Archive for avril 2016

Was the Nobel price for artemisinin a fatal error

avril 14, 2016

Was the Nobel prize for artemisinin a fatal error?

April 2, 2016 – 06:26 — Irene Teis
In 2015 a Nobel Price was attributed to Youyou Tu, almost 50 years after a report describing artemisinin’s structure, pharmacology, and efficacy had been published in 1979 by the “Qinghaosu Anti-Malarial Coordinating Research Group,” where she was a member of. Mr Huang Shuze, Deputy Minister of Health, stated in his 1981 summary report “Project 523 mobilized multiple departments ; thirty scientific research units and medical schools in 1975”.

WHO for decades hesitated in considering this traditional medicine approach. Only at the end of the nineties, when chloroquine’s resistance became overwhelming did first clinical trials take place. But artemisinin was not water soluble, hardly bioavailable, metabolized very rapidly and gave premature signs of resistance. WHO then prescribed in 1998 extremely high doses up to 1 200 mg of artemisinine for a person of 60 kg on the first day of treatment (WHO/MAL/98.1086) , at the verge of severe neurotoxicty and hepatoxicity.

A RECENT PAPER RINGS AN ALARM BELL. Plasmodium chabaudi malaria parasites through a step-wise increase in artesunate dose evolve extremely rapidly slow clearance rates. These slower clearance rates provide fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. Removal of only the susceptible parasites by artesunate treatment led to substantial increases in the densities of resistant parasites (LC Pollit et al., PloS Pathogens 2014, 10,4, e1004019). The traditional view has been that aggressive chemotherapy , involving high doses applied for sufficiently long time to eliminate parasites, best minimizes the evolution of resistance. For this reason WHO in several statements has condemned the use of Artemisia annua herbal treatment because of low artemisinin concentrations in the infusions. But numerous clinical trials, small and large, demonstrated that Artemisia annua and Artemisia afra infusion or powdered leaves reduce parasitaemia much more efficiently than ACTs and eliminate all gametocytes (see Breaking News for clinical trials with Artemisia plants, on http://www.malariaworld.org).

Previous work using the anti-malarial pyrimethamine has shown that removing susceptible competitors through drug treatment can lead to dramatic increases in the density of resistant parasites.

Resistance can also be affected by the dormancy effect (A. Codd et al., Malaria Journal, 10:56, 2011). One of the side effects of the higher doses of artemisinin is this effect induced in plasmodium. The parasite encapsulates itself against the aggressive peroxide artesunate and reawakens at the end of the treatment. The same effect is called quiescence by a French research team (B. Witkowski et al., Antimicrob Agents Chemother. Doi:10.1128/AAC.01636-09). Under a very high dose of artesunate, a Plasmodium falciparum ring-stage sub-population persists in culture and continues its cycle of development normally after drug removal. This may be one of the causes of resistance.

During the Ebola crisis in West Africa. Medecins sans Frontières administered 1.5 million treatments of artesunate-amodiaquine in Sierra Leone in a mass drug administration campaign. This is the largest-ever mass distribution of antimalarials. It is impossible to find any results on PubMed? Was it a failure with dramatic consequences, deathtoll or resurgence?

Irene Teis

MSF-Coarsucam clinical trial with horrendous death toll

Submitted by Marc Vanacker (not verified) on April 4, 2016 – 17:46
ERRATUM

There is indeed a peer reviewed paper (E Guignoux et al., NEJM, 2016 ;374 :23-32) which refers to the MDA clinical trials made by Médecins sans Frontières with artesunate-amodiaquine during the 2014 Ebola crisis. Not in Sierra Leone but in Liberia. Not with 1 500 000 patients but with 382 (three hundred eighty two).
As per Table 2 there were three branches in the trial : 194 patients for Coartem, 71 for Coarsucam and 63 with no antimalarial drug prescription.
In the Coartem group 125 (64.4%) died, in the Coarsucam group 36 (50.7%) and in the no drug group 41 (65.1%).
It is surprising that the total number of patients quoted in the abstract : 382, does not match the total number of patients in table 1 : 278, neither in table 2: 328, nor table 3: 282 nor in table 4: 295. This needs to be clarified as the statistics become dubious
Whatever, the authors make the dazzling claim that the 71 patients who were prescribed artesunate-amodiaquine had a lower risk of death than did patients who were prescribed artemether-lumefantrine.
A pyrrhic victory for Médecins sans Frontières on a bloody battlefield. Sanofi-Aventis will evidently continue to subsidize them. Amodiaquine is banned in France and artesunate-amodiaquine will now probably become available in French pharmacies

Artemisia afra will save Africa

avril 14, 2016

March 23, 2016 – 16:23 — Pierre Lutgen lutgenp@gms.lu
A very recent paper of a South African research team shows that among 8 medicinal plants Artemisia afra has the lowest IC50 for impairing the development of late stage gametocytes (P Moyo et al., J of Ethnopharmacology, acceopted 15 March). A very important finding as not many plants have such a significant gametocytocidal effect.

