How Effective Is Artesunate for Malaria?

During the Vietnam War in the 1960s, the prevalence of malaria in tropical jungles in Vietnam caused serious non-combatant attrition among Chinese and Vietnamese soldiers. Chinese science and technology workers have worked hard to finally develop a new antimalarial drug, artemisinin and its derivatives, which is another important milestone in the history of antimalarial drugs in the world. Chinese researchers have conducted strict and systematic clinical research on artemisinin suppositories, artesunate, artemether, and dihydroartemisinin, a new class of six drugs and six preparations, using internationally accepted standards for up to 10 years .

Introduction to antimalarial drugs

Antimalarial drugs are an important means of controlling malaria. None of the existing antimalarial drugs can kill all aspects of the life cycle of the malaria parasite.

In accordance with the Law of the People's Republic of China on the Prevention and Treatment of Infectious Diseases, the Law of the People's Republic of China on Drug Administration and the actual needs of malaria control, China has formulated the Principles and Programs for the Use of Antimalarials (Revised Draft) ^[1] .

Representative drugs: chloroquine phosphate, primary aminoquine phosphate, pyrimidine, quinine, artemisinin, artemether (artemether), artesunate, etc.

Introduction to the antimalarial drug Plasmodium

There are four types of protozoa that cause human malaria: Plasmodium vivax, Plasmodium vivax (causes P. vivax, all of which occur once every 48 hours), Plasmodium vivax (causes P. malaria, which occurs once every 72 hours), and malignant Plasmodium (causes Plasmodium falciparum to occur every 48 hours or has a relaxation fever).

The life history of Plasmodium can be divided into two stages, sexual reproduction and asexual reproduction. The former occurs in female Anopheles and the latter in humans. The asexual reproduction in human body is divided into primary extra-erythrocytic phase (hereinafter referred to as the primary infrared phase), secondary extra-erythrocytic phase (hereinafter referred to as the secondary infrared phase), intra-erythrocytic phase (hereinafter referred to as the inner red phase), etc. stage. Various antimalarial drugs exert their antimalarial effects by affecting the different developmental stages of the life cycle of the Plasmodium.

Antimalarial in vitro phase

The development and reproduction of male and female gametophytes in mosquitoes include two stages of gamete reproduction and spore proliferation.

Antimalarial in vivo phase

Primary infrared phase

People who are bitten by Anopheles mosquitoes infected with Plasmodium spores infuse human saliva with their saliva, invade parenchymal cells, and undergo merozoite. After 6 to 12 days of maturation, a large number of merozoites are formed, which escape liver cells and enter red blood cells. This period occurs before entering the red blood cells, does not occur clinical symptoms, is the incubation period of malaria. Application of drugs effective for this period, such as pyrimethamine, has a preventive effect.

2. Secondary infrared phase

Some spores enter the hepatocytes slowly or temporarily without development. They are called dormant bodies. After 4 to 6 months, the dormant body proliferates and divides into a secondary infrared phase, which is the source of malaria recurrence. It is known that Plasmodium falciparum and Plasmodium falciparum do not have this period and will not recur after treatment with chloroquine or quinine. Plasmodium vivax and Plasmodium ovale have this period, so relapses often occur. Primary aminoquine, acetaminophen and other drugs can act at this stage, so they can be combined with chloroquine to cure vivax malaria.

3. Red period

The merozoites that enter the red blood cells develop into spores, and then become merozoites. Finally, the merozoites mature to release a large number of merozoites and invade other red blood cells again, repeating their merozoal proliferation. When a large number of merozoites escape the red blood cells, malaria symptoms occur. Drugs capable of killing schizonts such as chloroquine and quinine can control the symptoms of malaria.

After 3 to 5 generations of schizont proliferation in erythrocytes, merozoites in the erythrocytes are differentiated into male and female gametophytes because the human body conditions are not favorable for schizont proliferation. When Anopheles mosquitoes suck blood, they enter the mosquito body for sexual reproduction, and eventually form sporophytes that cause transmission and epidemic. Because gametophyte is the root cause of malaria epidemic and transmission, the application of drugs that kill or inhibit gametophyte, such as acetaminophen, primary aminoquine, and pyrimethamine, can prevent malaria transmission.

