Magnesium Gluconate "Stuff" and Kinetics of Gluconic Acid and 1,5-Gluconolactone Interconversions; Silica Delights

In my view, the use of magnesium gluconate (a.k.a. magnesium di-D-gluconate) would be advantageous, in comparison to the uses of magnesium salts of tricarboxylic acid cycle intermediates or magnesium aspartate or various other magnesium salts, for a number of reasons. A significant issue with the use of organic magnesium salts is that the counterion, such as aspartate or glycine or citrate or gluconate, etc., to magnesium needs to be both tolerable and "safe" when a person ingests the counterion in relatively large amounts. In each of the organic salts of magnesium, the percentage of magnesium is quite low. Anhydrous magnesium di-D-gluconate is about 5.9 percent magnesium, and the percents of magnesium in other organic salts are in the range of 10-20 percent or so. A tablet that supplies 30 mg of magnesium from anhydrous magnesium gluconate supplies 481 mg of gluconate, and this shows that the intake of magnesium from magnesium gluconate, in doses that are at all significant, will provide significant amounts of gluconate. I'm not impressed with the effects of magnesium salts of tricarboxylic acid (TCA) cycle intermediates, such as citrate or fumarate or alpha-ketoglutarate, given that the TCA cycle intermediates tend to produce intestinal osmoregulatory disturbances and can cause nausea or diarrhea in relatively low dosages, for whatever reason. I've seen researchers sort of explain this in terms of the fact that TCA cycle intermediates are trianions at physiological pH and are likely to also be partially ionized at gastric pH, and weak acids that are water-soluble would be expected to be very poorly absorbed through the gastric mucosal cells (compounds are absorbed through the stomach) [Milne et al., 1965: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898658/); (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898658/pdf/procrsmed00189-0022.pdf)]. Another aspect might be differences in the lipophilicity of the protonated species of, for example, citrate and gluconate. The log P (octanol/water) coefficient for gluconic acid is -1.97 (http://www.chem.unep.ch/irptc/sids/OECDSIDS/gluconates.pdf), and I'll bet the log P values of the monoanion species (dihydrogen citrate is, I guess, the term for the species) of citrate would be even lower, at various ionic strengths, etc. [Avdeef, 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8445533)]. One can do the calculations oneself, but, loathe as I am to link to it, wikipedia provides a decent graph of the percentages of citrate species present across the acidic pH range, and one sees that the monoanion would be expected to exist in significant amounts at gastric pH (http://en.wikipedia.org/wiki/Acid_dissociation_constant). I found this article that I can't get the full text of but that probably includes log P data on citrate species [Avdeef, 1992: (http://www3.interscience.wiley.com/journal/118640091/abstract?CRETRY=1&SRETRY=0)]. Citrate also disturbs systemic acid-base balance, in the sense that exogenous citrate can produce an elevation in serum bicarbonate, but gluconate does not elevate serum bicarbonate. I don't have time to put up the rest of the references now, but I will soon. An important point is that gluconate does not undergo lactonization [Shimahara et al., 1970: (http://www.ncbi.nlm.nih.gov/pubmed/5437655)], and negligible amounts of the 1,4-lactone are formed at or above pH 2.5. That's the basis for the calculation of the rate equation and concentration-vs.-time curves, as shown below. I used this physical chemistry textbook as a guide [Tinoco et al., 1995: (http://books.google.com/books?id=I34mAAAACAAJ&dq=tinoco+physical+chemistry+1995+%22principles+and+applications%22)], but the authors didn't do any of the derivations. The derivation I did shows the general rate equation for a single-step, reversible, first-order, spontaneous reaction, and the final, concentration-vs.-time equations are also general results. That textbook is actually really good, incidentally. This is a terrific article that just provides this trick of substitution that allows one to integrate various second-order rate equations and find concentration-vs.-time curves, assuming one has the kinetic constants and the equilibrium constant for the reaction [Lavabre, 1993: (http://pubs.acs.org/doi/abs/10.1021/j100122a024)]. It's just a factoring trick and tricks of substitution. I, incidentally, found that it's advisable to distinguish between the terms "[reactant or product]eq" and [r or p]. I mean that one can write something like this, for the reaction A <---> B, and end up making silly errors, subsequently: "At equilibrium, k1[A] = k-1[B], and [B]/[A] = K1 = k1/k-1." One can end up making an invalid substitution, based on something like that, by looking and thinking that [B] = (k1/k-1)[A], when this is not the case. In actuality, [B]eq = (k1/k-1)[A]eq. I didn't look at all of the cases presented by Lavabre et al. (1993), but it looks like they basically used something similar or identical to the x and x(sub)e substitutions that are commonly used. I think the R and R(sub)e terms presented by Lavabre et al. (1993) are the same quantities, along with more complexity for 2nd-order equations, that the terms x and x(sub)e encompass. They're similar, in any case. I did part of the calculation for the case of A + B <---> C, to estimate the actual kinetics of the Mg2+ + G- <---> (MgG)+ equilibrium, and the general equation is very complex but wouldn't seem complex if one substituted some of the experimental constants in at a relatively early stage in the calculation, etc. Anyway, it's useful to be able to use these.

