Another Rambler on Influenza

One of the reasons the CDC's authoritarian approach to dispensing swine flu vaccines is ineffective is that a series of "feed-forward" failures can occur, such that the shortage causes people to become frantic in the short-term and to direct their attention elsewhere in the longer term. I saw one news article in which the author was saying that the state health department basically doesn't appear to trust anyone enough to provide them with the actual information about the locations of the flu clinics. The person was basically saying that the people at the health department are afraid people are going to storm the clinics, in effect, and, therefore, have been restricting information about the locations of the clinics. As a result, the so-called high-risk groups are not getting the vaccines. And now that there's supposedly a "downturn" in the numbers of cases (many of the cases discussed in the Fall were not, in fact, influenza cases, in my opinion, as discussed in many past postings), the CDC has basically lost their chance to vaccinate a lot of people. The so-called high-risk groups are not, really, substantially more likely than anyone else to experience a complication from the flu, given the wild quality with which otherwise healthy individuals' liver or kidney function, for example, can deteriorate in response to a flu infection. There are endless reports of "healthy" people having to go in to get dialysis treatments or being on the verge of liver failure from influenza, given all the hemolysis and thrombogenicity, etc.

I tried using the Google flu shot finder thing, and it didn't work at all. Maybe I used it incorrectly and need to try it again. It looks like very few people would be able to find swine flu vaccines, these days. In any case, I'm going to try to get the live attenuated swine flu vaccine tomorrow, at the U. We'll see if there's room for a little bit of flexibility. I'm not expecting to get one, but it doesn't hurt to try. But there's a strange kind of attitude that seems to accompany that kind of CDC-based authoritarianism. This ties into the concept (a good one, in my opinion) that one should never pass up a chance to vaccinate someone, and it's this assumption that the CDC is going to actually be able to get people's attention when there isn't a shortage of vaccines. There are just all sorts of invalid assumptions underlying their approach, and it's been a failed approach. They wound up with vast numbers of unused vaccines in the 2004-05 season, when they rationed vaccines. Even if they had a perfect system for dispensing the vaccines, there would still be all sorts of problems.

I'm surprised that the CDC and other health officials can't communicate information about effective approaches to hand disinfection. Maybe people still wouldn't get benefit from it, given that so many people end up having to or choosing to touch their faces, etc. But it's not that complicated. A lot of research has shown that it takes a long time (45-120 seconds) and a lot of scrubbing to remove, to an acceptable degree, something like rotavirus from one's hands with soap, but the 62-65-percent alcohol gels don't require any more than 20-30 seconds, at most, and are substantially more reliable, in my opinion, based on the research. There's tons and tons of research on the issue. One thing I was getting at with the last posting is that I think there can be this tendency of people to not want to wash their hands for a long time or disinfect them, for fear of becoming "the boy who couldn't stop washing," as the title of the book went, or something along those lines. ("Suh-loppy boy. Now, do like I tell you and go wash them @#$%&$ HANDS, boy, and do it before you sit down for supper and do your chores, too, like I done when I was a boy. By God, it was good enough for me.") I have no idea what that means, but hand-washing is associated with obsessive-compulsive disorder in a sort-of-specific way. I suppose people might not think it would make a difference to use the alcohol-based sanitizer gel. In a lot of the articles on infectious disease transmission, researchers go through all of these scenarios and calculate the numbers of virions that could be transferred from one surface to another, at each step along a chain of events that might allow for the transfer the virions. I just think it's good to be able to get in the habit of thinking about that, in case one wants to make use of the thorough infection-control methods at specific times. For example, as I've said before, cleaning surfaces, in my opinion, is never going to be as effective, in controlling the transmission of viruses, as hand disinfectant use and individual behaviors are likely to be, in my view. One can't cover the entire surface with disinfectant, and there's research showing, for example, that some high percentage (I forget the number) of home health care workers can have rotavirus on their hands at any one time. One needs to take that seriously in considering the effectiveness of "cleaning a whole building" or cleaning surfaces at all. The person doing the cleaning can essentially, transport the virus from one surface to another, and that could bypass the supposed 5-10-minute limit on the survival of influenza on the hands. Thomas et al. (2008) [Thomas et al., 2008: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394922/pdf/0076-08.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18359825)] found that some strains of influenza A virus can live for 17 days outside of a host, on money ("banknotes"), when respiratory mucus is present along with the virus. A lot of the articles have estimated that influenza viruses can only survive for 6-12 hours on porous surfaces, and money would be an example of that type of surface [Collignon and Carnie, 2006: (https://www.mja.com.au/public/issues/185_10_201106/col10881_fm.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17115953)]. I just wouldn't be inclined to think of these things in terms of strict rules, given that some of these methods for evaluating the capacity of influenza to survive on surfaces can be problematic, depending on the precise conditions (i.e. the presence or absence of respiratory mucus, etc.). Some viruses that cause GI symptoms can live for months at freezing temperatures and remain infectious. I saw one article reporting the survival of a virus for six months outside a host, at cold temperatures, and many of those GI viruses can live for more than a week outside of a host.

