Artemisinin - Now and On

Artemisinins, a unique class of antimalarial drugs, are gaining attention for their potential to be repurposed to treat a variety of diseases, including cancer. As cancer remains a leading cause of death worldwide, especially in Low and Middle Income Countries (LMICs) where financial constraints limit conventional treatment options, the search for cost-effective alternatives is crucial. Artemisinins have demonstrated promising cytotoxic effects against viruses, fungi, and multiple types of cancer, along with significant anti-inflammatory properties in animal models of various diseases such as asthma, sepsis, arthritis, pancreatitis, and systemic lupus erythematosus. Derived from Sweet wormwood (Artemisia annua L), artemisinins include derivatives like artesunate, artemether, and arteether, which are partially or fully converted into the active metabolite dihydroartemisinin (DHA), showcasing their multifaceted therapeutic potential.

The mechanism of action of artemisinins is thought to involve a two-step process. Initially, the artemisinin molecule is activated by the heme-iron present within the parasite. This activation catalyzes the cleavage of the endoperoxide bridge in the artemisinin structure, leading to the formation of a highly reactive free radical intermediate. This intermediate then exerts its cytotoxic effects by alkylating and damaging vital malarial proteins, thereby killing the parasite. This unique mode of action not only makes artemisinins effective against malaria but also suggests their potential in targeting cancer cells, which similarly rely on iron and are susceptible to oxidative damage.

Studies involving artemisinins in in-vitro experiments and animal models have revealed their extensive anti-cancer activity, exhibiting pro-apoptotic, anti-proliferative, anti-angiogenesis, and anti-metastatic effects. Artesunate, in particular, has shown cytotoxic effects against a wide range of cancer cell lines, including those of colon, breast, leukemia, melanoma, central nervous system, ovarian, renal, and prostate cancers. The active metabolite, dihydroartemisinin (DHA), has demonstrated antineoplastic effects in breast, glioma, colon, lung, ovarian, pancreatic, renal cell, and leukemia cancer cell lines. The mechanisms through which artemisinins exert these effects include attenuating inflammatory pathways, blocking angiogenesis, invasion, and metastasis, inducing DNA damage responses, inhibiting cancer cell proliferation, promoting cancer cell death, and disrupting critical cancer cell signaling pathways.

Artemisinins represent a promising frontier in cancer therapy, building on their well-established antimalarial efficacy. Through mechanisms that include activation by heme-iron, resulting in the generation of cytotoxic free radicals, artemisinins exhibit potent anti-cancer properties. Their ability to induce apoptosis, inhibit cell proliferation, block angiogenesis, and prevent metastasis across a variety of cancer cell lines highlights their broad therapeutic potential. The diverse mechanisms of action, including the modulation of inflammatory pathways and the disruption of critical signaling pathways, underscore the multifaceted nature of artemisinins. As research continues to explore and validate these effects, artemisinins may offer an innovative and cost-effective option for cancer treatment, especially in resource-limited settings.

1. Xu, C., Zhang, H., Mu, L., & Yang, X. (2020, October 6). Artemisinins as anticancer drugs: Novel therapeutic approaches, molecular mechanisms, and clinical trials. Frontiers in pharmacology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573816/ 

2. SR;, M. (n.d.). Artemisinin antimalarials: Mechanisms of action and resistance. Medecine tropicale : revue du Corps de sante colonial. https://pubmed.ncbi.nlm.nih.gov/10212891/#:~:text=Artemisinin%20is%20believed%20to%20act%20via%20a%20two-step,poisoning%20one%20or%20more%20essential%20malarial%20protein%20%28s%29. 

3. Augustin, Y., Staines, H. M., & Krishna, S. (2020, December). Artemisinins as a novel anti-cancer therapy: Targeting a global cancer pandemic through drug repurposing. Pharmacology & therapeutics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564301/

Artemisinins, derived from extracts of sweet wormwood (Artemisia annua), have a strong track record in treating malaria, even against strains resistant to many drugs. Additionally, they demonstrate effectiveness against other parasitic infections, such as schistosomiasis, despite being phylogenetically unrelated. Furthermore, recent research highlights their potent and wide-ranging anti-cancer properties, as evidenced in both cell lines and animal studies. 

The discovery of Artemisinin for malaria treatment by Chinese scientists in the 1970s is considered one of the most significant landmark achievements in 20th century medicine. However, interestingly enough, the details surrounding its discovery have been obscured in mystery and controversy. While this topic has been extensively discussed in various reviews, a recently published book titled "A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin)", edited by Jianfang Zhang and six other scientists involved in the project, delves into the debates over the credit for artemisinin's discovery, attributing it to the collaborative efforts of approximately 600 Chinese scientists. Several factors, including the initial classification of the work as a secret military project, cultural norms discouraging publication in Western journals, and language barriers, may have contributed to delays in reporting this groundbreaking discovery. The project leading to artemisinin’s discovery was initiated by a request from North Vietnamese leaders grappling with malaria-related casualties during the Vietnam War. A meeting, known as “Project 523,” was convened on May 23, 1967 that outlined the objectives for developing antimalarial therapies. Immediate solutions were desired for soldiers in the battlefield, resulting in the development and testing of drug combinations providing rapid relief. Concurrently, a comprehensive search for novel antimalarial drugs was launched, focused on the development of combination therapies, surveying endemic treatment practices, and chemical synthesis and screening. 

As briefly mentioned, artemisinin is a novel category of antimalarial compounds and is a sesquiterpene lactone distinguished by an endoperoxide bridge crucial for its antimalarial efficacy. Due to the low solubility of the parent compound of artemisinin in both water and oil, the carbonyl group of artemisinin undergoes reduction to yield dihydroartemisinin (DHA) and its derivatives, including the water-soluble artesunate and the oil-soluble artemether and arteether, which exhibit enhanced antimalarial properties. Despite several attempts at total chemical synthesis of artemisinin and various endeavors to produce the compound using genetically modified microorganisms, artemisinin continues to be primarily sourced from the Artemisia plant commercially. However, the yields of artemisinin from these plants can vary significantly depending on growth conditions.

Artemisinins exhibit antimalarial activity both in laboratory studies and in real-world studies, believed to operate by releasing free radicals into the vacuoles of the parasite. They are presently considered the most potent antimalarial drugs and are widely used globally, typically in conjunction with other antimalarial agents to mitigate the risk of resistance, such as amodiaquine and mefloquine. Various oral and injectable formulations of artemisinin derivatives are available worldwide. Specifically, in the United States, the combination of artemether 20 mg and lumefantrine 120 mg is approved for treating P. falciparum malaria and is distributed under the brand name “Coartem.” The recommended dosage for adults taking this medication is four tablets taken twice daily for three days (a total of six doses). Additionally, artesunate (Adamsunate) can be obtained on a named-patient basis through the CDC Malaria hotline. Common side effects of artesunate include nausea, vomiting, loss of appetite and dizziness. There is also a risk of potentially severe adverse effects such as QTC prolongation and cardiac arrhythmias. 

Resources: 

Cui L, Su XZ. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther. 2009;7(8):999-1013. doi:10.1586/eri.09.68

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Artemisinin. [Updated 2017 Feb 8]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548419/

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.