I don't have time to post any more of this right now, but other issues to consider are the amounts of calcium or silica (or even stearic acid, as opposed to magnesium stearate) in magnesium gluconate supplements. The amounts of calcium that supplemental magnesium gluconate could provide, in the form of the dicalcium phosphate or tricalcium phosphate or calcium silicate used as excipients in the tablets, have the potential to be very large and to "ruin" the beneficial effects of magnesium supplementation. I've seen tablets, whose manufacturers actually choose to list the amounts of elemental calcium in a tablet, that are smaller than a US dime ("US currency") and that supply 85 mg of calcium from the excipient. That ends up supplying a lot of calcium, if one uses reasonable dosages of magnesium. Those forms of calcium are also going to be absorbed to just as great an extent as highly-soluble forms of calcium, despite the fact that they're "insoluble" or "sparingly-soluble" in water and aren't supposed to be absorbed, as shown in this article [Heaney et al., 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2110852)]. I only found about three brands that contain no calcium as an excipient, and all but one also contain silica.

Incidentally, there's a large amount of research suggesting that colloidal silica can be absorbed, even in polymeric form (Sripanyakorn et al., 2009, cited below), that it's an indestructable antigen that can undergo phagocytosis by intestinal antigen-presenting cells (Powell et al., 1996, cited below), that it shows up in the Peyer's patch lymphoid tissue, that epithelial-cell-based granulomas in the GI tract contain silica and are associated with the development of ulcerative colitis or Crohn's disease [Powell et al., 1996: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1383324/)], that absorbed silica can "concentrate" in the kidneys, etc. Sounds fantastic. In any case, if one wants to remove a meaningful percentage of the colloidal silica from suspension in water, the idea is that one would want a sub-micron pore-size mechanical filter that doesn't adsorb metals (as in magnesium). This means that one would not want activated carbon as a component of the filter mechanism, and there are a couple of cheap camping filters that satisfy those requirements and have pore sizes of 0.01 microns (10 nm) or 0.02 microns (20 nm) and that would be expected to filter much of the suspended, solid colloidal silica particles, although some of the particles can be as small as 5 nm. But the pore size isn't the only variable that determines the capacity of a filter medium to retain the suspended solid. And the silica particles tend to aggregate into larger "superstructures." Traditionally, ultrafiltration membranes have been thought to be required to remove colloidal silica from suspension, but the electrostatic forces that begin to occur in filter media with extremely small pore sizes could begin to produce adsorption of metals in solution (i.e. magnesium). Anyway, I really can't say if those camping filters would work, but I just put this information up for all the freaks like me who don't like the idea of ingesting quartz and feldspar and whatnot and who appreciate scientific and systematic approaches to solving problems. I'll put up references for this stuff, but some statements in the literature imply, in my opinion, that some of the silica used in supplements may, apparently, exist as particulate silica in network-covalent form (as in "rock" dust or extremely-finely-grained, particulate quartz). Apparently, some "polymeric" silica may "actually" be "particulate" silica (Sripanyakorn et al., 2009, cited below) and may, as implied here [Rowsell et al., 1958: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196625/)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196625/pdf/biochemj00829-0067.pdf)], exist as suspended particles, in a solid phase, of network-covalent quartz or feldspar or another form. Here's a quote from an article showing the absorption of several different forms of silica: "what is referred to by the manufacturers as ‘colloidal silica’ is really particulate silica" [Sripanyakorn et al., 2009: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744664/)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744664/pdf/ukmss-27619.pdf)] So some particulate "silicates" are soluble and may exist, at least partially, as quartz or feldspar [Rowsell et al., 