Degrees of Freedom in "Personal-Freakshow-Style" Infection Control: Turning Away from the Masses When One Wants To

I meant to post this on here.

When I was dealing with immunosuppression from infectious mono several years ago, I "developed" some methods for preventing viral infections that might be applicable to the prevention of influenza infections. As I've said, it's my opinion that many, if not most, influenza infections are a result of self-inoculation, in which a person touches a surface that contains influenza virions/virus particles and then touches, either indirectly or directly, a mucosal surface on his or her face, such as on the eyes (touching the eyes or eyelids can allow the virions to be transferred to the conjunctival mucosal surfaces, around the eyes) or mouth or nose. The best way I've found to avoid this is to get in the habit of never touching one's face in public. I never touch my face in public, and I've basically gotten so I do touch my face at home, just in passing or in thought, etc., but do not really touch mucosal surfaces, even at home. That's almost not conscious on my part, but it's the type of thing that provides a "redundancy" in the prevention of self-inoculation. But, to be aggressive in the prevention of viral infections, one has to abandon the social pressure to do things in a reasonable way. I'm not saying I use these extreme sorts of approaches anymore, but the fact remains that the "normal" or "average" person, either at a hospital or elsewhere, is not effective at preventing the transmission of infections. If I had ever gotten into the business of trying to adhere to "normal" standards or habits, I would never have learned anything or gotten anything done, basically. In any case, the idea is just to think about ways to recognize that any surface that's entering the house from a public area could contain live viruses. I saw some expert on tv who was saying that influenza can't live for more than 5-10 minutes, or something, on a person's hand but, as is well-known, can live for 48-72 hours on a smooth surface. I can't verify that that's accurate, about the hands, though, because the person was making other statements that were inaccurate. But what constitutes a smooth surface? I would consider anything, such as mail, food packaging, packages that have been delivered, items from a drugstore, etc., to be potentially infectious. There isn't really any downside to treating them as such. It could get kind of excessive to open the food package, disinfect one's hands, and then unload the food, put the package in the cupboard or refrigerator, and then disinfect one's hands again, before eating the food, but I'm just saying that one shouldn't, in my opinion, guide one's behavior and "decisions," in that area, on some fear of being "obsessive" or of going against the sloppy behaviors of the masses. Some viruses can survive freezing and rethawing and can survive winters in barns and remain infectious, and I don't know what length of time influenza may be able to survive in a refrigerator or freezer. I wouldn't trust something an expert says on tv, however, because some people base their statements, inappropriately, on one set of flawed experiments or on 50-year-old research or medical folk wisdom and beliefs or something, etc. The most important thing, in my opinion, is to consider the use of large amounts of the alcohol-containing hand sanitizer gel when returning from a public place or touching items that have definitely been in public areas, in the presence of "other humans," recently. It's basically necessary to cover the entire surface of the hands with alcohol, to avoid rhinovirus or, for example, rotavirus infections, and I don't know if it's true that influenza can't survive on the hands for more than 5-10 minutes. I would assume it's not true, personally. When one uses a disinfectant like that, one does so with the knowledge that there is not likely to be a danger of infection in most instances, on most days. The point is to develop a habit and effective procedure, in the event that one's hands are carrying viruses.