It confirms the in vivo results obtained end of 2015 in a large scale, double blind randomized clinical trials in Maniema, RDCongo (see Breaking news from clinical trials with Artemisia plants) where Artemisia afra was one of the branches of the test. Artemisia herbal tea completely eliminated gametocytes but they were still present on day 28 in 10% of those treated with Coartem In 2013 already Dr Constant Kansongo in Katanga had found in a trial with 44 Plasmodium falciparum infected patients that after 7 days of treatment with 20 gr of capsules containing A afra powder the gametocytes had completely disappeared, except for one patient. Artemisia afra does not contain any artemisinin. The best explanation available is the high arginine content of Artemisia plants (see « Arginine, a deadly weapon against gametocytes » on malariaworld.org). Frank van der Kooy at the University of Leiden found that Artemisia afra has anti-HIV properties stronger than Artemisia annua.

The situation is completely different for artemisinin derivatives and ACTs, it is even alarming. A paper from Mali published in February clearly shows it (AA Djimbe et al., Parasite, 2016. 23, 3). Artesunate does not clear mature gametocytes during oral artesunate treatment and does not prevent the appearance of new gametocytes. The same recrudescence with oral artemisinin monotherapy had already been observed in Vietnam in 2001 (PT Giao et al., Am J Trop Med Hyg, 2001 65 690-695). The conclusion of the authors was that artemisinin monotherapy may offer rapid recovery and fast parasite clearance, but recrudescence is frequent. For up to 20 percent of the cases on day 28, although gametocytes had completely disappeared on day 7. Extending the duration of the monotherapy from 5 to 7 days did not reduce recrudescence. A study from Kenya had also found that gametocyte carriage was much lower on day 14 than on day 28 and 42 for artemether lumefantrine, but not for dihydroartemisinin-piperaquine (P Sawa et al., J Infect Dis, 2013, 207, 1637-45). It is well known that artemisinin drugs are gametocytocidal for immature, but not mature gametocytes (GO Ghotosho et al., Mem Inst Oswaldo Cruz 2011, 106 no5). A paper of the Swiss Tropical and Public Health Institute (BJ Huho et al., Malaria Journal, 2012 11:118) comes to the conclusion that in high perennial transmission settings case management with ACT may have little impact on overall infectiousness of the human population. They even found in their study, that the most direct indicator of human-to-mosquito transmission, namely oocyst prevalence was substantially higher after ACT introduction. A study from Burkina Faso found in a recheck 12 months after a clinical trial with ACTs that the number of symptomatic malaria episodes was even slightly higher in the ACT arm than in the control arm and that after several treatments the prevalence of gametocyte carriers was the same in both arms (AB Tiono et al.,Malaria Journal 2013, 12:79). Another study found that ACT did not significantly reduce the proportion of infectious children. Submicroscopic gametocytaemia is common after treatment and contributes considerably to mosquito infection. (JT Bousema J Infect Dis., 2006, 193, 1151-59). Because of the short half-life of artemisinin and because high doses induce dormancy in the asexual parasite, asexual forms, mostly rings, remaining after completion of ACT may develop into mature gametocytes 7-15 days later. Some patients have the first appearance of gametocytemia 4-8/day after completion of a 3 day-ACT. (Wilairatana P, et al.,Southeast Asian J Trop Med Public Health. 2010 Nov;41(6):1306-11). What worries the authors of the study from Mali is not only that similar results had been found in a study in 2002-2004, but the fact that baseline gametocyte carriage was significantly higher 6 years after deployment of ACTs in this setting. If artemisinin derivatives really enhance recrudescence and gametocyte carriage, this is indeed alarming. It would mean that ACTs will not eradicate malaria but enhance it in the long run.

When IFBV-BELHERB had raised this concern with WHO Geneva and ITG Antwerp the blunt answer received from one of the experts was: “Your arguments do not make any sense from a public health point of view ».

Artemisia afra is growing wild from The Cape to Addis Abeba.

