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Archive 1Archive 2

Untitled

I removed the advertisement from the bottom of this page. Unless the author can cite references for what is said from "Performance Benifits" on it should be removed. Gravitate (talk) — Preceding unsigned comment added by Gravitate (talk • contribs) 21:47, 11 July 2006‎ (UTC)

I've removed the lot. All the other contribs by the same person were all similar spammings - MPF 21:28, 16 July 2006 (UTC)

Discovered by

I added this sentence because Dr. Steve Nissen originally discovered and patented it as a nutritional supplement and I thought that merited inclusion. I attempted to make it unbiased and if there is any slant please feel free to change the wording of it. Just make sure to include that he introduced it based on research that he did (at Iowa State University). Here's some links to verify that he did introduce it [1] [2] Quadzilla99 11:21, 31 August 2006 (UTC)

I believe he did not discover it as it was around in the 50s and 60s so perhaps the sentance should be revised. —Preceding unsigned comment added by 194.73.108.219 (talk) 15:44, 9 April 2009 (UTC)

Above links are now dead. I will remove reference to ‘discovery’. ☸ Moilleadóir ☎ 02:48, 28 January 2014 (UTC)

Melting point

Melting point cant be -80C... seems erronous. 123.50.129.156 (talk) 21:56, 27 February 2008 (UTC)

That is the value given at the link in the reference provided ... which in turn references the Beilstein database. Unless there is a contradictory value in another reference you can find, I don't think there is any reason to doubt it. -- Ed (Edgar181) 22:12, 27 February 2008 (UTC)

-80 sounds too low but I've seen a couple sources that say its a liquid at room temp. which is possible considering the intramolecular hydrogen bonding. —Preceding unsigned comment added by Pelirojopajaro (talk • contribs) 01:01, 8 January 2009 (UTC)

129 studies

I think this is misleading. The review has 129 REFERENCES, it doesn't go over 129 studies that dealt with HMB. I would say that less than 40 of them were actually original research on HMB. I don't want to go through and count them, but I think the 129 references is misleading. -Rjkd12 —Preceding unsigned comment added by 24.148.46.214 (talk) 18:09, 22 October 2008 (UTC)

SVG diagram of File:ISSN HMB statement Fig 1.jpg (Leucine metabolism in humans)

A .jpg diagram of leucine metabolism in humans (File:ISSN HMB statement Fig 1.jpg)

@Slashme: Hey, would you be interested in working with me to recreate File:ISSN HMB statement Fig 1.jpg as a wikitext-annotated SVG diagram for the en: and af: Wikis? I think you did a great job on the svg diagram for {{Tryptophan metabolism by human microbiota}}, so I figured I'd ask if you were interested in creating an svg version of this diagram (without image text). The jpg image file is also used on the ja: Wiki; so, if you're willing to create the blank SVG diagram, I could probably find someone that can read/write Japanese to re-annotate the image text for that Wiki as well. Seppi333 (Insert 2¢) 21:46, 27 November 2017 (UTC)

My motivation for creating an annotated SVG version of this image is that I'm trying to get this article promoted to featured article status within the next 3–6 months. Seppi333 (Insert 2¢) 21:52, 27 November 2017 (UTC)

Sure! I'll do it this weekend at the very latest; maybe tomorrow. --Slashme (talk) 23:35, 27 November 2017 (UTC)
Thanks! Seppi333 (Insert 2¢) 23:49, 27 November 2017 (UTC)
Duplicate pathways that should be merged into 1
Duplicated pathway (1)
                    
                    
                    
                    
                    
Duplicated pathway (2)
@Slashme: I've asked for feedback on the annotated diagram at WT:MCB#Template:Leucine metabolism in humans; so, it might be best to wait until tomorrow for other editors to provide their suggestions for changes before working on the svg version. Seppi333 (Insert 2¢) 20:36, 2 December 2017 (UTC)
OK, will check there before starting. --Slashme (talk) 00:07, 3 December 2017 (UTC)

@Slashme: I don't expect that the section on WT:MCB is going to garner further input; so, if you're still willing to create the svg image background, let me know once you've uploaded it and I'll update the annotated image. Seppi333 (Insert 2¢) 22:04, 16 December 2017 (UTC)

@Slashme: The consensus at WT:MCB is that the image should be recreated with the two pathways shown on the right merged into a single pathway so that these compounds aren't shown twice in the image. If you're still interested in recreating this image in svg format, let me know; otherwise, I intend to draw this myself when I have the time. Seppi333 (Insert 2¢) 05:45, 24 January 2018 (UTC)

Draft version of {{Leucine metabolism in humans}} (under construction)

Part of this section is transcluded from Template:Leucine metabolism in humans. (edit | history)
Annotated image and reflist
Diagram of leucine, HMB, and isovaleryl-CoA metabolism in humans
The image above contains clickable links
Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine.[1][2][3] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[1][2][3]