I once saw that Howie Mandell say that he had been told, by a doctor, that the frequent use of hand sanitizer would cause "all the antibodies" to disappear from his hands or some nonsense like that. It's not true and is something that was meant to "scare him straight," to scare him into being "not obsessive." One isn't going to fall down a "slippery slope" of obsessiveness or go "kway-thee" by going outside the boundaries of normal behavior in specific instances or contexts. The pressure on people to behave in the ways everyone else behaves and to be desperately afraid of being obsessive about something is, in my opinion, one of the most destructive forces that exists. If one embraces that approach, there is the risk that everything novel and original and powerful will be stripped away from oneself, over the long term. The normal practices of the masses and drive toward normalization create a stripped-down, beaten-down, powerless state of being and of ignorance, essentially, in many areas. Anyway, I'm exaggerating a little, but it's true in a lot of ways.

Mechanism of Acyl Migration in an Acyl Glucuronide and Formation of a Lysyl Adduct of a Drug

This shows an acyl migration reaction in an acyl glucuronide conjugate of a drug, R. The acyl migration is separate from the adduct formation and doesn't "lead" to it in any specific way, but the acyl migrations can cause the glucuronide conjugates to be poorer substrate of enzymes that exhibit glucuronidase activity (tissue-specific esterase enzymes, mainly, are the enzymes that the beta-2-O-acyl-glucuronide and beta-3 and beta-4 conjugates are poor substrates of), in the intestinal tract or in "extraintestinal" cells. Those positional isomers of the beta-1-O-acyl glucuronides can (just as the beta-1 isomer can) also allow the drug and the glucuronic acid moiety to be linked to the protein covalently, and that can impact the immunogenicity, etc. (I didn't show that example).

Discussion of Some Issues, Reported in the Literature, Related to the Potential for Contamination in Creatine Supplements

