CN110604733A - Application of artemisinin drugs in preparation of antimalarial drugs by combining with other drugs - Google Patents
Application of artemisinin drugs in preparation of antimalarial drugs by combining with other drugs Download PDFInfo
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- CN110604733A CN110604733A CN201910888053.4A CN201910888053A CN110604733A CN 110604733 A CN110604733 A CN 110604733A CN 201910888053 A CN201910888053 A CN 201910888053A CN 110604733 A CN110604733 A CN 110604733A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention relates to an application of artemisinin drugs and other drugs in preparation of antimalarial drugs. The invention provides application of the artemisinin or the analogs thereof in preparation of antimalarial drugs by combining with non-pigment target drugs. The application of the artemisinin or the analog thereof in preparing the drug for killing artemisinin-sensitive plasmodium and the application of the non-pigment target drug in preparing the drug for killing artemisinin-resistant plasmodium, wherein the artemisinin-resistant plasmodium refers to plasmodium which cannot be killed by the artemisinin or the analog thereof. Compared with the prior art, the invention does not aim at preventing or slowing the generation of the resistance of the insect body to the southernwood drugs, but the drug application method guided by the theory of the invention can simultaneously treat malaria caused by resistant or sensitive insect strains regardless of the generation of the resistance and can provide accurate individual treatment.
Description
Technical Field
The invention belongs to the field of life medicine science, and particularly relates to an application of artemisinin drugs and other drugs in preparation of antimalarial drugs.
Background
Malaria is still an important infectious parasitic disease in the world and in our country. As the first-line medicine artemisinin drugs begin to face the risks of generation and spread of resistant insect strains, the drug effect begins to decline and the range of resistant insects is increasingly expanded. Developing according to the trend, people face no drug-cure risk for malaria in the near future. Therefore, there is a high need to research and develop a new generation of antimalarial drugs. At present, the combination therapy (ACT) proposed at home and abroad has various combinations and random composition, even if the combination therapy has an insect-resistant effect, the insect-resistant principle is unclear, and the phenomena of different treatment effects of different patients can occur, so that the accurate treatment is difficult to achieve. In addition, targeted and unambiguous updating and adjustment of combinations in which the therapeutic effect of the patient is not optimal is difficult to achieve quickly and flexibly.
Chinese patent CN106074502A discloses the use of artemisinin and/or iron chelators as parasiticides for parasites. The specific scheme comprises the following steps: artemisinin is used as a pesticidal agent for common parasites or for iron chelator resistant parasites, or an iron chelator is used as a pesticidal agent for common parasites or for artemisinin resistant parasites, or a combination of artemisinin and an iron chelator is used as a pesticidal agent for artemisinin resistant parasites or for iron chelator resistant parasites. Based on the theory that artemisinin and derivatives thereof prevent the utilization of organism iron and the theory that an iron chelator prevents the utilization of organism iron, artemisinin or derivatives thereof and a griddle mixture are matched and selectively used to improve the insecticidal effect on artemisinin-resistant insect strains or griddle mixture-resistant insect strains.
The objectives of currently available ACT therapies: firstly, killing insects; secondly, the generation of the resistance of the worm body to the southernwood drugs is prevented or delayed, and a mode of combining two drugs is often adopted. However, the effect is different for different patients, and the principle of matching two drugs is unclear.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the application of the artemisinin medicine and other medicines in preparing the antimalarial medicine.
The present inventors have found through research that although resistant insect strains develop resistance to artemisinin and its analogs, they also pay the expense of reproductive and vitality losses. Therefore, the invention develops a new application of the artemisinin and the analogs thereof as the preparation of the antimalarial drug according to the research so as to realize personalized, accurate and flexible treatment and adapt to the current and future with the increasing popularization of the artemisinin resistance.
The purpose of the invention can be realized by the following technical scheme:
the research of the invention finds that the plasmodium is a protozoan which is seriously dependent on iron to live and cause diseases, and the pathogenicity is closely related to the iron-dependent characteristic. Therefore, the invention provides a novel application method of artemisinin and analogs thereof as antimalarial drugs by utilizing the growth and reproduction characteristics of plasmodium dependent iron, namely provides an application of the artemisinin or the analogs thereof and non-pigment target drugs in combination as antimalarial drugs.
When artemisinin or analogs thereof and non-pigment target drugs are used for preparing anti-malarial drugs to treat malaria patients, the treatment is divided into two stages. Stage one: the artemisinin or the analog thereof is used for killing artemisinin sensitive insects in a patient. If the patient is not cured and there is an artemisinin resistant insect infection, the second phase is entered. And a second stage: follow-up treatment with non-pigment target antimalarial drugs and adjust the drug types according to the curative effect until the patient recovers. Thus, the essence of the invention can be expressed as "artemisinin + X". X is a non-pigment target drug. The therapy has the advantages of individuation and accurate treatment.