In recent years, drug-resistant Plasmodium strains have appeared in Central, South America, and Southeast Asia. The increase in the number of chloroquine-resistant strains of Plasmodium falciparum has made the problem even more serious. Plasmodium is more likely to develop resistance to chloroquine and pyrimethamine, followed by quinine and primary quinine. The experimental results showed that the dihydrofolate reductase increased significantly or the binding force with diethylpyrimidine was significantly reduced, which caused the inhibitory effect of diethylpyrimidine on the parasite. In order to prevent the emergence of drug resistance, clinical use of antimalarial drugs, that is, combination of antimalarial drugs at different points of action, is now being promoted, so that different metabolic links of the Plasmodium are affected by drugs. For example, combined use of pyrimethamine (or trimethoprim) and sulfa (or sulfones such as dapsone), the former inhibits dihydrofolate reductase and the latter inhibits dihydrofolate synthetase. Protozoa's folic acid metabolism has a double blocking effect, so its nucleic acid synthesis is inhibited, and the nucleus cannot divide and reproduce.

Classification of antimalarial drugs

Antimalarials control symptoms

1. Chloroquine:

Synthetic 4-aminoquinoline derivatives

(1) It has a killing effect on the erythrocytic intraperitoneal schizonts of various Plasmodium and can quickly control the symptoms. It can also be used for the prevention of symptoms. It is characterized by high efficacy and fast effect. It has no effect on the exoerythrocytic period. Because it affects DNA replication and RNA transcription and causes amino acid deficiency, it inhibits the division and reproduction of Plasmodium.

(2) Anti-intestinal amoebiasis.

(3) Suppress the immune response, used for rheumatoid arthritis, butterfly lupus erythematosus, etc. Conventional doses have few and mild adverse reactions, and large doses can cause visual impairment and liver and kidney damage.

2. Quinine:

It has a killing effect on the erythrocyte trophozoites of various Plasmodium and can control clinical symptoms. Adverse reactions include cinchona response, myocardial inhibitory effect, atopic response, uterine excitatory effect and central inhibitory effect. Mainly used for the treatment of chloroquine-resistant or multidrug-resistant malaria, especially cerebral malaria.

3. Artemisinin and Artemether:

The peroxy group of artemisinin can generate free radicals, which have a killing effect on the trophozoites of the red blood cells. It is used to treat vivax and falciparum, and it still has a good effect on cerebral malaria and chloroquine-resistant strains of infection. But the biggest disadvantage is the high recurrence rate. Adverse reactions are rare. However, large doses have toxic effects on animal embryos and are contraindicated in pregnant women. Artemether has stronger antimalarial activity than artemisinin, has a lower recurrence rate in the near future, and has less adverse reactions.

4. Methylquinoline mefloquine:

It is effective for P. vivax and P. falciparum, with complete insecticidal and long-lasting effects, but slow control of symptoms, and is compatible with artemether.

Antimalarial drugs control relapse

Primaquine

It has a strong killing effect on the secondary erythrocyte phase of P. vivax and various gametophytes of Plasmodium. It is the most effective drug to eradicate P. vivax and control the spread of malaria. This drug is highly toxic, and patients with glucose 6-phosphate dehydrogenase deficiency are prone to acute hemolytic anemia and methemoglobinemia.

Etiological prevention of antimalarials

Pyrimethamine

It has an inhibitory effect on the primary erythrocytes of P. falciparum and P. vivax and is the drug of choice for etiological prevention. It can also prevent the spore proliferation of mosquitoes in the mosquito and control the spread of erythrocytes. Of immature schizonts used to control the onset of chloroquine-resistant malaria symptoms, but with a slower effect. Inhibits the dihydrofolate reductase of Plasmodium and prevents nucleic acid synthesis. Often used in combination with dihydrofolate synthase inhibitors sulfa or sulfones to enhance the efficacy of chloroquine resistant malaria There are few adverse reactions, and large doses can cause megaloblastic anemia. Mistakes by children can cause convulsions and death.