I already discussed this, but I thought I'd mention it here. About 2-3 weeks ago, I switched to a brand of supplemental creatine monohydrate that I hadn't taken in a long time and developed objective and recognizable manifestations of a hypersensitivity reaction to some constituent of that supplement. In my opinion, the brand was contaminated with one or more of the compounds that researchers have sometimes identified in creatine preparations [(http://scholar.google.com/scholar?q=contaminant+%22creatine%22+supplement+OR+commercial&hl=en&as_sdt=2001&as_sdtp=on); (http://scholar.google.com/scholar?hl=en&q=%22creatine%22+cyanoguanidine+OR+dicyandiamide+OR+dihydrotriazole&as_sdt=2000&as_ylo=&as_vis=0)]. I can reasonably rule out a contribution of the excipients in the product, given that I, prior to this incident, had taken another supplement from the same brand for a long time and had experienced no hypersensitivity reaction from the same excipients in that supplement. I actually took this brand of creatine about two or three years ago, for a relatively brief interval of time, and felt strongly, then, that it was contaminated. In my opinion, one or more guanidino/guanidinium or azo-/azide-based contaminants may have led to the formation of covalent adducts on various proteins and produced the hypersensitivity reaction. The symptoms resolved, mostly, within 12-24 hours of switching back to the brand I'd previously taken. I take a very small dose of creatine, and I've discussed the potential for adverse effects from metabolites (not contaminants) of creatine in many past postings on this blog. But many people would not be able to recognize signs of hypersensitivity reactions or make the connection, etc. I see at least one article, in one of those searches I linked to, that sounds like it could also have been a result of an "allergic"/autoreactive hypersensitivity reaction, in which there's an antibody response or even cytotoxic T-cell response, in more extreme cases, to a covalently-bound compound (such as a drug or drug metabolite). One explanation for this type of thing is that free drugs tend to be too small to be immunogenic but can sometimes become immunogenic when covalently bound (or, less commonly, tightly or "pseudoirreversibly") to the larger structure of the protein or other macromolecule, such as DNA. Many guanidinium compounds are well known to be reactive toward the formation of covalent adducts, [Lu et al., 2004: (http://www.unm.edu/~dd39/117.pdf); (http://scholar.google.com/scholar?hl=en&q=nucleophilic+adduct+guanidinium+OR+guanidino&as_sdt=2000&as_ylo=&as_vis=0)] and there are all sorts of reactions that can occur with reactive diamines and other nitrogen-containing compounds in vivo [Kalgutkar et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12093357)]. One could look at some of the other side effects, including rhabdomyolysis and interstitial nephritis (http://scholar.google.com/scholar?hl=en&q=%22creatine%22+supplement+rhabdomyolysis+OR+nephritis&as_sdt=2000&as_ylo=&as_vis=0), associated with the use of creatine and say that hyperosmotic stress, due to the increase in extracellular fluid volume and electrolyte-derangements that the use of high-dose creatine has been associated with, or creatine-derived creatinine or formate or formaldehyde or some strange, semicarbazide-sensitive-amine-oxidase-derived nitrogen-containing compound was to blame in a given case, but another possibility is that contaminant-induced hypersensitivity reactions produced some of those cases of rhabdomyolysis or interstitial nephritis. Drug-induced (as in xenobiotic-induced) hypersensitivity syndromes are known to be major causes of interstitial nephritis (http://scholar.google.com/scholar?hl=en&q=interstitial+nephritis+drug+hypersensitivity&as_sdt=2000&as_ylo=&as_vis=0) or