I have heard the reason Vietnam has almost zero deaths
Why McDonald’s Flopped In Vietnam
Vietnam has zero coronavirus deaths. Here’s why. | CNBC Reports
Rappler Talk Investigative: Guy Thwaites on Vietnam's effective strategy against coronavirus
https://www.tropicalmedicine.ox.ac.uk/news/coronavirus-how-overreaction-made-vietnam-a-virus-success
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644094/
Malaria risk factors and care-seeking behaviour within the private sector among high-risk populations in Vietnam: a qualitative study
Background
Over the past 15 years, malaria mortality has dropped by approximately 62% globally, fueling ambitions to eradicate malaria by 2040 [1, 2]. As malaria endemicity declines, countries preparing for malaria elimination strive to identify, treat, and document all cases [3, 4]. Often, the remaining cases during elimination stages tend to be clustered in certain ecologies, where risk of ongoing transmission is contingent on human behaviour patterns and select groups of individuals have higher risks of infection [5, 6].
In Southeast Asia, where anopheline vectors often preferentially feed on human hosts in outdoor environments, malaria ecology presents multiple challenges [7]. Not only do outdoor biters such as Anopheles minimus, Anopheles epiroticus, and Anopheles dirus vector complexes need to be confronted in this region, but this must be done rapidly, as Southeast Asia is the nucleus of Plasmodium falciparum drug resistance against the first-line artemisinin-class drugs, a global threat that has emerged repeatedly in the region since 2006 [8–10].
Against this backdrop, Vietnam, where the malaria caseload has been effectively reduced by 93% between 2000 and 2015 (from 274,910 down to 19,252 cases), is currently confronting challenges to malaria elimination [11]. Malaria in Vietnam is concentrated in rural, forested areas, particularly in the central highlands and areas bordering southern Lao PDR and southeastern Cambodia. Moreover, it is a disease of the rural poor, with the highest risk of infection presiding among migrant workers and ethnic minorities [12–14]. Drug resistance against both dihydroartemisinin and piperaquine, the two components of the recommended first-line treatment for P. falciparum malaria, has been reported in-country [15, 16]. To counter artemisinin resistance, Vietnam has issued a ban on oral artemisinin monotherapies (Decision No 4718/QD-BYT issued by MOH in 2014).
In order to achieve malaria elimination in Vietnam, malaria cases among at-risk populations must be detected, treated and documented. However, these individuals are believed to seek malaria treatment through informal, private healthcare providers, a poorly described part of the health sector escaping the reach of the many interventions delivered through the public sector [1, 17]. There is no formal documentation on how often the private sector is used in Vietnam for malaria care, which types of private providers are accessed, nor the types of clientele that seek care through this sector [18]. This qualitative study investigates the current composition and role of private providers in malaria care-seeking behaviour, as well as the context and characteristics of their clientele, to inform malaria programme design in Vietnam.
Methods
Study overview
This study was comprised of two components: (1) Semi-structured key informant interviews were conducted with individuals working on malaria control efforts in Vietnam and/or with the informal private sector, in order to gain expert opinion and insight on the composition and role of the private sector in rural areas nationwide, in particular those that are endemic with malaria (January to March, 2016); (2) semi-structured interviews were conducted with private providers and patient/at-risk individuals in remote malaria-endemic locales, to contextualize and characterize providers and their clientele (December 2015 to January 2016). For providers, this included an exploration of what they were selling, what their operating practices were, and how they communicated, to establish potential methods they could use to report malaria cases currently missed by the public sector surveillance system. Clientele selection focused on those at risk of malaria, seeking to establish high risk behaviours threatening malaria elimination efforts that need to be addressed, as well as contextual factors such that interventions can be designed to maximize adherence from individuals at risk. In areas selected for field study, the highest malaria transmission occurs during the rainy season, from April through November, and high-risk individuals are usually workers in forests and farms, many of whom are migrants [19, 20].
Sampling and locations
Key informant interviews
Key informant interviews were conducted in Hanoi, where many non-governmental organizations (NGOs), the Ministry of Health, and other healthcare organizations are located. Key informants were selected using purposive sampling through networks of programme and organizational staff members (through the University of California, San Francisco (UCSF) Global Health Sciences department and Population Services International (PSI) Vietnam), and any colleagues suggested by members of those networks, to identify approximately ten key informants.
Provider, patient and at-risk individual interviews
Preliminary feasibility assessments for study sites were conducted in three provinces in the central highlands, where malaria endemicity is highest in Vietnam. All provinces investigated also have the presence of artemisinin-resistant P. falciparum parasites, thus taking place where malaria elimination efforts are most urgently needed. All areas assessed were remote, rural and mountainous malaria endemic areas with poor infrastructure and living conditions.
In each district, researchers sought to establish the density of private providers involved in malaria treatment and/or diagnostic practices. This included speaking with village leaders and local authorities, and asking village leaders, motorcycle drivers, tea shop and restaurant owners, and/or small grocery shop operators to identify patients and providers, who were then sought using a variety of interpersonal approaches to build rapport. The interview questionnaires were also piloted in these locations, and revised following insights gained.
The final selection of provinces was based on a combination of high malaria endemicity, higher numbers of private providers found, as well as the political feasibility of acquiring permits to conduct research in each area (Fig. 1; Table 1). Areas selected for study included Binh Phuoc, located in Southwestern Vietnam, was known to be a province with high malaria endemicity and the presence of artemisinin-resistant parasites (Tier 1), and Kon Tum, where artemisinin-resistant P. falciparum malaria (Tier 2) was documented. Kon Tum also contains porous borders with both Laos and Cambodia thought to be crossed by migrant workers, posing a risk of malaria importation from neighbouring countries (Fig. 2) [21].
Table 1
Malaria epidemiology in provinces selected for feasibility assessments
| Province | Percentage of individuals at risk for malaria (%) | Deaths attributed to malaria | Confirmed cases | |||
|---|---|---|---|---|---|---|
| All malaria infections | P.f | P.v. | Mixed infections | |||
| Quảng Nam | 0.66 | 0 | 369 | 125 | 242 | 2 |
| Kon Tum | 1.06 | 0 | 179 | 79 | 99 | 1 |
| Đắk Lắk | 0.53 | 1 | 779 | 347 | 424 | 8 |
| Bình Phước | 1.92 | 1 | 1799 | 1000 | 706 | 93 |
P.f., Plasmodium falciparum; P. v., Plasmodium vivax malaria
Provinces of field study, qualitative studies December 2015–January 2016, Vietnam
In Binh Phuoc, which had a total population of approximately one million individuals, there were 1799 confirmed cases of malaria in 2016 (one death attributed to malaria), 56% were P. falciparum infections, 39% were Plasmodium vivax infections, and the remaining 5% were mixed infections. Binh Phuoc is a predominantly rural province, with only 15% of the population living in towns. This province is divided into 11 district-level subdivisions. The majority of individuals in Binh Phuoc are Vietnamese, although ethnic minorities are present throughout the province, comprising of Xtiêng, Nùng, Tày, and Khmer minorities. Binh Phuoc is one of the most agriculturally productive provinces of Vietnam, whose economy heavily relies on cash crops such as cashew nuts and rubber.
In Kon Tum, which had a population of approximately 330,000 in 2016, there were 179 confirmed malaria cases (zero deaths attributed to malaria); 44% were P. falciparum infections, 55% were P. vivax infections, and the remaining 1% were mixed infections. Kon Tum also has a primarily agricultural economy, and is one of the least populated provinces in Vietnam. The capital, Kon Tum, is its own municipality. There are 76 communes, 10 wards, and 6 towns. Ethnic minorities make up 51% population of Kon Tum, and are mostly comprised of the Ba Na, Xo Dang, Gie Trieng, Gia Rai, B’Rau, and Ro Man minorities, many of whom work on fields in the mountains.
Recruitment of providers, patients, and at-risk individuals
In each province, Binh Phuoc and Kon Tum, 15 providers and 10 patients or individuals at risk of malaria were interviewed. These participants were identified through conversations with local contacts including village leaders, motorbike taxi drivers, grocery store workers, and mobile vendors. Patients and at-risk individuals, once identified, also helped to refer the study team to providers, and vice versa. In some cases, providers were identified when at-risk individuals used a ‘mystery client’ approach, presenting at private outlets and reporting to have malaria symptoms. If anti-malarial medications and/or malaria rapid diagnostic tests (RDTs) were found on site through this approach, the study team would return to these outlets, approaching providers for interviews. The study team also visited community health stations to search for documented lists of malaria patients, but no cases were reported through this approach.
Inclusion criteria
Key informants
Inclusion criteria for key informant interviews required that each individual interviewed have experience working on malaria control activities and/or engaging informal private providers in Vietnam. All interviews were conducted in the English or Vietnamese language.
Private providers
All providers interviewed were either owners or workers in the shop that reported to have anti-malarial drugs in stock within the past 3 months prior to the day of the interview. Additionally, providers were required to be ≥ 18 years of age, and were fluent speakers of the Vietnamese language and/or minority languages.
Patients and at-risk individuals
All patients interviewed reported to have either sought healthcare from a private provider for themselves or for a family member (within a year from the date of interview) and were diagnosed with a malaria infection according to public and/or private providers within the last year. All at-risk individuals of malaria reported to have stayed in the forest or on a farm or plantation for at least one night in the last 3 months, a practice that researchers anticipated would identify farmers and forest workers, many of whom are migrant workers. All potential patients and at-risk individuals interviewed were ≥ 18 years of age, and were fluent speakers of the Vietnamese language and/or minority languages.
Data collection
Key informant interviews
A total of 11 key informant interviews were conducted; six key informant interviews were conducted in English (IC), and five interviews were conducted in Vietnamese (HNTT). A semi-structured interview guide was used, and prompts were used to guide the interview (English version shown in Additional file 1. Semistructured Interview guide: key informant). All interviews took place in a private location, were between 45 and 90 min in duration, and were audio recorded and accompanied by hand-written notes. All key informants interviewed agreed to be audio recorded.
Interviews with providers, patients, and at-risk individuals
A total of 30 interviews with providers, 9 interviews with patients, and 11 interviews with at-risk individuals were conducted in Binh Phuoc (border districts: Loc Ninh, Bu Gia Map, and Bu Dop; and non-border district Bu Dang) and Kon Tum (border districts: Sa Thay, Ngoc Hoi, Dak Glei; and non-border districts Dak Re and Kon Tum). All interviews were conducted using a semi-structured interview guide (English version of interview guides shown in: Additional file 2. Semistructured Interview Guide: private provider; Additional file 3. Semistructured Interview Guide: malaria patient; and Additional file 4. Semistructured Interview Guide: individual at risk of malaria). Interviews lasted between 45 and 90 min, and were conducted by a researcher (PTT in Binh Phuoc, HNNT in Kon Tum) with a note-taker present. Interviews with providers were conducted in shops, and interviews with patients and at-risk individuals were conducted in locations easily accessible to interviewees, including tea or coffee shops, or in their homes. All interviewees agreed to be audio recorded with the exception of one provider from Binh Phuoc.
Provider stock audit
For all providers who had anti-malarial drugs and/or malaria RDTs in stock on the day of the visit (25 providers), a short anti-malarial and malaria RDT stock audit (English version shown in Additional file 5. Provider antimalarial/RDT stock form) was also conducted either before or after the in-depth interview, according to provider preference.
Data analysis
Key informant interviews
After all interviews were conducted, researchers (IC and HNTT) developed codes based on interview guides and perceptions gained from interviews. All audio recordings were reviewed and themes and representative quotes were identified and recorded in Atlas TI™ (Version 7.5.10, GmBH) (English by IC, Vietnamese by HNNT). All quotes in Vietnamese language were translated to the English language, and themes were identified and recorded in Atlas TI™ (by IC). All themes collected from key informant interviews were organized by code, and their frequency of appearance was documented.
Patient, provider and at-risk individual interviews
After all interviews were conducted, a researcher (HNTT) developed codes based on interview guides as well as perceptions gained from interviews, and discussion and review with researchers present during field interviews. Each interview was transcribed word-for-word, transcripts were uploaded to Atlas TI™, and organized by code. Thematic analysis was then conducted, and representative quotes were translated into the English language.
Provider stock audit
For the anti-malarial and malaria RDT stock audit, the anti-malarial active ingredients, RDT types, manufacturers, formulas and packaging details, retail prices from outlets to clients, and wholesale prices from distributors to outlets were collated in Microsoft Excel (2010 version, Microsoft).
Results
A total of 61 interviews were conducted. The 11 key informant interviews were conducted across seven NGOs and government organizations in Hanoi, illustrating expert perceptions of risk factors for malaria nationwide, as well as the composition of the private sector in malaria endemic areas in Vietnam. All key informants approached (11/11) agreed to be interviewed. In Binh Phuoc and Kon Tum, 37 private outlets were approached, 30 of which agreed to participate in the study (outlet types detailed in Table 2). Non-participants refused because were not willing to talk about malaria, refused to answer questions on anti-malarials, were too busy or not available at the time of visit, or did not provide relevant information even though they were willing to participate. Most of the private pharmacies included in this study (10/13) were registered with the Department of Health and, therefore, permitted to provide anti-malarials to customers with a prescription. The same ten pharmacies also have a basic pharmaceutical license, received following completion of a 12–18 month training course. Most of the private clinics included in this study were registered (8) whereas some were not registered (2). Nine interviews with patients, and 11 interviews with at-risk individuals, all of whom were mobile workers, were also conducted (Table 2); all patients and at-risk individuals approached (20/20) agreed to be interviewed.
Table 2
Overview of interviews with providers, patients, and at-risk individuals
| Individuals interviewed | Binh Phuoc Province | Kon Tum Province |
|---|---|---|
| Providers | ||
| Pharmacy operators | 6 | 7 |
| Private clinic operators | 5 | 5 |
| Grocery shop operators | 4 | 3 |
| Total providers | 15 | 15 |
| Patients and at-risk individuals | ||
| Malaria patients | 4 | 5 |
| At-risk individuals | 6 | 5 |
| Total individuals | 10 | 10 |
Key informant perspectives on the context of malaria elimination in Vietnam
Key informants described Vietnam’s commitment to malaria elimination by 2030 (Decision No 4717/QĐ-BYT, issued 2014). Recent plans focus on the implementation of test and treat strategies in both public and private health facilities (described in Decree No 1920/QĐ-TTg issued by Prime Minister in 2013), including requirements for rapid case reporting (Decision No 4717/QD-BYT, issued by MOH in 2014). Although these objectives are written in policy, at the time of interview, a key informant noted that specific plans to address private sector treatment, diagnosis and case reporting had not been developed:
“On paper… they have some activity [plans] to try to educate the private sector into the malaria one, try to promote for public and private partnership, but they do not have any [activities] currently… That is the main malaria topic, they are trying to involve and engage private, but there are not yet plans.”
—KI8
Consistent with these priorities described in national level policies, key informants expressed consensus that to achieve malaria elimination in Vietnam, the biggest priorities for the malaria program are to target treatment to vulnerable populations in remote locations, and to strengthen surveillance systems. Suggestions for targeting treatment to vulnerable populations included the potential to bring malaria services to people, for example through village health workers, mobile teams, or malaria posts placed either at the border or on a main road leading to the forest. Key informants also noted that surveillance and reporting could be improved by introducing electronic record systems to replace paper-based reports, which could help to provide the means for rapid response for detected cases, and also inform the supply chain for anti-malarials if needed.
Key informant perspectives on malaria risk factors nationwide
Throughout Vietnam, key informants described the mountainous areas in the central highlands as having the greatest risk of ongoing malaria transmission. They described malaria as a disease of the rural poor in remote areas, often comprising of ethnic minorities. Migration, travel and forest working were also identified as risk factors for malaria. Migrants included those flying returning from work in Africa, travelling across international land borders between Cambodia and Laos, or migrating internally from north to south for seasonal work in the forest. Migrants introduce the risk of importing malaria to receptive areas, which, if not detected quickly, could potentially escalate into an outbreak. Forest workers were characterized as those working on plantations, construction, farms, mines (including gold mines), as well as fishermen. Within this group, the most vulnerable included small-scale farmers and forest goers, as well as individuals working for illegal mines, because other forest jobs (including construction and official mines) sometimes include the provision of healthcare on site. Forest workers present challenges for malaria elimination in being the most difficult to reach, particularly those working in illegal mines that are hidden and trying to escape detection from public authorities.
Key informant overview of public and private providers in malaria endemic areas nationwide
Key informants provided an overview of both public and private facilities where people seek care for malaria, and that furthermore, self-treatment is a common practice in Vietnam:
“Self treatment also very common in Vietnam, you know. So [in] everyone’s household, they have some basic types of medicine at their house already, so when they get fever, or minor illness, they treat themselves, that’s very common practice… People treat themselves for minor illness, and if it doesn’t work, they seek care.”
—KI10
Public facilities included district and provincial hospitals, the commune health station (CHS), and village health workers. The CHS was described as the most common source of care for serious or severe diseases, and the main source of care for malaria in the public sector. At the CHS, malaria diagnosis is provided using microscopy, and treatment and diagnosis are free of charge. The CHS also provides standby drugs to people travelling to areas at risk of malaria, provided that these areas do not have documented drug resistance following Decision No 3232/QD-BYT, issued in 2013.
Key informants expressed that the private sector has a strong role in rural areas at risk of malaria. Private facilities for malaria care included private pharmacies, private clinics, grocery stores, and mobile vendors. Reasons for accessing the private sector rather than the public sector included convenience, improved reputation and quality of service, in particular a need for trust between providers and their clientele.
Pharmacies were described by key informants as the usual first point of care for mild illnesses in very rural areas. Generally, rural pharmacies are operated as a family business with multiple family members involved in operations. Pharmacies serve both local and migrant customers, given their ability to sell medication to all/any customers regardless of insurance coverage. Individuals working in pharmacies do not receive training for malaria diagnosis and treatment.
According to national policies, registered pharmacies are authorized to provide anti-malarials following prescription by medical doctors (Policy Decision #4718, Circular No 1517/BYT-KCB/2008, and Pharmaceutical Law 2016). Key informant interviews revealed that this was an area of confusion; only one key informant recognized that pharmacies are allowed to sell anti-malarial drugs, and several key informants had the misconception that pharmacies are not legally allowed to sell medicines for artemisinin-based combination therapy (ACT).
Private clinics are community level clinics often run by doctors working in the public sector after work hours, either early in the morning or in the evening. These individuals are the only link between public and private healthcare providers mentioned, as there are no formal public–private partnerships widely used in Vietnam. Private clinics usually offer basic curative care, including infusion, injection, and medication, and are legally allowed to provide treatment for non-complicated P. falciparum malaria infection, as well as malaria infection in pregnant women (Policy Decision No 3232/QD-BYT/2013). Key informants stated that only doctors in registered private clinics are authorized to diagnose and treat malaria cases, and that sometimes these providers offer anti-malarial drugs that they acquired from public facilities.
Grocery stores were described as highly informal outlets located in remote and border areas, usually operated by retailers without health training. They sell basic groceries, medicine and other household items, their clientele are a combination of local customers and migrants, particularly for shops near border areas. Officially, grocery outlets are not authorized to offer either malaria diagnosis or treatment, but can sell preventive items such as insecticide-treated nets, repellents, and coils.
Mobile vendors were described as highly informal, common sellers of basic medications, which are stocked by demand. Key informants mentioned that mobile vendors are well known by the community, and visit at fixed times and locations known by the community.
Private provider perspectives and modes of operation in Binh Phuoc and Kon Tum
Stocking practices
Private pharmacies, clinics, and grocery store employees were interviewed in field sites. Three mobile vendors were identified, but were not interviewed because they reported that they did not stock anti-malarials. In outlets screened, anti-malarial medications were found in stock at 25 of the 30 outlets surveyed, most commonly consisting of quinine, chloroquine, and then ACT (Table 3). For context, the first-line treatment for P. falciparum malaria is dihydroartemisinin–piperaquine (3 days), first-line treatment for P. vivax malaria is chloroquine (3 days) and primaquine (0.25 mg/kg for 14 days), first-line treatment for mixed infection is dihydroartemisinin–piperaquine (3 days) and primaquine (0.25 mg/kg for 14 days), and second-line treatment for malaria is quinine (7 days) and doxycycline (7 days) or clindamycin (7 days).