Reasonable use of antimalarials

Antimalarial Drug Selection

Control of symptoms: Sensitive to chloroquine: chloroquine

Cerebral malaria: chloroquine phosphate, quinine dihydrochloride, artemisinin-like needles

Chlorquine-resistant malaria: quinine, mefloquine, artemisinin

Resting period: pyrimethamine + primary aminoquine

Preventive medication: pyrimethamine (cause prevention)

Chloroquine (symptom control)

Combination of antimalarials

At present, there is no single drug that has an effect on all aspects of the life history of Plasmodium. Combined medication is generally used in clinical practice.

Benign malaria: chloroquine + primary aminoquine

Relapse prevention: pyrimethamine + primary aminoquine

Efficacy: pyrimethamine + sulfa

Chlorquine-resistant P. falciparum: artemisinin + mefloquine (or solanidine)

Antimalarial drug types

Antimalarial quinolinols

Research on antimalarial drugs began with the extraction of Quinine from cinchona bark, one of the few drugs in history that has relieved human suffering. The cinchona bark was known to treat fever and malaria as early as the 17th century, and quinine was extracted from the cinchona bark in 1820. The complete synthesis of quinine by Woodward and Doering in 1945 is an important milestone in modern organic synthetic chemistry.

Quinine

Containing two bases, two nitrogen atoms of quinoline ring and quinoline base respectively, pK is 4.2, 8.8, and its sulfate or dihydrochloride is used clinically.

Quinine combines with the DNA of Plasmodium to form a complex, which inhibits the replication of DNA and the transcription of RNA, thereby inhibiting the protein synthesis of the protozoa. In addition, quinine can reduce the oxygen consumption of Plasmodium, inhibit the phosphorylase in Plasmodium and interfere with its glucose metabolism.

Quinine has four chiral carbons in its molecule, namely C-3 (R), C-4 (S), C-8 (S), and C-9 (R). The optical stereoisomeric activities are different. . Quinine isomers obtained from plants include Quinidine, Cinchonine, and Cinchonidnie. Among them, quinidine (3 R, 4S, 8R, 9S) is 2 to 3 times more active than quinine in chloroquine-resistant and resistant Plasmodium falciparum species, and it has the same results in vivo, except that quinidine is a sodium channel blocker. Stagnation agents have greater side effects and lower blood pressure on the heart than quinine.

Quinine can produce cinchona responses when the daily dosage is more than 1g, that is, headache, tinnitus, dazzling, nausea, vomiting, vision and hearing loss.

Quinine can inhibit or kill (P. vivax, P. vivax) and P. falciparum during the red intraperitoneal period, and has antipyretic and uterine contraction effects. Clinically used to control the symptoms of malaria.

Quinine is oxidized and metabolized into 2,2-dihydroxyquinine in vivo, and its antimalarial effect is greatly weakened. Blocking the 2 position can prevent the biological oxidation of such drugs. Therefore, new 2-substituted quinolinol antimalarial drugs have been developed, such as mefloquine.

Aminoquinoline

Studies on the structure-activity relationship of quinine found that isoquinoline compounds with amino side chains may be the basic structure of antimalarial drugs. Therefore, the basic side chain was introduced into 4-aminoquinoline to obtain the most effective insecticidal derivative against Schizoplasma. Among them, the most active was Chloroquine. Although drug-resistant P. falciparum has appeared in most regions of the world, chloroquine has been very sensitive to both P. vivax and P. ovale, and it still maintains high therapeutic value for P. vivax.

In the study of 8-aminoquinoline derivatives, it was found that Primaquine has strong antimalarial effect and low toxicity.

1. Chloroquine Phosphate

It is a 4-aminoquinoline drug. After entering the Plasmodium, its molecule is inserted between the double-helix strands of the Plasmodium DNA to form a stable complex, which affects DNA replication, RNA transcription and protein synthesis. Chloroquine and its derivatives have amino and chlorine atoms at the 4- and 7-positions, respectively, and the two nitrogen atoms of the amino side chain are 4 carbons each. The distance is suitable, so that N + at both ends and P043- on the two strands of DNA form an ion bond, and Cl at position 7 generates electrostatic attraction with the positively charged amino group on the guanine in the double helix. As a result, the drug molecule was firmly inserted between the DNA double helices.