The research of the invention finds that the plasmodium is a serious iron-dependent protozoan. On the one hand, both sexually and asexually, the polypide contains a large amount of iron stored in the form of pigment, see FIG. 1. Furthermore, after red blood cells are infected by plasmodium, a large number of iron-related genes and heme-related genes are highly expressed, much higher than toxoplasma and babesia, which are also phylum apicomplexa, as shown in fig. 2. It is seen that the plasmodium is heavily dependent on iron, which, in turn, becomes the weak point of the insect, and that iron chelators kill the body of the insect, as is well documented.
Artemisinin and its analogs require iron activation to exert an anti-insect effect. Therefore, artemisinin becomes a specific antimalarial drug. When the plasmodium undergoes genetic or physiological variation and is no longer heavily dependent on iron, the pigment content of the parasite decreases sharply, which results in artemisinin resistance, but at the same time the fertility, viability and pathogenicity decrease. Thus, at this time, although the worm bodies have artemisinin resistance, sensitivity to other drugs is enhanced. Therefore, the compound is the theoretical basis and the use basis of the combined medicine.
The invention utilizes the characteristics of the polypide to put forward a new drug combination mode: artemisinin + X (non-pigment target group). Because artemisinin acts on pigment and the anti-insect effect is lost to prevent function overlapping, the drug combination object of the invention takes non-pigment target drugs as the main (the possibility that some pigment target drugs and artemisinin drugs are overlapped in function and have better effect is not excluded, but not preferred).
The invention provides an application of artemisinin and analogs thereof in preparing an anti-malaria drug, and an application of the artemisinin or the analogs thereof in preparing a drug for killing artemisinin-sensitive malaria parasites.
Furthermore, the invention provides the application of the artemisinin or the analogs thereof in combination with non-pigment target drugs for preparing antimalarial drugs.
Further, the application of the artemisinin or the analog thereof in preparing the drug for killing artemisinin-sensitive plasmodium and the application of the non-pigment target drug in preparing the drug for killing artemisinin-resistant plasmodium refers to the plasmodium which cannot be killed by the artemisinin or the analog thereof.
Further, the non-pigment target drug refers to a drug that does not target blocking, interfering with pigment formation.
Further, the non-pigment target drug is selected from drugs with drug action sites on cell membranes, cell nuclei or non-food vacuole organelles. Further, the non-pigmented target drug is selected from folic acid antagonists. While chloroquine, for example, can interfere with pigment formation, is a pigment target drug and is not a non-pigment target drug in the present invention. Combination with artemisinin is possible as long as it is a non-pigment target drug. Through insect-resistant effect experiment screening, the optimal combination, dosage and dosage form are found out.
Furthermore, when the artemisinin or the analogs thereof are combined with a non-pigment target drug to prepare the antimalarial drug, the ratio of the artemisinin or the analogs thereof to the non-pigment target drug is determined according to the drug resistance of a patient, and the dosage of the artemisinin or the analogs thereof can be reduced or the dosage of the non-pigment target drug can be increased for the patient with artemisinin resistance.
Further, the analog of artemisinin refers to artemisinin derivatives, including artemether, artesunate or dihydroartemisinin.
Compared with the prior art, the method does not aim at preventing or slowing down the generation of the resistance of the insect body to the southernwood drugs, but can simultaneously treat malaria caused by resistant or sensitive insect strains and realize accurate individual treatment by using the drug combination method and the concept guided by the theory of the invention regardless of the generation of the resistance.
The invention can guide the combination mode of the combined medicines and can adjust the combination in time according to the curative effect of different patients. The method has strong individuation, accuracy and targeting. Is a feature not present in the ACT combinations at present. Compared with the existing ACT therapy, the invention does not consider whether the patient is infected by artemisinin sensitive insects or resistant insects, does not consider whether the drug resistance is generated, and only achieves the aim of accurate cure by timely and accurately adjusting the combination of artemisinin drugs and non-pigment target drugs according to the treatment effect of the patient and the dependence of plasmodium iron based on an individualized means.
Drawings
FIG. 1 internal ferrichrome of Plasmodium.
A, pigment particles (black arrows) and merozoites (white arrows) in the vegetative stage macrotrophozoites and schizonts; b, pigment granules in gametes at sexual reproduction stage (black arrows); and C, analyzing the pigment particles containing iron by electron microscope energy spectrum.
FIG. 2 comparison of iron and heme-related gene expression profiles after infection of cells with three protozoa.
A, 58 percent (a) of plasmodium high-expression iron-related genes, 51 percent (a) of heme-related genes and 31 percent (a) of calcium are contained; b, the toxoplasma is 34%, 25% and 9% respectively; c, 13%, 17% and 9% of babesia.