rhabdomyolysis, individually (http://scholar.google.com/scholar?hl=en&q=rhabdomyolysis+drug+hypersensitivity&as_sdt=2000&as_ylo=&as_vis=0). A hypersensitivity syndrome could account for the report of reversible liver dysfunction in a person who had been taking creatine (or who had been taking non-creatine guanidino or azo -containing compounds, etc.) [(http://hardcorephysiologyfun.blogspot.com/2009/04/expression-of-creatine-kinase-by.html);(http://hardcorephysiologyfun.blogspot.com/2009/04/report-of-liver-dysfunction-or-damage.html)]. Why do the supposed hypersensitivity reactions to some creatine-containing supplement preparations appear to not be characterized by the kinds of wild and devastating qualities that drug-induced hypersensitivity reactions can be characterized by? One possibility is that there's thymic tolerance or acquired tolerance to protein adducts, formed as byproducts of normal rates of reactive oxygen species formation, etc., of endogenous guanidinium compounds and that the tolerance causes the xenobiotic-specific antibody response to be dampened or offset by the presence of antibodies to guanidinoacetyl protein adducts, or something like that, that cross-react with the xenobiotic-guanidium-containing adducts, etc. Maybe the abundance of endogenous guanidinium-containing adducts means that there's a high "dose of antigen," in the form of adducts of endogenous guanidino/guanidinium compounds, and that this favors the development of Th2-type responses to some xenobiotic adducts of guanidino compounds. Or maybe other mechanisms could account for the effects, etc. In any case, these are just my opinions. I should mention that covalent adducts/conjugates of drugs to proteins are thought to be a major, if not the major, cause of drug-induced liver injury, and the adducts or conjugates can form by lots of different mechanisms. There are endogenous molecules, such as some geometric isomers, I guess, of bilirubin, that can become covalently bound to proteins and become mildly immunogenic, etc. And protein tyrosine nitration and all sorts of other covalent modifications of proteins can occur normally. But there's likely to be relatively significant immune tolerance to proteins with nitrotyrosine residues, etc. Additionally, some types of drug-protein adducts are much more wildly immunogenic than others. One interesting question is why acetyl esters of endogenous compounds or of, for example, lipid-soluble vitamins don't seem to cause hypersensitivity reactions (apparently not, in my opinion). Maybe the covalent adducts are formed, via O-to-N acyl migration reactions or anomeric shifts of acyl glucuronides or reactions of acyl-CoA thioesters or other transesterification reactions or whatever other chaotic reactions, but are not immunogenic. There may be so many acetylated proteins, formed during protein acylation reactions, etc., or uridylylated RNA molecules or uridylyl or acyl enzyme intermediates that most or all of the possible neoantigens are tolerogenic or not immunogenic. I would guess that a random adduct of a non-xenobiotic would be less immunogenic than a random adduct of a xenobiotic, but that's just my guess. Another point I'd make is that people can be given the impression that drug-induced adverse effects are random, unpredictable, all-or-nothing events that can just be lumped together into a big heap of vagueness and bewilderment, etc. In many cases, the mechanisms underlying some of the potential adverse effects of a drug have been researched in tremendous detail and are reported in chemistry or pharmacology-related journal articles. It's usually possible to get a fairly clear picture of what's going on with a lot of these things, in my view, but that's just my opinion. And these are all just my opinions, obviously.