Chloroquine has a chiral carbon, and its d, l and dl isomers have the same activity, but the d isomer is less toxic to mammals than the l isomer. The racemate is used clinically. The main metabolite of chloroquine is N-desethylchloroquine. For sensitive malaria, deethylchloroquine is equivalent to chloroquine. For drug-resistant P. falciparum, the activity of this metabolite is obviously decrease.

Chloroquine phosphate can kill pre-erythrocytic plasmodium and gametophyte, and can control the recurrence and transmission of malaria, but it is more toxic. Chloroquine phosphate can also effectively control the symptoms of malaria, with fast and long-lasting effects and strong efficacy, and is an effective drug for the treatment of malaria symptoms. Clinically used for treatment: chloroquine-sensitive P. falciparum, P. vivax and P. vivax, and can be used for the preventive prevention of malaria symptoms, as well as for the treatment of parenteral amoebiasis, connective tissue disease, and light-sensitive diseases ( Such as sun erythema) and so on.

2. Primaquine Phosphate

It is an 8-aminoquinoline drug, which is transformed into a quinoline quinone derivative with strong oxidizing properties in the body, which can convert reduced glutathione (GSH) in red blood cells to oxidized glutathione (GSSH) When the latter is reduced, it is necessary to consume reduced coenzyme II (NADPH). Coenzyme (NADP) was consumed in the development of liver parenchymal cells in the infrared phase of Plasmodium, and the action of primary aminoquine interfered with the reduction of Coenzyme , which reduced Coenzyme and severely damaged the glucose metabolism and oxidation of Plasmodium. .

Primaquine, as an antimalarial drug to prevent the recurrence and transmission of malaria, has a strong killing effect on various types of Plasmodium gametophytes in the merozoites of benign malaria in the infrared period, so it is used to control the recurrence of benign malaria. Because primary aminoquine can kill the gametophyte of various types of Plasmodium in the blood of the fever body, it can block the spread of malaria. It is used clinically to prevent and control the recurrence and transmission of vivax malaria and malaria, and to prevent the spread of malaria.

The main metabolites of primary aminoquine are 8- (3-carboxy-1-methylpropylamino) -6-methoxyquinoline, 5-hydroxyprimary aminoquine, and 5-hydroxy-6-demethylprimary aminoquine. . Primary aminoquine can cause hypotension when injected, so it can only be taken orally.

24- Antimalarial 2,4-diaminopyrimidines

Based on the fact that 2,4-diaminopyrimidine can inhibit the dihydrofolate reductase of Plasmodium, it is envisaged that such derivatives may also have antimalarial activity. It has been found that both Pyrimethamine and Nitroquine have good effects on malaria. Prevention and treatment.

Pyrimethamine

It is a dihydrofolate reductase inhibitor. By inhibiting the dihydrofolate reductase of Plasmodium, it interferes with the normal generation of folic acid of Plasmodium and reduces the synthesis of nucleic acids, thereby inhibiting the division of the nucleus of Plasmodium and the reproduction of Plasmodium.

Pyrimethamine is effective in the early stages of P. falciparum and Plasmodium erythrocytes and is often used as a causative agent. It is characterized by long-lasting effects, and the effect can be maintained for more than one week with one dose. In order to kill the pyrimethamine-resistant strain, in recent years abroad, pyrimethamine and dihydrofolate synthase inhibitor sulfadoxine have been combined to form a compound preparation, which has a dual inhibitory effect.

In addition, pyrimethamine can also inhibit the development of Plasmodium in mosquitoes, so it can block transmission. Clinically used to prevent malaria and apnea anti-relapse therapy.

When used in a therapeutic amount of pyrimethamine, oral toxicity is usually low and the application is safe. Folic acid deficiency symptoms such as nausea, vomiting, abdominal pain, diarrhea, etc. may occur during long-term large-scale application, and megaloblastic anemia and leukocyte deficiency may occasionally occur. However, if you regularly check your blood routine and stop medicine early, you can recover on your own. Administration of calcium folic acid can improve bone marrow hematopoietic function.

Artemisinins

1. Artemisinin

It is a new type of sesquiterpene lactone compound extracted from the asteraceae plant Artemisia annua Linn by Chinese scientists for the first time in 1971.

