Open questions concerning artemisinin and its derivatives
We selected three papers among many others raising concerns about the failure of ACTs.
In the Chinese paper from Liu AR et al (Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 2000;18(2):76-8 (http://www.ncbi.nlm.nih.gov/pubmed/12567719) ) it was documented that essential oil from a plant (also called patchouli oil) had extraordinary
synergistic properties with artesunate. This essential oil even reverses the resistance against Plasmodium berghei in mice. Why were ACTs (artemisia combined therapy) based on chemical and not on natural molecules?
The inhibition of Plasmodium with extracts from the Artemisia ludoviciana plant from Mexico is up to 98,6%. The plant does not contain artemisinin (F Malagon et al. Parasitologia. 1997 ;39(1):3-7 (http://www.ncbi.nlm.nih.gov/pubmed/9419840) ).
The paper from Vietnam (V Ha et al. Trans R Soc Trop Med Hyg. 1997 Jul-Aug;91(4):465-7 (http://www.ncbi.nlm.nih.gov/pubmed/9373657) ) claims that there is no significant difference between artemisinin, artemether, artesunate treatment! Why than produce ACT pills with artemisinin derivatives?
Artemisia annua was rediscovered by the Chinese during the Vietnam War and the infusion from the plant (not molecules chemically extracted from the plant) did wonders. During the Vietnam War the Vietcong were desperate because most of their soldiers in the jungle died of malaria, and not under American gunfire. They asked the Chinese for help and these discovered that 2000 years ago and still in present times A. annua is used in different herbal forms to cure malaria. So they provided the Vietcong with the A. annua herb which was grown in the gardens in many villages in China. The infusion did miracles for the Vietminh, and the US headquarters never could understand why their soldiers, black or white or yellow, succumbed to malaria and the Vietcong did not.
The Chinese had found one molecule in A. annua which is present only at lower concentrations in other artemisia varieties: artemisinine. The
exact date of the discovery of this molecule remains clouded in mystery. It remains an open question why only in 2011 the Lasker price was
awarded to Tu Youyou for the isolation of the artemisinin molecule in 1971 when the publication of Project 523 gives the credit in a Chinese scientific paper to Ke Xue Tong Bao for the same discovery of artemisinin in 1979.
After the Vietnam War A. annua tea was forgotten for some 15 years. WHO knew about the properties of the plant but neglected to further look into it; there was no financial benefit for pharmaceutical companies in selling a herb.
When chloroquine resistance was causing a disaster in many countries because of the build-up of resistance Western drug companies jumped
on the artemisinin molecule, extracted it from the plant and made artemisinin pills. But with this monotherapy they soon ran into a
resistance and recrudescence problem, which they related to low bioavailability already in the early 1990s. With the laboratories of the US
Army, they tried to produce an artemisinin-based product with a higher bioavailability but this attempt failed.
They then decided to make a visit to China. Together they figured out a joint business based on molecules extracted from this herb i.e. molecules with a higher solubility and bioavailabity. This could partially be achieved by chemically transforming artemisinin into artesunate or artemether, precursors of DHA. The only way to achieve this was in the laboratory by reaction with boronhydride. But DHA is a very unstable and reactive molecule. Especially when sold in pills in tropical countries. The shelf-life of ACT pills stored in hot and humid climates does not exceed a few months  . A. annua tea leaves, when stored in a ventilated place in the shade, stay efficient for more than three years as many studies have confirmed, thereby contradicting the “Statement” published on the WHO web page and a claim on short shelf-life of dried herb which is not based on any published papers.
All this chemistry was probably a mistake. In the human body artemisinin is never metabolized into DHA, no paper has been able to document this. How artemisinin and its derivatives work nobody really knows, despite several thousand papers published on the subject and a vast array of hypotheses. Artemether and artesunate are very aggressive molecules with a much shorter half life than artemisinin: 240 minutes. To guarantee efficiency and reduce failures of the artesunate or artemether drugs WHO in 1998 prescribed daily doses of 500 to 1000 mg per day for an adult (WHO/MAL/98.1068); 100 times more than the well documented IC50 of these molecules.
