Artemisinin
Written by Tommy Li and Jerry Lau
Artemisinin is one of the most widely used therapies against malaria worldwide.It is also called Qinghao, which was extracted from Artemisia annua (sweet wormwood). First isolated through Eastern medicine and tested in the 1970s in China, Artemisinin and its derivatives have a complex mode of action and can cause widespread injury to many parts of the parasite (1). In the ancient time, herbs containing artemisinin were used to treat outspread malaria. Recently, in the rise of an unprecedented pandemic, even more promising uses of Artemisinin have been found and are being studied. It has been shown to possess selective anticancer properties with demonstrated cytotoxic effects in vitro and in vivo. But why does Artemisinin show these aforementioned properties? It appears they are in part due to mediated artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple known indicators of cancer (2). However more information is needed to provide a definitive answer on placing the medication as a recognized therapy in the oncology field.
Besides treating cancers, Artemisinin and the class of drugs it belongs to, antimalarials. Artemisinin is sesquiterpene lactone endoperoxide with an active moiety, dihydroartemisinin. The endoperoxide bridge is activated by heme iron binding, resulting in oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes, and a decrease in parasite growth and survival. Once an infected female anopheles mosquito bites a person, malarial parasites enter the body. They then entered the hepatocytes via circulation and began its asexual reproduction alled exoerythrocytic stage. The hepatocytes then rupture, releasing more merozoites in the blood and the asexual erythrocytic stage begins to show symptoms. Erythrocytic schizonts replicate and release, and infect other erythrocytes. Artemisinins treats the erythrocytic schizonts. However, no drugs act on sporozoites. So complete prophylaxis is not possible. No one agent can target all the stages and hence combination therapy is needed (4). Note that WHO does not recommend artemisinin use in first trimester pregnant women.
During the recent 2019 - 2021 COVID - 19 pandemic, Artemisinin has also been recognized as a promising treatment to tackle the COVID-19. For example, in a 2021 Trends in Parasitology Journal, it was shown that Artemisinin based combination therapies (known as ACTs for short) inhibited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The study shows anti inflammatory effects especially pronounced in interleukin-6 (IL-6). This interleukin plays a key role in the development of severe coronavirus disease 2019 (COVID-19). This sort of evidence is sufficient enough to support more approval of clinical studies that investigate this relationship between use of ACTs and antiviral activity shown in COVID-19 patients (3).
Artemisinin, a drug that has a secret two thousands of years of history, hides in the Chinese herbalists. It has shown the world its power to solve malaria problems globally when combined with other malaria medicines. Today, there are still many secret formulas hiding in the ancient book and waiting for us to discover their effects and exact mechanisms. Only dedications with good luck can uncover their mysterious mechanism of actions. The world is waiting for them to shine again.
References
Talman AM, Clain J, Duval R, Ménard R, Ariey F. Artemisinin Bioactivity and Resistance in Malaria Parasites. Trends Parasitol. 2019;35(12):953-963.
Wong YK, Xu C, Kalesh KA, et al. Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action. Med Res Rev. 2017;37(6):1492-1517.
Krishna S, Augustin Y, Wang J, et al. Repurposing Antimalarials to Tackle the COVID-19 Pandemic [published correction appears in Trends Parasitol. 2021 Apr;37(4):357]. Trends Parasitol. 2021;37(1):8-11.
Daher, A., Aljayyoussi, G., Pereira, D. et al. Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine. Malar J 18, 325 (2019). https://doi.org/10.1186/s12936-019-2950-4
Daher, A., Pereira, D., Lacerda, M.V.G. et al. Efficacy and safety of artemisinin-based combination therapy and chloroquine with concomitant primaquine to treat Plasmodium vivax malaria in Brazil: an open label randomized clinical trial. Malar J 17, 45 (2018). https://doi.org/10.1186/s12936-018-2192-x
Artesunate
Written by: Hillary Pham and Jae Chang
Artesunate is a medication that belongs in the artemisinin category of drugs. Hence, this medication is considered as a derivative of artemisinin. This medication is useful in treating the disease called malaria. Malaria is an infectious disease that is caused by the Plasmodium species with P. falciparum being the most virulent and responsible for the majority of malarial morbidity and mortality recorded worldwide. In 2018, there were about 228 million cases of malaria globally and resulted in 405,000 deaths, of which 94% of the mortality was from the African region.