The structure of artemisinin contains peroxygen bonds, and when the potassium iodide test solution is oxidized to precipitate iodine, starch indicator is added, and it is immediately purple. Artemisinin contains a lactone structure, which is hydrolyzed by adding a sodium hydroxide aqueous solution. When it meets the hydroxylamine hydrochloride test solution and ferric chloride solution, it produces a deep purple iron hydroxamate.

The metabolites of artemisinin in the body are dihydroartemisinin, deoxydihydroartemisinin, 3-hydroxydeoxydihydroartemisinin, and 9,10-dihydroxydihydroartemisinin.

Artemisinin has a very good antimalarial effect. It is a highly effective and fast-acting antimalarial drug, including P. falciparum infection that is resistant to chloroquine. This product is mainly effective for vivax malaria, falciparum, and cerebral malaria, but the recurrence rate is slightly higher. It has low oral activity and low solubility.

Studies on the relationship between the structure and activity of artemisinin have shown that endogenous peroxides are necessary for the existence of the activity, and deoxyartemisinin (the dioxin bridge is reduced to monooxygen) has completely lost its antimalarial activity. Although the endoperoxide structure is necessary to produce antimalarial activity, only the endoperoxide cannot produce sufficient antimalarial activity. The existence of artemisinin's antimalarial activity is attributed to the endoperoxide-ketal-acetal- Structure of lactone. Further research suggests that the existence of hydrophobic groups and the position of the peroxide bridge are critical to its activity.

Dihydroartemisinin (Dihydroartemisinin) is reduced by reducing the carbonyl group of artemisinin, and its anti-mouse malaria is 1 times stronger than artemisinin. Dihydroartemisinin was etherified to obtain artemether and artemether.

2.Artemether

In order to transform the artemisinin into a semi-synthetic antimalarial drug, this product has two configurations, namely a type and Lu type. Candied type is viscous oil, and its melting point is 9-100 ° C after curing; Lu type is colorless flake crystal with a melting point of 86 to 88%. It is clinically used as a mixture of type and type, but Lu type is mainly used , Greater solubility in oil than artemisinin. [] + 168 ° to 173 °.

This product has a killing effect on the Plasmodium erythrozoic schizont, can quickly control symptoms and kill Plasmodium, and has almost no cross-resistance with chloroquine. It is also particularly active against chloroquine-resistant P. falciparum. The antimalarial effect is 10-20 times stronger than artemisinin. The main metabolite in the body is deetherized methyl to produce dihydroartemisinin.

Artemether is less toxic than artemisinin, and satisfactory results have been obtained in the treatment of Plasmodium falciparum, Plasmodium vivax, and Malaria.

3.Artemotil

It is a derivative of artemisinin, which has a powerful and rapid killing effect on the red stage of Plasmodium and can quickly control clinical attacks and symptoms.

Artemether is characterized by a long half-life and accumulation during treatment. After intramuscular injection, the drug slowly enters the circulatory system and reaches the highest plasma concentration in 3-12h, and its half-life is 20-24h. Artemether is mostly metabolized into dihydroartemisinin in the body, and then combined with glucuronic acid to pass through the bile Excretion, a smaller part (20% to 30%) is excreted from the urine as a dihydroartemisinin glucuronide conjugate.

Artemether has a higher effect on chloroquine-tolerant strains of artemisinin than artemisinin, and it has a good clinical effect on various types of malaria. Plasmodium is cleared quickly and easy to use. It can also be used for patients who cannot take other antimalarial drugs. It has a direct killing effect on the red inner stage of Plasmodium and has no effect on the pre-red stage and tissue stage.

Artesunate is a water-soluble drug obtained by esterifying dihydroartemisinin with succinic acid. It can be administered orally or intravenously. After oral administration, it is widely distributed in the body, with higher intestines, liver, and kidneys. It is mainly metabolized in the body, and only a small amount is excreted by urine and feces.

Artesunate has a strong killing effect on plasmodium asexuals, can quickly control malaria outbreaks, treats P. vivax, and the average protozoa turns negative faster than chloroquine. No toxic side effects were seen in clinical treatment.

The effect of artesunate on normal strains of malaria is equivalent to intravenous chloroquine, but it kills insects faster than chloroquine. Suitable with rescue malaria patients and critically comatose malaria patients.