof for the preparation of a pharmaceutical composition according to any one of claims 1 to 8; preferably, the artemisinin derivatives include artesunate, artemether, arteether, dihydroartemisinin; more preferably, the artemisinin derivative is dihydroartemisinin.
Use of PfEMP1 and artemisinin or a derivative thereof in the manufacture of a medicament for the prevention or treatment of malaria; preferably, the medicament is a pharmaceutical composition according to any one of claims 1 to 7, the artemisinin derivative comprises artesunate, artemether, arteether, dihydroartemisinin; more preferably, the artemisinin derivative is dihydroartemisinin.
CN202010365552.8A 2020-04-30 2020-04-30 An artemisinin enhanced pharmaceutical composition for preventing or treating malaria Pending CN111514300A (en)

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Cited By (1)

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CN114617842A (en) * 2022-01-05 2022-06-14 沈阳农业大学 Preparation method and application of dihydroartemisinin-sodium carboxymethylcellulose solution

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Application publication date: 20200811