Kinetic vs. Thermodynamic Variables Governing Protein Tyrosyl Radical Migration and Reduction in Heme Binding Proteins

One point that comes out of these articles [Reeder et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18215735); Reeder et al., 2008b: (http://www.ncbi.nlm.nih.gov/pubmed/18215736)] and that I think is important is that, in view of the fact that protonated, protein-bound perferryl heme is thought to contribute heavily to the damaging effects of acellular myoglobin or hemoglobin and that the concentration of the most damaging, protonated ferryl heme species (which is likely to consist, primarily, of protein-bound perferryl heme with a tyrosyl radical, given that ferryl heme, as in compound II, apparently is protonated under normal circumstances, constitutively) was estimated to be one-10-millionth of the concentrations of the deprotonated species (Reeder et al., 2008b), protein-bound, protonated perferryl heme may be as much as ten million times as damaging as deprotonated perferryl (and ferryl) hemes are. More importantly, the "through-protein" radical transfer reactions and also the capacities of reductants, such as those that concentrate in lysosomes as lysosomotropic amines that exhibit net charges of -3 at pH 7.4 and of +1 at the lysosomal pH range of 4-5, to reduce perferryl heme appear to be governed more by thermodynamic variables than kinetic variables (Reeder et al., 2008b), meaning that the rates of reduction are slow and plateau at concentrations that are relatively low. That seems to me to be a key point that emerges from the articles, and Reeder et al. (2008b) are basically saying that the reductions, by some of these reductants, of tyrosyl radicals on myoglobin are slow and that pH (in this case, acidic pH), which is a thermodynamic variable [Mongan and Case, 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15837173)] that can affect the redox potentials for redox reactions (see Schaefer and Buettner, 2001, cited in past postings), causes a fraction of myoglobin to exist as a species in which perferryl heme is protonated and a tyrosyl radical near to the heme binding site is deprotonated. In essence, some reductants seem to be able to gain "thermodynamically-privileged" access, as reductants, to this species, given that other reductants' charge distribution or intracellular localization may hinder, in pH-dependent manners, their capacities to serve as reductants of this particular fraction of protein-bound perferryl heme. The pH and other thermodynamic variables cause tyrosyl radicals to form and be reduced slowly by reductants, perhaps in a manner that's specific to the pH-dependence of the charge distribution on the reductant. These authors [Al-Ayash and Wilson, 1979: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1186415&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/35158)] suggested, similarly, that the failure of ascorbate to reduce an "alkaline isomer" of cytochrome c might have been explainable in terms of thermodynamic variables and not kinetic ones. The within-protein radical transfer reactions that govern the location of a protein radical, at any given time, also tend to be driven by thermodynamics and not kinetics. For example, the thermodynamic "product" of within-protein, radical transfer reactions in equine myoglobin, in one case, was a tyrosyl radical that was closer to the site at which the radical initiated (namely, heme), and the kinetic "transfer product" was an indolyl radical on a tryptophan residue that was farther from the initiation site than the tyrosyl radical was. That's not the scenario one would expect to see if the within-protein radical transfer migration were governed by kinetics. The protein tyrosyl radicals that have been identified in many heme binding proteins are long-lived, and this contrasts with the extremely short half-life of other protein tyrosyl radicals and of free tyrosyl radicals. Additionally, some reductants are inefficient reductants of free tyrosyl radicals because of kinetic factors that make those reactions unfavorable. Anyway, it's an interesting area. Another factor, other than charge distribution per se, could be the presence of amide groups that don't serve as ligands in organometallic "complexation" reactions but that have been shown to be sites at which prokaryotic serine proteases cleave the reductants [Winkelmann et al., 1999: (http://www.bashanfoundation.org/hartmann/hartmannirakense.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/10581690); Zaya et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9734303)]. Given that some reductants are substrates of prokaryotic serine proteases, some of the protein reductions might be lysosomal-protease-specific in some way or involve the kinds of amide-aromatic or amide-tyrosyl-specific interactions that are known to be important in determining the tertiary and quaternary structures of proteins [Toth et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11340654); (http://scholar.google.com/scholar?hl=en&q=%22aromatic+amide%22+OR+%22amide+aromatic%22&as_sdt=2000&as_ylo=&as_vis=0); (http://scholar.google.com/scholar?hl=en&q=amide+aromatic+interactions&as_sdt=2000&as_ylo=&as_vis=0)]. Ayala et al. (2002) [Ayala et al., 2002: (http://pubs.acs.org/doi/abs/10.1021/ja0164327)] found evidence for a sequence-specific interaction between amide groups and tyrosyl radicals, etc., as one might expect, given that tyrosine is, obviously, a major aromatic amino acid (and given that histidine is an aromatic molecule at all pH values but is not classified as being an aromatic amino acid, given that it is basic, aromatic, and carries a net charge) and, along with histidine, tends to be present near to or as part of the heme binding sites of heme-binding proteins (or as an axial ligand of heme) [(http://scholar.google.com/scholar?hl=en&q=amide+interactions+aromatic+tyrosyl+OR+tyrosine&as_sdt=2000&as_ylo=&as_vis=0); (http://scholar.google.com/scholar?hl=en&q=amide+interactions+aromatic+histidyl+OR+histidine&as_sdt=2000&as_ylo=&as_vis=0)].