Table 3
Antimalarial drugs and malaria rapid diagnostic tests from stock audit
| Products | Manufacturer | Formula/packaging | Retail price (from outlets to clients) | Wholesale price (from distributor to outlets) | Outlet types |
|---|---|---|---|---|---|
| Antimalarial drugs | |||||
| Quinine sulphate (250 mg) | Mekophar Vietnam | Tablet 180T/pot | 1200–1500 VND/tablet ($0.05–$0.07 USD) | 180 VND/tablet ($0.01 USD) | 5 clinics, 4 pharmacies and 2 grocery stores |
| Chloroquine phosphate (250 mg) | Mekophar Vietnam | Tablet 200T/pot | 500–1500 VND/tablet ($0.02–$0.05 USD) | 180 VND/tablet ($0.01 USD) | 3 clinics, 3 pharmacies and 2 grocery stores |
| Arterakin (dihydroartemisinin 40 mg + piperaquine phosphate 320 mg) | Phabacor Vietnam | Tablet 10 T/1 blister pack | 2000 VND/tablet ($0.09 USD) | 200 VND/tablet ($0.01 USD) | 3 clinics, 3 pharmacies and 1 grocery store |
| CV8 (dihydroartemisinin (32 mg) + piperaquine (90 mg) +trimethoprim (90 mg) +primaquine phosphate (5 mg) | OPC Vietnam | Tablet 8 T/1 blister pack | 1200 VND/tablet ($0.05 USD) | No information given regarding source/price | 2 private clinics and 1 pharmacy |
| Artesunat artesunate (50 mg) monotherapy | Phabacor Vietnam | Tablet 12T/1 blister pack | Offered freely to clients | Reportedly obtained from CHS | 1 private clinic in Kon Tum |
| Malaria rapid diagnostic tests | |||||
| Malaria Ag P.f/P.v | Standard diagnostic | N/A | 15,000–35,000 VND/test ($0.66–$1.64 USD) | 3500–7000 VND/test ($0.15–$0.31 USD) | 2 private clinics and 1 pharmacy |
Conversion to USD: 22,727 VND/$1 USD (rate on August 30, 2017)
Expired anti-malarial drugs were found in 3/25 outlets, and in these cases, outlet operators emphasized that they had no plans to sell expired products but had simply not yet disposed of them. One of the expired drugs found was artemisinin monotherapy, potentially left over from before these were banned in Vietnam. RDTs were only found in stock in 3 of the 30 outlets audited, some of which were expired (June 2015). Only one type of RDT was found: Malaria Ag P.f/P.v by Standard Diagnostic.
The five outlets without stock on the day of the survey reported that they had recently sold out of quinine and/or chloroquine, the anti-malarials that are typically available at their outlets. Providers also mentioned that they tended to stock anti-malarial drugs more commonly during the rainy season (April to September), and that the time of study (December) was during low malaria season. Only one outlet reported sale of any anti-malarial within the past 7 days; Arterakin.
When providers were asked about where they obtain supplies, they were generally hesitant to disclose details but stated that they maintain stock levels using telephone orders from pharmaceutical distributors in provincial capitals or regional companies. Some providers reported receiving supplies from the CHS, either through family or friends who work there, or because they themselves work there.
Grocery store operators expressed that they often sell drugs based on their own personal experiences, or based on advice from pharmacists. They source medication from pharmacies in larger cities, often pharmacies in which they have a familial or otherwise personal connection with:
“I sell drugs based on my personal experiences, I have no medical training. At the beginning I usually went to city to purchase goods for my grocery and my neighbour asked me help to buy some medicine for them. Since then I have stocked simple medicines.”
—A grocery shop owner, Binh Phuoc
Private provider perceptions of anti-malarial laws
Although registered pharmacies are authorized to provide anti-malarials following prescription by medical doctors (see ‘Provider Overview’ section), there may be a disconnect between national policies and local government understanding, and thereby enforcement of these policies. Pharmacy operators described recent inspections by the local Department of Health, where financial consequences and license suspensions were imposed for stocking anti-malarial medications:
“Everything related to malaria has been banned from the private sector and therefore any malaria care at a private pharmacy or clinic is illegal.”
—A pharmacy operator, Kon Tum
“The DOH conducts an annual inspection of all pharmacies and clinics in this province. If the outlet is stocking any malaria medication they face fines and/or license suspension or loss.”
—A pharmacy operator, Binh Phuoc
Private provider diagnostic and treatment practices
Many of the private providers interviewed expressed that they diagnose malaria symptomatically, which may be consistent with stock audit findings on the low availability of RDTs in outlets audited. For pharmacies, only one outlet audited had RDTs in stock. Providers from private clinics also described that they did not trust RDT results:
“I only conduct diagnosis based on signs and symptoms reported by my patients. I do not test. But previously there were some patients who visited me, I tested with a malaria rapid test and got negative results. No drugs were effective until I used Chloroquine, then the fever disappeared.”
—A private clinic employee, Kon Tum
For treatment practices, a pharmacy operator in Kon Tum mentioned that they dispense anti-malarials with a variety of other medications:
“If a customer come with symptoms of fever and cold for 3 continuous days I give this package consisting of flu drugs, fever reliever, and chloroquine. But normally I start with a basic drug such as paracetamol. If the fever continues, then I give them [artesunate].”
—A pharmacy operator, Kon Tum
Malaria training among private providers
Many of the private providers interviewed reported having received little to no official training on malaria, or if they did receive training through medical school, had not received updates on malaria treatment and testing since then. Some providers participated in trainings, however these were integrated programmes that were not specific to malaria, and providers felt they did not offer sufficient information on malaria. As a result of the lack of formal training on malaria, private providers rely on instinct, experience and self-taught methods to provide malaria care to their clients/customers:
“I also work at a CHS, so I’m invited to the district health centre for annual malaria training, but I haven’t had time to attend, so I only received the documents and read them myself to treat patients.”
—A private clinic employee and CHS worker, Kon Tum
“I learned about malaria treatment by myself, but do not offer any official treatment regime. I have cured patients based on my experience.”
—A pharmacy operator, Binh Phuoc
Private provider motivations
When asked about their motivation as providers, respondents expressed that profit remains their primary incentive. In the context of Vietnam’s low and decreasing malaria burden, providers explained that they were less motivated to stock malaria products, given a relatively low and seasonal demand:
“As malaria is not a big health issue, we do not stock anti-malarials regularly. However, if there is a malaria patient asking for drug, I can provide it to them.”
—A pharmacy operator, Kon Tum
Providers also expressed that most of their clients are regular clients, and that they are motivated by altruism, given their role as caregivers within the community:
“I am happy when I saw my patient recover or happy when someone come back to me and say thank as I treated his/her well.”
—A pharmacy operator, Kon Tum
Links between the public and private sector
There were no formal links between the public and private sector in Vietnam, confirming that malaria cases treated through the informal private sector are not reported to the public surveillance system. However, there are informal links between the public and private sector, a significant one being that many private clinic providers work at the CHS during the day. Both pharmacy providers and those in private clinics also described referral practices to the public sector, which they explained were for serious illness, as well as in cases where the treatment they offer does not resolve symptoms:
“We generally will make referrals to the public facilities if the patient is seriously ill, or if our offered treatment does not work well.”
—A pharmacy operator, Kon Tum
Communication channels for private providers
The providers interviewed were asked about popular methods of communication, as providers may be willing to use these methods for reporting malaria cases to public facilities. The providers interviewed stated that the phone was the most popular and main communication method. Almost all interviewed private providers also had internet access, but mentioned that access was not stable:
“I am not often searching information on the internet, also we only have 3G internet which is not stable.”
—A private clinic employee, Binh Phuoc
Private clinic operators communicate with each other and nearby pharmacies, using text messages and “Zalo” to share information about government inspections, refer clients for drugs they do not have in stock, and more.
At-risk individuals in field sites: care-seeking behaviour
In the field sites selected for study, patients described private pharmacies, clinics, and grocery stores as their main first point of care, a finding consistent with those found in Key Informant interviews. Patients described these outlets as being relatively accessible, usually being located within 1–5 km from their community. The CHS, on the other hand, was approximately 3–12 km from the communities visited, and 30 km from the forest where interviewees worked. Patients mentioned that they did not use the CHS due to ‘hidden’ costs such as transportation and consultation fees, and furthermore, treatment was only free for those with insurance:
“Just 4 months ago was my fourth time having malaria. I did not test, but I knew [I had malaria] because the symptoms were similar. I went to the commune health station once. They gave me CV8 [DHA-PIP] for treatment. I had to pay for consultation and services. But I did not recover so I went to the newly opened private clinic close to my home. They charged me the same amount for the same drugs I got from the CHS before [showed the drugs]. So I think that nothing is free.”
—A malaria patient, Kon Tum
Patients and forest goers described that they preferred to visit pharmacies and/or private clinics due to convenience, patient-appropriate hours of operation, and perceived higher quality of care including provider friendliness.
“If you get ill on Sunday or Saturday, you have to wait until Monday to get treatment from CHS, if you wait until then, you will die. I normally go to the pharmacy first and ask for treatment. If the symptoms do not go away, I go to CHS later.”
—A malaria patient, Kon Tum
“I have never visited the CHS. If I am ill, I go to the private clinics close to the road and ask for treatment. I’m scare to go to the CHS. For any disease they will take my blood for testing –they recommend that I do not know.”
—A malaria patient, Kon Tum
Patients also described self-treatment as a common practice, another finding consistent with perceptions noted by Key Informants. In some instances, individuals in the community gave anti-malarial medications they had on hand to their friends, or went to the pharmacy to purchase anti-malarials for their friends:
“My friend told me what malaria symptoms are and gave me some medicine that he took before, and told me to visit Dr… a private provider, for treatment. Fortunately, after taking his medicine my symptoms went away.”
—A local forest goer, Binh Phuoc
In other cases, mobile workers reported travelling with medication on-hand, given difficulty accessing health care on or near farm or forest sites. Medications chosen were usually cocktails of drugs to treat common illnesses, including malaria, to be used while they are working in the field for days or weeks at a time. These cocktails were often purchased from rural grocery shops close to home or near entry points into the forest:
“In the forest, we have no time to leave for testing and treatment, so we normally bring some drugs with us for when we get malaria in the forest. In Cambodia, it is easier to purchase these medicines.”
—A migrant forest goer, Kon Tum
Patients and forest goers mentioned that payments were not an impediment to accessing treatment from private providers. While cash was the most popular way of payment for treatment, some providers were willing to accept trade payments and/or credit or deferred payments. However, credit/deferred payments were only an option for patients who were regular clients to the provider:
“When we do not have money, we can still come to get drug and pay later. We know each other very well. The doctor knows everyone in this village”
—A local forest goer, Kon Tum
“We have only cash and pay in cash, we travel frequently from this area to others, the owners do not know who I am, how they can give us treatment without money”
—A migrant forest goer, Kon Tum
At-risk populations in field sites: characteristics, perceptions of malaria, and communication channels
The at-risk individuals interviewed included forest goers (three local, two migrant), three plantation workers, and three farmers who spent at least one night within the last 3 months within or near a forest in the study area.
Forest goers comprise of men, ages 20–50 years, who travel to the forest without their families. There are two general types of forest goers; those that are local, and those that are migrants. Local forest goers are typically ethnic minorities (X’tieng, Gia Lai, Ede, Bana, Van Kieu, Tay and Nung) that live in villages close to forests. They typically stay in the forest for a few days during the dry season, collecting supplies and sometimes crossing the border. They visit the forest primarily during the dry season, and reported earning between 1.2 and 2.8 million VND ($60 to $110 USD) per month from the sale of items forest items. Migrant forest goers tend to be Kinh, the majority ethnic group in Vietnam, and travel from other provinces and/or across international borders. They reported staying in the forest for up to a month at a time, returning to their home province a few times a year. Migrant forest goers reported earning between 3.5 and 5.7 million VND ($150 to $270 USD) per month.
Ethnic minorities face a number of challenges, including living in remote, rural areas with limited access to care, and limited access to information. Most of them are poor, living in bamboo houses and following traditional lifestyle habits, for example, not using mosquito bednets. They also face challenges with language barriers with the Vietnamese majority group. Money and family are primary motivators for forest goers:
“If we are lucky, for example, hunting many animals, we can earn 7–8 million Vietnam Dong [$308–352 USD] each time for a group of 5–6 people.”
—A local forest goer, Kon Tum
Forest goers reported bringing medicines to the forest, to treat common illnesses. Many forest goers in border districts also reported easy access to malaria drugs through outlets across the border, in Cambodia. Both local and migrant forest goers reported avoiding forest rangers, due to the risk that encounters will require bribe payments from the rangers.
“We bring some drugs to treat common illnesses, including malaria. We purchase these drugs from a private clinic or pharmacy or, more frequently, from a non-health outlet — like an FMCG [Fast Moving Consumer Goods; mobile vendor].”
—A migrant forest goer, Binh Phuoc
The other main group at risk for malaria is small-scale farmers, who work on small, informal farms or plantations in or near the forest. They usually travel to town on a weekly basis to restock supplies at home and local markets.
Perceptions of malaria
Individuals at risk of malaria mostly perceived the risk of malaria to be low, and understood that malaria is transmitted by mosquitoes. However, myths and misconceptions exist; that malaria only infects unhealthy individuals, or that malaria is transmitted through wind or water:
“No, I am not at risk as malaria is not a problem and can be treated easily, also it only infects those who are not healthy.”
—A farmer, Binh Phuoc
At-risk individuals expressed a very basic knowledge of malaria symptoms, described to be similar to fever or cold. There was little knowledge or use of RDTs, and very limited knowledge of malaria drugs; patients explained that they received very little information from providers related to diagnosis and/or the medication provided.
Treatment adherence rates were also reportedly low; most interviewees who had been diagnosed with malaria previously reported that they never completed the full course of drugs acquired from their health provider. Both providers and at-risk individuals described patients taking the medicine until their symptoms went away (even when diagnosed at the CHS), often buying partial courses of treatment due to financial constraints:
“They only purchase medicine for 1 or 2 doses, then if the symptoms persist they come back and order more. There are many reasons, such as no money, but it is mainly due to their knowledge—they do not think it is necessary.”
—A private clinic employee, Kon Tum
At-risk individuals described two main malaria prevention methods: hammocks and mosquito nets. Preventive measures are not used consistently; a farmer explained that not enough nets are available on the farm, and a forest goer expressed a misconception that drinking alcohol can prevent mosquito bites:
“We normally sleep after drinking so we often do not use the net, mosquitoes do not bite drunk people.”
—A local forest goer, Kon Tum
Hammocks nets were less common; some at-risk individuals had never heard of them, others stated they were hard to find:
“I bought this hammock net in Cambodia. I cannot find this here in Vietnam. Even in Cambodia, you have to know where to buy this, it is not common, it is mostly used for the military.”
—A migrant forest goer, Kon Tum
Communication channels accessible to high risk groups
Given the remote, rural areas where they live and work, forest goers and small-scale farmers reported having relatively limited access to communication channels. Health information was usually provided to high-risk populations by village health workers through traditional communication channels managed by local authorities, such as the commune loudspeaker announcements and community hall signboards, in addition to word of mouth from friends, family and local leaders.
Mobile phones were noted as the main source of communication, however coverage was very limited in forests and remote farm areas. Additionally, border crossing posed further barrier to mobile phone use, as migrant forest goers expressed the need to buy new SIM cards when crossing borders to Cambodia or Laos.
The internet was seldom used to access information, and only used by a few forest goers and small-scale farmers interviewed. Television was used for information, but most at-risk populations do not own televisions, and viewed television at cafes or at their neighbor’s place.
Discussion
Malaria elimination programmes share a common goal of providing testing, treating, and tracking for all infections. Currently, all three of these goals are threatened by practices in the private sector, the main first point of care in rural, malaria endemic areas [3, 4]. This study is the first to describe and characterize the private health sector accessed by high-risk populations of malaria in Vietnam, as well as their clientele’s characteristics and care-seeking behaviour, providing crucial insights for the Vietnamese malaria programme as the country prepares for malaria elimination.
The results from this study suggest that improved malaria treatment and diagnostic practices should be targeted to private pharmacies, private clinics, and grocery stores in remote, malaria endemic areas. Currently, treatment is given on the basis of symptoms, leaving no room to discriminate between P. falciparum malaria, P. vivax malaria, and other non-febrile illnesses. Ideally, this practice should be replaced with an effective training programme on RDT use, accompanied by subsidized provision of RDTs, as providers otherwise do not receive training on malaria treatment and diagnostic practices. There is also a need to incorporate a surveillance and referral mechanism within the informal private sector; current cases remain unreported, preventing the malaria programme from tracking, and thereby responding to cases and outbreaks. The findings in the study suggest that pharmacies and grocery stores do not have formal links with the public sector, and furthermore, that they prefer to communicate using mobile phones. Thus, mobile phones offer a potential method for case reporting and referral to public facilities. Also, the study found that doctors at private clinics commonly work at the CHS in the public sector during the day, such that these doctors may be asked to report cases to the CHS during their day job.
An interesting gap found in this study is the misconception of national policies, that registered pharmacies are allowed to provide anti-malarial drugs provided they are accompanied by a formal prescription. This gap was noted through contradictions in key informant interviews, as well as provider interviews in the field, who noted that they would be fined if they carry anti-malarial drugs. Efforts should be made to clarify this national policy at the provincial level.
Among malaria patients and at-risk individuals, this study identified a few key factors may threaten efforts to eliminate malaria. First, individuals cited a limited understanding of malaria transmission and prevention, including misconceptions that malaria is spread by wind or water, and that mosquitoes do not bite individuals who are drunk. Second, individuals reported not completing their courses of anti-malarial medications, a dangerous practice that threatens the further emergence of drug resistance [22]. Third, individuals reported that they often stock medications at home and practice self-medication, a practice that has been documented previously, and was also noted by KIs [23]. Education is needed among at-risk populations to improve on their knowledge and awareness of malaria, including encouraging the use of preventive measures, communicating the importance of acquiring diagnosis using a test, and emphasizing the importance of completing full courses of treatment.
At-risk individuals also expressed that insecticide-treated hammock nets were difficult to acquire, a preventive measure that may be important in Southeast Asian settings, where many Anopheline species are outdoor biters. Further research is needed, both to assess the efficacy of insecticide-treated hammock nets, and to explore additional methods to combat outdoor-biting mosquitoes, particularly for individuals who sleep outside.
One area that must be emphasized is that reaching these populations will require an engagement strategy to optimize delivery, as in the absence of effective delivery, even the strongest interventions may be lost to poor adherence and uptake. This study provides insight for engagement strategies, finding that providers care about both profit and altruism, and that at-risk individuals mostly comprise of men staying in the forest for days or weeks at a time, often drinking with their peers in the evening. These insights can be used in malaria elimination programme plans, as a foundation for how to reach and motivate providers and at-risk individuals, promoting early diagnosis, treatment, and adherence. Indeed, these types of insights have laid the foundation for behaviour change communication (BCC) strategies in many countries including Cambodia and Myanmar, where ACT and RDT use have been piloted using BCC strategies, successfully creating product awareness and encouraging uptake [24, 25]. In these studies, the authors emphasize the importance of BCC for RDT use, which requires complex messaging when targeted to providers in the informal private sector. In Vietnam, the use of BCC approaches have not been documented for malaria control and elimination, but have shown to be effective for injection drug users at risk of HIV [26]. Malaria elimination efforts in Vietnam can likely be accelerated through BCC, targeting improved treatment, diagnosis, and reporting practices to private providers and at-risk individuals.
This study is limited to inference drawn from qualitative insights across a small group of respondents in target areas, and is not nationally representative. However, given the concordance between providers noted by key informants and results found in the field, the findings on private providers and at-risk populations in this study are likely to be largely generalizable across malaria endemic areas of Vietnam. However, the care-seeking behaviour found in this study may be more specific to the locations studied, given different compositions of ethnic minorities and their respective traditions, as well as different migration patterns, lending to subtle differences between at-risk populations in the two provinces studied. This study did not include at-risk populations in large plantations and worksites that provide their own healthcare, nor did it address the issue of international migrants from Africa, which are gaps that should be addressed by future studies.
Authors’ contributions
IC wrote the study protocol, obtained ethical approvals from UCSF, conducted and analysed key informant interviews, and wrote the first draft of this paper. HNTT obtained ethical approvals from the Hanoi School of Public Health, led field interviews, and conducted data analysis on field interviews. PTT, TVL, and HNT conducted field interviews. AL supported project design, collaboration, and paper revisions. NDT reviewed the paper. JN and AB oversaw this study and reviewed paper drafts. All authors read and approved the final manuscript.