References

  1. ^ a b Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.
  2. ^ a b Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 978-0-12-387784-0. Retrieved 6 June 2016. Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds
    Figure 8.57: Metabolism of L-leucine

Upcoming systematic review

"Beta-hydroxy-beta-methylbutyrate free acid improves resistance training-induced muscle mass and function: a systematic review" - anticipated completion (publication?) date: September 2016

Research question: What is the effect of HMB-FA on resistance training-induced muscle mass and function?
Primary outcomes:
  • Effects on skeletal muscle in sedentary, active and recreationally-trained subjects and HMB-supplemented compared with placebo.
  • Change in lean mass from baseline to final intervention.
  • Change in strength and biochemical parameters from baseline to final intervention.

Seppi333 (Insert 2¢) 11:45, 31 July 2016 (UTC)

Page name

The page name doesn't seem to be the most obvious choice to be. Thinking about WP:NAMINGCRITERIA I might suggest as alternatives (in rough order of preference):

  • HMB, on the grounds of Conciseness and Recognizability. It might then require the existing HMB to be moved to HMB (disambiguation)
  • beta-hydroxyisovaleric acid, on the grounds of Naturalness (MESH heading term)
  • 3-hydroxy-3-methylbutanoic acid, on the grounds of Precision (IUPAC name)

Thoughts? If there is a decision for no change, then I think the last 2 terms should also be redirects here. Klbrain (talk) 18:38, 3 August 2016 (UTC)

I'll respond to these in reverse order:
  • 3-hydroxy-3-methylbutanoic acid is neither more nor less precise than the current article name, both names only specify one molecule.
  • The main issue with beta-hydroxyisovaleric acid is that the common acronym, HMB, doesn't work for it. Additionally it seems that it isn't the preferred term in current literature.
  • There are specific naming guidelines based off of the topic. WP:NCMED gives the naming guidelines for medical articles and states "The article title should be the scientific or recognised medical name that is most commonly used in recent, high-quality, English-language medical sources". Furthermore it states that drugs should be titled based off their International Nonproprietary Name, although I'm fairly certain HMB does not have an INN, and the line between drug and supplement is blurry. The chemistry naming guidelines at WP:NCCHEM generally recommend this quoted section from the general naming conventions: "Generally, article naming should give priority to what the majority of English speakers would most easily recognize, with a reasonable minimum of ambiguity, while at the same time making linking to those articles easy and second nature". I think it might be best to look at other dietary supplements for guidance, and looking at other dietary supplement articles it appears using an acronym in place of the chemical name is not normally done, although perhaps a broader discussion should be had on the topic in a more general forum. M. A. Bruhn (talk) 20:46, 3 August 2016 (UTC)
The vast majority of literature that has been published on this compound from the past 20 years has used the terms "β-hydroxy β-methylbutyrate" [213 hits] or "β-hydroxy β-methylbutyric acid" [10 hits] (some sources also hyphenate "hydroxy-β"), depending on whether the study involved the conjugate base or acid. Prior to that, the 3- and β- "hydroxyisovalerate/hydroxyisovaleric acid" terms were more common. For comparison, the MESH name "beta-hydroxyisovaleric acid" gets only 8 results out of the 247 papers that are found from an unfiltered search using any of the MESH-indexed synonyms. The IUPAC name is seldom used in published literature.
Most commercial products contain the calcium salt of this compound and refer to it as "calcium hydroxymethylbutyrate", "calcium β-hydroxy β-methylbutyrate", or "calcium β-hydroxy β-methylbutyrate monohydrate" (again, some also hyphenate "hydroxy-β"), so I imagine that most of the incoming traffic to this article uses one of those terms. I'm more inclined to use the conjugate base as the page name since it's more prevalent in published literature, but it seems more common to use the acid than the base as the page title when there aren't separate articles for the conjugate acid/base forms of a compound (in this case, the acid/base forms of HMB should be covered in the same article). Consequently, I think the current page name is acceptable even though it's not the most common name. I'm open to renaming the article though. Seppi333 (Insert 2¢) 22:01, 3 August 2016 (UTC)

Comment about safety

I'd like to start off by stating that I hope my commenting here does not turn away any potential GA reviewers since I believe these concerns can be addressed quickly, so much so that I'm tempted to go ahead and make them myself rather than post here, but I believe the prose will be more consistent if these changes are made by those who have written the majority of the article already.

In the opening there is a stand-alone sentence discussing HMB's safety in "young or old individuals", but to me that is a little unclear. The first source cited for that statement says "Chronic consumption of HMB is safe in both young and old populations", so I looked through it to see what they consider young. It appears they are referring to young adults as later in the paper they state that no research has been carried out on infants and very little research has been carried out on adolescents. Additionally no research appears to have been carried out on pregnant women.

