Archive for janvier 2014

Peer review and false science

janvier 18, 2014

Nihil obstat, Imprimatur and index of forbidden books

 

Peer review often makes me think about what was common in my small catholic country in my catholic youth.

Some experts at the bishop’s office decided what might be published or read.

I found a document written by Pr.Dr. Cornelia Oertle Bürkl of the Berner Fachhochschule, unfornately in German. I translated a few excerpts 

 

»Falsifications, Freedom and Objectivity in Research »

 

The 21st century is probably going to enter history as the century of falsifications

Even the elitist ETH of Zürich had to digest in 2009 a research, peer reviewed paper, which was based on fake chemical data.

The reasons for these deviations are multiple: not only the « publish or perish » pressure, but mainly the fact that it Germany to-day 70% of research is sponsored by industry. This is to walk on a sharp ridge: how to maintain freedom and integrity when the sponsor expects results which are in his interest. Matthew and Luke said 2000 years ago: „No one can serve two masters“. And Max Weber 100 years ago: » Facts are more important than interests ».

 

There is also the blog entry of Bart Knols on MalariaWorld of 4 June 2013

List of Predatory Open Access Publishers 

“As long as there is much money to be made in academic publishing we will continue to see an increase of these misleading claims that look good but are all geared towards one thing: money”. Who is in charge of peer review in these journals where you have to pay large amounts for the publication of your paper?

And there is also the famous book of Federico Di Trocchio

 

“Le Bugie della Scienza” (The big Swindle in Science)

 

Again the translation of a few excerpts: “ The history of Galileo is well known, but it is less known that the Nazis rejected Einstein’s relativity theory and replaced it by a “ Deutsche Physik”, that Stalin promoted the biology of Lyssenko to a creed,

It has become vital for the manager of an academic research laboratory to-day to do a lot of PR-work to find sponsors, be it from industry or his own government. He knows that a few key words in a research project can open the doors: climate change, sustainability, future generations, toxic health effects, even for innocuous molecules.

The origin of this corrupted research system started in the US. It may have led to some major breakthroughs in science, but it also led to obedience. Creativity is stifled.

Peer reviewers are recruited from this school: they too often are mercenaries.”

They leave little chance to young research teams from the South to see their papers published in glorious Journals from the North.

 

Why do many people prefer their paper to be peer reviewed?

The new work is submitted to what amounts to a committee of people who are (at least presumed to be) eminent in the field.

The trouble is that the reviewers, being eminent in the field, are by definition wedded to whatever the conventional wisdom may be on that subject. Anything new or startling, especially if it contradicts the current “consensus”, is virtually certain to be rejected. Peer review only partially fulfills the requirement for questions and critics from the rest of the scientific community. Scientists abdicate their responsibility to examine and attempt to disprove discoveries in favor of turning over to gatekeepers who ensure that nobody rocks the boat. It’s particularly pernicious when funding is involved. A bureaucrat charged with deciding who gets the money for experiments is unlikely to be deeply knowledgeable about the field, and must therefore play it safe by going with what the reviewers say is reasonable. It means, ultimately, that the pace of scientific discovery is slowed to a crawl.

So it is, today, with “climate science”. There does exist a consensus — that the Earth is warming, that the result of the warming will be disastrous, and that human activities are responsible for it — and contrary views or assertions are savagely attacked as “denialist“. While “researchers” who echo the Conventional Wisdom are allowed to conceal or even destroy data that might contradict their thesis.  In peer reviewed papers!

Let’s hope that what happened to Climate Science will not happen to Malaria Science.

Publicités

How legal is bio-engineered artemisinin

janvier 8, 2014

The FDA-CDER regulation from 2004 on Botanical Drug Products states : the term botanicals includes plant, materials, algae, macroscopic fungi, and combinations thereof.

It does not include fermentation products (i.e. products produced by fermentation of yeast, bacteria and other microscopic organisms… and products produced by fermentation of plant cells), even if such products are previously approved for drug use or accepted for food use in the United States.

It is also the regulation followed by EFSA (European Food Safety Agency) and EMA (European Medicin Agency).

This would mean that artemisinin produced by the bio-engineered synthesis in California, Berlin oor South Africa may not be considered for antimalarial drugs, unless it has previously been approved by these authorities.