Acknowledgements
The authors would like to thank the following individuals for valuable insight: all the study participants, collaborators at NIMPE and the WHO, and Megan Littrell and Cynthia Whitman from PSI.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
The data used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the University of California, San Francisco Committee for Human Research (UCSF CHR-Approval # 154331) on the 23rd of July 2015, and by the Hanoi School of Public Health on the 12th of October 2015 (Approval # 282/2015/YTCC-HD3). All interviewees provided informed written consent for participation.
Funding
This project is supported by the Bill and Melinda Gates Foundation, Award A122394.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Footnotes
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-017-2060-0) contains supplementary material, which is available to authorized users.
Contributor Information
Ingrid Chen, Email: ude.fscu@nehc.dirgnI.
Huong Ngo Thi Thanh, Email: nv.gro.isp@ogngnouh.
Andrew Lover, Email: ude.fscu@revol.werdna.
Phung Thi Thao, Email: moc.liamg@cctyoaht.
Tang Viet Luu, Email: nv.gro.isp@gnatuul.
Hoang Nghia Thang, Email: moc.liamg@5k2gnahtaihgn.
Ngo Duc Thang, Email: moc.oohay@nvepmingnaht.
Josselyn Neukom, Email: nv.gro.isp@mokuenj.
Adam Bennett, Email: ude.fscu@ttenneb.mada.
References
https://www.sciencedirect.com/science/article/pii/S2095809918305423
Research Traditional Chinese Medicine—ReviewArtemisinin, the Magic Drug Discovered from Traditional Chinese Medicine
Keywords
1. Introduction
Malaria has been a debilitating disease with global influence since ancient times and continues to be one of the most widespread and damaging infectious diseases today [1]. With the cause of disease having long been misattributed to “bad air,” the transmissible and parasitic nature of malaria remained unknown until the works of Charles Louis Alphonse Laveran and Ronald Ross in the late 1800s. Their findings established that protozoa belonging to the genus Plasmodium caused malaria, and that Anopheles mosquitoes were the primary vectors of malarial infections. These observations made Laveran and Ross two of the earliest recipients of the Nobel Prize in Physiology or Medicine [2].
In the decades following their discoveries, ground-breaking progress has been made in the battle against the disease. The crusade launched by the Chinese government in the late 1960s to search for cures for malaria ultimately culminated in the discovery of artemisinin. Artemisinin (and its various derivatives, which we will refer to collectively as “artemisinin” unless otherwise specified) is a sesquiterpene lactone compound (Fig. 1) with a unique chemical structure derived from the sweet wormwood plant, Artemisia annua L. (Fig. 2). Since its discovery, it has become the most important and effective antimalarial drug [3].
Fig. 1. Artemisinin and its clinically used derivatives.
Fig. 2. Artemisia annua L. in the field.
In many ways, artemisinin is a truly fascinating drug. From the tumultuous process of its discovery, which was deeply tied to traditional Chinese medicine (TCM), to its remarkable potency and impact as an antimalarial drug, it is not surprising that artemisinin has captured a great deal of attention since its introduction to the world stage [1]. Over 40 years after its discovery, artemisinin remains our bulwark against malaria and is the foundation of all major antimalarial therapies [4]. Years of research spanning a range of disciplines have gone into the exploration and elucidation of the mechanisms of artemisinin in its antimalarial role [5]. Beyond that, efforts have been made to repurpose artemisinin for non-malarial applications, thereby raising considerable anticipation over the future development of this drug [6].
With that in mind, we feel that it is a good time to broadly review the timeline of this influential drug, spanning its past, present, and future. Beginning with a look back at the story of the discovery and development of artemisinin, we then review and discuss the contemporary understanding of the mechanism of action (MOA) of artemisinin in malaria. We conclude by looking ahead at current efforts to repurpose artemisinin for possible roles outside of malaria. We believe that this article will provide a well-rounded background of artemisinin, along with relevant insights into the salient topics surrounding this remarkable drug.
2. The journey of discovery
We begin with a brief tracing of the remarkable journey that led to the discovery and development of artemisinin. Records of malaria in TCM date back thousands of years, and the same is true for the usage of Artemisia (Qinghao) plants as medicinal herbs. First mentioned as a specific remedy for malarial symptoms in Ge Hong’s Zhouhou Beiji Fang (Handbook of Prescriptions for Emergency) dating back to the Eastern Jin Dynasty (317–420 AD), the application of Qinghao and other techniques for malarial relief was subsequently noted in a series of historical Chinese medical writings that included the influential Bencao Gangmu (Compendium of Materia Medica) by Li Shizhen (Ming Dynasty, 1368–1644 AD). This wealth of ancient knowledge would later prove to be instrumental in the discovery and development of artemisinin.
In the years following World War II, the development and deployment of the potent insecticide dichloro-diphenyl-trichloro-ethane (DDT) and new antimalarial drugs such as chloroquine (CQ) resulted in great progress in combating malaria. However, the World Health Organization (WHO)’s campaign in the 1950s to combat and eradicate malaria around the world was eventually met with challenges related to resistance. The emergence of DDT-resistant vectors and drug-resistant parasites led to a rebound of the disease, especially in regions such as Southeast Asia and sub-Saharan Africa [7]. This setback prompted an urgent need for novel antimalarial drugs. Significant efforts had been made by the United States due to the Vietnam War and the prevalence of drug-resistant malaria in that region. The Chinese government also initiated efforts in malarial research around this time. In particular, a national project called Project 523 (named after its date of inauguration, 23 May 1967) was set up to consolidate malarial research on a national level [8].
In 1969, Professor Youyou Tu was selected to lead a research group within the project that focused on screening TCM for novel antimalarial drugs. This work took place at the Institute of Chinese Materia Medica of the China Academy of Chinese Medical Sciences. Drawing from a massive repository of TCM knowledge that included ancient literature, folklore, and oral interviews with practitioners, Tu and colleagues worked from a list of over 2000 herbal remedies, of which some 640 were deemed to be possible “hits.” From this selection, over 380 extracts from approximately 200 herbs (including Qinghao/Artemisia extracts) were eventually collected and tested, mostly giving unsatisfactory results [1], [9]. The Qinghao extract nevertheless drew particular interest starting around 1971, as it produced promising but inconsistent results [1]. This finding prompted a revisitation of the literature, and led to perhaps the most important breakthrough in the discovery process.
Returning to the earliest record of the use of Qinghao to treat malarial symptoms, which was in Ge Hong’s Zhouhou Beiji Fang (Handbook of Prescriptions for Emergency), Tu noted that the instructions for the Qinghao prescription involved consuming the strained “juice” of the Qinghao plant immersed in water. It was notable that the instruction made no mention of heating the medicine—something that was otherwise common for prescriptions in TCM. Drawing from the literature and her own knowledge of TCM, Tu arrived at the idea to modify the extraction process to use low-temperature conditions. The extracts produced from this new procedure were further purified by separation of the acidic and neutral phases in order to retain active components while reducing the toxicity of the original extract. The resultant substance displayed a striking 100% effectiveness against rodent malaria in experiments carried out around October 1971. This remarkable result was then fully reproduced in monkey malaria experiments carried out in late December of the same year, thus establishing the efficacy of the Qinghao extract beyond doubt [1].
The breakthrough had been made, but the journey of drug development was by no means complete. Conditions in China at that time made it difficult to perform clinical trials of new drug candidates to ascertain their safety for humans. In an attempt to accelerate the process due to the seasonal and time-sensitive nature of malarial research, Tu and colleagues decided to volunteer themselves as the first human subjects for toxicity and dose-finding tests [8]. This act established the safety profile of the Qinghao extract and enabled clinical trials to be carried out immediately, in the latter half of 1972. The trials (which were carried out in Hainan Province and at the 302 Hospital PLA (now incorporated into the Fifth Medical Center of the Chinese PLA General Hospital) in Beijing) proved successful, and paved the way for Qinghao research to be pushed to the national level. A subsequent concerted effort on the part of the Chinese scientific community at large drove further research and development of Qinghao forward. The active component of the Qinghao extract, artemisinin (also known as Qinghaosu) itself, was isolated in November 1972 by Tu’s team at the Institute of Chinese Materia Medica. The team would later go on to develop dihydroartemisinin (DHA), which remains one of the most pharmacologically relevant derivatives today. In collaboration with other institutes across China, further groundwork in drug development, including the determination of the stereo-structure of artemisinin and further derivatization of artemisinin, was carried out in the following decade [10], [11]. These efforts, among others, culminated in the fourth meeting of the Scientific Working Group on the Chemotherapy of Malaria held in Beijing in 1981, where the findings were presented by Tu for the first time. The results were published in 1982 as a series of papers under the name “China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials” [12], [13]; thus the gift from Chinese medicine was delivered to the rest of the world.
In the subsequent years of the 1980s, artemisinin and its derivatives were successfully employed in China to treat thousands of malaria patients [1]. As the problem of drug-resistant malaria continued to worsen elsewhere, it was not long before the commencement of clinical studies with artemisinin in other endemic regions in Asia [14], [15], [16], [17], [18], [19]. Consistent and encouraging results led to the expansion of such studies, particularly toward Africa [19], [20], [21], [22], [23], [24]. The evidence was clear that artemisinin-based therapy, especially in combination with a slower-acting antimalarial such as mefloquine or piperaquine, led to significant improvements in parasite clearance and a rapid diminishing of symptoms for both uncomplicated and severe Plasmodium falciparum malaria infection. At the same time, its tolerability was shown to be excellent, as reports of toxicity and safety concerns remained minimal [25]. Across more than a decade’s worth of independent randomized clinical studies and meta-analyses, the outstanding efficacy and safety of artemisinin-based therapy became increasingly clear. Finally, in 2006, the WHO announced an alteration of its strategy to fully employ artemisinin combination therapies (ACTs) as the first-line treatment against malaria [26]. ACTs remain the most effective and recommended antimalarial therapies today [4].
3. The search for a mechanism of action
It has been more than a decade since the implementation of ACTs as the official first-line treatment for malaria and over three decades since the discovery of artemisinin. In this time, the clinical and pharmacological characteristics of artemisinin therapy have been extensively scrutinized and reported [27], [28], [29], [30]. Although the specifics of various derivatives can differ, artemisinin drugs are characterized by rapid action and potency, low toxicity, and a short half-life, which makes combination therapy with longer-acting antimalarial drugs ideal and recommended [30]. Apart from its pharmacological properties, elucidating the MOA of a drug is important for optimizing treatment regimens. Dosages, drug combinations, and even considerations of drug resistance are closely related to the molecular basis of a drug’s activity. It is thus somewhat surprising that despite decades of widespread application, our understanding of the MOA of artemisinin remains fairly incomplete. Here, we provide a brief overview of the prevailing understanding as well as more recent developments in mechanistic studies of artemisinin [31], [32]. In general, the outstanding therapeutic properties of artemisinin can be thought of as a result of two major processes: its unique mechanism of activation, and its downstream activity and drug targets. These mechanisms combine to yield a highly potent, yet highly specific, drug.
3.1. Drug activation
Artemisinin and its derivatives are sesquiterpene lactones that bear the 1,2,4-trioxane moiety as the pharmacophore [33]. In particular, the endoperoxide bridge within this group is well understood to be essential for the pharmacological activity of artemisinin [13], [34], [35]. Artemisinins are prodrugs in two senses: first, many derivatives are rapidly converted to DHA in vivo, and second, their MOA depends on activation by cleavage of the endoperoxide bridge. The mechanism of this cleavage remains an issue in active research [36]. Malarial parasites are characterized by extensive hemoglobin uptake and digestion during the erythrocytic stage of their life cycle [37], [38]. This releases copious amounts of free redox-active heme and free ferrous iron (Fe2+), which are thought to underlie the parasite specificity of artemisinin. Indeed, hemoglobin digestion has been strongly linked with artemisinin susceptibility in parasites [38], [39]. Multiple models have been proposed with regard to the mechanism of endoperoxide cleavage by either free redox-active heme or free ferrous iron, and the downstream molecular events that follow cleavage [36], [40], [41], [42], [43], [44], [45], [46], [47], [48]. These proposals differ in terms of the nature of the cleavage and the identity of the reactive intermediates produced by drug activation. In general terms, however, they explain the parasite-specific drug activation through which reactive species are produced, leading to cellular damage and parasite killing. Recent evidence suggests that free redox-active heme may play a predominant role in drug activation [49], [50]. A 2008 study provided in vitro data that indicated that ferrous heme may be a stronger activator of artemisinin than other iron-containing species, including hemin, free ferrous iron, and undigested hemoglobin [49]. Similar observations were made in live parasites, in which artemisinin activation was blocked by inhibiting hemoglobin digestion but not by the chelation of free ferrous iron [47]. Thus, the process of hemoglobin digestion in infected erythrocytes, which is required for parasite growth, is the key to the specificity of artemisinin activation [38].
Interestingly, in studies using yeast cells as a proxy for malaria parasites [51], [52], it was found that mitochondria were directly involved in both the activation and action of artemisinin, thus further linking artemisinin action to reactive oxidative species (ROS) production and oxidative damage. It is also plausible that multiple redundant activation pathways may exist in different environments or localities, where the conditions and magnitude of activation can differ [53]. Looking ahead, it will be crucial to consider the pivotal role of drug activation in the activity of artemisinin and to further elucidate its mechanisms under different conditions.
3.2. Downstream mechanism
The crucial step in elucidating a drug’s MOA is to identify its cellular targets. In the conventional understanding of drug design and mechanisms, a drug modifies one or more specific cellular targets, such as proteins, in order to effect downstream changes. However, the exceedingly fast-acting and potent nature of artemisinin activity, taken together with its ability to alkylate targets, may be due to quite a different mechanism.
First of all, heme releases from hemoglobin digestion functions that lie beyond drug activation, as previously outlined. Excess heme is converted in infected erythrocytes to hematin, which is toxic to the parasite via oxidative damage and direct lysis of cell membranes [54]. Malarial parasites have therefore evolved a detoxifying mechanism that converts hematin to the nontoxic and inert crystallized hemozoin via a biocrystallization process [55]. Activated artemisinin has been reported to prevent the formation of hemozoin by alkylating heme; therefore, it functions in a similar capacity to other antimalarial drugs that act on hemozoin formation, such as CQ [45], [56], [57], [58]. Thus, free heme from hemoglobin digestion serves as both the activator and the target of artemisinin [45].
Given that activated artemisinin is thought to generate ROS, it is unsurprising that artemisinin has also been reported to directly alkylate protein targets [59], [60]. The translationally controlled tumor protein (TCTP) and the Plasmodium sarco/endoplasmic reticulum Ca2+-ATPase PfATP6 were among the first targets of interest that were identified as interacting partners of artemisinin [61], [62], [63]. Consideration of the role of single targets in the activity of artemisinin has now evolved into MOAs that may depend on multiple targets, as later studies have shown [64], [65], [66], [67]. Using unbiased proteomics methods, it has been observed that artemisinin targeting may be promiscuous rather than monotarget-specific. In the first study that systematically reported artemisinin binding targets, over 100 proteins were identified in live parasite strains [47]. An independent study carried out by Ismail et al. [68] led to consistent findings. These results support a promiscuous mechanism of artemisinin targeting in which activated artemisinin alkylates and damages many cellular proteins, thereby disrupting multiple key biological functions and resulting in toxicity and lethality in parasites [47], [48], [50]. Interestingly, PfATP6 and other key transporters such as PfCRT and Pfmdr1 are consistently labeled in these types of experiments. These findings are consistent with PfATP6 being an important target for artemisinins [47], [68]. As an independent line of evidence, the mapped binding sites of artemisinin to TCTP further support a heme-activated promiscuous mechanism in which modification sites are proximity-based and essentially random [50].
Our current knowledge of artemisinin paints a picture of a drug with a unique and elegant mechanism. Artemisinin and its derivatives are prodrugs that absolutely require endoperoxide group cleavage for drug activation and subsequent anti-parasite activity. Artemisinin activation is dependent on a heme-rich environment, which is specific to infected erythrocytes as well as being an unavoidable outcome of parasite metabolism. The heme-rich environment itself is then exploited by the activated drug to achieve efficient parasite killing. This mechanism essentially links infection and parasite growth to drug activation, thus ensuring both the outstanding specificity and the tolerability of artemisinin therapy. At the same time, activated artemisinin indiscriminately damages proximal proteins and cellular structures. Rather than targeting a single protein or cellular function, like the majority of conventional drugs (including most antimalarials), artemisinin acts like a less-discriminative “bomb” that detonates upon activation to cause widespread damage. The specificity of artemisinin may therefore be seen to be based on its activation rather than on its targets. These unique properties of artemisinin make it almost the ideal weapon against malaria, especially in combination with other drugs that act via distinct mechanisms and complement the pharmacological profile of artemisinin. An obvious advantage of a promiscuously targeting drug is also worth noting here: The development of drug resistance is much more difficult when mutation in one or a few specific targets is not sufficient to seriously impact drug activity. This advantage could well explain why artemisinin has remained generally efficacious despite its ubiquitous use over decades.
Nevertheless, recent trends have signaled the incidence and rise of malaria that is being cleared more slowly by ACTs, especially in the Asian endemic regions [69]. This topic has been comprehensively covered from various angles by recent reviews and commentaries [69], [70], [71], [72], [73], [74], [75]. Regardless of the controversies about the exact definition of “artemisinin resistance” in the field, the threat is undoubtedly real, given the place that artemisinin occupies in the control of malaria [76], [77]. To resolve this burning issue, two major challenges must be overcome: ① A full understanding of the MOA of artemisinin must be achieved; and ② the genetic and physiological features of the newly emerged artemisinin-resistant strains must be defined. Even though the MOA of artemisinin has been largely demystified in the past few years, the molecular characterization of artemisinin-resistant malaria is far from clear. Continued efforts are required to achieve a complete picture of how artemisinin resistance relates to its mode of action. Based on this new knowledge, new therapeutic strategies can then be developed and tested.
4. Repurposing artemisinin
Artemisinin therapy is characterized by its outstanding tolerability and relative affordability. This combination of proven safety and accessibility make artemisinin a drug of exceptional interest for repurposing studies. Indeed, interest in non-malarial applications of artemisinin has increased steadily over time since artemisinin was first made known to the world [78]. While malaria remains the only disease for which artemisinin is an approved treatment, the potential applications of artemisinin in anti-cancer, anti-inflammatory, anti-parasitic (outside of malaria) and anti-viral roles, among others, have been explored in earnest over the years [78], [79], [80], [81], [82]. Here, we briefly comment on some promising research in artemisinin repurposing, especially in the field of cancer treatment, as a window into future drug development.
The efficacy of artemisinin in cancer cultures was first reported in 1993, and has since been expanded on and extensively characterized [83], [84], [85]. It is now well-reported that artemisinin and its derivatives display selective cytotoxicity against a range of cancer types in both in vitro and in vivo studies [86]. Forays into clinical testing have been generally promising, if limited in number and scale [87], [88], [89]. More than two decades of research on the basis of artemisinin action in cancer has uncovered a plethora of implicated targets and mechanisms. Artemisinin has been reported to induce mitochondrial apoptosis and other forms of cell death such as necroptosis, inhibit cancer angiogenesis and metastasis, and arrest the cancer cell cycle [90], [91], [92], [93], [94], [95], [96], [97]. These outcomes are reportedly mediated by a combination of oxidative damage, DNA damage, alteration of gene expression, and interactions with a wide array of signaling pathways including mammalian target of rapamycin (mTOR), NF-κB, mitogen-activated protein (MAP) kinases, and Wnt/β-catenin, among many others [82], [98], [99], [100], [101], [102]. These pathways and mechanisms have been extensively reviewed in recent publications [79], [80], [81], [82].