With this in mind I would suggest further clarifying in the lead the lower bound of the age of individuals for which HMB supplementation appears safe. In addition the description of its safety in humans in the side effects section should be qualified so that it excludes human sub-populations that HMB hasn't been well studied in. Lastly the first sentence of that section implies that safety for animals in general has been established—"the safety profile of HMB in humans and animals"—this should be reworded/expanded to convey either which animals it has been found to be safe for, and/or to describe how animal models have been used to help establish the safety profile in humans. M. A. Bruhn (talk) 05:13, 3 August 2016 (UTC)

@M. A. Bruhn: I agree that this should be clarified.
  • I think specifying "young adults and older adults" should adequately address the ambiguity in the current phrasing. I actually wasn't aware that any clinical testing with the compound had been conducted on individuals who are younger than 18.
  • I imagine that based upon the current wording, one might infer that its safety status has been shown to be analogous to a US pregnancy category A drug; this isn't true, since as far as I know there hasn't been any RCT testing with HMB supplementation on pregnant women. While it's very likely true that the compound isn't teratogenic, we can't say this and it shouldn't be implied without an appropriate citation. I'll add a clause stating that no clinical testing has been conducted with supplemental HMB in pregnant women.
  • I'd intended to add data on toxicity testing in animal models earlier but later decided to forego it since I figured most people would be interested in clinical information in humans. If you think it's worth adding, I'd be happy to include this. IIRC, animal testing has involved daily doses of 15 g in rats for a duration of 1+ months w/o adverse effects, but I'll need to double check that. (edit: the doses given to rats were actually much higher based upon PMID 23374455 and PMID 25099672) I'll add the information about the animal, dose/dosage, and duration of testing to the article sometime today or tomorrow when I find the review that covers it. As for humans, clinical testing has involved 3 g daily doses for up to a year w/o adverse effects and 6 g daily doses for a couple of months w/o adverse effects in young adults. This would probably also be worth mentioning in the side effects section, so I'll include this as well when I add the information on animal testing.
    On a related note, the only thing I could probably put into an OD section is the LD50 for rodent species; since LD50 in non-human animals seldom accurately reflects the LD50 for humans, I decided to forego the overdose section altogether.
I'll start working on making these changes now. Please let me know if you have any other suggestions for improvement; I'd be happy to act on them. Also, feel free to edit the article yourself and make any changes that you know are supported by references. I don't bite. Seppi333 (Insert 2¢) 06:02, 3 August 2016 (UTC)
I'm going to add the information on high-dose animal testing a little later since I need to log off for now. I think I've addressed most of the issues you've raised here, so let me know what you think when you get a chance. Seppi333 (Insert 2¢) 07:23, 3 August 2016 (UTC)
  • Those changes have mostly addressed everything for me. The only concern I have is with the ambiguity of "animals". From the context it can be reasonably inferred by the average reader to refer to animals commonly used in research to predict effects in humans, but not all readers might make inference. Although it's unlikely that someone's going to believe it's referring to coral reefs and bumble bees, the statement as it is presently worded is grammatically stating that HMB is safe for animals in general. I think it just needs to be slightly reworded so that instead stating "The safety profile of HMB in ... animals has been well-established...” it instead more explicitly conveys that the animals which HMB appears safe in are animals used to gauge safety for humans. Maybe something along the lines of "The safety profile of HMB in adult humans has been well-established by medical reviews looking at a combination of randomized controlled trials in humans as well as extensive animal testing." I haven't read the medical reviews so I don't know if this is a good characterization or not.
  • I agree that data on animal models is probably irrelevant to add. I said that information on safety of specific animals could be added just on the off chance that there was information that was useful in it of itself, for instance if there had been any research on using HMB supplementation to bulk up livestock. But if that's not the case then there wouldn't seem to be a reason to make any specific mention of animal testing except in cases where it introduces something that human testing hasn't covered, such as with the pregnant pigs. I think making an OD section just for the LD50 might be giving it undue weight. I notice that the chem infoboxes have an LD50 parameter but the drug infoboxes do not, so perhaps that is an indication that LD50's for drugs shouldn't be presented in the infoboxes either. I'm neither for or against addition of such information, and think you should just do what you prefer.
I'll let you know if I see anything else or feel free to do it myself. Thanks and good luck with your editing.M. A. Bruhn (talk) 08:35, 3 August 2016 (UTC)
I used your proposed wording, which was accurate, and indicated that most of the animal testing has involved lab rats, pigs, chickens, and turkeys. Edit: the review on HMB supplementation in animals (PMID 25099672) states that "the utility of HMB supplementation in animals has been shown in numerous studies, which have demonstrated enhanced body weight gain and carcass yield in slaughter animals", but I'm going to look for other sources that cover its use in livestock for this purpose before covering it in the article since I don't know how common/notable this practice is. Seppi333 (Insert 2¢) 09:24, 3 August 2016 (UTC); edited at 14:17, 3 August 2016 (UTC)

@M. A. Bruhn: How would you feel about the addition of this statement to the paragraph on pregnancy?