Artemisinin is a lactone peroxide that is isolated from the leaves of Artemesia annua or Qinghao in China. It is a 15-carbon compound with endoperoxide bridge, and it is from this compound that gives the crucial antimalarial activity. Artemisinin is generally effective against early gametocyte stages of P. falciparum. However, with the prolonged use of artemisinin to treat malaria worldwide, the effectiveness has begun to decrease in many countries as malaria has been gaining resistance. Therefore, other medications such as artesunate have been made to target malarial parasites that artemisinin is not effective against. Artesunate, also known as dihydroartemisinin-12-a-succinate, is a compound derived from artemisinin by reduction and esterification using DIBAL and succinic anhydride. This compound is better than its parent compound due to its improved solubility, absorption, and pharmacokinetics. The mechanism of action is that Artesunate is able to metabolize to a compound called DHA. The DHA metabolite then is able to generate free radicals that help to inhibit the function of the malaria cells, also known as the Plasmodium parasites. Artesunate is a semisynthetic derivative of artemisinin and is used in combination with selected active antimalarial drugs to prevent or delay the emergence of resistance to artemisinin drugs. Over the years, many techniques including preparation of hybrid compounds, combination therapy, chemical modification, use of synthetic materials to enhance solubility and delivery of artesunate have been used to increase the efficacy of antimalarial activity of artesunate.
Artesunate is given intravenously at a dose of 2.4mg/kg/dose at every 0 hours, 12 hours and 24 hours, as a weight-based therapy. But, at least 4 hours after the last dose is given at 24 hours, the doctors must check the parasite density within the patient’s body to reassess the proper treatment for the patient. Furthermore, after reassessment of the patient’s parasite status, the doctor can then readjust the therapy based on the findings. If the parasite density is less than or equal to 1%, the patient will transition to therapy as an oral regimen. On the other hand, if the parasite density is less than or equal to 1% but the patient is unable to receive an oral therapy, then the patient will continue with the medication Artesunate at 2.4mg/kg/dose once daily via IV for up to 6 more days. This means that the patient has received the medication for a total of 7 days as an IV treatment instead. Patients can resume with full treatment orally only after these 7 days have passed. Now in the case that the parasite density is more than 1%, patients must continue with Artesunate at the same dose of 2.4mg/kg/dose for as long as the parasite density is less than 1%. Although, there is a maximum day treatment of 7 days while on IV medication. Thereafter, the patients can start an oral regimen once the parasite density is less than 1%. Artesunate has a short life of approximately 20 and 45 minutes by oral route. It may be given as oral, rectal, intramuscular and intravenous medication for uncomplicated and severe malaria. It is metabolized via esterase-catalyzed hydrolysis to dihydroartemisinin, which is the active metabolite that provides the antimalarial activity. Dihydroartemisinin is then converted to the inactive form by glucuronidation. Some adverse effects associated with artesunate involve hemoglobinuria, acute renal failure, and jaundice.
It is important for patients to note that they should avoid taking Isoniazid, Letrozole, or even Nizoral while on this medication. Additionally, while on this medication, especially via IV, it is common to have a loss of appetite for a few days after starting the medication. This may upset lots of people, but it will reside within the first few days. It is also very common that Artesunate may cause nausea and dizziness in some patients as well. When using this medication, patients should be mindful of the more serious side effects. However, despite the negative effects that this medication may give, artesunate is an effective medication against malaria that is artemisinin resistant. Therefore, healthcare professionals should weigh the benefit vs risk before prescribing this medication.
References:
“Artesuante” Lexicomp. 06/04/2020.
Adebayo JO, Tijjani H, Adegunloye AP, Ishola AA, Balogun EA, Malomo SO. Enhancing the antimalarial activity of artesunate. Parasitol Res. 2020 Sep;119(9):2749-2764. doi: 10.1007/s00436-020-06786-1. Epub 2020 Jul 7. PMID: 32638101; PMCID: PMC7340003.