While pathway validation is an important aspect of mechanistic study, it is also necessary to consider the big picture in terms of unifying drug activation and downstream activity in a manner similar to what was done in malaria studies. As is the case with malarial parasites, the activation mechanism of artemisinin in cancer cells is likely to be heavily linked to its specificity of action. Thus, the role of free ferrous iron versus free redox-active heme is once again being put under scrutiny, especially considering that iron is intimately linked to artemisinin-induced cytotoxicity in cancer [103], [104]. Recent studies have once again shed light on the role of heme in artemisinin activation in cancer cells, thereby drawing parallels with the case in malaria. In particular, a range of methodologies have been used to demonstrate that modulation of heme synthesis and availability clearly correlates with cytotoxicity [105], [106], [107], [108]. It is also important to note that cancer cells have been reported to possess enhanced levels of heme metabolism and synthesis, and that this could underpin the cancer specificity of artemisinin in a similar manner to the case in malaria [109], [110], [111]. Specific targeting of artemisinin to mitochondria (the site of mammalian cell heme synthesis) or enhancement of heme levels by treatment with the heme precursor aminolevulinic acid (ALA) both improved anti-cancer activity [112], [113], [114]. A heme-centric mechanism of activation and an iron-dependent mechanism of downstream cytotoxicity could possibly be a point of reconciliation between the roles of those two species in the anti-cancer activity of artemisinin [115]. Further work to fully understand the basis of artemisinin specificity in cancer will be critical for future therapeutic applications.
At the same time, it is necessary to consider the appropriate direction when moving forward in terms of validating artemisinin MOAs in cancer. Consider the case in malaria, where artemisinin is proposed to indiscriminately attack adjacent targets upon activation. If artemisinin is activated in a similar manner in cancer cells, it is plausible that the same promiscuous multi-target mechanism would take place. This would explain the remarkable range of cellular effects and implicated pathways that have already been reported, as multiple targets and functional pathways are likely to be simultaneously affected by such a mechanism. Indeed, recent unbiased studies of artemisinin cancer targets using proteomics approaches have revealed a similar multi-target MOA by artemisinin in cancer cells [48], [113], [114]. The mechanism of cytotoxicity itself is also a matter of great interest, especially with regard to non-apoptotic forms of cell death. Recent work has closely linked artemisinin-induced cytotoxicity to oxidative damage and lysosomal function, with a focus on the role of iron in contributing to the iron-dependent form of cell death known as ferroptosis [116], [117], [118]. In particular, lysosome-mediated degradation of ferritin under autophagy conditions (termed ferritinophagy) releases free ferrous iron, which in turn contributes to both ferroptosis and iron-mediated generation of ROS [93], [119]. Autophagy itself is a cellular process that is reportedly activated by artemisinin, but has ambiguous effects on cancer cell survival and the cytotoxicity of artemisinin [115], [119]. It is clear that the relationship between autophagy, lysosomal activity, free ferrous iron, and iron-dependent ferroptotic cell death following artemisinin exposure represents a major area of uncertainty in the anti-cancer mechanism of artemisinin. However, efforts in unveiling novel, cancer-specific targets and mechanisms are steadily ongoing and continue to contribute to a grand view of artemisinin as an anti-cancer drug. Artemisinin-mediated effects on cancer stem cells, immunomodulation, cancer metastasis, cancer metabolism including the regulation of glycolysis, and a plethora of signaling pathways including signal transducer and activator of transcription 3 (STAT3), NF-κB, mTOR, and CREBP signaling are among recent reports, and indicate novel directions for further validation [115], [120], [121]. In particular, the potential ability of artemisinin to serve as an immunomodulator in cancer by regulating regulatory T cell (Treg) activity and the production of pro-cancer-survival immunosuppressive cytokines such as prostaglandin E2 (PGE2) is noteworthy, given the complex role of immunomodulatory drugs in cancer therapy [122], [123], [124], [125]. Finally, efforts to improve the formulation and delivery of artemisinin-based drugs have shown promise in delivering enhanced efficacy and reduced susceptibility to drug resistance. These results include novel synthetic dimers, trimers, and drug conjugates (especially transferrin-conjugated systems), in addition to combination therapies; they represent an exciting ongoing area of research that has been reviewed comprehensively in recent publications [126], [127], [128], [129], [130], [131], [132], [133], [134], [135].
In addition to the possible applications of artemisinin in cancer treatment, active research is taking place on its potential roles in addressing a range of other diseases. In particular, anti-inflammatory effects against autoimmune diseases and allergic asthma, among other conditions, have been reported in a range of disease models [78]. Some of these results correlate with observations of immunosuppression in patients undergoing artemisinin therapy for malaria [136]. Strong anti-viral effects of artemisinin have also been reported in herpes and in hepatitis B and C viruses, and other parasitic diseases including schistosomiasis have also been shown to respond to artemisinin treatment [137], [138], [139], [140], [141]. Recent findings have even identified a remarkable—if controversial—role of artemisinin in diabetes through inducing transdifferentiation of pancreatic α cells to generate β cells [142], [143]. The MOA for these alternative applications is frequently discussed in terms of the canonical model of ROS generation and oxidative damage induction upon endoperoxide cleavage; however, non-canonical (including endoperoxide-independent) mechanisms have also been proposed, especially in the case of immunomodulation [78], [144]. It will be essential to pursue a clear view of how drug mechanisms and functions may differ under varying applications and conditions, while considering the importance of the conditions of drug activation. It is also worth noting that repurposing research might be best carried out in patients and regions that are not burdened with or at risk of malaria, in order to avoid possible interference or complications. Every care must be taken to ensure that the full potential of artemisinin can be realized without compromising its current applications.
5. Conclusion
The artemisinins are a class of remarkable drugs that have redefined the landscape of antimalarial therapy. A combination of outstanding potency, safety, and accessibility has put artemisinin at the forefront of the ongoing battle against the malaria scourge, where it has already impacted millions of lives. Since its discovery, a concerted effort by the global community has assembled a picture of a drug with a unique set of properties that makes it almost the ideal antimalarial drug. Active research in other fields has also revealed a broad spectrum of promising applications for artemisinin outside of malaria. We believe that it is only logical to seek to maximize the utility of this drug in a range of capacities. In the context of malaria, doing so means to continue to clarify the mechanisms of activation and action of artemisinin, while working to further improve its pharmacological properties both alone and in combination [145]. Combined with a firm grasp of the principles of artemisinin activity, this could be the key to clearing the uncertainties of artemisinin resistance. Such efforts would ensure that the drug can continue to perform in a similar or even greater capacity within the role that it has served for so long. Looking ahead, repurposing studies driven by a robust understanding of differential MOAs in different diseases and systems will also be instrumental in defining the future of artemisinin. Ultimately, it is our sincere hope that this gift from Chinese medicine can continue to serve the pursuit of health for people all around the world, for many years to come.
Acknowledgements
This work was supported, in whole or in part, by the projects of the National Natural Science Foundation of China (81641002 and 81473548); Major National Science and Technology Program of China for Innovative Drug (2017ZX09101002-001-001-05 and 2017ZX09101002-001-001-3); and the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ10-024 and ZXKT18003). We would like to thank Dr. Lina Chen, Li Xiang, and Yuhua Shi for providing the photo of Artemisia annua L. We thank Prof. Sanjeev Krishna and Prof. Svetlana Tsogoeva for their valuable comments and assistance for polishing our manuscript.
Compliance with ethics guidelines
Jigang Wang, Chengchao Xu, Yin Kwan Wong, Yujie Li, Fulong Liao, Tingliang Jiang, and Youyou Tu declare that they have no conflict of interest or financial conflicts to disclose.
References
- [1]
- Y. TuArtemisinin—a gift from traditional Chinese medicine to the world (Nobel lecture)Angew Chem Int Ed, 55 (35) (2016), pp. 10210-10226
- [2]
- F.E. CoxHistory of the discovery of the malaria parasites and their vectorsParasit Vectors, 3 (1) (2010), p. 5
- [3]
- S. Krishna, L. Bustamante, R.K. Haynes, H.M. StainesArtemisinins: their growing importance in medicineTrends Pharmacol Sci, 29 (10) (2008), pp. 520-527
- [4]
- World Health OrganizationWorld malaria report 2017World Health Organization, Geneva (2017)
- [5]
- X.C. Ding, H.P. Beck, G. RasoPlasmodium sensitivity to artemisinins: magic bullets hit elusive targetsTrends Parasitol, 27 (2) (2011), pp. 73-81
- [6]
- T. Efferth, M.R. Romero, A.R. Bilia, A.G. Osman, M.E. Sohly, et al.Expanding the therapeutic spectrum of artemisinin: activity against infectious diseases beyond malaria and novel pharmaceutical developmentsWorld J Tradit Chin Med, 2 (2) (2016), pp. 1-23
- [7]
- U. D’Alessandro, H. ButtiënsHistory and importance of antimalarial drug resistanceTrop Med Int Health, 6 (11) (2001), pp. 845-848
- [8]
- Y. TuThe discovery of artemisinin (Qinghaosu) and gifts from Chinese medicineNat Med, 17 (10) (2011), pp. 1217-1220
- [9]
- F. LiaoDiscovery of artemisinin (Qinghaosu)Molecules, 14 (12) (2009), pp. 5362-5366
- [10]
- Collaboration Research Group for Qinghaosu. A new sesquiterpene lactone—Qinghaosu. Chin Sci Bull 1997;3:142. Chinese.
- [11]
- M.Y. WangPublication process involving the discovery of artemisinin (Qinghaosu) before 1985Asian Pac J Trop Biomed, 6 (6) (2016), pp. 461-467
- [12]
- China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials. Chemical studies on Qinghaosu (artemisinine). J Tradit Chin Med 1982;2(1):3–8. Chinese.
- [13]
- D.L. KlaymanQinghaosu (artemisinin): an antimalarial drug from ChinaScience, 228 (4703) (1985), pp. 1049-1055
- [14]
- J.B. Jiang, G.Q. Li, X.B. Guo, Y.C. Kong, K. ArnoldAntimalarial activity of mefloquine and QinghaosuLancet, 2 (8293) (1982), pp. 285-288
- [15]
- S. Looareesuwan, C. Viravan, S. Vanijanonta, P. Wilairatana, P. Suntharasamai, P. Charoenlarp, et al.Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malariaLancet, 339 (8797) (1992), pp. 821-824
- [16]
- F. Nosten, C. Luxemburger, F.O. ter Kuile, C. Woodrow, J.P. Eh, T. Chongsuphajaisiddhi, et al.Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combinationJ Infect Dis, 170 (4) (1994), pp. 971-977
- [17]
- T.H. Tran, N.P. Day, H.P. Nguyen, T.H. Nguyen, T.H. Tran, P.L. Pham, et al.A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malariaN Engl J Med, 335 (2) (1996), pp. 76-83
- [18]
- S. Looareesuwan, P. Wilairatana, C. Viravan, S. Vanijanonta, P. Pitisuttithum, D.E. KyleOpen randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malariaAm J Trop Med Hyg, 56 (6) (1997), pp. 613-617
- [19]
- M. Adjuik, A. Babiker, P. Garner, P. Olliaro, W. Taylor, N. White, et al.International Artemisinin Study Group. Artesunate combinations for treatment of malaria: meta-analysisLancet, 363 (9402) (2004), pp. 9-17
- [20]
- L. Von Seidlein, S. Jaffar, M. Pinder, M. Haywood, G. Snounou, B. Gemperli, et al.Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697J Infect Dis, 176 (4) (1997), pp. 1113-1116
- [21]
- L. Von Seidlein, K. Bojang, P. Jones, S. Jaffar, M. Pinder, S. Obaro, et al.A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African childrenAm J Trop Med Hyg, 58 (5) (1998), pp. 638-644
- [22]
- J.F. Doherty, A.D. Sadiq, L. Bayo, A. Alloueche, P. Olliaro, P. Milligan, et al.A randomized safety and tolerability trial of artesunate plus sulfadoxine—pyrimethamine versus sulfadoxine-pyrimethamine alone for the treatment of uncomplicated malaria in Gambian childrenTrans R Soc Trop Med Hyg, 93 (5) (1999), pp. 543-546
- [23]
- A.M. Dondorp, C.I. Fanello, I.C. Hendriksen, E. Gomes, A. Seni, K.D. Chhaganlal, et al.AQUAMAT Group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trialLancet, 376 (9753) (2010), pp. 1647-1657
- [24]
- WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group. Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient dataBMC Med, 13 (2015), p. 212
- [25]
- T. Efferth, B. KainaToxicity of the antimalarial artemisinin and its derivativesCrit Rev Toxicol, 40 (5) (2010), pp. 405-421
- [26]
- World Health OrganizationGuidelines for the treatment of malariaWorld Health Organization, Geneva (2006)
- [27]
- X.D. Luo, C.C. ShenThe chemistry, pharmacology, and clinical applications of Qinghaosu (artemisinin) and its derivativesMed Res Rev, 7 (1) (1987), pp. 29-52
- [28]
- N.J. WhiteClinical pharmacokinetics and pharmacodynamics of artemisinin and derivativesTrans R Soc Trop Med Hyg, 88 (Suppl 1) (1994), pp. S41-S43
- [29]
- P.J. De Vries, T.K. DienClinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malariaDrugs, 52 (6) (1996), pp. 818-836
- [30]
- P.I. German, F.T. AweekaClinical pharmacology of artemisinin-based combination therapiesClin Pharmacokinet, 47 (2) (2008), pp. 91-102
- [31]
- A. Robert, O. Dechy-Cabaret, J. Cazelles, B. MeunierFrom mechanistic studies on artemisinin derivatives to new modular antimalarial drugsAcc Chem Res, 35 (3) (2002), pp. 167-174
- [32]
- J. Li, B. ZhouBiological actions of artemisinin: insights from medicinal chemistry studiesMolecules, 15 (8) (2010), pp. 1378-1397
- [33]
- M.A. Van Agtmael, T.A. Eggelte, C.J. van BoxtelArtemisinin drugs in the treatment of malaria: from medicinal herb to registered medicationTrends Pharmacol Sci, 20 (5) (1999), pp. 199-205
- [34]
- S.R. Meshnick, T.E. Taylor, S. KamchonwongpaisanArtemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapyMicrobiol Rev, 60 (2) (1996), pp. 301-315
- [35]
- G.H. Posner, P.M. O’NeillKnowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxidesAcc Chem Res, 37 (6) (2004), pp. 397-404
- [36]
- P.M. O’Neill, V.E. Barton, S.A. WardThe molecular mechanism of action of artemisinin—the debate continuesMolecules, 15 (3) (2010), pp. 1705-1721
- [37]
- V.L. Lew, T. Tiffert, H. GinsburgExcess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cellsBlood, 101 (10) (2003), pp. 4189-4194
- [38]
- N. Klonis, M.P. Crespo-Ortiz, I. Bottova, N. Abu-Bakar, S. Kenny, P.J. Rosenthal, et al.Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestionProc Natl Acad Sci USA, 108 (28) (2011), pp. 11405-11410
- [39]
- S.C. Xie, C. Dogovski, E. Hanssen, F. Chiu, T. Yang, M.P. Crespo, et al.Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisininsJ Cell Sci, 129 (2) (2016), pp. 406-416
- [40]
- F. Zhang, D.K. Gosser Jr, S.R. MeshnickHemin-catalyzed decomposition of artemisinin (Qinghaosu)Biochem Pharmacol, 43 (8) (1992), pp. 1805-1809
- [41]
- G.H. Posner, C.H. Oh, D. Wang, L. Gerena, W.K. Milhous, S.R. Meshnick, et al.Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin: the importance of a carbon-centered radical for antimalarial activityJ Med Chem, 37 (9) (1994), pp. 1256-1258
- [42]
- W.M. Wu, Y. Wu, Y.L. Wu, Z.J. Yao, C.M. Zhou, Y. Li, et al.Unified mechanistic framework for the Fe(II)-induced cleavage of Qinghaosu and derivatives/analogues. The first spin-trapping evidence for the previously postulated secondary C-4 radicalJ Am Chem Soc, 120 (14) (1998), pp. 3316-3325
- [43]
- P.A. Stocks, P.G. Bray, V.E. Barton, M. Al-Helal, M. Jones, N.C. Araujo, et al.Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugsAngew Chem Int Ed, 46 (33) (2007), pp. 6278-6283
- [44]
- R.K. Haynes, W.C. Chan, C.M. Lung, A.C. Uhlemann, U. Eckstein, D. Taramelli, et al.The Fe2+-mediated decomposition, PfATP6 binding, and antimalarial activities of artemisone and other artemisinins: the unlikelihood of C-centered radicals as bioactive intermediatesChemMedChem, 2 (10) (2007), pp. 1480-1497
- [45]
- B. Meunier, A. RobertHeme as trigger and target for trioxane-containing antimalarial drugsAcc Chem Res, 43 (11) (2010), pp. 1444-1451
- [46]
- R.K. Haynes, K.W. Cheu, D. N’Da, P. Coghi, D. MontiConsiderations on the mechanism of action of artemisinin antimalarials: part 1—the ‘carbon radical’ and ‘heme’ hypothesesInfect Disord Drug Targets, 13 (4) (2013), pp. 217-277
- [47]
- J. Wang, C.J. Zhang, W.N. Chia, C.C. Loh, Z. Li, Y.M. Lee, et al.Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparumNat Commun, 6 (2015), p. 10111
- [48]
- Y. Zhou, W. Li, Y. XiaoProfiling of multiple targets of artemisinin activated by hemin in cancer cell proteomeACS Chem Biol, 11 (4) (2016), pp. 882-888
- [49]
- S. Zhang, G.S. GerhardHeme activates artemisinin more efficiently than hemin, inorganic iron, or hemoglobinBioorg Med Chem, 16 (16) (2008), pp. 7853-7861
- [50]
- W. Li, Y. Zhou, G. Tang, Y. XiaoCharacterization of the artemisinin binding site for translationally controlled tumor protein (TCTP) by bioorthogonal click chemistryBioconjug Chem, 27 (12) (2016), pp. 2828-2833
- [51]
- W. Li, W. Mo, D. Shen, L. Sun, J. Wang, S. Lu, et al.Yeast model uncovers dual roles of mitochondria in action of artemisininPLoS Genet, 1 (3) (2005), Article e36
- [52]
- J. Wang, L. Huang, J. Li, Q. Fan, Y. Long, Y. Li, et al.Artemisinin directly targets malarial mitochondria through its specific mitochondrial activationPLoS One, 5 (3) (2010), Article e9582
- [53]