Who knows more?

lutgenp@gms.lu

The digestive vacuole and malaria resistance ; the weakness of artesunate.

janvier 4, 2014

The diffusion of antimalarials into infected red blood cells has been studied by several authors. For example, three times more chloroquine accumulates in CQ sensitive strains than in the CQ resistant ones (KJ Saliba et al., Biochem Pharmacol. 1998, Aug 1 ;56, 313-20)  Thediffusion of artemisinin into parasitized RBCs was found to be rapid, saturable, temperature dependent, irreversible. In contrast, simple passive diffusion of artemisinin was seen in nonparasitized RBCs.(N Vyas, Antimicro Ag Chemother, Jan 2002, 105-109). But it was also 43% lower in resistant strains than in sensitive strains of Plasmodium yoelii (D Walkeret al., Antimicrob Ag Chemotherapy Feb 2000, 344-347). The partitioning is subject to competitive inhibition. The cross resistance between artemisinin and other antimalarials has been described already 20 years ago (Doury JC, Ringwald P et al., Trop Med Parasitol 1992, 43 :3 197-8). Comparing monotherapy with the combined action of artesunate and amodiaquine it was found that the total exposure to both drugs was reduced significantly when they were given in combination, 67 % lower for artesunate and 65% for amodiaquine (C Orrell et al., Eur J Clin Pharmacol , 64. 683,90, 2008).   Other molecules present in the Artemisia plant also may interfer with the artemisinin uptake into the RBC as they do for glucose needed by the parasite for the anaerobic glycolysis.Chalcones inhibit permeation pathways induced by the parasite in the host erythrocyte membrane (ML Go Antimicro Ag Chemotherapy Sept 2004, 3241-45). Some Artemisia annua genotypes like the one from Luxembourg are rich in artemisia ketones.

Inside the RBC artemisinin or other antimalarials are transported to the DV by hemoglobin transport vehicles. The accumulation of the antimalarial in the DV depends on many factors. Hemozoin nucleation occurs at the DV inner membrane. The effect of antimalarials after penetration into the parasite and the DV may vary. Some like artesunate abolish the movement of the trophozoite and the malaria pigment, others  like quinine and piperaquine do not. (J Wongtanachei et al., Southeast Asian J Trop Med Public Health. 2012 Jan;43:1, 1-9). They may finally lead to a destruction of the DV membrane and total desorganisation of the parasites.

The human malaria parasite has a homologue of the human multidrug resistance P-glycoprotein that pumps drugs from the cancer cells. Pgh1 influences the sensitivity of malaria parasites to a diverse range of antimalarial drugs, reducing their concentration at the site of action. But the efflux can be inhibited by other drugs, verapamil for example. Chloroquine accumulation in erythrocytes is energy dependant. After glucose addition the uptake is markedly different in CQR and CQS strains. It decreases in the first and increases in the second (CP Sanchez et al., Biochemistry 42, 9283-94).  Mutations in the Pgh can confer resistance to mefloquine, quinine and eventually to the structurally unrelated compound artemisinin. At least, in the jejunum. artemisinint is not a an inducer of P-glycoprotein and the permeability of artemisinin remains high at low or high artemisin treatment or after multiple appications.  (U Svensson et al., Drug Metabolism and Disposition 27.2, 1999, 227-232). In fact the MDR1-Pgh1protein is localized on the digestive vacuole (A Cowman et al., J Cell Biology, 113 :5 1999, 1033-1042.

A German team has compared the pathways of 21 selected antimalarials and their metabolites. (A Burk et al., Brit J Pharmacology, 2012, 167, 666-671). It investigated their effect on 2 xenosensing receptors CAR and PXR, but also on CYP3A4, Caco-2 cells and MDR1/Pgh1 efflux pump. Their results are surprising : Only artemisinin is converted to an enzyme-inducing metabolite, the ostracized deoxyartemisinin. Artesunate was the only drug of the artemisin class scoring lower for its agonist properties. Even at 300 microM artesunate and DHA did not show a coactivator interaction. All antimalarials, except artemisinin and its derivatives, were cytotoxic at 100 microM. The properties of metabolites like deoxyartemisinin (persistance of induction for five days) might explain the action of artemisinin in vivo.

An Italian team recently found that dihydroartemisinin (DHA), a metabolite of artesunate, induces significant depletion of early embryonic  erythroblasts in animal models. Artemisinin does not generate DHA but only the metabolite deoxyartemisinin which did not have this erythro-toxic effect which could be harmful for stem cells during pregnancy ( S Finaunini et al., Toxicology, 2012, 300, 57-66)

The DV is an important site of antimalarial activity. The destruction of the food vacuole membrane leads to a total desorganization of the parasites (Y Maeno et al.,Am J Trop Med Hyg, 1993, 49 :4, 485-91). It leaves individual hemozoin crystals in direct contact with the parasite cytoplasm. The action of artemisinin on disruption of DV membrane has been compared to that of novel synthetic endoperoxides (Crespo et al., Antimicrob Agents and Chemother., 52.1, 2008, 98-109). The latter do not. This is understandable, the pharmacokinetics and pharmacodynamics of artesunate and artemisinin are completely different. The first desintegrates into the very reactive DHA, the second into molecules which have lost their peroxide bridge and show now antiplasmodial activity, at least in vitro. But the two have been compared very little in vivo. No clinical trial on humans has been run with pure artemisinin over the last 30 years.