Detailed Description
Provides an application of the artemisinin or the analogs thereof in preparing antimalarial drugs by combining with non-pigment target drugs.
The application of the artemisinin or the analog thereof in preparing the drug for killing artemisinin-sensitive plasmodium and the application of the non-pigment target drug in preparing the drug for killing artemisinin-resistant plasmodium, wherein the artemisinin-resistant plasmodium refers to the plasmodium which can not be killed by the artemisinin or the analog thereof. When artemisinin or analogs thereof and non-pigment target drugs are used for preparing anti-malarial drugs to treat malaria patients, the treatment is divided into two stages. Stage one: the artemisinin or the analog thereof is used for killing artemisinin sensitive insects in a patient. If the patient is not cured and there is an artemisinin resistant insect infection, the second phase is entered. And a second stage: follow-up treatment with non-pigment target antimalarial drugs and adjust the drug types according to the curative effect until the patient recovers.
Wherein, the non-pigment target drug refers to a drug which does not target the formation of the blocking and interference pigment. The non-pigment target drug is selected from drugs with drug action sites on cell membranes, cell nuclei or non-food vacuole organelles. Further, the non-pigmented target drug is selected from folic acid antagonists. While chloroquine, for example, can interfere with pigment formation, is a pigment target drug and is not a non-pigment target drug in the present invention.
Combination with artemisinin is possible as long as it is a non-pigment target drug. Through insect-resistant effect experiment screening, the optimal combination, dosage and dosage form are found out.
When the artemisinin or the analogs thereof are combined with the non-pigment target drugs for preparing the antimalarial drugs, the ratio of the artemisinin or the analogs thereof to the non-pigment target drugs is determined according to the drug resistance condition of a patient, and the dosage of the artemisinin or the analogs thereof can be adjusted to be lower or the dosage of the non-pigment target drugs can be increased for the patient with artemisinin resistance.
The artemisinin analogue refers to artemisinin derivatives, including artemether, artesunate or dihydroartemisinin.
The invention is described in detail below with reference to the figures and specific embodiments.
The following treatment regimens were provided for a malaria patient:
by orally taking artesunate, 100mg for the first time, and then 2 times a day, 50mg once for 5 consecutive days; following treatment with a population of non-pigmented target drugs, which may be drugs currently used in ACT formulations or drugs historically used to be effective against malaria, in the event that the patient is ill. The effect of the artemisinin sensitive insect plant is not obvious when the artemisinin drugs are used alone, but the artemisinin drugs are used for forming hierarchical collocation, namely, the artemisinin drugs are used for eliminating the sensitive insect plant firstly, and then the individualized and effective non-pigment target drugs are screened out according to the insect-resistant effect to be used as a second echelon to form a echelon treatment scheme, so that the aim of thoroughly killing insects in an experiment is fulfilled.
The selection of non-pigment target drugs can be realized according to the following procedures: respectively selecting insect membrane destroying drugs, metabolism blocking drugs, electron transfer chain blocking drugs, fatty acid synthesis inhibiting drugs and the like. Only one kind of artemisinin and non-pigment target drugs is selected once in the screening, so that the best individualized 'artemisinin and non-pigment target drug' insect-resistant combination is found. For special cases, when the screening is not performed, the combination of artemisinin, non-pigment target drugs 1, non-pigment target drugs 2 and non-pigment target drugs 3 … can be adopted. The non-pigment anti-insect drug is used at present or used once, although the non-pigment anti-insect drug cannot be completely treated, the effective drug is selected as a target, the dosage used at present or at the moment is taken as a reference, and the dosage is increased or decreased or the combination type is adjusted according to the treatment effect.
Example 1
The following treatment regimens were provided for a malaria patient:
orally taking artesunate or other artemisinin analogs for 50-200mg for the first time, and then taking 2 times a day and 50mg once for 10 consecutive days; if the patient is not good, other antimalarial drugs can be added.
Such as: can increase pyrimethamine (influencing folic acid metabolism), 18-30mg, 3 times a day, 5-10 days for a treatment course, and if the effect is not ideal, the compatibility of medicines can be adjusted.
Firstly, a new combination is added on the basis of pyrimethamine, such as following the treatment of non-pigment target drug group, such as sulfadoxine (preventing the synthesis of tetrahydrofolic acid and the synthesis of protein), and the two are respectively orally taken at 30-100mg and 200-2000 mg.
Secondly, the externally applied medicine changes pyrimethamine and the like and is adjusted to atovaquone and the like (the action part of the medicine is a cytochrome bcl binding point which influences an electron transfer chain.) for oral administration for 1000 times and 3 times per day at 300 times. And so on.
In addition, newly discovered or invented antimalarial drugs can be continuously supplemented to enrich the drug combination.