1958: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196625/)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196625/pdf/biochemj00829-0067.pdf)]? But particulate silica wouldn't even have to be soluble to be absorbed, given that small percentages (how small and how variable?) of colloidal silica, which consists of solid silica particles suspended in water, such that the particles are of, apparently, indeterminate size, can be absorbed from the GI tract into the lymphatic fluid and reach the systemic circulation [Sripanyakorn et al., 2009; references cited here: (http://hardcorephysiologyfun.blogspot.com/2009/11/quartz-silica-goodies.html)]. It's not clear to me that anyone can know what the hell silica in supplements actually is, and it's all just this big mess of nonsense, basically, with the experimental findings staring people in the face, in my opinion, in "technicolor horror." I'm joking with that, but I don't like this kind of haphazard "attention," or lack thereof, to detail in manufacturing. Yeah, here are several more reports of silica-containing kidney stones in humans, in addition to the recent one I linked to [Flythe et al., 2009: (http://linkinghub.elsevier.com/retrieve/pii/S0272638608016132), cited here: (http://hardcorephysiologyfun.blogspot.com/2009/11/quartz-silica-goodies.html)] [see related articles on pubmed, related to this article: Alpaugh et al., 1984: (http://www.ncbi.nlm.nih.gov/pubmed/6091262)]. So there was quartz (network-covalent SiO2) in their silica-containing kidney stones, and the crystal structure of the quartz was consistent with the crystal structure of glacial sand (Alpaugh et al., 1984). Polymeric and monomeric silica cannot be converted into a network-covalent structure in the absence of tremendous heat and pressure, as in the forces that occur in "geology," over "geological time." So the people had been ingesting network-covalent silica, meaning quartz or other rock dust. Had the people who developed quartz-containing kidney stones been eating rocks or sand? I seriously doubt it. It seems to me that the silica might have come from supplements or foods, but that's just my opinion. There are lots and lots of reports of silica-containing kidney stones (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=6091262). This article shows that some silica can be present in gallstones [Yamamoto et al., 1985: (http://www.ncbi.nlm.nih.gov/pubmed/3920818)], implying that silica can reach the liver, and these authors [Marinaccio et al., 2006: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077997/)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077997/pdf/762.pdf)] found evidence of an increase in the incidence of liver cancer among people who had had silicosis in their lungs due to the inhalation of silica dust. Particulate silica is toxic to the Kupffer cells that constitute the major population of monocyte-macrophage-lineage cells of the liver [Kolb-Bachofen, 1992: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC443241/)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC443241/pdf/jcinvest00053-0193.pdf)]. Anyway, these articles aren't great to see, but no one knows if silica actually contributes to any diseases. I'm not suggesting that I know if the ingestion of quartz particles does or does not produce meaningfully-harmful effects in any given disease state, but it doesn't sound great to me.

I wanted to find out if significant amounts of 1,5-gluconolactone (abbreviated GL), which can be formed from gluconic acid (but not the gluconate anion) spontaneously or in an acid-catalyzed reaction, could be formed in the gastric luminal fluid, following the ingestion and protonation of gluconate, from magnesium gluconate. GL is an inhibitor of glycogen phosphorylase, and the inhibition of glycogen phosphorylase would be undesirable. Significant amounts of GL are very unlikely to be formed in vivo, but I figured I'd use this problem as a way of practicing chemical kinetics problems. Only about 5 percent would be converted into GL within 30 minutes, and this is consistent with the data from the articles (it's precisely the percentage that Zhang et al. (2009) [Zhang et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19320439)] calculated for pH 4, although I did my "derivation" or "calculation" on data collected at pH 2.5). I'm going to paste the pictures and put up the citations later.

<--->

<--->

Conversion of 1,5-gluconolactone into 1,4-gluconolactone:

"Quartz (Silica) Goodies"