As of 2016, Metabolic Technologies Inc., the company that grants licenses to include HMB in dietary supplements, advises pregnant and lactating women not to take HMB due to a lack of safety studies conducted with this population.[1]

I'm hesitant to add this, although I think it's notable since this is the company that grants licenses to allow the inclusion of HMB in dietary supplements. The reference is a primary source for the statement, but the statement itself is advisement as opposed to a medical claim. Seppi333 (Insert 2¢) 02:45, 23 August 2016 (UTC)

Edit: I decided to add this material to a newly created "Contraindications" section, since IMO this content is most appropriate there. Seppi333 (Insert 2¢) 04:19, 23 August 2016 (UTC)
I'm not sure how I feel about this source's inclusion. Companies will produce statements instructing consumers not to use their products in certain ways simply because 1) they want to avoid liability and 2) they know their consumers will ignore them anyways (like with consumers using Q-tips to clean their ears). When you first posted I spent some time trying to find a more MEDRS compliant source to use instead, I found several RS sources, but no MEDRS though. If it is qualified as "Company X says Y" then it isn't really an issue of accuracy (since they do indeed state this) so much as weight. I'm not sure if it is undue weight or not. If this were a drug then it would be easy to find alternative sources, but since it is a supplement our options are limited. I suppose I am leaning more towards its inclusion, but would prefer it if a better source could replace it. M. A. Bruhn (talk) 06:42, 29 August 2016 (UTC)
fwiw I think that Seppi is trying like crazy to cover all the sections in MEDMOS and cover the things we usually cover; for medicines we usually give the formal pregnancy category. A drug label will generally give the information as to whether the drug has been tested in pregnant women, or not and the label will give the negative information. In this case neither the label for Juven nor the label for the medical food Ensure discusses pregnancy. Neither of the current FDA draft guidances on medical food (not this and not this discuss pregnancy categories, and I am ~guessing~ that this is because medical food is well, food. Not something strange like a drug.
Because of all that, Seppi, I think there is no need to talk about the pregnancy thing; not until this is marketed as a drug (which I am guessing it never will be)
That said, I still think including the statement by the company, with attribution as suggested by M A Bruhn above, is a very good move. Jytdog (talk) 07:00, 29 August 2016 (UTC)
Yeah... I've been looking for medical sources that make a statement about HMB use during pregnancy or that cover a rather obvious drug interaction between HMB and rapamycin and/or mTOR inhibitors in general, but haven't really found suitable sources for either. In the case of the pregnancy statement in the article, I figure I can get away with that source since it doesn't really make any medical claims about HMB. It's basically just the company's advice, so I agree that it is more of a WP:DUE issue than a WP:RS/MEDRS issue.
As for the HMB/rapamycin interaction, their opposing effects on MTORC1 activation and protein synthesis is mentioned only in this primary source, which I can't use to cite a drug interaction. Seppi333 (Insert 2¢) 21:09, 29 August 2016 (UTC)

Reflist

References

  1. ^ "Who should not take HMB?". Metabolic Technologies, Inc. Retrieved 23 August 2016. Pregnant or lactating women are advised against taking HMB because safety studies have not yet been conducted for these populations.

New sources

@Jytdog: Thanks for doing a literature search and posting these sources here; I really appreciate it! I'll read through and use them to write new content when I get a chance later today or tomorrow. Seppi333 (Insert 2¢) 21:26, 9 September 2016 (UTC)

I've been busier than I expected off-wiki over the past few days. I should have time to follow-up on this tomorrow night. Seppi333 (Insert 2¢) 22:48, 12 September 2016 (UTC)
@Jytdog: My bad for not doing this yet; I'm going to stop trying to give myself further deadlines that I can't meet due to how busy I've been this past week. I will, however, use the sources that you linked below to add content before I look for sources to cite for adding a statement on the calcium content of HMB-Ca. Seppi333 (Insert 2¢) 23:40, 16 September 2016 (UTC)
That's OK - the fitzpatrick book is already used and there is not much else here that is useful. I was mostly recording my work actually trying to track down sales.. Jytdog (talk) 23:43, 16 September 2016 (UTC)
@Jytdog: Oh. Well, I'll still look through them anyway - might have something worth adding. Also, one of the refs that you linked to at FAC mentioned something you might be interested in (see the bold+underlined text below). As of when this ref was published, all of MTI's products contained HMB, as stated in the quote. As of now, they also sell or license one product which contains no HMB: an adenosine triphosphate (ATP) supplement which they call "betaATP". Seppi333 (Insert 2¢) 00:44, 17 September 2016 (UTC)
FWIW, based upon the prices of currently available HMB-Ca and HMB-FA supplements and the relative efficacy in primary studies between HMB-FA and HMB-Ca, I really doubt MTI is making close to $10,000,000 annually on HMB-FA alone. Seppi333 (Insert 2¢) 00:51, 17 September 2016 (UTC)
Metabolic Technologies 2011 sales + 5-year sales projections