- C. Sun, J. Li, Y. Cao, G. Long, B. ZhouTwo distinct and competitive pathways confer the cellcidal actions of artemisininsMicrob Cell, 2 (1) (2015), pp. 14-25
- [54]
- C.D. Fitch, R. Chevli, P. Kanjananggulpan, P. Dutta, K. Chevli, A.C. ChouIntracellular ferriprotoporphyrin IX is a lytic agentBlood, 62 (6) (1983), pp. 1165-1168
- [55]
- T.J. EganRecent advances in understanding the mechanism of hemozoin (malaria pigment) formationJ Inorg Biochem, 102 (5–6) (2008), pp. 1288-1299
- [56]
- J. Cazelles, A. Robert, B. MeunierAlkylation of heme by artemisinin, an antimalarial drugAcad Sci Chem, 4 (2) (2001), pp. 85-89
- [57]
- A. Robert, F. Benoit-Vical, C. Claparols, B. MeunierThe antimalarial drug artemisinin alkylates heme in infected miceProc Natl Acad Sci USA, 102 (38) (2005), pp. 13676-13680
- [58]
- C. Loup, J. Lelièvre, F. Benoit-Vical, B. MeunierTrioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquineAntimicrob Agents Chemother, 51 (10) (2007), pp. 3768-3770
- [59]
- Y.Z. Yang, B. LittleMeshnick SR. Alkylation of proteins by artemisinin. Effects of heme, pH, and drug structureBiochem Pharmacol, 48 (3) (1994), pp. 569-573
- [60]
- S.R. MeshnickArtemisinin: mechanisms of action, resistance and toxicityInt J Parasitol, 32 (13) (2002), pp. 1655-1660
- [61]
- J. Bhisutthibhan, X.Q. Pan, P.A. Hossler, D.J. Walker, C.A. Yowell, J. Carlton, et al.The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisininJ Biol Chem, 273 (26) (1998), pp. 16192-16198
- [62]
- U. Eckstein-Ludwig, R.J. Webb, I.D. Van Goethem, J.M. East, A.G. Lee, M. Kimura, et al.Artemisinins target the SERCA of Plasmodium falciparumNature, 424 (9651) (2003), pp. 957-961
- [63]
- A.C. Uhlemann, A. Cameron, U. Eckstein-Ludwig, J. Fischbarg, P. Iserovich, F.A. Zuniga, et al.A single amino acid residue can determine the sensitivity of SERCAs to artemisininsNat Struct Mol Biol, 12 (7) (2005), pp. 628-629
- [64]
- S. Krishna, S. Pulcini, F. Fatih, H. StainesArtemisinins and the biological basis for the PfATP6/SERCA hypothesisTrends Parasitol, 26 (11) (2010), pp. 517-523
- [65]
- B. Arnou, C. Montigny, J.P. Morth, P. Nissen, C. Jaxel, J.V. Møller, et al.The Plasmodium falciparum Ca2+-ATPase PfATP6: insensitive to artemisinin, but a potential drug targetBiochem Soc Trans, 39 (3) (2011), pp. 823-831
- [66]
- L. Cui, Z. Wang, H. Jiang, D. Parker, H. Wang, X.Z. Su, et al.Lack of association of the S769N mutation in Plasmodium falciparum SERCA (PfATP6) with resistance to artemisininsAntimicrob Agents Chemother, 56 (5) (2012), pp. 2546-2552
- [67]
- S. Krishna, S. Pulcini, C.M. Moore, B.H. Teo, H.M. StainesPumped up: reflections on PfATP6 as the target for artemisininsTrends Pharmacol Sci, 35 (1) (2014), pp. 4-11
- [68]
- H.M. Ismail, V. Barton, M. Phanchana, S. Charoensutthivarakul, M.H. Wong, J. Hemingway, et al.Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7Proc Natl Acad Sci USA, 113 (8) (2016), pp. 2080-2085
- [69]
- E.A. Ashley, M. Dhorda, R.M. Fairhurst, C. Amaratunga, P. Lim, S. Suon, et al.Tracking Resistance to Artemisinin Collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malariaN Eng J Med, 371 (5) (2014), pp. 411-423
- [70]
- A.M. Dondorp, S. Yeung, L. White, C. Nguon, N.P. Day, D. Socheat, et al.Artemisinin resistance: current status and scenarios for containmentNat Rev Microbiol, 8 (4) (2010), pp. 272-280
- [71]
- L. Paloque, A.P. Ramadani, O. Mercereau-Puijalon, J.M. Augereau, F. Benoit-VicalPlasmodium falciparum: multifaceted resistance to artemisininsMalar J, 15 (2016), p. 149
- [72]
- L. Tilley, J. Straimer, N.F. Gnädig, S.A. Ralph, D.A. FidockArtemisinin action and resistance in Plasmodium falciparumTrends Parasitol, 32 (9) (2016), pp. 682-696
- [73]
- J. Wang, C. Xu, Z.R. Lun, S.R. MeshnickUnpacking ‘artemisinin resistance’Trends Pharmacol Sci, 38 (6) (2017), pp. 506-511
- [74]
- J.P. Gil, S. Krishnapfmdr1 (Plasmodium falciparum multidrug drug resistance gene 1): a pivotal factor in malaria resistance to artemisinin combination therapiesExpert Rev Anti Infect Ther, 15 (6) (2017), pp. 527-543
- [75]
- T. Hanscheid, D.W. HardistyHow “resistant” is artemisinin resistant malaria?—The risks of ambiguity using the term “resistant” malariaTravel Med Infect Dis, 24 (2018), pp. 23-24
- [76]
- S. MeshnickPerspective: artemisinin-resistant malaria and the wolfAm J Trop Med Hyg, 87 (5) (2012), pp. 783-784
- [77]
- World Health OrganizationArtemisinin and artemisinin-based combination therapy resistance. ReportWorld Health Organization, Geneva (2016)Apr
- [78]
- W.E. Ho, H.Y. Peh, T.K. Chan, W.S. WongArtemisinins: pharmacological actions beyond anti-malarialPharmacol Ther, 142 (1) (2014), pp. 126-139
- [79]
- G.L. Firestone, S.N. SundarAnticancer activities of artemisinin and its bioactive derivativesExpert Rev Mol Med, 11 (2009), Article e32
- [80]
- M.P. Crespo-Ortiz, M.Q. WeiAntitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drugJ Biomed Biotechnol, 2012 (2012), Article 247597
- [81]
- H.C. Lai, N.P. Singh, T. SasakiDevelopment of artemisinin compounds for cancer treatmentInvest New Drugs, 31 (1) (2013), pp. 230-246
- [82]
- T. EfferthArtemisinin—second career as anticancer drug?World J Tradit Chin Med, 1 (4) (2015), pp. 2-25
- [83]
- H.J. Woerdenbag, T.A. Moskal, N. Pras, T.M. Malingré, F.S. el-Feraly, H.H. Kampinga, et al.Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cellsJ Nat Prod, 56 (6) (1993), pp. 849-856
- [84]
- H. Lai, N.P. SinghSelective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrinCancer Lett, 91 (1) (1995), pp. 41-46
- [85]
- T. Efferth, H. Dunstan, A. Sauerbrey, H. Miyachi, C.R. ChitambarThe anti-malarial artesunate is also active against cancerInt J Oncol, 18 (4) (2001), pp. 767-773
- [86]
- T. Efferth, A. Sauerbrey, A. Olbrich, E. Gebhart, P. Rauch, H.O. Weber, et al.Molecular modes of action of artesunate in tumor cell linesMol Pharmacol, 64 (2) (2003), pp. 382-394
- [87]
- Z.Y. Zhang, S.Q. Yu, L.Y. Miao, X.Y. Huang, X.P. Zhang, Y.P. Zhu, et al.Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trialJ Chin Integr Med, 6 (2) (2008), pp. 134-138
- [88]
- F.H. Jansen, I. Adoubi, K.C. JC, T. DE Cnodder, N. Jansen, A. Tschulakow, et al.First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markersAnticancer Res, 31 (12) (2011), pp. 4417-4422
- [89]
- S. Krishna, S. Ganapathi, I.C. Ster, M.E. Saeed, M. Cowan, C. Finlayson, et al.A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancerEBioMedicine, 2 (1) (2014), pp. 82-90
- [90]
- T. Efferth, G. Rücker, M. Falkenberg, D. Manns, A. Olbrich, U. Fabry, et al.Detection of apoptosis in KG-1a leukemic cells treated with investigational drugsArzneimittelforschung, 46 (2) (1996), pp. 196-200
- [91]
- J.A. Willoughby Sr, S.N. Sundar, M. Cheung, A.S. Tin, J. Modiano, G.L. FirestoneArtemisinin blocks prostate cancer growth and cell cycle progression by disrupting Sp1 interactions with the cyclin-dependent kinase-4 (CDK4) promoter and inhibiting CDK4 gene expressionJ Biol Chem, 284 (4) (2009), pp. 2203-2213
- [92]
- L. Steinbrück, G. Pereira, T. EfferthEffects of artesunate on cytokinesis and G2/M cell cycle progression of tumour cells and budding yeastCancer Genomics Proteomics, 7 (6) (2010), pp. 337-346
- [93]
- A. Hamacher-Brady, H.A. Stein, S. Turschner, I. Toegel, R. Mora, N. Jennewein, et al.Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species productionJ Biol Chem, 286 (8) (2011), pp. 6587-6601
- [94]
- L. Anfosso, T. Efferth, A. Albini, U. PfefferMicroarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisininsPharmacogenomics J, 6 (4) (2006), pp. 269-278
- [95]
- R.W. Button, F. Lin, E. Ercolano, J.H. Vincent, B. Hu, C.O. Hanemann, et al.Artesunate induces necrotic cell death in schwannoma cellsCell Death Dis, 5 (2014), Article e1466
- [96]
- E. Buommino, A. Baroni, N. Canozo, M. Petrazzuolo, R. Nicoletti, A. Vozza, et al.Artemisinin reduces human melanoma cell migration by down-regulating αVβ3 integrin and reducing metalloproteinase 2 productionInvest New Drugs, 27 (5) (2009), pp. 412-418
- [97]
- T. Chen, M. Li, R. Zhang, H. WangDihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapyJ Cell Mol Med, 13 (7) (2009), pp. 1358-1370
- [98]
- P.C. Li, E. Lam, W.P. Roos, M.Z. Zdzienicka, B. Kaina, T. EfferthArtesunate derived from traditional Chinese medicine induces DNA damage and repairCancer Res, 68 (11) (2008), pp. 4347-4351
- [99]
- J. Hou, D. Wang, R. Zhang, H. WangExperimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of actionClin Cancer Res, 14 (17) (2008), pp. 5519-5530
- [100]
- N. Berdelle, T. Nikolova, S. Quiros, T. Efferth, B. KainaArtesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cellsMol Cancer Ther, 10 (12) (2011), pp. 2224-2233
- [101]
- C. Huang, Q. Ba, Q. Yue, J. Li, J. Li, R. Chu, et al.Artemisinin rewires the protein interaction network in cancer cells: network analysis, pathway identification, and target predictionMol Biosyst, 9 (12) (2013), pp. 3091-3100
- [102]
- X. Li, Q. Ba, Y. Liu, Q. Yue, P. Chen, J. Li, et al.Dihydroartemisinin selectively inhibits PDGFR α-positive ovarian cancer growth and metastasis through inducing degradation of PDGFR α proteinCell Discov, 3 (2017), p. 17042
- [103]
- T. Efferth, A. Benakis, M.R. Romero, M. Tomicic, R. Rauh, D. Steinbach, et al.Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous ironFree Radic Biol Med, 37 (7) (2004), pp. 998-1009
- [104]
- Q. Ba, N. Zhou, J. Duan, T. Chen, M. Hao, X. Yang, et al.Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1PLoS One, 7 (8) (2012), Article e42703
- [105]
- S. Zhang, G.S. GerhardHeme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation targetPLoS One, 4 (10) (2009), Article e7472
- [106]
- L.H. Stockwin, B. Han, S.X. Yu, M.G. Hollingshead, M.A. ElSohly, W. Gul, et al.Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress inductionInt J Cancer, 125 (6) (2009), pp. 1266-1275
- [107]
- S. Zhang, H. Chen, G.S. GerhardHeme synthesis increases artemisinin-induced radical formation and cytotoxicity that can be suppressed by superoxide scavengersChem Biol Interact, 186 (1) (2010), pp. 30-35
- [108]
- A.E. Mercer, I.M. Copple, J.L. Maggs, P.M. O’Neill, B.K. ParkThe role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarialsJ Biol Chem, 286 (2) (2011), pp. 987-996
- [109]
- J. Hooda, D. Cadinu, M.M. Alam, A. Shah, T.M. Cao, L.A. Sullivan, et al.Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cellsPLoS One, 8 (5) (2013), Article e63402
- [110]
- J. Hooda, A. Shah, L. ZhangHeme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processesNutrients, 6 (3) (2014), pp. 1080-1102
- [111]
- J. Hooda, M. Alam, L. ZhangMeasurement of heme synthesis levels in mammalian cellsJ Vis Exp, 101 (2015), Article e51579
- [112]
- X. Zhang, Q. Ba, Z. Gu, D. Guo, Y. Zhou, Y. Xu, et al.Fluorescent coumarin-artemisinin conjugates as mitochondria-targeting theranostic probes for enhanced anticancer activitiesChemistry, 21 (48) (2015), pp. 17415-17421
- [113]
- C.J. Zhang, J. Wang, J. Zhang, Y.M. Lee, G. Feng, T.K. Lim, et al.Mechanism-guided design and synthesis of a mitochondria-targeting artemisinin analogue with enhanced anticancer activityAngew Chem Int Ed, 55 (44) (2016), pp. 13770-13774
- [114]
- J. Wang, J. Zhang, Y. Shi, C. Xu, C. Zhang, Y.K. Wong, et al.Mechanistic investigation of the specific anticancer property of artemisinin and its combination with aminolevulinic acid for enhanced anticolorectal cancer activityACS Cent Sci, 3 (7) (2017), pp. 743-750
- [115]
- Y.K. Wong, C. Xu, K.A. Kalesh, Y. He, Q. Lin, W.S.F. Wong, et al.Artemisinin as an anticancer drug: recent advances in target profiling and mechanisms of actionMed Res Rev, 37 (6) (2017), pp. 1492-1517
- [116]
- S.J. Dixon, K.M. Lemberg, M.R. Lamprecht, R. Skouta, E.M. Zaitsev, C.E. Gleason, et al.Ferroptosis: an iron-dependent form of nonapoptotic cell deathCell, 149 (5) (2012), pp. 1060-1072
- [117]
- N. Eling, L. Reuter, J. Hazin, A. Hamacher-Brady, N.R. BradyIdentification of artesunate as a specific activator of ferroptosis in pancreatic cancer cellsOncoscience, 2 (5) (2015), pp. 517-532
- [118]
- E. Ooko, M.E. Saeed, O. Kadioglu, S. Sarvi, M. Colak, K. Elmasaoudi, et al.Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cellsPhytomedicine, 22 (11) (2015), pp. 1045-1054
- [119]
- N.D. Yang, S.H. Tan, S. Ng, Y. Shi, J. Zhou, K.S. Tan, et al.Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritinJ Biol Chem, 289 (48) (2014), pp. 33425-33441
- [120]
- T. EfferthFrom ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapySemin Cancer Biol, 46 (2017), pp. 65-83
- [121]
- M.L. Abba, N. Patil, J.H. Leupold, M.E.M. Saeed, T. Efferth, H. AllgayerPrevention of carcinogenesis and metastasis by artemisinin-type drugsCancer Lett, 429 (2018), pp. 11-18
- [122]
- S. Noori, Z.M. HassanDihydroartemisinin shift the immune response towards Th1, inhibit the tumor growth in vitro and in vivoCell Immunol, 271 (1) (2011), pp. 67-72
- [123]
- V. Farsam, Z.M. Hassan, A. Zavaran-Hosseini, S. Noori, M. Mahdavi, M. RanjbarAntitumor and immunomodulatory properties of artemether and its ability to reduce CD4+CD25+FoxP3+ T reg cells in vivoInt Immunopharmacol, 11 (11) (2011), pp. 1802-1808
- [124]
- L.X. Zhang, Z.N. Liu, J. Ye, M. Sha, H. Qian, X.H. Bu, et al.Artesunate exerts an anti-immunosuppressive effect on cervical cancer by inhibiting PGE2 production and Foxp3 expressionCell Biol Int, 38 (5) (2014), pp. 639-646
- [125]
- C. Cui, H. Feng, X. Shi, Y. Wang, Z. Feng, J. Liu, et al.Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor β1 and interleukin-10Int Immunopharmacol, 27 (1) (2015), pp. 110-121
- [126]
- C. Reiter, T. Fröhlich, L. Gruber, C. Hutterer, M. Marschall, C. Voigtländer, et al.Highly potent artemisinin-derived dimers and trimers: synthesis and evaluation of their antimalarial, antileukemia and antiviral activitiesBioorg Med Chem, 23 (17) (2015), pp. 5452-5458
- [127]
- T. Fröhlich, A. Çapcı Karagöz, C. Reiter, S.B. TsogoevaArtemisinin-derived dimers: potent antimalarial and anticancer agentsJ Med Chem, 59 (16) (2016), pp. 7360-7388
- [128]
- T. Fröhlich, B. Ndreshkjana, J.K. Muenzner, C. Reiter, E. Hofmeister, S. Mederer, et al.Synthesis of novel hybrids of thymoquinone and artemisinin with high activity and selectivity against colon cancerChemMedChem, 12 (3) (2017), pp. 226-234
- [129]
- T. EfferthCancer combination therapies with artemisinin-type drugsBiochem Pharmacol, 139 (2017), pp. 56-70
- [130]
- T. Fröhlich, F. Hahn, L. Belmudes, M. Leidenberger, O. Friedrich, B. Kappes, et al.Synthesis of artemisinin-derived dimers, trimers and dendrimers: investigation of their antimalarial and antiviral activities including putative mechanisms of actionChemistry, 24 (32) (2018), pp. 8103-8113
- [131]
- C. Horwedel, S.B. Tsogoeva, S. Wei, T. EfferthCytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cellsJ Med Chem, 53 (13) (2010), pp. 4842-4848
- [132]
- C. Reiter, A. Herrmann, A. Çapci, T. Efferth, S.B. TsogoevaNew artesunic acid homodimers: potent reversal agents of multidrug resistance in leukemia cellsBioorg Med Chem, 20 (18) (2012), pp. 5637-5641
- [133]
- C. Reiter, A. Capcı Karagöz, T. Fröhlich, V. Klein, M. Zeino, K. Viertel, et al.Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonol-derived hybrid molecules against Plasmodium falciparum and multidrug-resistant human leukemia cellsEur J Med Chem, 75 (2014), pp. 403-412
- [134]
- C. Reiter, T. Fröhlich, M. Zeino, M. Marschall, H. Bahsi, M. Leidenberger, et al.New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4-trioxane-ferrocene hybridsEur J Med Chem, 97 (2015), pp. 164-172
- [135]
- I. Leto, M. Coronnello, C. Righeschi, M.C. Bergonzi, E. Mini, A.R. BiliaEnhanced efficacy of artemisinin loaded in transferrin-conjugated liposomes versus stealth liposomes against HCT-8 colon cancer cellsChemMedChem, 11 (16) (2016), pp. 1745-1751
- [136]
- D. Bunnag, C. Viravan, S. Looareesuwan, J. Karbwang, T. HarinasutaClinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand. A preliminary reportSoutheast Asian J Trop Med Public Health, 22 (3) (1991), pp. 380-385
- [137]
- T. Efferth, M.R. Romero, D.G. Wolf, T. Stamminger, J.J. Marin, M. MarschallThe antiviral activities of artemisinin and artesunateClin Infect Dis, 47 (6) (2008), pp. 804-811
- [138]
- J. Keiser, J. UtzingerArtemisinins and synthetic trioxolanes in the treatment of helminth infectionsCurr Opin Infect Dis, 20 (6) (2007), pp. 605-612
- [139]
- M.E.M. Saeed, S. Krishna, H.J. Greten, P.G. Kremsner, T. EfferthAntischistosomal activity of artemisinin derivatives in vivo and in patientsPharmacol Res, 110 (2016), pp. 216-226
- [140]
- N.S. Lam, X. Long, X.Z. Su, F. LuArtemisinin and its derivatives in treating helminthic infections beyond schistosomiasisPharmacol Res, 133 (2018), pp. 77-100
- [141]
- T. EfferthBeyond malaria: the inhibition of viruses by artemisinin-type compoundsBiotechnol Adv, 36 (6) (2018), pp. 1730-1737
- [142]
- J. Li, T. Casteels, T. Frogne, C. Ingvorsen, C. Honoré, M. Courtney, et al.Artemisinins target GABAA receptor signaling and impair α cell identityCell, 168 (1–2) (2017), pp. 86-100.e15
- [143]
- T. Van der Meulen, S. Lee, E. Noordeloos, C.J. Donaldson, M.W. Adams, G.M. Noguchi, et al.Artemether does not turn α cells into β cellsCell Metab, 27 (1) (2018)218 25.e4
- [144]
- W.E. Ho, C. Cheng, H.Y. Peh, F. Xu, S.R. Tannenbaum, C.N. Ong, et al.Anti-malarial drug artesunate ameliorates oxidative lung damage in experimental allergic asthmaFree Radic Biol Med, 53 (3) (2012), pp. 498-507
- [145]
- B. Isacchi, S. Arrigucci, G. la Marca, M.C. Bergonzi, M.G. Vannucchi, A. Novelli, et al.Conventional and long-circulating liposomes of artemisinin: preparation, characterization, and pharmacokinetic profile in miceJ Liposome Res, 21 (3) (2011), pp. 237-244
https://www.sciencedirect.com/topics/medicine-and-dentistry/artemisinin
Artemisinin derivatives
In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016
General
Artemisinin is metabolized in vitro by CYP2B6, CYP3A4, and CYP2A6. Since artemisinin induces CYP2C19, the question arises whether artemisinin also induces some of the cytochromes involved in its own metabolism and thus increases its own elimination (autoinduction) [67]. During treatment with oral artemisinin for 10 days (250 mg/day for 9 days and 500 mg on the tenth day), artemisinin oral clearance increased 5.3 times in six poor CYP2C19 metabolizers and eight extensive metabolizers. The underlying mechanism was probably induction of CYP2B6. Induction of CYP2B6 by artemisinin could affect the metabolism of drugs given concomitantly and lead to suboptimal artemisinin concentrations towards the end of artemisinin treatment.