Acid-Catalyzed Aldol Condensation of Pyruvate to Form Parapyruvate and Enol-Lactone Derivative

This shows a mechanism for the acid-catalyzed dimerization of pyruvate, and the dimer, which is parapyruvate, can undergo a reversible cyclization to a lactone that then tautomerizes to the enol lactone form that's the predominant tautomer. The structures of the lactone, which is supposedly the predominant species that's present initially and forms within 20 minutes or so, and parapyruvate, which predominates subsequently, at least under the conditions used by the authors, are shown here [Montgomery & Webb, 1956: (http://www.jbc.org/cgi/reprint/221/1/359.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/13345826)].

Discussion of Methyl Pyruvate and Alkyl Pyruvates

I should probably not even mention this, given that "some of" these sources are fringe-ish, evidently. But I came across this web site on which people were talking about methyl pyruvate being available as a supplement, and this is not the website but is a link to a google search (http://www.google.com/search?hl=en&num=100&q=%22methyl+pyruvate%22+tablespoon+energy&aq=f&oq=&aqi=). Yeah--that's a teeth-chatterer. It literally causes shivering. Ethyl pyruvate has been much more heavily researched (http://scholar.google.com/scholar?hl=en&q=%22methyl+pyruvate%22+neuron+OR+axon+OR+protect+OR+protective+OR+protection&as_sdt=2000&as_ylo=&as_vis=0), and that'll probably become available eventually. But one issue with either ethyl pyruvate or methyl pyruvate, apart from methyl pyruvate's apparent lability (http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3p0610) and apparent capacity to undergo polymerization in the presence of a metal catalyst, at least, at room temperature (http://scholar.google.com/scholar?hl=en&q=%22methyl+pyruvate%22+polymerises&as_sdt=2000&as_ylo=&as_vis=0), might be that, at least in the case of methyl pyruvate, the compound(s) can serve as substrates, prior to their deesterification, of alanine aminotransferase, lactate dehydrogenase, and presumably other enzymes that metabolize pyruvate or other alpha-keto acids [Jijakli et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8914921)]. The problem I could imagine would be the loss of stereoselectivity in the conversion of O-alkylpyruvate esters to lactate by lactate dehydrogenase (LDH). LDH normally forms only (S)-lactate (L-lactate) from pyruvate, which is achiral (ethyl and methyl pyruvate are also achiral), but there's some evidence that prokaryotic enzymes, such as xylose reductase, can form both (R)-ethyl lactate and (S)-ethyl lactate from ethyl pyruvate [Kratzer and Nidetzky, 2007: (http://www.rsc.org/delivery/_ArticleLinking/ArticleLinking.asp?JournalCode=CC&Year=2007&ManuscriptID=b616475g&Iss=10)]. The other product, formed by the reaction of ethyl or methyl pyruvate with alanine aminotransferase, would be ethylalanine or methylalanine, I think. But would the L- or D-alkylalanines be formed (or both)? It's possible that there wouldn't be any issues with it. D-lactate is metabolized much more slowly than L-lactate is, although "nanomolar" amounts of D-lactate are supposedly formed, under normal circumstances, by the metabolism of methylglyoxal [Khan and Garner, 2007: (http://www.ramcjournal.com/2007/jun07/khan.pdf)]. In this abstract [Kou and Guan, 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18344089)], ethyl pyruvate improved intestinal barrier function and reduced sepsis-associated elevations in plasma D-lactate, which was of prokaryotic origin (produced by colonic microorganisms) [Schoorel et al., 1980: (http://adc.bmj.com/cgi/reprint/55/10/810.pdf)]. That's a separate issue but could be a source of confusion or something. And then methyl pyruvate's deesterification yields methanol, rather than ethanol (for ethyl pyruvate). Aspartame also yields methanol, upon the deesterification of its methyl ester moiety (Jijakli et al., 1996). There's all this research saying that the amounts of methanol derived from aspartame aren't damaging, etc., but I dunno. "Slurping wood alkey (wood alcohol, a.k.a. methanol) dudn't sound too good to meeeeeee. I'm not saying I won't take a nip, because I like the taste of that s#$&, but..." It's probably not a very large amount, but anyway...My main concern would be the potential for racemic products to be formed, but it's possible that the eukaryotic and mammalian enzymes retain their stereoselectivity/enantioselectivity in the utilization of alkylpyruvates as substrates. Here's a search to potentially answer that question (http://scholar.google.com/scholar?hl=en&q=NADH+%22ethyl+pyruvate%22+%22R-lactate%22+OR+%22D-lactate%22+OR+%22%28R%29-lactate%22+OR+%22ethyl+R-lactate%22+OR+%22ethyl+D-lactate%22+OR+%22ethyl+%28R%29-lactate%22&as_sdt=2000&as_ylo=&as_vis=0), but I can't address the question to an adequate degree. Then, I wonder if there could be the acyl-glucuronidation-mediated-conjugation issue, etc. These authors discuss some of their research that had shown ethyl pyruvate to be a substrate/competitive inhibitor of glyoxylase-1 [Santel et al., 2008: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567432/pdf/pone.0003508.pdf)], and, given that D-lactate is a product of glyoxylase enzymes and that GSH is a cofactor and that GSH has sometimes been shown to be depleted, evidently in association with therapeutic effects [Zingarelli, 2004: (http://critcaremed.org/pt/re/ccm/pdfhandler.00003246-200407000-00022.pdf)], by ethyl pyruvate, it follows that some ethyl pyruvate may well be a substrate of glyoxylase-1 and that D-ethyllactate and, by extension, D-lactate, upon the deesterification of D-ethyllactate, might be formed as products of the reaction(s). The metabolism of methanol consumes GSH, though, too, by some relatively specific mechanism and acetaldehyde could, presumably, produce some of that effect. Alkylpyruvates and other acyl esters of nutrients can, incidentally, serve as substrates for a lot of different enzymes with esterolytic activity, such as carbonic anhydrase enzymes, in the case of methyl pyruvate [Pocker et al., 1978: (http://scholar.google.com/scholar?hl=en&q=%22methyl+pyruvate%22+%22carbonic+anhydrase%22&as_sdt=2000&as_ylo=&as_vis=0), etc.]. In any case, these issues may not be issues at all, but it was something to think about.