Commercial Potential for the HMB Delivery System for Iowa: Metabolic Technologies, Inc. (MTI) is a small research and development company located in the Iowa State University Research Park in Ames, Iowa, with current sales just under $2 million annually. MTI was founded in 1990 with the vision of developing and marketing naturally derived products that enhance health, performance, and well-being. Central to this vision, MTI ensures that products are not marketed before quality manufacturing is guaranteed, safety is proven, and effectiveness is scientifically verified. MTI’s vision results in highly effective products that have definably superior safety margins. In addition, the vitality of the company is assured by focusing on strong patent protection for the products developed.

Developed Products: The first commercial product developed was HMB® or β-hydroxy-β- methylbutyrate. This naturally occurring leucine metabolite has become a standard bearer in the sports nutrition market by having superior efficacy and safety data available. HMB is now protected under several patents. HMB is currently sold as a calcium salt, CaHMB.

The second commercial product MTI developed was Juven®. Juven® is a combination of arginine, glutamine, and HMB. Clinical studies showed that this product enhanced maintenance and restoration of muscle mass in both AIDS and cancer patients. In 2003, the rights to market Juven® were acquired by Abbott Nutrition. Abbott Nutrition currently markets Juven® for AIDS, cancer-cachexia, and wound healing.

Although not commercially developed yet, a third product, Re-Vigor®, was researched and designed by MTI. Re-Vigor® is a combination of arginine, lysine, and HMB, and is intended to slow down muscle wasting in the elderly. In 2008, the rights to this product were acquired by Abbott Nutrition.

Current Product: We anticipate that the HMB free acid gel delivery system will replace the need for three daily doses of CaHMB, and thus will be a more efficient form of delivery and use in the exercise market. In addition, we anticipate that the ease of delivery of the free acid gel form will expand the current market potential for use of HMB as a nutritional supplement aimed at ameliorating tissue inflammation a condition that is prevalent in many diseases such as obesity, type 2 diabetes, rheumatoid arthritis, cardiovascular diseases and others. Data generated from this proposal will be used to apply for NIH Phase I and Phase II SBIR grants with potential funding of $1,150,000. In addition, the results from the proposed studies will be used to support a provisional U.S. patent that was filed in December of 2009.

Based on our current sales of CaHMB, we anticipate that the sales of HMB free acid gel in the exercise market will reach $10,000,000 annually by the 5th year. Our projected sales in the larger nutritional supplement market could easily exceed this amount and could reach 20-30 million USD by the 5th year. As previously stated, MTI has been successful in transitioning HMB from an “exercise commodity” to that used by medical nutritional products (Juven® and Abound®-- Abbott Nutritional Laboratories). We anticipate adding 10-20 new full-time positions within the next 3-5 years. These positions would be in the areas of research and development, quality control, sales, marketing, advertising and accounting.
— The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011

sources for extent of use of HMB

am looking for sources for this, will record what I find here. others are free to add of course...

This is really hard as MTI is a private company so have no obligation (and don't) report sales.

  • Nuckols, Greg (July 20, 2016). "The HMB Controversy: Better than Steroids?". Strengtheory. (not a great ref, but guy who runs it seems to be not insignificant in world of lifers, see here). Has a blog entry focused on primary sources PMID 24599749 published in 2014 and the followup PMID 24714541 published this July and their remarkable results, and writes: "A supplement that’s been around for a long time, but which isn’t all that popular, works better than steroids?". "which isn't all that popular". Not much but something.
  • Eichner, E. Randy; King, Douglas; Myhal, Mark; Prentice, Bill; Ziegenfuss, Tim N. (1999). "Roundtable: "Muscle Builder" Supplements" (PDF). RT#37. 10 (3). again really slim. From 1999. One of roundtable participants says: "HMB sales declined rapidly after it was introduced because it had no perceived effect on muscle mass and was expensive." Same person also said: "Likewise, HMB has not lived up to its marketing hype as an anabolic agent" Another, " Among athletes who want to gain muscle mass, protein and creatine supplements are popular, especially in football, wrestling, and track and field. HMB and the banned substances DHEA and the “andros” are used by few or none"

This is all I found in a google search 10 pages out. Will check my library... Jytdog (talk) 21:10, 9 September 2016 (UTC)

sources on business background and marketing

  • Conis, Elena (29 May 2011). "Muscle drink with HMB targets the middle-aged". Los Angeles Times. -- "hook" was launch of Ensure Muscle Health; discusses that HMB is marketed to older/middle aged folks who want to start getting into shape, because that is who benefits the most (citing the 2009 review again)
  • Kane, Ed (September 2014). "Nutritional Supplements in Horses" (PDF). Insider. Animal Health International, Inc. pp. 11–15. - a trade rag, notes that HMB is marketed for horses but there is "little to no data to support its use in horses".