Development & Modification of Bioactivity
Toshiya Muranaka, Kazuki Saito, in Comprehensive Natural Products II, 2010
3.17.3.3 Sesquiterpenoids
Artemisinin, a sesquiterpene lactone obtained from Artemisia annua (Asteraceae), is a new and highly effective antimalarial drug (see Chapter 1.16). Artemisia annua has a long history of use in traditional Chinese medicine and this plant is currently the only source of artemisinin; therefore, extensive molecular genetic and chemical studies to find the gene for biosynthesis of this sesquiterpenoid have been undertaken. Recently, three enzymes (1) amorpha-4, 11-diene synthase (ADS), a sesquiterpene synthase;169 (2) CYP71AV1, a P-450 monooxygenase oxidizing amorpha-4,11-diene to artemisinic acid;170,171 and (3) artemisinic aldehyde Δ11(13) reductase172 have been shown to have key roles in artemisinin biosynthesis. Transformation protocols to obtain hairy roots containing artemisinin from this plant have been reported.173,174 Because artemisinin biosynthetic genes are highly expressed in trichomes, and only expressed in trace amounts in root tissue, identification of artemisinin from root extracts by nuclear magnetic resonance (NMR) and mass spectrometry analysis is required. Liu et al. reported the production of artemisinin in shoot cultures and tested various types of bioreactors for artemisinin production from shoot cultures, finding that nutrient mist bioreactors produced more than multiplate radius-flow bioreactors or modified airlift bioreactors.175
Increasing opportunities of drug repurposing for treating breast cancer by the integration of molecular, histological, and systemic approaches
Harras J. Khan, ... Q. Ping Dou, in Drug Repurposing in Cancer Therapy, 2020
Artemisinin—summary
ART was originally developed in order to combat malaria and has saved millions of lives and is also seen as one of the largest contributions of China to global health. The 2015 Nobel Prize in Physiology or Medicine was awarded to Professor Youyou Tu for her contribution in the discovery of this drug. ART and its derivatives, however, have now been seen to have some anticancer activity, indicating that these drugs may be effective cancer therapeutic agents. Clinical studies have shown that the cytotoxic effects of ART can cause patients to experience drug related toxicities.
Volume 1
Kathy Abascal BS, JD, RH(AHG), Eric L. Yarnell ND, RH(AHG), in Textbook of Natural Medicine (Fifth Edition), 2020
Drug Interactions
Artemisinin compounds generally show more rapid parasite clearance and fever reduction when combined with mefloquine than either agent given by itself, according to a meta-analysis of clinical trials.18 Mefloquine’s neurological toxicity does not appear to be altered by combination with artemisinin compounds, although the tendency to induce severe vomiting may be slightly lessened.
Artemisinin compounds can be combined safely with doxycycline and tetracycline, according to the results of two clinical trials, although at least one of these trials suggested the combination was less effective than artemether combined with mefloquine.43,44 Another double-blind trial found that the combination of artesunate and tetracycline was equally effective and much safer than quinine and tetracycline.45
Artemisinin may interfere slightly with sulfadoxine-pyrimethamine. In one trial, artemisinin by itself led to insignificantly more rapid parasite clearance than artemisinin combined with sulfadoxine-pyrimethamine.46 Fever relief was achieved equally rapidly, and adverse effects were absent in both groups. Further research is necessary to determine for certain if there is any negative effect from combining these two agents.
Grapefruit juice initially increases the bioavailability of oral artemether, although it does not stop the inevitable decline in bioavailability of this compound that occurs with repeated dosing over a few days.47
Single case studies suggest that artesunate may increase the risk of hepatotoxicity in cancer patients being treated with the drug temozolomide.48
Approaches to Design and Synthesis of Antiparasitic Drugs
Satyavan Sharma, Nitya Anand, in Pharmacochemistry Library, 1997
5.2 Artemisinin (qinghaosu) and its analogues
Qinghaosu does not inhibit carbohydrate metabolism of the plasmodia, though it markedly affects protein and nucleic acid synthesis [29], Qinghaosu, dihydroqinghaosu and artemether inhibit the uptake of 3H-isoleucine by human erythrocytes infected with P. falciparum at a concentration of 5-50 μmol/litre. The above compounds have also been shown to inhibit the uptake of [3H]-hypoxanthine. Thus, protein synthesis was envisaged to be the primary site of attack by qinghaosu and its derivatives, which is possibly due to the oxidative damage to the protein synthesis machinary [153–155]. Later it was shown that qinghaosu and artesunate are involved in increased oxidant stress on the infected red blood cells [155]. Artesunate has further been demonstrated to inhibit cytochrome oxidase in P. berghei at high concentrations [156], The activity of artemisinin may, therefore, be mediated through generation of activated oxygen species such as superoxide, hydrogen peroxide and hydroxyl radicals [155,157–159].
Although the antimalarial activity of artemisinin has been attributed to its ability to generate reactive oxygen species, the basis of selective toxicity of this drug to Plasmodium parasites is not clearly understood. Meshnick et al. [160] have demonstrated the role of intracellular hemin in the antimalarial action of artemisinin. These authors suggested that the antimalarial activity of artemisinin may be mediated by a reaction with intraparasitic hemin with subsequent formation of free radicals [157–160], This was based on the fact that malaria parasites are rich in hemin (called hemozoin), which is derived from the digestion of host haemoglobin, possibly without breaking down hemin.
Zhang and coworkers [161] experimentally established the role of hemin in catalysing the reductive decomposition of artemisinin and dehydroartemisinin leading to cleavage of the oxygen-oxygen bond. The role of intraparasitic a hemin (hemozoin) in catalysing the decomposition of artemisinin through formation of a hemin-artemesinin adduct [He-Fe(III)-Artemisinin] and subsequent antimalarial action was supported by Peters and coworkers [162], who demonstrated that artemisinin was more than 50 times less effective against a chloroquin-resistant P. berghei strain lacking hemozoin. Further, it has been shown that no hemin-artemisinin ad- ducts are formed when uninfected red cells are incubated with radiolabelled artemisinin [160]. This suggests that artemisinin does not react with haemoglobin-bound hemin. This observation, therefore, explains the selective toxicity of artemisinin for malaria parasite [161].
Development & Modification of Bioactivity
Toshiya Muranaka, Kazuki Saito, in Comprehensive Natural Products II, 2010
3.17.3.3 Sesquiterpenoids
Artemisinin, a sesquiterpene lactone obtained from Artemisia annua (Asteraceae), is a new and highly effective antimalarial drug (see Chapter 1.16). Artemisia annua has a long history of use in traditional Chinese medicine and this plant is currently the only source of artemisinin; therefore, extensive molecular genetic and chemical studies to find the gene for biosynthesis of this sesquiterpenoid have been undertaken. Recently, three enzymes (1) amorpha-4, 11-diene synthase (ADS), a sesquiterpene synthase;169 (2) CYP71AV1, a P-450 monooxygenase oxidizing amorpha-4,11-diene to artemisinic acid;170,171 and (3) artemisinic aldehyde Δ11(13) reductase172 have been shown to have key roles in artemisinin biosynthesis. Transformation protocols to obtain hairy roots containing artemisinin from this plant have been reported.173,174 Because artemisinin biosynthetic genes are highly expressed in trichomes, and only expressed in trace amounts in root tissue, identification of artemisinin from root extracts by nuclear magnetic resonance (NMR) and mass spectrometry analysis is required. Liu et al. reported the production of artemisinin in shoot cultures and tested various types of bioreactors for artemisinin production from shoot cultures, finding that nutrient mist bioreactors produced more than multiplate radius-flow bioreactors or modified airlift bioreactors.175
Artemether
Eric Scholar, in xPharm: The Comprehensive Pharmacology Reference, 2007
Introduction
Artemisinin and its derivatives are sesquiterpene lactone peroxides derived from the leaves of wormwood (Artemisia annua). Developed in China, they are used increasingly in Asia and Africa. They are not licensed for use in North America or Europe. Artemether is a methyl ether derivative of artemisinin, which is used in the treatment of Plasmodium falciparummalaria. Artemether is more active than the parent artemisinin. Artemether is an oil-soluble derivative that can be administered i.m. Artemisinin and its derivatives kill all stages of the malaria parasite by interacting with heme to produce carbon-centered free radicals that alkylate protein and damage the parasite microorganelles and membranes. Various artemisinin-related compounds are currently used worldwide for the treatment of malaria. These compounds are rapid-acting, effective, and safe at doses used for the treatment of severe malaria, including infections due tochloroquine- and multidrug-resistant strains of P. falciparum.
Increasing opportunities of drug repurposing for treating breast cancer by the integration of molecular, histological, and systemic approaches
Harras J. Khan, ... Q. Ping Dou, in Drug Repurposing in Cancer Therapy, 2020
Artemisinin—summary
ART was originally developed in order to combat malaria and has saved millions of lives and is also seen as one of the largest contributions of China to global health. The 2015 Nobel Prize in Physiology or Medicine was awarded to Professor Youyou Tu for her contribution in the discovery of this drug. ART and its derivatives, however, have now been seen to have some anticancer activity, indicating that these drugs may be effective cancer therapeutic agents. Clinical studies have shown that the cytotoxic effects of ART can cause patients to experience drug related toxicities.
Volume 1
Kathy Abascal BS, JD, RH(AHG), Eric L. Yarnell ND, RH(AHG), in Textbook of Natural Medicine (Fifth Edition), 2020
Drug Interactions
Artemisinin compounds generally show more rapid parasite clearance and fever reduction when combined with mefloquine than either agent given by itself, according to a meta-analysis of clinical trials.18 Mefloquine’s neurological toxicity does not appear to be altered by combination with artemisinin compounds, although the tendency to induce severe vomiting may be slightly lessened.
Artemisinin compounds can be combined safely with doxycycline and tetracycline, according to the results of two clinical trials, although at least one of these trials suggested the combination was less effective than artemether combined with mefloquine.43,44 Another double-blind trial found that the combination of artesunate and tetracycline was equally effective and much safer than quinine and tetracycline.45
Artemisinin may interfere slightly with sulfadoxine-pyrimethamine. In one trial, artemisinin by itself led to insignificantly more rapid parasite clearance than artemisinin combined with sulfadoxine-pyrimethamine.46 Fever relief was achieved equally rapidly, and adverse effects were absent in both groups. Further research is necessary to determine for certain if there is any negative effect from combining these two agents.
Grapefruit juice initially increases the bioavailability of oral artemether, although it does not stop the inevitable decline in bioavailability of this compound that occurs with repeated dosing over a few days.47
Single case studies suggest that artesunate may increase the risk of hepatotoxicity in cancer patients being treated with the drug temozolomide.48
Malaria Diagnosis and Treatment
Kathrine R. Tan, Paul M. Arguin, in The Travel and Tropical Medicine Manual (Fifth Edition), 2017
Artemisinin-Based Combination Therapies (ACTs)
Artemisinin (qinghaosu) and its derivatives (artesunate, artemether, dihydroartemisinin) are the most rapidly effective of all antimalarials. They are active against all malaria species. Artemisinin derivatives are used in combination with a drug with a slower rate of elimination to increase efficacy, reduce transmission of the infection, and provide mutual protection from drug resistance. Artemether-lumefantrine (Coartem®, Riamet®) is a highly effective, well-tolerated, fixed combination drug for use in both children and adults. Reliable absorption of this lipophilic drug is dependent on coadministration with food containing fat. Currently, artemether-lumefantrine is the only ACT approved by the FDA for use in the United States. Other ACTs in use in other countries include artesunate-mefloquine, artesunate-amodiaquine, artesunate-sulfadoxine-pyrimethamine, and dihydroartemisinin-piperaquine.
Malaria (Plasmodium Species)
Rick M. Fairhurst, Thomas E. Wellems, in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015
Artemisinin-Based Combination Therapies
Artemisinin-based combination therapies (ACTs)522 are the first-line recommended treatments for uncomplicated P. falciparum malaria,523 including in children and pregnant women during the second and third trimesters.524 An ACT is a 3-day regimen of artemisinin or one of its derivatives (i.e., artesunate, artemether, and dihydroartemisinin) in combination with a partner drug (i.e., amodiaquine, mefloquine, lumefantrine, piperaquine, and pyronaridine). Although artemisinins are potent and fast acting, they have a very short half-life (1 to 2 hours) in plasma; therefore, long-acting partner drugs are needed to prevent parasite recrudescence and treatment failure.525 Patterns of resistance to partner drugs determine which ACT should be used in particular geographic locations. Because of widespread resistance to chloroquine, ACTs that contain amodiaquine or lumefantrine are commonly used in Africa.526 Because of declining efficacy of mefloquine along the Thailand-Cambodia border, ACTs that contain piperaquine are increasingly being used in Southeast Asia.527-535 The ongoing use of piperaquine, however, may also be threatened by the rise of resistance to this drug. Artesunate-pyronaridine has been shown to be an effective treatment in Western Cambodia, where multidrug-resistant P. falciparum is highly prevalent.536,537
A fixed-dose combination of artemether-lumefantrine (Coartem)538 is the only ACT approved for use in the United States. Combinations of dihydroartemisinin-piperaquine (Eurartesim)539 and artesunate-pyronaridine (Pyramax)540 are licensed for use in Europe.
https://www.webmd.com/cancer/artemisinin-cancer-treatment
Artemisinin for Cancer Treatment
If you lived in China a thousand years ago and had a fever, inflammation, or malaria, a tea made from a flowering plant called Artemisia annua might have been your treatment. You may know it better as sweet wormwood.
The plant contains a compound called artemisinin. It's the basis for a malaria drug called artesunate that doctors prescribe today.
Some people believe that artemisinin may be an alternative to more aggressive cancer treatments. While cancer cells often become resistant to most chemotherapy drugs, that doesn’t seem to happen with artemisinin. And unlike many cancer treatments, artemisinin isn't toxic. It's also cheap and easy to give.
What Could It Do?
Cancer cells rely on iron to spread. When iron and artemisinin enter a cancer cell together, they form atoms called free radicals that kill cancer cells without harming normal ones.
Studies show that artemisinin may slow the spread of tumors. It could also cause cancer cells to:
- Self-destruct
- Stop dividing and spreading
- Get cut off from their blood supply
Does It Work?
There have been just a few small clinical trials that looked at artemisinin’s role in treating cancer. What research has been done used artemisinin in conjunction with normal cancer care, not as an alternative. We need more research to know for sure if it can help. So far, those small studies have some experts feeling optimistic about its potential role as a treatment for some types of cancer, including:
Colorectal. In a study of 20 people with colon cancer, nine were treated with artesunate while the rest were not. Those that received artesunate saw 12% more of their cancer cells die than those who didn't.
Melanoma. When taken in combination with a second drug, artesunate showed promise for people with melanoma of the eye that had spread. One person was still alive 47 months after they found out they had this form of skin cancer. By comparison, survival for this type of cancer is usually about 2-5 months.
Lung cancer. Researchers followed 120 cases of advanced non-small-cell lung cancer. People treated with a combination of artesunate and chemotherapy saw their cancer progress more slowly than those in a second group who didn't take these medicines together.
Advanced cervical cancer: Doctors treated 10 women with a form of artemisinin for 28 days. All 10 went into remission and saw symptoms like pain and vaginal discharge go away.
Risks
Possible side effects include:
Because there hasn't been much research on the use of artemisinin for treating cancer, there are lots of unknowns. If you're thinking about this as a potential treatment, you should talk with your medical team. They can tell you if there's a clinical trial available and if you could be a participant.
https://en.wikipedia.org/wiki/Artemisinin
Artemisinin
 | |
 | |
| Clinical data | |
|---|---|
| Pronunciation | /ɑːrtɪˈmɪsɪnɪn/ |
| Other names | Artemisinine, qinghaosu |
| Routes of administration | Oral |
| ATC code | |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.110.458  |
| Chemical and physical data | |
| Formula | C15H22O5 |
| Molar mass | 282.336 g·mol−1 |
| 3D model (JSmol) | |
| Density | 1.24 ± 0.1 g/cm3 |
| Melting point | 152 to 157 °C (306 to 315 °F) |
| Boiling point | decomposes |
  (what is this?) (verify) | |
Artemisinin (/ˌɑːtɪˈmiːsɪnɪn/) and its semisynthetic derivatives are a group of drugs used against malaria due to Plasmodium falciparum.[1] It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her discovery.[2] Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium.[3] Artemisinin is isolated from the plant Artemisia annua, sweet wormwood, a herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically-engineered yeast, which is much more efficient than using the plant.[4]
Chemically, artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This endoperoxide 1,2,4-trioxane ring is responsible for the drug's mechanism of action. Few other natural compounds with such a peroxide bridge are known.[5]
Artemisinin and its derivatives have been used for the treatment of malarial and parasitic worm (helminth) infections. They have the advantage over other drugs in having an ability to kill faster and kill all the life cycle stages of the parasites.[6] But low bioavailability, poor pharmacokinetic properties and high cost of the drugs are major drawbacks of their use.[7] Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization,[8] as there have been signs that malarial parasites are developing resistance to the drug. Therapies that combine artemisinin or its derivatives with some other antimalarial drug are the preferred treatment for malaria.[9]
Medical use[edit]
Uncomplicated malaria[edit]
Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence. The World Health Organization (WHO) is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins.[10]
The WHO has recommended artemisinin combination therapies (ACT) be the first-line therapy for Plasmodium falciparum malaria worldwide.[11] As short-acting drugs, artemisinin compounds are given with one or two long-acting drugs like amodiaquine, mefloquine, sulfadoxine/pyrimethamine or lumefantrine.[6] Combinations are effective because the artemisinin component kills the majority of parasites at the start of the treatment, while the more slowly eliminated partner drug clears the remaining parasites.[12]
Several fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ),[13] lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin), and pyronaridine (Pyramax). Increasingly, these combinations are being made to GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and Southeast Asia.[14][15]
Artemisinins are not used for malaria prevention because of the extremely short activity (half-life) of the drug. To be effective, it would have to be administered multiple times each day.
