• Journal of Applied Biological Chemistry
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• v.65 no.3
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• pp.167-172
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• 2022

Pathophysiological reaction of platelets in the blood vessel is an indispensable part of thrombosis and cardiovascular disease, which is the most common cause of death in the world. In this study, we performed in vitro assays to evaluate antiplatelet activity of artemether in human platelets and attempted to identify the mechanism responsible for protein phosphorylation. Artemether is a derivative of artemisinin, known as an active ingredient of Artemisia annua, which has been reported to be effective in treating malaria, and is known to function through antioxidant and metabolic enzyme inhibition. However, the role of artemether in platelet activation and aggregation and the mechanism of action of artemether in collagen-induced human platelets are not known until now. In this study, the effect of artesunate on collagen-induced human platelet aggregation was confirmed and the mechanism of action of artemether was clarified. Artemether inhibited the phosphorylation of PI3K/Akt and Mitogen-activated protein kinases, which are phosphoproteins that are known to act in the signal transduction process when platelets are activated. In addition, artemether decreased TXA₂ production and decreased granule secretion in platelets such as ATP and serotonin release. As a result, artemether strongly inhibited platelet aggregation induced by collagen, a strong aggregation inducer secreted from vascular endothelial cells, with an IC₅₀ of 157.92 μM. These results suggest that artemether has value as an effective antithrombotic agent for inhibiting the activation and aggregation of human platelets through vascular injury.

• Journal of Applied Biological Chemistry
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• v.65 no.4
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• pp.239-245
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• 2022

Although normal activation of platelets is important in the process of hemostasis, excessive or abnormal activation of platelets can lead to cardiovascular diseases. Therefore, the discovery of novel substances capable of regulating or inhibiting platelet activation may be helpful in the prevention and treatment of cardiovascular diseases. Artemether is a derivative of artemisinin, known as an active ingredient of Artemisia annua, which has been reported to be effective in treating malaria, and is known to function through antioxidant and metabolic enzyme inhibition. However, the role of artemether in platelet activation and aggregation and the mechanism of action of artemether in collagen-induced human platelets are not known until now. This study investigated the effects of artemether on platelet activation and thrombus formation induced by collagen. As a result, cAMP level was significantly increased by artemether, and VASP and IP3R, substrates of cAMP-dependent kinase, were phosphorylated. IP3R phosphorylation by Artemether inhibited Ca²⁺ recruitment into the cytoplasm, and phosphorylated VASP inhibited fibrinogen binding by inactivating αIIb/β3 located on the platelet membrane. Consequently, artemether inhibited thrombin-induced fibrin clot formation. Therefore, we propose that artemether can act as an effective prophylactic and therapeutic agent for cardiovascular diseases caused by excessive platelet activation and thrombus formation.

• Korean Journal of Pharmacognosy
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• v.53 no.2
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• pp.64-69
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• 2022

When blood vessels are damaged, a rapid hemostatic response should occur in order to lower blood loss and keep normal circulation, and platelet activation and aggregation are essential. Nevertheless, abnormal or excessive platelet aggregation can be a reason of cardiovascular diseases including thrombosis, atherosclerosis, and stroke. Therefore, the screening for a substance which can regulate platelet activation and suppress aggregation reaction is very important for treatment and prevention of cardiovascular diseases. Artemether is a methyl ether derivative of artemisinin, which is isolated from the antimalarial plant Artemisia annua, but research on platelet aggregation or its mechanisms is still insufficient. This study identified the effects of artemether on U46619-induced human platelet aggregation and their granule secretion (ATP and serotonin release). In addition, the effects of artemether on the phosphorylation of PI3K/Akt or MAPK, which are related to signal transduction in platelet aggregation, were studied. As the results, artemether significantly lowered PI3K/Akt and MAPK phosphorylation, which inhibited platelet aggregation through granule secretion (ATP and serotonin release) dose-dependently. Therefore, we suggest that artemether is an antiplatelet substance that regulates PI3K/Akt and MAPK pathway and is of value as a therapeutic and preventive agent for platelet-derived cardiovascular diseases.