In summary, the present application is based on artemisinin and kills insects by preventing iron utilization, while further enhancing the drug effect by increasing other metabolic or pass-through blocking drugs. In use, the compatibility types can be continuously adjusted according to different people and different effects until the accurate cure aiming at different patients is achieved.
In addition, unlike current ACT therapies, artemisinin is not used simultaneously with other drugs, but rather, artemisinin-like drugs are first used and followed when the body of the insect cannot be completely killed and, in use, the dosage and type of drug is adjusted in combination with the therapeutic effect.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (8)
1. The application of artemisinin or an analog thereof in preparing an antimalarial drug is characterized in that the artemisinin or the analog thereof is used in preparing a drug for killing artemisinin-sensitive plasmodium.
2. The use of artemisinin or its analogs as a drug for the manufacture of an anti-malarial drug according to claim 1, wherein artemisinin or its analogs is used in combination with a non-pigmented target drug for the manufacture of an anti-malarial drug.
3. The use of artemisinin or its analogs as a drug for the manufacture of a drug against malaria according to claim 2, wherein artemisinin or its analogs are used for the manufacture of a drug for the killing of artemisinin-sensitive malaria parasites,
the non-pigment target drug is used for preparing a drug for killing artemisinin-resistant plasmodium, wherein the artemisinin-resistant plasmodium refers to plasmodium which cannot be killed by artemisinin or analogues thereof.
4. The use of artemisinin and its analogs as claimed in claim 2 or 3 for the preparation of antimalarial drugs, wherein the non-pigment target drugs are those that do not target blocking, interfering with pigment formation.
5. The use of artemisinin and its analogs as drugs in the preparation of drugs against malaria according to claim 4, wherein the non-pigmented target drugs are selected from drugs with drug action sites on the cell membrane, nucleus or non-food vacuolar organelles.
6. The use of artemisinin and its analogs as drugs against malaria according to claim 5, wherein the non-pigmented target drugs are selected from folic acid antagonists.
7. The use of artemisinin or its analogs as a drug for the preparation of an anti-malarial drug according to claim 2, wherein the use of artemisinin or its analogs in combination with a non-pigmented target drug for the preparation of an anti-malarial drug,
the ratio of artemisinin or analogs thereof to non-pigment target drugs is determined according to the drug resistance of patients, and the dosage of artemisinin or analogs thereof can be adjusted to be low or the dosage of non-pigment target drugs can be increased for patients with artemisinin resistance.
8. The use of artemisinin and its analogues as claimed in claim 1 or 2 for the preparation of anti-malarial drugs, wherein the analogue of artemisinin is an artemisinin derivative including artemether, artesunate or dihydroartemisinin.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283458A (en) * | 1999-07-05 | 2001-02-14 | 屠呦呦 | Compound dihydroartemisinin as new antimalarial |
| CN100998569A (en) * | 2006-12-30 | 2007-07-18 | 桂林制药有限责任公司 | Compound antimalarial three-layered tablets containing artemisinin or its derivatives and its preparing method |
| US20110160254A1 (en) * | 2008-02-06 | 2011-06-30 | Sanofi-Aventis | Combination of a bis-thiazolium salt or a precursor thereof and artemisinin or a derivative thereof for treating acute malaria |
| CN106074502A (en) * | 2016-07-29 | 2016-11-09 | 同济大学 | Arteannuin and/or iron chelating agent are used as the application of parasite insecticide |
| CN107837270A (en) * | 2017-09-21 | 2018-03-27 | 广东艾时代生物科技有限责任公司 | A kind of application of combination medicine in malaria is treated |
-
2019
- 2019-09-19 CN CN201910888053.4A patent/CN110604733A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283458A (en) * | 1999-07-05 | 2001-02-14 | 屠呦呦 | Compound dihydroartemisinin as new antimalarial |
| CN100998569A (en) * | 2006-12-30 | 2007-07-18 | 桂林制药有限责任公司 | Compound antimalarial three-layered tablets containing artemisinin or its derivatives and its preparing method |
| US20110160254A1 (en) * | 2008-02-06 | 2011-06-30 | Sanofi-Aventis | Combination of a bis-thiazolium salt or a precursor thereof and artemisinin or a derivative thereof for treating acute malaria |
| CN106074502A (en) * | 2016-07-29 | 2016-11-09 | 同济大学 | Arteannuin and/or iron chelating agent are used as the application of parasite insecticide |
| CN107837270A (en) * | 2017-09-21 | 2018-03-27 | 广东艾时代生物科技有限责任公司 | A kind of application of combination medicine in malaria is treated |
Non-Patent Citations (1)
| Title |
|---|
| 苏新专 等: "青蒿素与疟疾: 药物激活、作用机理及抗药性的研究进展", 《科学通报》, vol. 62, no. 18, 5 April 2017 (2017-04-05), pages 1928 - 1937 * |
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Application publication date: 20191224 |