Severe malaria[edit]
Artesunate administered by intravenous or intramuscular injection has proven superior to quinine in large, randomised controlled trials in both adults[16] and children.[17] Combining all trials comparing these two drugs, artesunate is associated with a mortality rate that is approximately 30% lower than that of quinine.[17] Reasons for this difference include reduced incidence of hypoglycaemia, easier administration and more rapid action against circulating and sequestered parasites. Artesunate is now recommended by the WHO for treatment of all cases of severe malaria. Effective treatment with ACT (artemisinin combination therapy) has proven to lower the morbidity and mortality from malaria within two years by around 70%.[18]
Helminthiasis[edit]
A serendipitous discovery was made in China in the early 1980s while searching for novel anthelmintics for schistosomiasis that artemisinin was effective against schistosomes,[19][20][21] the human blood flukes, which are the second-most prevalent parasitic infections, after malaria. Artemisinin and its derivatives are all potent anthelmintics.[22] Artemisinins were later found to possess a broad spectrum of activity against a wide range of trematodes, including Schistosoma japonicum, S. mansoni, S. haematobium, Clonorchis sinensis, Fasciola hepatica, and Opisthorchis viverrini. Clinical trials were also successfully conducted in Africa among patients with schistosomiasis.[23]
Cancer[edit]
Artemisinin and its derivatives are under laboratory research for their potential anti-cancer effects.[24] As of 2018, only preliminary clinical research had been conducted using artemisininin derivatives in various cancers, with no approved clinical applications.[25]
Autoimmune disease[edit]
Artemisinin derivatives are known for their ability to suppress immune reactions such as inflammation. One derivative, SM934, was approved in 2015 by the China Food and Drug Administration for clinical trial as a drug for systemic lupus erythematosus.[26] Experiments in animal models have given good results. It can regulate T cell subsets, inhibit the activation of B cells, block the production of inflammatory cytokines and NF-κB signal transduction pathway.[27]
Adverse effects[edit]
Artemisinins are generally well tolerated at the doses used to treat malaria.[28] The side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, loss of appetite, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic reaction.[28][29] One case of significant liver inflammation has been reported in association with prolonged use of a relatively high-dose of artemisinin for an unclear reason (the patient did not have malaria).[30] The drugs used in combination therapies can contribute to the adverse effects experienced by those undergoing treatment. Adverse effects in patients with acute P. falciparum malaria treated with artemisinin derivatives tend to be higher.[31]
Chemistry[edit]
An unusual component of the artemisinin molecules is an endoperoxide 1,2,4-trioxane ring. This is the main antimalarial centre of the molecule.[32] Modifications at carbon 10 (C10) position give rise to a variety of derivatives which are more powerful than the original compound.[33] Because the physical properties of artemisinin itself, such as poor bioavailability, limit its effectiveness, semisynthetic derivatives of artemisinin have been developed. Derivatives of dihydroartemisinin were made since 1976. Artesunate, arteether and artemether were synthesised in 1986. Many derivatives have been produced of which artelinic acid, artemotil, artemisone, SM735, SM905, SM933, SM934, and SM1044 are among the most powerful compounds.[34][35] There are also simplified analogs in preclinical research.[36] Over 120 other derivatives have been prepared, but clinical testing has not been possible due to lack of financial support.[32]
Artemisinin belongs to a class of sesquiterpene lactones. The solid is poorly soluble in oils and water. Therefore, it is mostly applied through the digestive tract, either by oral or rectal administration. Some chemical modification are suitable for administration by injection. Artesunate is the only artemisinin compound available for all types of administration procedure.[37] A synthetic compound with a similar trioxolane structure (a ring containing three oxygen atoms) named RBx-11160[38] showed promise in in vitro testing. Phase II testing in patients with malaria was not as successful as hoped, but the manufacturer decided to start Phase III testing anyway.[39]
Mechanism of action[edit]
As of 2018, the exact mechanism of action of artemisinins has not been fully elucidated.[40] Artemisinin itself is a prodrug of the biologically active dihydroartemisinin. This metabolite undergoes cleavage of its endoperoxide ring inside the erythrocytes. As the drug molecules come in contact with the haem (associated with the haemoglobin of the red blood cells), the iron(II) oxide breaks the endoperoxide ring.[41] This process produces free radicals that in turn damage susceptible proteins, resulting in the death of the parasite.[42][43] In 2016 artemisinin was shown to bind to a large number of targets suggesting that it acts in a promiscuous manner. Artemisinin's endoperoxide moiety is however less sensitive to free iron(II) oxide, and therefore more active in the intraerythrocytic stages of P. falciparum.[44] In contrast, clinical practice shows that unlike other antimalarials, artemisinin is active during all life cycle stages of the parasite.[45]
Resistance[edit]
Clinical evidence for artemisinin drug resistance in southeast Asia was first reported in 2008,[46] and was subsequently confirmed by a detailed study from western Cambodia.[47][48] Resistance in neighbouring Thailand was reported in 2012,[49] and in northern Cambodia, Vietnam and eastern Myanmar in 2014.[50][51] Emerging resistance was reported in southern Laos, central Myanmar and northeastern Cambodia in 2014.[50][51] The parasite's kelch gene on chromosome 13 appears to be a reliable molecular marker for clinical resistance in Southeast Asia.[52]
In April 2011, the WHO stated that resistance to the most effective antimalarial drug, artemisinin, could unravel national Indian malaria control programs, which have achieved significant progress in the last decade. WHO advocates the rational use of antimalarial drugs and acknowledges the crucial role of community health workers in reducing malaria in the region.[53]
Two main mechanisms of resistance drive Plasmodium resistance to antimalarial drugs. The first one is an efflux of the drug away from its action site due to mutations in different transporter genes (like pfcrt in chloroquine resistance) or an increased number of the gene copies (like pfmdr1 copy number in mefloquine resistance). The second is a change in the parasite target due to mutations in corresponding genes (like, at the cytosol level, dhfr and dhps in sulfadoxine-pyrimethamine resistance or, at the mitochondrion level, cytochrome b in atovaquone resistance). Resistance of P. falciparum to the new artemisinin compounds involves a novel mechanism corresponding to a quiescence phenomenon.[54]
Synthesis[edit]
Biosynthesis in A. annua[edit]
The biosynthesis of artemisinin is believed to involve the mevalonate pathway (MVA) and the cyclization of farnesyl diphosphate (FDP). It is not clear whether the non-mevalonate pathway can also contribute 5-carbon precursors (IPP or DMAPP), as occurs in other sesquiterpene biosynthetic systems. The routes from artemisinic alcohol to artemisinin remain controversial, and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photo-oxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation finish the biosynthesis of artemisinin.
Chemical synthesis[edit]
The total synthesis of artemisinin has been performed from available organic starting materials, using basic organic reagents, many times. The first two total syntheses were a "remarkable... stereoselective synthesis" by Schmid and Hofheinz at Hoffmann-La Roche in Basel starting from (−)-isopulegol (13 steps, ~5% overall yield) and a concurrent synthesis by Zhou and coworkers at the Shanghai Institute of Organic Chemistry from (R)-(+)-citronellal (20 steps, ~0.3% overall yield).[55] Key steps of the Schmid–Hofheinz approach included an initial Ohrloff stereoselective hydroboration/oxidation to establish the "off-ring" methyl stereocenter on the propene side chain; two sequential lithium-reagent mediated alkylations that introduced all needed carbon atoms and that were, together highly diastereoselective; and further reduction, oxidation, and desilylation steps performed on this mono-carbocyclic intermediate, including a final singlet oxygen-utilizing photooxygenation and ene reaction, which, after acidic workup closed the three remaining oxacyclic rings of the desired product, artemisinin, in a single step.[55][56][57](In essence, the final oxidative ring closing operation in these syntheses accomplishes the closing three biosynthetic steps shown above.)
A wide variety of further routes continue to be explored, from early days until today, including total synthesis routes from (R)-(+)-pulegone, isomenthene,[55] and even 2-cyclohexen-1-one,[58] as well as routes better described as partial or semisyntheses from a more plentiful biosynthetic precursor, artemisinic acid—in the latter case, including some very short and very high yielding biomimetic synthesis examples (of Roth and Acton, and Haynes et al., 3 steps, 30% yield), which again feature the singlet oxygen ene chemistry.[59][55][60][61]
Synthesis in engineered organisms[edit]
The partnership to develop semisynthetic artemisinin was led by PATH’s Drug Development program (through an affiliation with OneWorld Health), with funding from the Bill & Melinda Gates Foundation. The project began in 2004, and initial project partners included the University of California, Berkeley (which provided the technology on which the project was based – a process that genetically altered yeast to produce artemisinic acid)[62] and Amyris (a biotechnology firm in California, which refined the process to enable large-scale production and developed scalable processes for transfer to an industrial partner).
In 2006, a team from UC Berkeley reported they had engineered Saccharomyces cerevisiae yeast to produce small amount of the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly US$0.25 per dose. In this effort of synthetic biology, a modified mevalonate pathway was used, and the yeast cells were engineered to express the enzyme amorphadiene synthase and a cytochrome P450 monooxygenase (CYP71AV1), both from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.[63]
The Berkeley method was augmented using technology from various other organizations. The final successful technology is based on inventions licensed from UC Berkeley and the National Research Council (NRC) Plant Biotechnology Institute of Canada.
Commercial production of semisynthetic artemisinin is now underway at Sanofi's site in Garessio, Italy. This second source of artemisinin is poised to enable a more stable flow of key antimalarial treatments to those who need them most.[64] The production goal is set at 35 tonnes for 2013. It is expected to increase to 50–60 tons per year in 2014, supplying approximately one third of the global annual need for artemisinin.
On May 8, 2013, WHO's Prequalification of Medicines Programme announced the acceptability of semisynthetic artemisinin for use in the manufacture of active pharmaceutical ingredients submitted to WHO for prequalification, or that have already been qualified by WHO.[65] Sanofi’s active pharmaceutical ingredient (API) produced from semisynthetic artemisinin (artesunate) was also prequalified by WHO on May 8, 2013, making it the first semisynthetic artemisinin derivative prequalified.
In 2010, a team from Wageningen University reported they had engineered a close relative of tobacco, Nicotiana benthamiana, that can also produce the precursor, artemisinic acid.[66]
Production and price[edit]
China and Vietnam provide 70% and East Africa 20% of the raw plant material.[67] Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using a solvent, typically hexane. Alternative extraction methods have been proposed.[68] The market price for artemisinin has fluctuated widely, between US$120 and $1,200 per kilogram from 2005 to 2008.[69]
The Chinese company Artepharm created a combination artemisinin and piperaquine drug marketed as Artequick. In addition to clinical studies performed in China and southeast Asia, Artequick was used in large scale malaria eradication efforts in the Comoros. Those efforts, conducted in 2007, 2012, and 2013–14, produced a 95–97% reduction in the number of malaria cases in the Comoros.[70]
After negotiation with the WHO, Novartis and Sanofi-Aventis provide ACT drugs at cost on a nonprofit basis; however, these drugs are still more expensive than other malaria treatments.[71] Artesunate injection for severe malaria treatment is made by the Guilin Pharmaceutical factory in China where production has received WHO prequalification.[72] High-yield varieties of Artemisia are being produced by the Centre for Novel Agricultural Products at the University of York using molecular breeding techniques.[69]
Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 metres and produce 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières, ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. However, the World Health Organization (WHO) does not recommend the use of A. annua plant materials, including tea, for the prevention and treatment of malaria.[73]
In April 2013, Sanofi announced the launch[64] of a production facility in Garessio, Italy, to manufacture the antiplasmodial drug on a large scale. The partnership to create a new pharmaceutical manufacturing process was led by PATH’s Drug Development program (through an affiliation with OneWorld Health), with funding from the Bill & Melinda Gates Foundation and based on a modified biosynthetic process for artemisinic acid, initially designed by Jay Keasling at the University of California, Berkeley and optimized by Amyris. The reaction is followed by a photochemical process creating singlet oxygen to obtain the end product. Sanofi expects to produce 25 tons of artemisinin in 2013, ramping up the production to 55–60 tonnes in 2014. The price per kilogram will be US$350–400, roughly the same as the botanical source.[74] Despite concerns that this equivalent source would lead to the demise of companies, which produce this substance conventionally through extraction of A. annua biomass, an increased supply of this drug will likely produce lower prices and therefore increase the availability for ACTs treatment. In August 2014, Sanofi announced the release of the first batch of semisynthetic artemisinin. 1.7 million doses of Sanofi's artesunate amodiaquine Winthrop (ASAQ Winthrop), a fixed-dose artemisinin-based combination therapy will be shipped to half a dozen African countries over the next few months.[75]
A 2016 systematic review of four studies from East Africa concluded that subsidizing artemisinin-based combination (therapy ACT) in the private retail sector in combination with training and marketing led to increased availability of ACTs in stores, increased use of ACTs for febrile children under five years of age, and decrease in the use of older, less effective antimalarials among children under five years of age; the underlying studies did not determine if the children had malaria nor determine if there were health benefits.[76]
Metabolism[edit]
In the liver artemisinin is converted to different inactive metabolites such as deoxyartemisinin, deoxydihydroartemisinin, crystal 7, and 9,10-dihydrodeoxyartemisinin. The metabolites have lost the endoperoxide group and become ineffective. The reaction is catalysed by an enzyme CYP2B6, while another enzyme CYP3A4 acts as a secondary catalyst. In the absence of CYP2B6, CYP3A4 becomes the primary enzyme. These enzymes belong to cytochrome P450 group present in the smooth endoplasmic reticulum. Artemisinin derivatives are metabolised differently. They are first converted to dihydroartemisinin (DHA). DHA itself is a strong antimalarial molecule and is active in the blood circulation for two to three hours. The antimalarial activity of artesunate is actually only through DHA. (Artemisinin, arteether, artemether, etc. are directly antimalarials.) Artesunate is converted to DHA within a minute of its absorption. About 90% of the total DHA normally binds to blood plasma.[33] In the liver, cytochrome P450 enzyme system (including CYP2A6, CYP3A4, and CYP3A5) convert DHA into inactive metabolites. All the metabolites undergo glucuronidation after which they are excreted through the urine or faeces. UDP-glucuronosyltransferases, in particular UGT1A9 and UGT2B7, are responsible for the process. DHA is also removed through bile as minor glucuronides, such as tetrahydrofurano acetate. Due to fast metabolism, artemisinins are relatively safe drugs.[6]
History[edit]
Etymology[edit]
Artemisinin is an antimalarial lactone derived from qinghao (青蒿, Artemisia annua or sweet wormwood). The medicinal value of this plant has been known to the Chinese for at least 2,000 years. In 1596, Li Shizhen recommended tea made from qinghao specifically to treat malaria symptoms in his Compendium of Materia Medica. The genus name is derived from the Greek goddess Artemis and, more specifically, may have been named after Queen Artemisia II of Caria, a botanist and medical researcher in the fourth century BCE.[77]
Discovery[edit]
Artemisia annua is a common herb found in many parts of the world, and has been used by Chinese herbalists for more than 2000 years in the treatment of malaria. The earliest record dates back to 200 BCE, in the Fifty-two Prescriptions unearthed from the Mawangdui.[78] Its antimalarial application was first described in Zhouhou Beiji Fang (The Handbook of Prescriptions for Emergencies, Chinese: 肘後備急方), edited in the middle of the 4th century CE by Ge Hong; in that book, 43 malaria treatment methods were recorded.[79] Images of the original scientific papers that record the history of the discovery, have been available online since 2006.[80]
In 1967, a plant screening research program, under a secret military programme code-named "Project 523", was set up by the People's Liberation Army to find an adequate treatment for malaria; the program and early clinical work were ordered of Mao Zedong at the request of North Vietnamese leaders to provide assistance for their malaria-ridden army.[81] In the course of this research in 1972, Tu Youyou discovered artemisinin in the leaves of Artemisia annua.[82]
Named qinghaosu (Chinese: 青蒿素; lit. 'compound of green-blue wormwood'),[82][83] it was one of many candidates tested as possible treatments for malaria by Chinese scientists, from a list of nearly 5,000 traditional Chinese medicines.[citation needed] Tu Youyou also discovered that a low-temperature extraction process could be used to isolate an effective antimalarial substance from the plant. Tu says she was influenced by a traditional Chinese herbal medicine source The Handbook of Prescriptions for Emergency Treatments written in 340 CE by Ge Hong saying that this herb should be steeped in cold water.[84] This book contained the useful reference to the herb: "A handful of qinghao immersed with two litres of water, wring out the juice and drink it all."
Tu's team subsequently isolated a useful extract.[82] Results were published in the Chinese Medical Journal in 1979.[82][85][5] The extracted substance, once subject to purification, proved to be useful starting point to obtain purified artemisinin.[82] A 2012 review reported that artemisinin-based therapies were the most effective drugs for treatment of malaria at that time;[86] it was also reported to clear malaria parasites from patients' bodies faster than other drugs. In addition to artemisinin, Project 523 developed a number of products that can be used in combination with artemisinin, including lumefantrine, piperaquine, and pyronaridine.[82]
In the late 1990s, Novartis filed a new Chinese patent for a combination treatment with artemether and lumefantrine, providing the first artemisinin-based combination therapies (Coartem) at reduced prices to the World Health Organization.[87] In 2006, after artemisinin had become the treatment of choice for malaria, the WHO called for an immediate halt to single-drug artemisinin preparations in favor of combinations of artemisinin with another malaria drug, to reduce the risk of parasites developing resistance.[88]
In 2011, Tu Youyou was awarded the Lasker-DeBakey Clinical Medical Research Award for her role in the discovery and development of artemisinin.[82][89] On October 5, 2015, she was awarded half of the 2015 Nobel Prize in Physiology or Medicine for discovering artemisinin, "a drug that has significantly reduced the mortality rates for patients suffering from malaria".[2] The other half of the prize was awarded jointly to William C. Campbell and Satoshi Ōmura for discovering avermectin, "the derivatives of which have radically lowered the incidence of River blindness and Lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases".[2]
See also[edit]
- Artemisia (genus), hardy herbaceous plants and shrubs known for the powerful chemical constituents in their essential oils
- Artemisin, a hydroxylated derivative of santonin
- Santonin, an anthelminthic, a drug expelling parasitic worms (helminths) by paralyzing them
References[edit]
This article contains public domain text from the CDC as cited
- ^ White NJ (July 1997). "Assessment of the pharmacodynamic properties of antimalarial drugs in vivo". Antimicrobial Agents and Chemotherapy. 41 (7): 1413–22. doi:10.1128/AAC.41.7.1413. PMC 163932. PMID 9210658.
- ^ a b c "The Nobel Prize in Physiology or Medicine 2015". Nobel Foundation. Retrieved 2020-10-12.
- ^ WHO (2015). Guidelines for the Treatment of Malaria. World Health Organization (Third ed.). Geneva. pp. 9–11. ISBN 978-92-4-154912-7. OCLC 908628497.
- ^ Arsenault PR, Wobbe KK, Weathers PJ (2008). "Recent advances in artemisinin production through heterologous expression". Current Medicinal Chemistry. 15 (27): 2886–96. doi:10.2174/092986708786242813. PMC 2821817. PMID 18991643.
- ^ a b Brown G (July 2006). "Artemisinin and a new generation of antimalarial drugs". Education in Chemistry. Vol. 43 no. 4. Royal Society of Chemistry. pp. 97–99. Retrieved 2018-03-09.
- ^ a b c Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. (October 2012). "Pharmacogenomics knowledge for personalized medicine". Clinical Pharmacology and Therapeutics. 92 (4): 414–7. doi:10.1038/clpt.2012.96. PMC 3660037. PMID 22992668.
- ^ "Development of Novel Antimalarials". MalariaWorld. September 6, 2010. Retrieved 2016-10-22.
- ^ "WHO calls for an immediate halt to provision of single-drug artemisinin malaria pills". WHO. 19 January 2006.
- ^ Pelfrene E, Pinheiro MH, Cavaleri M (July 2015). "Artemisinin-based combination therapy in the treatment of uncomplicated malaria: review of recent regulatory experience at the European Medicines Agency". International Health. 7 (4): 239–46. doi:10.1093/inthealth/ihv017. PMC 4492341. PMID 25855638.
- ^ Rehwagen C (May 2006). "WHO ultimatum on artemisinin monotherapy is showing results". BMJ. 332 (7551): 1176. doi:10.1136/bmj.332.7551.1176-b. PMC 1463909. PMID 16709988.
- ^ Guidelines for the Treatment of Malaria. Geneva: World Health Organization. 2006. ISBN 978-92-4-154694-2.
- ^ White NJ (April 2004). "Antimalarial drug resistance". The Journal of Clinical Investigation. 113 (8): 1084–92. doi:10.1172/JCI21682. PMC 385418. PMID 15085184.
- ^ Krudsood S, Looareesuwan S, Tangpukdee N, Wilairatana P, Phumratanaprapin W, Leowattana W, et al. (September 2010). "New fixed-dose artesunate-mefloquine formulation against multidrug-resistant Plasmodium falciparum in adults: a comparative phase IIb safety and pharmacokinetic study with standard-dose nonfixed artesunate plus mefloquine". Antimicrobial Agents and Chemotherapy. 54 (9): 3730–7. doi:10.1128/AAC.01187-09. PMC 2935027. PMID 20547795.
- ^ "Malaria drugs recalled in Kenya". BBC News. 17 August 2007.
- ^ Newton P, Proux S, Green M, Smithuis F, Rozendaal J, Prakongpan S, et al. (June 2001). "Fake artesunate in southeast Asia". Lancet. 357 (9272): 1948–50. doi:10.1016/S0140-6736(00)05085-6. PMID 11425421. S2CID 27929151.
- ^ Dondorp A, Nosten F, Stepniewska K, Day N, White N (2005). "Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial". Lancet. 366 (9487): 717–25. doi:10.1016/S0140-6736(05)67176-0. PMID 16125588. S2CID 173027.
- ^ a b Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. (November 2010). "Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial". Lancet. 376 (9753): 1647–57. doi:10.1016/S0140-6736(10)61924-1. PMC 3033534. PMID 21062666.
- ^ Bhattarai A, Ali AS, Kachur SP, Mårtensson A, Abbas AK, Khatib R, et al. (November 2007). "Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar". PLOS Medicine. 4 (11): e309. doi:10.1371/journal.pmed.0040309. PMC 2062481. PMID 17988171.
- ^ Le WJ, You JQ, Mei JY, Wang GF, Xie RR (August 1981). "[Antischistosomal action of some Qing Hao Su derivatives in infected mice (author's transl)]". Yao Xue Xue Bao = Acta Pharmaceutica Sinica. 16 (8): 561–3. PMID 7324954.