No further need to import Nobel prize validated pharmaceutical drugs from China or Europe

Malaria, folates and PABA

avril 14, 2016

Malaria, folates and PABA

April 13, 2016 – 17:38 — Pierre Lutgen

Folates combine three molecules : pretidine & para-aminobenzoic acid (PABA) & glutamate. They were discovered around 1940 and first isolated from spinach leaves. The term folate is derived from the latin word folium.
The malaria parasite has a unique feature of being able to salvage exogenous folate derivatives and/or synthesize them de novo. Due to its high rate of replication, the parasite has a high demand for folates. Folate metabolism is the target of several antimalarials.
Food fortified with folic acid has been available for consumption in North America for over two decades. African countries are now embracing this concept; however, because folate promotes malaria parasite division, as it does in cancer cells, there is a possibility of malaria exacerbation if folate intake is increased. (Nzila A1Food Nutr Bull. 2016 Mar 4. pii: 0379572116634511).
The detrimental role of PABA (para-amino benzoic acid) on malaria has already been described 60 years ago (F Hawking, British Medical Journal, 1954, Feb, 425-429). Rats fed on a milk diet were insusceptible to infection with Plasmodium berghei. Milk does not contain PABA or only traces. This insusceptibility was reversed by the addition of PABA or folic acid. The same experiences were repeated on monkeys and gave the same results. It is likely that the relative immunity to malaria shown by infants in many parts of the tropics may be due to a deficiency of PABA in their mother’s milk.
In 1991 it was found that feeding wistar albino rats on low protein and low energy diet caused suppression of P berghei parasitaemia. When PABA was added to the diet parasitaemia re-elevated (A Bhatia et al Indian J Malariol 1991, 28 237-42). The same effect had already been inadvertely noticed in in vitro trials (CF Gilks et al., Parasitology, 1989 89 175-177).
Another research team showed that dietary folate deficiency protects primates against malaria (KC Das et al., Blood, 1992, 80-281). Blood infected with Plasmodium cynomolgi was injected into-folate deficient animals and folate-replete control animal. All control animals developed malaria and several died.
A more recent study extensively studies the effect of dietary PABA on murine Plasmodium yoelii infection (GA Kiczska et al., JID, 2003, 188, 1776-81). Plasmodium species, unlike humans, can utilize PABA for de novo generation of folate. The authors show that, despite the presence of biosynthetioc machinery to synthesize PABA, Plasmodium yoelii, a rodent malaria species, requires exogenous dietary PABA for survival. Mice fed low-PABA-diets do not die from lethal doses of P.yoelii. The initiation of a PABA-deficient diet after P.yoelii infection is established, leads to the clearance of parasites and subsequent resistance to infection by P. yoelii. An intact immune system is not necessary for protection given that mice with severe combined immunodeficiency were also protected by PABA-deficient diet.
In a trial made in The Gambia involving 600 children with uncomplicated falciparum malaria, among children who received the antifolate sulfadoxine-pyrimethamine, the treatment failure rate was significantly higher in those given folic acid than those given placebo (MB van Hensbroek et al., Trans R Soc Prop Med Hyg 1995,89, 672-6). And the authors suggest that the WHO recommendation of universal folic acid supplementation should exclude children in areas of high prevalence.
In a randomized, double blind prophylactic trial in Zanzibar the authors had to conclude that the routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. (Sazawal S et al., Lancet. 2006 28;367(9507):302.
Another more recent study confirmed that high dietary folate in mice alters immune response and reduces survival after malarial infection (DN. Meadows, et al., PLOS One 2015 Nov 24. doi: 10.1371/journal.pone.0143738)
In case of malaria infection diet should be low in folates or PABA. Swamping Africa with multiple micronutrient powders (MNPs)from Switzerland, , nutraceuticals from the US, “compléments alimentaires” from France, all containing folates, is questionable. The folic acid fortified milk market is booming. Business on the verge of crime.
A plant which could be detrimental during malaria infection is Moringa oleifera. The average folate in vegetables is 40 microg/100g but in Moringa oleifera it goes up to 540 microg/100g DW (K Witt Echo Research Note No 1, 2012). Moringa is rich in glutamic acid – 5 times more than Artemisia- and para-aminobenzoic acid (PABA), two of the building blocks of folate (G Magnani et al., Biochem J, 2013455, 149-155). PABA is a major constituent in Moringa oleifera and soya (L Mbanga et al., Adv Biochem & Biotechnol., 2015, 1, 1-13). It was never detected in Artemisia annua. A recent paper studied the relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model. The bioavailability of folate from dried leaves was 81.9%, which is much higher than the values of 50% known for other plants (Saini RK et al., J Food Sci Technol. 2016 ;53:511-20).
Several recent large scale trials in RDCongo (see “Breaking news from clinical trials with Artemisia plants, malariaworld.org) have shown that Artemisia annua and Artemisia afra completely eliminate gametocytes from malaria infected patients.
This is very encouraging for those who really want to eradicate malaria.
But another research team found that PABA administered to gametocyte-carrying mice increased the number of oocysts in mosquitoes fed on them (W Peters Ann Trop Med Parasitol 1980, 74, 275-82). High PABA content in the diet leads to the selection of drug resistant parasites in mice. A higher yield of resistance was related to the higher parasitaemia generated by PABA (B Merkli et al., Exp Parasit 1983 55, 372-6).
That is worrying. We are supposed to know. But the malaria experts from WHO and Tropical Medicine Institutes close their eyes on it.
Pierre Lutgen