Same search as above. Jytdog (talk) 21:10, 9 September 2016 (UTC)

Mg of ionic calcium per gram of pure HMB from HMB-Ca

Need to find a WP:RS-quality source for this, since I think it's worth covering. Probably should be mentioned in the article since the {{mineral supplements}} navbox links here and most HMB-Ca brands don't appear to list this information on the supplement bottles. Seppi333 (Insert 2¢) 23:40, 16 September 2016 (UTC)

Placement of biosynthesis section

Biosynthesis is currently a subsection pharmacology/pharmacokinetics. Pharmacokinetics is what the body does to the drug, not how the body synthesizes it. Also some bugs and I assume many other "critters" synthesize HMB. Hence logically biosynthesis should not be a subsection of pharmacokinetics, but rather the chemistry (or possibly a new biochemistry) section. The reason I ask is that MC-CoA is used in the biosynthesis of a tetrasaccharide produced by Bacillus anthracis (anthrax bacteria) and HMB itself has been used in the laboratory synthesis of this tetrasaccharide (see PMID 15152001, 20614885). This new material would not be appropriate to add to the pharmacokinetics section but would be appropriate in a new biochemistry section. Thoughts? Boghog (talk) 09:13, 25 September 2016 (UTC)

I'm okay with moving it. I recognized that it wasn't really relevant to the PK section when I created it under that heading, but I put it there anyway simply because the HMB metabolism diagram also illustrates HMB biosynthesis. Seppi333 (Insert 2¢) 10:33, 25 September 2016 (UTC)

Expansion of chemistry section

Moved to Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive1

With thanks to Sizeofint for supplying database searches, I have expanded the synthesis section. There are several more syntheses that could be added, but most of these are obscure reactions or reactions where HMB is a side product. Hence I question the notability of these. Also there were some early syntheses reported (and associated physical data of the synthesized HMB) based on an aldol condensation without dehydration between acetone and ethyl acetate. However I think this would be highly unlikely since the dehydration is the driving force for the reaction. As far as physical data, there is not much more that could (or should) be added. By far, the most notable aspect of HMB is that is a naturally produced metabolite and a food additive . Much less has been published about its chemistry. Hence per WP:DUE, it is appropriate that the chemistry section of this article is significantly shorter than some of the other sections. Boghog (talk) 09:35, 25 September 2016 (UTC)

@Boghog: you should probably post this in Nergaal's review section to discuss with him what should or could be added about to HMB's chemistry. He's the only reviewer who has commented on the chemistry section thus far. Seppi333 (Insert 2¢) 17:52, 26 September 2016 (UTC)

History → Synthesis section split

@Boghog: I split part of the material that you added to the history section to the synthesis section and re-added a slightly duplicate statement about its very first reported synthesis to the history section in this edit. Is that okay with you? Seppi333 (Insert 2¢) 16:52, 9 November 2016 (UTC)

Yes. I was thinking of doing something similar. Thanks for taking care of that. Boghog (talk) 17:32, 9 November 2016 (UTC)

Reviews and CC-BY-2.0/CC-BY-4.0 diagrams

Diagrams and reviews
Human metabolic pathway for HMB and isovaleryl-CoA, relative to leucine.[1] Of the two major pathways, leucine is mostly metabolized into isovaleryl-CoA, while only 5% or so is metabolized into HMB.[1]
Absorbtion kinetics (content in blood plasma levels over time) from oral use of 1 gram of calcium vs free acid forms of HMB.[1]
Mechanism of action of HMB, as proposed by the International Society of Sports Nutrition in 2013.[1]
Diagram of the molecular signaling cascades that are involved in muscle protein synthesis in response to physical exercise and specific amino acids or their derivatives (primarily leucine and HMB).[2]
Abbreviations and schematic representations:
PLD: Phospholipase D; PA: phosphatidic acid; AMP: adenosine monophosphate; ATP: adenosine triphosphate; PGC‐1α: peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha; eIF4E: eukaryotic translation initiation factor 4E; RPS6: ribosomal protein S6; eEF2: eukaryotic elongation factor 2; ↑ represents activation; Τ represents inhibition