- ^ Le WJ, You JQ, Yang YQ, Mei JY, Guo HF, Yang HZ, Zhang CW (1982). "[Studies on the efficacy of artemether in experimental schistosomiasis (author's transl)]". Yao Xue Xue Bao. 17 (3): 187–93. PMID 7115549.
- ^ Le WJ, You JQ, Mei JY (August 1983). "[Chemotherapeutic effect of artesunate in experimental schistosomiasis]". Yao Xue Xue Bao = Acta Pharmaceutica Sinica. 18 (8): 619–21. PMID 6677044.
- ^ Xiao SH (2005). "Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins". Acta Tropica. 96 (2–3): 153–67. doi:10.1016/j.actatropica.2005.07.010. PMID 16112072.
- ^ Keiser J, Utzinger J (December 2007). "Artemisinins and synthetic trioxolanes in the treatment of helminth infections". Current Opinion in Infectious Diseases. 20 (6): 605–12. doi:10.1097/QCO.0b013e3282f19ec4. PMID 17975411. S2CID 34591129.
- ^ Konstat-Korzenny E, Ascencio-Aragón JA, Niezen-Lugo S, Vázquez-López R (February 2018). "Artemisinin and Its Synthetic Derivatives as a Possible Therapy for Cancer". Medical Sciences. 6 (1): 19. doi:10.3390/medsci6010019. PMC 5872176. PMID 29495461.
- ^ Raffetin A, Bruneel F, Roussel C, Thellier M, Buffet P, Caumes E, Jauréguiberry S (June 2018). "Use of artesunate in non-malarial indications" (PDF). Médecine et Maladies Infectieuses. 48 (4): 238–249. doi:10.1016/j.medmal.2018.01.004. PMID 29422423.
- ^ Shi C, Li H, Yang Y, Hou L (2015). "Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives". Mediators of Inflammation. 2015: 435713. doi:10.1155/2015/435713. PMC 4415672. PMID 25960615.
- ^ Mu X, Wang C (July 2018). "Artemisinins-a Promising New Treatment for Systemic Lupus Erythematosus: a Descriptive Review". Current Rheumatology Reports. 20 (9): 55. doi:10.1007/s11926-018-0764-y. PMID 30056574. S2CID 51866562.
- ^ a b Taylor WR, White NJ (2004). "Antimalarial drug toxicity: a review". Drug Safety. 27 (1): 25–61. doi:10.2165/00002018-200427010-00003. PMID 14720085. S2CID 28284347.
- ^ Leonardi E, Gilvary G, White NJ, Nosten F (2001). "Severe allergic reactions to oral artesunate: a report of two cases". Transactions of the Royal Society of Tropical Medicine and Hygiene. 95 (2): 182–3. doi:10.1016/S0035-9203(01)90157-9. PMID 11355556.
- ^ "Hepatitis Temporally Associated with an Herbal Supplement Containing Artemisinin — Washington, 2008". CDC.
- ^ Price R, van Vugt M, Phaipun L, Luxemburger C, Simpson J, McGready R, et al. (April 1999). "Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives". The American Journal of Tropical Medicine and Hygiene. 60 (4): 547–55. doi:10.4269/ajtmh.1999.60.547. PMID 10348227.
- ^ a b Robert A, Benoit-Vical F, Liu Y, Meunier B (January 2019). Sigel A, Freisinger E, Sigel RK, Carver PL (eds.). "Small Molecules: The Past or the Future in Drug Innovation?". Metal Ions in Life Sciences. de Gruyter mbH. 19: 17–48. doi:10.1515/9783110527872-008. ISBN 978-3-11-052691-2. PMID 30855103.
- ^ a b Woodrow CJ, Haynes RK, Krishna S (February 2005). "Artemisinins". Postgraduate Medical Journal. 81 (952): 71–8. doi:10.1136/pgmj.2004.028399. PMC 1743191. PMID 15701735.
- ^ Li Y (September 2012). "Qinghaosu (artemisinin): chemistry and pharmacology". Acta Pharmacologica Sinica. 33 (9): 1141–6. doi:10.1038/aps.2012.104. PMC 4003104. PMID 22922345.
- ^ Aderibigbe BA (February 2017). "Design of Drug Delivery Systems Containing Artemisinin and Its Derivatives". Molecules. 22 (2): 323. doi:10.3390/molecules22020323. PMC 6155641. PMID 28230749.
- ^ Posner GH, Parker MH, Northrop J, Elias JS, Ploypradith P, Xie S, Shapiro TA (January 1999). "Orally active, hydrolytically stable, semisynthetic, antimalarial trioxanes in the artemisinin family". Journal of Medicinal Chemistry. 42 (2): 300–4. doi:10.1021/jm980529v. PMID 9925735.
- ^ Morris CA, Duparc S, Borghini-Fuhrer I, Jung D, Shin CS, Fleckenstein L (September 2011). "Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration". Malaria Journal. 10 (1): 263. doi:10.1186/1475-2875-10-263. PMC 3180444. PMID 21914160.
- ^ Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FC, Chollet J, et al. (August 2004). "Identification of an antimalarial synthetic trioxolane drug development candidate". Nature. 430 (7002): 900–4. Bibcode:2004Natur.430..900V. doi:10.1038/nature02779. PMID 15318224. S2CID 4320974.
- ^ Unnikrishnan CH (September 21, 2007). "Blow to Ranbaxy drug research plans". livemint.com.
- ^ Krieger J, Smeilus T, Kaiser M, Seo EJ, Efferth T, Giannis A (July 2018). "Total Synthesis and Biological Investigation of (-)-Artemisinin: The Antimalarial Activity of Artemisinin Is not Stereospecific". Angewandte Chemie. 57 (27): 8293–8296. doi:10.1002/anie.201802015. PMID 29723442.
- ^ Tilley L, Straimer J, Gnädig NF, Ralph SA, Fidock DA (September 2016). "Artemisinin Action and Resistance in Plasmodium falciparum". Trends in Parasitology. 32 (9): 682–696. doi:10.1016/j.pt.2016.05.010. PMC 5007624. PMID 27289273.
- ^ Winzeler EA, Manary MJ (November 2014). "Drug resistance genomics of the antimalarial drug artemisinin". Genome Biology. 15 (11): 544. doi:10.1186/s13059-014-0544-6. PMC 4283579. PMID 25470531.
- ^ Cravo P, Napolitano H, Culleton R (August 2015). "How genomics is contributing to the fight against artemisinin-resistant malaria parasites". Acta Tropica. 148: 1–7. doi:10.1016/j.actatropica.2015.04.007. PMID 25910626.
- ^ Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, et al. (December 2015). "Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum". Nature Communications. 6: 10111. Bibcode:2015NatCo...610111W. doi:10.1038/ncomms10111. PMC 4703832. PMID 26694030.
- ^ German PI, Aweeka FT (2008). "Clinical pharmacology of artemisinin-based combination therapies". Clinical Pharmacokinetics. 47 (2): 91–102. doi:10.2165/00003088-200847020-00002. PMID 18193915. S2CID 24983411.
- ^ Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM (December 2008). "Evidence of artemisinin-resistant malaria in western Cambodia". The New England Journal of Medicine. 359 (24): 2619–20. doi:10.1056/NEJMc0805011. PMID 19064625.
- ^ Morelle R (20 October 2015). "Drug-resistant malaria can infect African mosquitoes". BBC News. Retrieved 20 October 2015.
- ^ Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. (July 2009). "Artemisinin resistance in Plasmodium falciparum malaria". The New England Journal of Medicine. 361 (5): 455–67. doi:10.1056/NEJMoa0808859. PMC 3495232. PMID 19641202.
- ^ Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, et al. (May 2012). "Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study". Lancet. 379 (9830): 1960–6. doi:10.1016/S0140-6736(12)60484-X. PMC 3525980. PMID 22484134.
- ^ a b Briggs H (July 30, 2014). "Call for 'radical action' on drug-resistant malaria". BBC News. Retrieved 2013-07-30.
- ^ a b Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. (July 2014). "Spread of artemisinin resistance in Plasmodium falciparum malaria". The New England Journal of Medicine. 371 (5): 411–23. doi:10.1056/NEJMoa1314981. PMC 4143591. PMID 25075834.
- ^ Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, et al. (January 2014). "A molecular marker of artemisinin-resistant Plasmodium falciparum malaria". Nature. 505 (7481): 50–5. Bibcode:2014Natur.505...50A. doi:10.1038/nature12876. PMC 5007947. PMID 24352242.
- ^ "Drugs immunity 'may' fail malaria fight". The Jakarta Post. April 23, 2011. Archived from the original on 4 March 2016.
- ^ Ouji M, Augereau JM, Paloque L, Benoit-Vical F (2018). "Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination". Parasite. 25: 24. doi:10.1051/parasite/2018021. PMC 5909375. PMID 29676250.
- ^ a b c d Pirrung MC, Morehead AT Jr (1997). "A Sesquidecade of Sesquiterpenes, 1980–1994: Part A. Acyclic and Monocyclic Sesquiterpenes, Part 1". In Goldsmith D (ed.). The Total Synthesis of Natural Products. 10. New York: John Wiley & Sons. pp. 90–96. ISBN 978-0-470-12962-3.
- ^ Schmid G, Hofheinz W (1983). "Total Synthesis of qinghaosu". Journal of the American Chemical Society. 105 (3): 624–625. doi:10.1021/ja00341a054.
- ^ Acton N, Klayman DL (October 1985). "Artemisitene, a New Sesquiterpene Lactone Endoperoxide from Artemisia annua". Planta Medica. 51 (5): 441–2. doi:10.1055/s-2007-969543. PMID 17342606.
- ^ Zhu C, Cook SP (August 2012). "A concise synthesis of (+)-artemisinin". Journal of the American Chemical Society. 134 (33): 13577–9. doi:10.1021/ja3061479. PMID 22866604.
- ^ "Chemical constituents from Artemisia annua". China Journal of Chinese Materia Medica. 2014-12-15. doi:10.4268/cjcmm20142423. ISSN 1001-5302.
- ^ Lévesque F, Seeberger PH (February 2012). "Continuous-flow synthesis of the anti-malaria drug artemisinin". Angewandte Chemie. 51 (7): 1706–9. doi:10.1002/anie.201107446. PMID 22250044.
- ^ Turconi J, Griolet F, Guevel R, Oddon G, Villa R, Geatti A, et al. (2014). "Semisynthetic artemisinin, the chemical path to industrial production". Organic Process Research & Development. 18 (3): 417–422. doi:10.1021/op4003196.
- ^ Ball P (2016). "Man Made: A History of Synthetic Life". Distillations. 2 (1): 15–23. Retrieved 20 March 2018.
- ^ Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, et al. (April 2006). "Production of the antimalarial drug precursor artemisinic acid in engineered yeast". Nature. 440 (7086): 940–3. Bibcode:2006Natur.440..940R. doi:10.1038/nature04640. PMID 16612385. S2CID 3199654.
- ^ a b Pantjushenko E. "Sanofi and PATH announce the launch of large-scale production of semisynthetic artemisinin against malaria". PATH.
- ^ Pantjushenko E. "Semisynthetic artemisinin achieves WHO prequalification". PATH. Retrieved 8 February 2014.
- ^ van Herpen TW, Cankar K, Nogueira M, Bosch D, Bouwmeester HJ, Beekwilder J (December 2010). Yang H (ed.). "Nicotiana benthamiana as a production platform for artemisinin precursors". PLOS ONE. 5 (12): e14222. Bibcode:2010PLoSO...514222V. doi:10.1371/journal.pone.0014222. PMC 2997059. PMID 21151979.
- ^ ole-MoiYoi, K; Rodriguez, W (2011). "Investing in Global Health: Botanical Extracts Ltd"(PDF). Global Health Delivery Project.
- ^ Lapkin AA, Peters M, Greiner L, Chemat S, Leonhard K, Liauw MA, Leitner W (2010). "Screening of new solvents for artemisinin extraction process using ab initio methodology". Green Chemistry. 12 (2): 241–251. doi:10.1039/b922001a. and literature cited therein
- ^ a b "Report of the Artemisinin Enterprise Conference 2008" (PDF). Archived from the original (PDF) on 2014-06-17. Retrieved 2011-07-12.
- ^ "Cure all?". The Economist. January 25, 2014. Retrieved 2016-10-22.
- ^ "Artemisinin combination therapies". CNAP Artemisia Project. University of York. Archived from the original on 2012-10-05. Retrieved 2011-07-12.
- ^ "Guilin Pharmaceutical ─ The world's first producer of WHO prequalified artesunate for injection for severe malaria". mmv.org. 2010. Archived from the original on 2016-10-22. Retrieved 2016-10-22.
- ^ "Effectiveness of Non-Pharmaceutical Forms of Artemisia annua L. against malaria". World Health Organization. Global Malaria Programme. Position Statement (June 2012). Retrieved April 2020.
- ^ Peplow M (April 2013). "Sanofi launches malaria drug production to maintain stability in artemisinin availability". Chemistryworld Online. RSC. Retrieved 2013-04-19.
- ^ Palmer E (19 August 2014). "Sanofi shipping new malaria treatment manufactured from 'semisynthetic artemisinin'". Fierce Pharma Manufacturing. Retrieved 2014-09-14.
- ^ Opiyo N, Yamey G, Garner P (March 2016). "Subsidising artemisinin-based combination therapy in the private retail sector". The Cochrane Database of Systematic Reviews. 3: CD009926. doi:10.1002/14651858.cd009926.pub2. PMC 4916935. PMID 26954551.
- ^ Centers for Disease Control and Prevention (CDC) (July 2014). "Etymologia: Artemisinin". Emerging Infectious Diseases. 20 (7): 1217. doi:10.3201/eid2007.ET2007. PMC 4073852.
- ^ "Medical manuscripts from Ma Wang Dui". Qinghaosu Project.
- ^ Burns W. "Zhou Hou Bei Ji Fang" [Handy Therapies for Emergencies]. Qinghaosu Project.
- ^ Burns W. "Qinghaosu Project website". Blogspot. Retrieved 8 August 2014.
- ^ Jianfang Z (2006). A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin). ISBN 9781622121649.
- ^ a b c d e f g Miller LH, Su X (September 2011). "Artemisinin: discovery from the Chinese herbal garden". Cell. 146 (6): 855–8. doi:10.1016/j.cell.2011.08.024. PMC 3414217. PMID 21907397.
- ^ Chinese Academy of Sciences, ed. (Nov 1999). Xiandai Hanyu Cidian 现代汉语词典[Contemporary Chinese Dictionary] (in Chinese) (3rd (revised) ed.). Beijing: Commercial Press. p. 1204. ISBN 7-100-01777-7. OCLC 41467509.
素：...5. 带有根本性质的物质 'substance with the fundamental properties of'
- ^ Hao C (2011-09-29). "Lasker Award Rekindles Debate Over Artemisinin's Discovery". Science. Retrieved 2014-01-07.
- ^ Qinghaosu Antimalaria Coordinating Research Group (December 1979). "Antimalaria studies on Qinghaosu". Chinese Medical Journal. 92 (12): 811–6. PMID 117984.
- ^ Fairhurst RM, Nayyar GM, Breman JG, Hallett R, Vennerstrom JL, Duong S, et al. (August 2012). "Artemisinin-resistant malaria: research challenges, opportunities, and public health implications". The American Journal of Tropical Medicine and Hygiene. 87 (2): 231–241. doi:10.4269/ajtmh.2012.12-0025. PMC 3414557. PMID 22855752.
- ^ Neil DM (January 17, 2012). "For Intrigue, Malaria Drug Gets the Prize". New York Times. Retrieved 20 April 2013.
- ^ "WHO calls for an immediate halt to provision of single-drug artemisinin malaria pills"(Press release). World Health Organization. January 19, 2006.
- ^ Weise E (September 12, 2011). "'America's Nobel' awarded to Chinese scientist". USA Today. Retrieved 2011-09-12.
Further reading[edit]
- Daviss B (2005). "Malaria, Science, and Social Responsibility: Nonprofit drug-development partnership seeks to cure the ills of developing nations". The Scientist. 19 (6): 42.
External links[edit]
- "Defeating the Curse". BBC Horizon.
Artemisinin has proven to be the most effective anti-malarial drug ever produced.
From the United States
There were actually THIRTY reviews with the word "cancer" in them, sofor what it's worth, I'm pasting those reviews here:
From the United States
So I got this for my husband’s and my health as a maintenance and to cleanse our body of unwanted parasites, biofilm, yeast, candida, etc.
So I started on empty stomach, with 2 in the morning and 2 at night with 18mg iron In AM only, also take black pepper for better absorption. Then on 2nd week rotation went up to 3 in AM and 3 in PM ( so important to take with iron, do your research, Dr. Henry Lai at Washington State University) iron is loved by cancer cells and when the cancer eats the iron the Artemesinin comes in and kills the bad cells. When this happens your body will have die off symptoms. I have definitely had an extremely tired with brain fog feeling, cold symptoms too. This is how I know it is working. We are on 2nd week of 5 days on 4 days off rotation. Rotation is important as your body gets used to herb and when you stop periodically and reboot the herb works stronger somehow. Will be using this long term along with many other natural supplements and herbs.
I did Buy 2 other brands, 1 from allergy research group and 1 from Longlifenutri. I wanted to get a few other brands to try as well. This brand is potent so I am impressed.
I wholeheartedly believe a person can heal and regenerate their body from within, no matter what sickness ails you, through raw fruits and veggies, detoxification and fasting. This is what I have learned and I have done tons of research over the years. I chose to no longer eat meat as well. Herbs are an added bonus but a person must choose to change their diet as well to become healthy. The Sad American Diet is causing so much havoc on people’s health. You can see it everywhere around you. My husband refuses to change his diet so it takes a lot of willpower to take care of yourself while being tempted with the unhealthy food around you. I did eventually conquer this hurdle, lol.
I hope this helps someone who wants to get started on this amazing plant extract which is a gift from God
FYI: Please do your research on doses and intervals, I have read so many reviews and most all reviews have varied dosing.
The most important thing I learned from Dr Lai is to take with Iron.
May the Blessings be
walk - other than that her health is good. Using Artemisinin along with Artemix and Butyrex to treat tumours.
so far it's working and tumours have shrunk about 50%. She now can move her back legs a little - hopeful
she will walk again - maybe depending on damage to nerves..
Update - Copper (brown dog in pic) can now hold her back legs in a normal position bent at the hip, and tumour
in neck is shrinking (not fast enough but it's cancer). Still cannot stand or walk but back legs and left front have
some nerve control - she can move them, but just cannot stand up. Pleased with Artemisinin so far
of fighting cancer possibilities. Artemiisinin is one of the five.
Update 4/29/19 - its been 6 months and I'm happy to say the tumor is completely gone. Again, I am not here to say that Artemisinin is the exact reason, but coupled with other supplements and raw diet our dog is cancer free.
https://malariajournal.biomedcentral.com/articles/10.1186/s12936-018-2372-8
https://www.webmd.com/cancer/artemisinin-cancer-treatment
https://www.tropicalmedicine.ox.ac.uk/news/coronavirus-how-overreaction-made-vietnam-a-virus-success
How Vietnam managed to keep its coronavirus death toll at zero
OUCRU
1 June 2020
Despite a long border with China and a population of 97 million people, Vietnam has recorded only just over 300 cases of Covid-19 and not a single death. The country very quickly enacted measures such as travel restrictions, monitoring and eventually closing border with China, closing schools and increasing health checks at borders and other vulnerable places. A vast and labour intensive contact tracing operation got under way. Quarantine on such a vast scale is key as evidence mounts that as many as half of all infected people are asymptomatic.
© Credit De an SunHow Vietnam managed to keep its coronavirus death toll at zero CNN interview with Guy Thwaites and Pham Quang Thai (former OUCRU PhD student), 30th May
BBC interview with Guy Thwaites, 15th May
Rappler Talk also interviewed Guy Thwaites on Vietnam’s effective strategy against coronavirus, 15th May
MANILA, Philippines, 15th May – Vietnam's handling of the coronavirus pandemic is perhaps the most efficient and effective, not just in Asia but in the whole world. While many countries are still reeling from the effects of the news virus, Vietnam came out of lockdown with only 288 cases and zero deaths.
Rappler editor-at-large Marites Vitug asked Guy Thwaites, OUCRU director since 2013 and expert on infectious diseases and microbiology, how Vietnam handled the coronavirus pandemic.
What can countries learn from Vietnam? And what's unique in its handling that proved to be an ace in the fight against the coronavirus pandemic?
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.