Hi, gg -
Thanks for that article. The effect of WF10 on the inflammatory process is known, and observed - but exactly how it achieves the effect is as elusive as the immune system itself: a labyrinth, a riddle - and WF10's place in it is an unexplained mystery.
I despaired that we'd ever see its potential revealed, until the MMC (Movement for Management Change) publicly challenged Dimethaid's dreadful management - or mismanagement, if you will. Now, there's hope.
From your article, "Years ago most cardiologists considered the inflammation idea to be "outlandishly irrelevant, a curiosity," says Brigham's Libby, a pioneer in the field. But evidence of the inflammation connection has been slowly building for two decades as researchers probed the causes of atherosclerosis, the buildup of fatty gunk in vessel walls."
The effect of WF10 on the inflammatory process is known, and observed - but exactly how it works is elusive. But you are correct to note its potential effect on chronic obstructive pulmonary diease.
"Patent claims cover potential treatment for autoimmune disease, organ transplant or graft rejection, lymphoma, and inflammation manifested as hepatitis or chronic obstructive pulmonary disease."
newswire.ca
It seems there are three aspects of WF10 to consider here:
1 - How, exactly does WF10 interact biochemically, in the body?
Peter Hagedoorn, from Delft University, began to explore the properties of chlorite dismutase (EC 1.13.11.49) - which is the natural analogue of WF10.
His research derived from the natural production of chlorite dismutase (CLD) by the bacterium Ideonella dechloratans. Now, CLD is not WF10, exactly - but it's so close that it's grouped in the same classification, as Hagedoorn notes in the article I posted last November
Message 19507340
I wrote to Peter. He stated that (unfortunately) he has discontinued research on CLD, so we'll just have to take what we can get from what he's published.
On CLD's biochemical interaction, Peter notes the following:
(a) - "Previous characterization of these enzymes has shown that the chlorate reductase is a molybdenum and iron/sulfur-containing enzyme [2], and the chlorite dismutase is an iron protoheme IX-containing enzyme [3]. However, little is known about the mechanism of action of these enzymes. The name chlorite dismutase is unfortunate, because the enzyme does not dismutate or disproportionate chlorite, but it reduces chlorite to chloride while producing molecular oxygen. A more correct name would be chloride–oxygen oxidoreductase or chlorite oxygen-lyase. However, as the name chlorite dismutase has been used in all references describing this enzyme, we will also use it until formal renaming." (My emphasis added)
(b) - "We also studied the binding of the substrate analogs hydrogen peroxide and nitrite to chlorite dismutase to obtain information to formulate a possible reaction mechanism. WF10 is a promising chlorite-based anti-AIDS drug. It was recently shown that the pharmacological activity of WF10 is based on its interaction with heme iron proteins [5]. Interaction of WF10 with heme proteins has been proposed to generate an oxoferryl species and hypochlorite. The reaction mechanism of WF10 with hemoproteins may be similar to the enzymatic reaction of chlorite with chlorite dismutase. Thus, the study of chlorite dismutase may provide information of medical relevance."
The research denoted by [5] is, of course, Schempp et al...
Chlorite-hemoprotein interaction as key role for the pharmacological activity of the chlorite-based drug WF10.
ncbi.nlm.nih.gov
"WF10 is a chlorite-based drug that modulates macrophages functional states and can be safely administered to humans. WF10 potentially modulates disease-related up-regulation of immune responses both in vitro and in vivo. Thus immune response is influenced in a way that inappropriate inflammatory reactions are downregulated. The molecular mechanisms involved are not completely understood. Biochemical data suggest the reaction of chlorite with hemoproteins as the central step in the activation process of the drug. Thereby a chlorinating agent is generated, resulting in the oxidation of reduced sulfur-containing molecules and in the conversion of amino residues into more or less stable chloramines. The most prominent chloramine in vivo is taurine chloramine. Taurine chloramine is a long-lived molecule with immunomodulatory properties."
Other research notes...
(a) - "Chlorite dismutase has been purified from the chlorate-metabolizing bacterium Ideonella dechloratans. The purified enzyme is tetrameric, with a relative molecular mass of 25,000 for the subunit, and contains about 0.6 heme/subunit as isolated. Its catalytic properties are similar, but not identical, to those found for a similar enzyme purified earlier from the bacterium GR-1. The heme group in Ideonella chlorite dismutase is readily reduced by dithionite, in contrast to the GR-1 enzyme, and redox titration gave a value of -21 mV for the midpoint potential at pH 7. The heme group has been characterized by optical and EPR spectroscopy. It is high-spin ferric at neutral pH, with spectroscopic properties similar to those found for cytochrome c peroxidase. In the alkaline pH range, a low-spin compound is formed. A 22-residue N-terminal amino acid sequence has been determined and no homologue has been found in the protein sequence databases."
Chlorite dismutase from Ideonella dechloratans
ncbi.nlm.nih.gov
(b) - In a bit of coincidence (this isn't really relevant, but interesting) ... "Judging from the subunit composition, cofactor content, and sequence comparisons, chlorate reductase belongs to class II of the dimethyl sulfoxide (DMSO) reductase family." (My emphasis and parentheses added)
A Gene Cluster for Chlorate Metabolism in Ideonella dechloratans
ncbi.nlm.nih.gov
2 - After the initial biochemical interaction, what immune processes are activated? What sub-processes?
I'm going to leave this one for now; the post is getting long.
3 - What, exactly, are we talking about? Inflammation, immune system... what are we measuring?
THIS IS A MUST-READ for any student of the subject. A fascinating paper by a leader in the field: Halliwell...
"Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean?"
brjpharmacol.org
"Whatever method you use to trap RS or measure oxidative damage, it is necessary to think carefully about how the method works, what is likely to confound it and how quantitative it can be (how, what and how much). With careful attention to understanding these points, erroneous interpretations can be minimized and the vibrant field of free radical research can continue to move forward. "
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Finally, another leader in the field (more specific to chronic obstructive pulmonary disease) is JW Heinecke. There is tantalizing research that shows how WF10 could be working. But tying all this together will have to wait for another day. Here's a link to Heinecke's papers, sorted chronographically...
ncbi.nlm.nih.gov
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So, gg, I think there's good reason to believe that WF10 shows promise in an area where once again the inflammatory process - the immune system itself - is the culprit: not some virus, not some bacteria, and not too much of this or that.
Regards,
Jim |