Levels where hepatotoxic, hematoxic, genotoxic, and cardiovascular  and neurotoxic effects could be noticed. And they definitely are
immuno-depressive. More recent data  shows that long-term administration of artesunate reduces sperm count, motility and viability.
Meanwhile however several people had run clinical trials with A. annua infusion and obtained surprisingly good results. Difficult to understand if artemisinin was not water soluble . It was found that artemisinin is absorbed faster from herbal tea preparations than from oral solid dosage forms . Of particular interest is the comparatively high level of transfer of artemisinin into the bloodstream from the plant material vs. the pure drug. There was 45 times more pure artemisinin fed to the mice than the amount fed via A. annua leaves, yet almost the same amount appeared in the bloodstream. It was also found that 100% of the artemisinin present in the gastrointestinal tract in humans is absorbed into the bloodstream
Since more than 5 years resistance to ACT pills has appeared in Thailand and is now spreading into the entire Far East, and even into South America and Africa. A. annua tea is used since 2000 years without causing any resistance and in the more recent use of this herbal tea by thousands of people not a single case of resistance could be detected and described in the scientific literature.
Over the years the error on the solubility and bioavailability of artemisinin became even more patent: artemisinin in a decoction or infusion of the dried herb may reach 84% extraction and solubility. Eventually more than in organic solvents used for industrial extraction of artemisinin. Polysaccharides and saponins probably are the reason for good solubility of artemisia in herbal tea.
Artemisia annua: from therapy to prophylaxis 
Since 5 years the associations IFBV and BELHERB  have established a working relationship with African universities, in close cooperation with other European research institutions. Several of these partners have run clinical trials with A. annua tea [9-17]. In all these trials a therapeutic effect of 95 % or higher was confirmed by the use over 7 days of whole leaf infusion, capsules or tablets. One of the surprising effects noticed in these trials was that that the artemisinin content had very little impact on the results. This led us to make an analysis as complete as possible of all the constituents, organic and inorganic , in a large series of A. annua samples from different origins . A. annua from Luxembourg, which had shown very promising antimalarial results, excellent bactericidal properties and a strong anti-inflammatory effect  contained only 0.1% of artemisinin but higher concentrations of certain essential oils. A literature survey has confirmed that several artemisia species like Artemisia maritima, apiacea, afra which don’t contain artemisinin are extensively used as antimalarials in herbal medicine . Elizabeth Hsu stated in her « Reflections on the discovery of the antimalarial qinghao” (Br J Clin Pharmacol 61(6), June 2006): ”Shen gua, and after him Shizhen valued A. apiacea more than A. annua”. A. annua, afra, herba alba, apiacea, sieberi, maritima, abrotanum, ludoviciana etc contain dozens of molecules which all have an antimalarial effect, against different stages:
sporozoite, trophozoite, merozoite, gametocyte. At the University of Johannesburg it was confirmed that several oils present in A.annua,
especially α-pinene have an IC50 against Plasmodium almost equivalent to quinine . At the University of Mayence it was confirmed that
several other molecules present in A. annua had IC50 values in the range of artemisinin  against HeLa carcinoma cells and against Trypanosoma brucei. Many of these molecules also boost the immune system. In Leiden  it was found that the anti-HIV activity of A. afra is even higher than for A. annua.
In our studies we found that the effect of water-soluble polysaccharides and saponins had been neglected in the past because most of the A. annua extracts had been obtained with organic solvents.
But the most important finding in several of these clinical trials, especially in Kenya and Uganda, was that people who continued to drink one or two cups of A. annua tea per week, after they had been cured, becomeimmune against malaria.
Artemisia herbal medicine is a polytherapy. Not only efficient in therapy, but also in prevention, and because of its multiple active
constituents unlikely to lead to resistance.
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