• Parasites, Hosts and Diseases
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• v.45 no.2 s.142
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• pp.111-114
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• 2007

Chloroquine remains the drug of choice for the treatment of vivax malaria in Thailand. Mixed infections of falciparum and vivax malaria are also common in South-East Asia. Laboratory confirmation of malaria species is not generally available. This study aimed to find alternative regimens for treating both malaria species by using falciparum antimalarial drugs. From June 2004 to May 2005, 98 patients with Plasmodium vivax were randomly treated with either artemether-lumefantrine (n = 47) or chloroquine (n = 51). Both treatments were followed by 15 mg of primaquine over 14 days. Adverse events and clinical and parasitological outcomes were recorded and revealed similar in both groups. The cure rate was 97.4% for the artemether-lumefantrine treated group and 100% for the chloroquine treated group. We concluded that the combination of artemether-lumefantrine and primaquine was well tolerated, as effective as chloroquine and primaquine, and can be an alternative regimen for treatment of vivax malaria especially in the event that a mixed infection of falciparum and vivax malaria could not be ruled out.

• Parasites, Hosts and Diseases
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• v.40 no.1
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• pp.1-7
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• 2002

The purpose of treatment for uncomplicated malaria is to produce a radical cute using the combination of: artesunate (4 mg/kg/day) plus mefloquine (8 mg/kg/day) for 3 days; a fixed dose of artemether and lumefantrine (20/120 mg tablet) named $Coartem^{\circledR}$ (4 tablets twice a day for three days for adults weighing more than 35 kg); quinine 10 mg/kg 8-hourly plus tetracycline 250 mg 6-hourly for 7 days (or doxycycline 200 mg as an alternative to tetracycline once a day for 7 days) in patients aged 8 years and over; $Malarone^{\circledR}$ (in adult 4 tablets daily for 3 days). In treating severe malaria, early diagnosis and treatment with a potent antimalarial drug is recommended to save the patient's life. The antimalarial drugs of choice are: intravenous quinine or a parenteral form of an artemisinin derivative (artesunate i.v./i.m. for 2.4 mg/kg followed by 1.2 mg/kg injection at 12 and 24 hr and then daily for 5 days; artemether i.m. 3.2 mg/kg injection followed by 1.6 mg/kg at 12 and 24 hrs and then dialy for 5 days; arteether i. m. ($Artemotil^{\circledR}$) with the same dose of artemether or artesunate suppository (5 mg/kg) given rectally 12 hourly for 3 days. Oral arlemisinin derivatives (artesunate, artemether, and dihydroartemisinin with 4 mg/kg/day) could replace parenteral forms when patients can tolerate oral medication. Oral mefloquine (25 mg/kg divided into two doses 8 hrs apart) should be given at the end of the artemisinin treatment course to reduce recrudescence.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.105-105
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• 2023

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.2
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• pp.494-498
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• 2009

The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Useful antimalarial drugs such as chloroquine have resistance in the world now. Moreover, other antimalarialdrugs such as mefloquine, halofantrine, atovaquone, proguanil, artemether and lumefantrine retain efficacy but have limitations, one of which is their high cost. New antimalarial drugs are clearly needed now. Cytotoxicity assay and susceptibility assay were performed for the selectivity of herb extracts in vitro. On the basis of high selectivity, 4-day suppressive test and survival test were progressed in Plasmodium berghei-infected mice. The selectivity of Areca catechu L. (ACL) and butanol extract of ACL (ACL-BuOH extract) were 3.4 and 3.0 in vitro, respectively. Moreover in vivo, 4-day suppressive test showed 39.1 % inhibition effect after treated with 150 mg/kg/day ACL-BuOH to P. berghei-infected mice. Survival test also showed 60% survival rate with ACL-BuOH-treated group while all other group mice died. In this study, ACL and ACL-BuOH were investigated for antimalarial activity in vitro and in vivo and they showed a potent antimalarial activity. In particular,ACL-BuOH could specifically lead higher survival rate of mice in vivo. Therefore ACL-BuOH would be a candidate of antimalarial drugs.