Recently (D.Wilson et al., Antimicrob Ag Chemotherapy, 2013, 57-3, 1455-67) studied the timing of action of  quinine and artemisinin derivatives against Plasmodium falciparum. Artemisinin is the only one which prevents the rupture of schizonts and the realease of merozoites. Artesunate and chloroquine and all others  do not.

As the authors sayfor artesunate : » A drug that allows the late-stage parasites to develop normally may not be ideal…Merozoite release and reinvasion may exarcerbate disease symptoms and the subsequent immune response… ».The huge problem of resistance to artemisinin derivatives already discovered in 1990 may be due to this. Indeed, so far no scientific paper has described resistance to pure artemisinin, while numerous papers descibe the resistance to artemisinin derivatives and to ACTs, not only in Asian countries, but also in many countries of Africa and South America. As the authors further  say : » The inhibitory action of artemisinin when added at the schizont stage is striking… a >600% increase in the number of unruptured schizonts ».

After rupture of the schizont the digestive vacuoles are selectively phagocytosed by leukocytes (PMNs). DVs generate also a lot of ROS and induce systemic inflammatory responses.  It is the DV membrane more than hemozoin which cause these effects. All this leads to a significant reduction of the bactericidal capacity of the immune system and could explain why children affected with severe malaria frequently suffer from septicemia due to bacteria that otherwise play no major role in this potentially fatal affliction (P. Dasari et al., Blood, 2011 118-18, 49-60 & Dissertation zur Erlangung des Doktorgrades, Uni.Marburg 2013). The liberated DV after schizont rupture appears to function as a decoy and is exploited by the parasite to perturb central elements of the innate immune system and to divert PMNs from the merozoites . Despite the fact, as occurs in vivo, that merozoites outnumber DVs by an order of magnitude, PMNs preferentially contain DVs. Periodic attacks of fever in malaria are associated with schizont rupture that stimulates production of TNF-alpha. Overproduction of this endogenic pyrogen leads to severe and cerebral malaria. Artemisia plants have a strong immunostimulating effect.  Infusions and capsules containing whole leaf powder might save thousands of children from coma and death.

All this may explain  why very small quantities of Artemisia annua are sufficient to cure and stop the disease and why Bigpharma-WHO has to work with astronomic doses of artemisinin derivatives to achieve a similar result, but still be plagued with recurrence due to dormancy of parasites and sequestration caused by these massive doses.

The in vivo trials which have been run by our partners in Cameroon, Kenya, Congo, Burundi, Senegal,  Central Africa, Uganda with Artemisia annua infusion or whole leaf tablets or capsules operate with artemininin doses far below 20mg/day and all give excellent results, even at 2mg/day. The bioavailabity of artemisinin is faster and four times higher if administered as tea (K Räth et al. Am J Trop Med Hyg, 2004, 70 :2, 128-132) and the therapeutic effect is even much higher if Artemisia annua is administered as whole leaf powder in lieu of pure artemisinin (M, Elfawal, P Weathers et al, PlosOne, Dec 2012, 7-12, e527446).

Quinine operates by inhibiting hemozoin formation, artemisinin derivatives do not (R Haynes et al., Antimicrob Ag Chemotherapy, Mar 2003, p 1175). The additional benefit of Artemisia tea infusion is that it also clearly shows this inhibitory effect. A mixture of Artemisia annua and Artemisia sieberi had a stronger inhibitory effect on beta-hematin formation than chloroquine, as demonstrated at the Al Quds university. (M Akkawi, P Lutgen et al., Brit J Pharm Toxicol, 2013, in press). Artemisia tea, or better even, whole leaf powder is a true polytherapy, containing dozens of antimalarial molecules, from essential oils to polyphenols, from coumarins to polysaccharides, from saponins to minerals. Plasmodium falciparum has very little chance to develop resistance simultaneously against them all.

It also has  been demonstrated that regular consumption of Artemisia annua tea is boosting the immune system and has a strong prophylactic action (PE Ogwang et al., Brit J Pharm Res 1 :4, 124-132)

Pierre Lutgen

lutgenp@gms.lu

Jan 2014