Most of these articles are currently available here. The file names reflect the ref names defined in the source code below. Seppi333 (Insert 2¢) 19:05, 23 May 2016 (UTC)

  1. February 2013 review, indicates the impracticality of obtaining a 3 gram dose through diet[1]
  2. Skeletal muscle homeostasis, 2016 review[2] (Available for free at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843955/)
  3. July 2010 review of various HMB-induced biomarker changes/athletic effects[3]
  4. Medical use in sarcopenia, November 2014 systematic review[4]
  5. Tentatively supports a more general statement about attentuating muscle damage in pathological states, December 2013 systematic review[5]
  6. Supplementation in older adults, September 2015 meta-analytic systematic review[6]
  7. Prevalence of use, pharmacodynamics, availability, and sports testing status, April 2015 performance-enhancing drugs review[7]
  8. Newest review on HMB: medical use in muscle wasting and sarcopenia, April 2016 review[8]
  9. Athletic performance-related effects of HMB, 2011 review[9]
  10. HMB for cancer cachexia, 2013 review[10]
  11. Effects of amino acid derivatives, 2015 review[11]
  12. Review with background info on molecular signaling cascades in protein synthesis/degradation, September 2015 review[12]
  13. HMB's clinical evidence in older adults, May 2016 review[13] (Available for free at http://www.mdpi.com/2072-6643/8/5/295/htm)
  14. Nutrition supplements for athletes, February 2014 review[14]
  15. HMDB entry[15]
  16. Sarcopenia, July 2015 review[16]
  17. HMB's in vivo intracellular pharmacodynamics in human skeletal muscle, 2013 primary study using muscle biopsies[17] - cited by [2][6][16]
  18. HMB in animals, June 2015 review,[18]
  19. Sarcopenia, May 2016 review[19]
  20. Very strong statements of efficacy for medical use, June 2016 review;[20] (note: this review explicitly states that HMB ingestion can improve every core symptom of sarcopenia and other forms of muscle wasting: the loss of muscle mass, function, and strength):
    This review supports the following statements:
    • HMB is a potent stimulator of MPS and a potent inhibitor of MPB.[20]
    • HMB potently inhibits and may reverse muscle loss in sarcopenic individuals and even in hypercatabolic disease states such as cachexia.[20]
    • Ingestion of HMB results in demonstrable muscle mass accretion.[20]
    • Ingestion of HMB can improve measures of muscle strength in sarcopenic individuals.[20]
    • Consumption of HMB with dietary protein can improve muscle function, resulting in functional muscle performance improvements.[20]
    • The overall treatment of muscle wasting conditions should include dietary supplementation with HMB.[20]
    • Ingestion of HMB and consumption of a high protein diet combined with regular resistance exercise is recommended for individuals that are at risk of developing or currently experiencing sarcopenia.[20]
  21. July 2014 review;[21] Covers trials involving Juven for various medical conditions w/ positive (AIDS-induced wasting, cancer cachexia) and negative findings (post-gastric bypass, rheumatoid arthritis) and an interesting trial involving Juven vs HMB alone vs placebo, where HMB alone significantly improved nitrogen balance relative to Juven or placebo.