In this article [Flythe et al., 2009: (http://linkinghub.elsevier.com/retrieve/pii/S0272638608016132)], Flythe et al. (2009) discussed a case of a person who developed silica (silicon dioxide) kidney stones after the ingestion of silica as an excipient in supplements. The stones stopped forming after the person discontinued the source of silica. There are actually lots of reports of silica urolithiasis [Ichiyanagi et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9792982); Joekes et al., 1973: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1588389/pdf/brmedj01539-0034.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4350443); (http://scholar.google.com/scholar?q=related:33eEpUxra-UJ:scholar.google.com/&hl=en)]. I don't think this is likely to be a big problem for a person whose kidneys are functioning normally, but it's always possible to say things like that. "A pathological disease mechanism is likely to be more pronounced in a person in a disease state." It wouldn't be very difficult to reduce the silica intake from supplements, if one wanted to. Some supplements just use magnesium stearate as an excipient in capsules or tablets. Or one could just put the silica-containing supplements in a glass of water, let the insoluble precipitate settle (silica and calcium silicate and other silicates are not very soluble in water), and drink the water but not the silica (or pour it through a coffee machine filter--I don't know--I'm not a silica chemist, but the easier thing would just be to take some brand with no silica). From what I can tell, however, the issue is not the solubility of the silica as much as it is the fact that 1-5 percent of some forms of colloidal silica can evidently be absorbed [see last page of Jugdaohsingh et al., 2000: (http://www.ajcn.org/cgi/content/full/71/4/944)(http://www.ncbi.nlm.nih.gov/pubmed/10731501)]. That means that someone can tell a person all day that silica is insoluble, but it doesn't matter. A colloidal suspension contains, by definition, an insoluble substance that's suspended in the water or other medium (it's not called a solvent because the substance isn't being solvated). A colloid is a suspension and isn't a solution. Milk is partly a colloidal substance and is basically a lot of highly-dispersed proteins and other constituents that are not solubilized. An emulsion could be called a colloidal suspension. So if the insoluble portion can be absorbed into the bloodstream or extracellular fluid in the intestinal tract, at least, it doesn't matter, in my opinion, that it can't enter solution. It's beside the point. I looked at a few articles, and it sounds like a real mess, in the sense that one doesn't even know what "form," as in oligomeric polymers or monomers, as discussed by Jugdaohsingh et al. (2000), the silica is being supplied in.

It actually doesn't sound good to me, given that silica, in vitro, can apparently promote collagen "mineralization" (i.e. soft-tissue calcification) [see discussion by Yendt, 1973: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1946599&blobtype=pdf)]. Most of the reports of autoimmune diseases, in association with silica "exposure," have been in people who have inhaled silica dust (it causes a granulomatous disease, basically, in the lungs, by activating the macrophages that try to phagocytose the silica crystals and can't break them down and go wild, releasing pro-inflammatory cytokines, etc.). However, Parks et al. (2002) [Parks et al., 2002: (http://service004.hpc.ncsu.edu/toxicology/websites/courses/TOX705/papers/Parks%20et%20al%202002.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/12124868)] cited research (reference 16) that had shown that silica ingestion could activate macrophages in animals (meaning that the expression and release of pro-inflammatory cytokines would be increased, etc.). It obviously can be absorbed. If it weren't absorbed, one wouldn't find cases of "pure" silica-containing kidney stones in people. Even if the issue were about solubility, the GI tract is not a system at equilibrium. If 0.5 percent or whatever of a given amount of silica is absorbed (because it's soluble) in 60 minutes, say, then 0.5 percent of the remaining amount can be absorbed over the next 60 minutes or 30 minutes or whatever. Just look at the shocking case of inulin, which is still being sold [(http://hardcorephysiologyfun.blogspot.com/2009/01/disturbing-articles-on-inulin.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/note-on-inulin.html)]. Here's another one showing inulin can be absorbed through the colon in rats [Ma et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7806033)], not just the small intestine. I'm not sure what to say, except "that's very serious business," in my opinion. It's problematic, in my opinion, to make safety determinations that are based solely, evidently, or almost solely on the supposed insolubility of a substance or on some flimsy notions about the "inviolability" of the "brush border" of the intestinal tract. I'm joking somewhat, but oh my God. It's a nonspecific immune adjuvant (Parks et al., 2002). I used to think it was essential, too, but I'm thinking that the standard "fact" about silica essentiality (that every 100th carbon, or something similar to that, in glycosaminoglycan chains is a silicon atom and that that's evidence of essentiality) isn't evidence of essentiality. That's just my opinion, but it sounds like it might just be precipitating in the extracellular matrix. Or it might be the case that some monomeric silica is being inappropriately incorporated into some of the GAG polymers? Now that I think about it, the whole thing sounds far-fetched. I doubt silica is all that harmful, but it seems like it's one of those things, like aluminum, that may not be the sole cause of a disease (such as Alzheimer's) but just shouldn't really be in foods, in my opinion. There's research showing that aluminum can exacerbate iron-mediated lipid peroxidation, for example. The FDA should have removed aluminum from the food supply 50 years ago, but that's just one of those FDA-associated horrors.