References

  1. ^ a b c d e Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". J. Int. Soc. Sports. Nutr. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455. The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature on the use of beta-hydroxy-beta-methylbutyrate (HMB) as a nutritional supplement. The ISSN has concluded the following. 1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations. 2. If consuming HMB, an athlete will benefit from consuming the supplement in close proximity to their workout. 3. HMB appears to be most effective when consumed for 2 weeks prior to an exercise bout. 4. Thirty-eight mg·kg·BM-1 daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized. 5. Currently, two forms of HMB have been used: Calcium HMB (HMB-Ca) and a free acid form of HMB (HMB-FA). HMB-FA may increase plasma absorption and retention of HMB to a greater extent than HMB-CA. However, research with HMB-FA is in its infancy, and there is not enough research to support whether one form is superior. 6. HMB has been demonstrated to increase LBM and functionality in elderly, sedentary populations. 7. HMB ingestion in conjunction with a structured exercise program may result in greater declines in fat mass (FM). 8. HMB's mechanisms of action include an inhibition and increase of proteolysis and protein synthesis, respectively. 9. Chronic consumption of HMB is safe in both young and old populations. ... HMB is naturally produced in animals and humans from the amino acid leucine [27]. The first step in production of HMB is the reversible transamination of leucine to α-keto-isocaproate (KIC) by the enzyme branched chain amino acid transferase [28] ... KIC is primarily metabolized into isovaleryl-CoA, with only approximately 5% of leucine being converted into HMB [28]. To put this into perspective, an individual would need to consume over 600 g of high quality protein to obtain the amount of leucine (60 grams) necessary to produce the typical 3 g daily dosage of HMB used in human studies [9]. Since consumption of this amount of protein is impractical, HMB is typically increased via dietary supplementation.
  2. ^ a b c Brook MS, Wilkinson DJ, Phillips BE, Perez-Schindler J, Philp A, Smith K, Atherton PJ (January 2016). "Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise". Acta Physiol (Oxf). 216 (1): 15–41. doi:10.1111/apha.12532. PMC 4843955. PMID 26010896. The mechanisms regulating loss of skeletal muscle mass with age still remain unclear; however, with the shrinkage of any organ (other than necrosis), they must be due to chronic imbalances between protein synthesis (MPS) and protein breakdown (MPB), that is MPB > MPS. ... Therefore, in the post‐absorptive state, rates of MPB > MPS leading to a net negative protein balance and hence a loss of muscle protein. Crucially, this negative protein balance is transiently reversed (MPS > MPB) after food intake (contingent on sufficient high‐quality protein), such that net protein balance is neutral on a daily basis (MPS = MPB). The mechanisms underlying the anabolic effects of food intake involve both the stimulation of MPS (Rennie et al. 1982) and suppression of MPB (Wilkes et al. 2009). The potent increase in MPS is driven almost entirely by essential amino acids (EAAs) (Smith et al. 1992), with the branched chain AA (BCAA: leucine, isoleucine and valine), in particular leucine [and its metabolite(s), e.g. β‐hydroxy β‐methylbutyric acid (HMB) (Van Koevering & Nissen 1992)] being central to these effects (Wilkinson et al. 2013). ... Despite extensive investment in pharmaceutical interventions (Onder et al. 2009) and the discovery of a number of potential novel targeted pharmaconutrients [ursolic acid (UA), HMB, PA, etc. (Vukovich et al. 2001, Kunkel et al. 2011, Hoffman et al. 2012)], RE with appropriate supportive nutrition remains the current most effective and safe means by which to maintain or increase muscle mass in older adults (Ivey et al. 2000, Parise & Yarasheski 2000, Häkkinen et al. 2001, Kumar et al. 2012). ... More recent studies have shown that some nutritional supplements such as the leucine metabolite HMB, which is known to have potent affects on both MPS and MPB (Wilkinson et al. 2013), have potential to prevent or slow the decline in bed rest‐related muscle loss (Deutz et al. 2013), indicating the importance of nutritional strategies for assisting in combating the accelerated mass loss (Magne et al. 2013).
  3. ^ Portal S, Eliakim A, Nemet D, Halevy O, Zadik Z (July 2010). "Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices". J. Pediatr. Endocrinol. Metab. 23 (7): 641–50. doi:10.1515/jpem.2010.23.7.641. PMID 20857835. S2CID 2209268. There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta-hydroxy beta-methylbutyrate (HMB). ... Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMB's mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription.
  4. ^ Cruz-Jentoft AJ, Landi F, Schneider SM, Zúñiga C, Arai H, Boirie Y, Chen LK, Fielding RA, Martin FC, Michel JP, Sieber C, Stout JR, Studenski SA, Vellas B, Woo J, Zamboni M, Cederholm T (November 2014). "Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS)". Age Ageing. 43 (6): 748–59. doi:10.1093/ageing/afu115. PMC 4204661. PMID 25241753. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not shown consistent benefits on muscle mass and function. ... Supervised resistance exercise is recommended for individuals with sarcopenia. EAA (with leucine) and HMB may improve muscle outcomes. ...
    HMB supplementation
    The effect of HMB alone [32, 36] or HMB in combination with ARG and LYS [34] or resistance exercise training [39] on muscle parameters has been investigated in four high-quality (PEDro score: 8–10) studies of 8–24-week duration in community-dwelling older adults [34, 36, 39] or in healthy older adults on extended bed rest [32]. HMB prevented muscle mass loss in one of four studies and did not improve muscle mass in the other three [32]; improved muscle strength in one [34] (and possibly two) [36] of four studies and improved physical performance in one of four studies [34].
    Overall, HMB showed some effects on muscle mass and function in these high-quality studies, but sample sizes were small.
  5. ^ Molfino A, Gioia G, Rossi Fanelli F, Muscaritoli M (December 2013). "Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials". Amino Acids. 45 (6): 1273–1292. doi:10.1007/s00726-013-1592-z. PMID 24057808. Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, is extensively used by athletes and bodybuilders in order to increase strength, muscle mass and exercise performance. ... The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. Most of the selected studies showed the effectiveness of HMB in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. Further, well-designed clinical studies are needed to confirm effectiveness and mode of action of HMB, particularly in pathological conditions.
  6. ^ a b Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K (September 2015). "Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis". Arch. Gerontol. Geriatr. 61 (2): 168–175. doi:10.1016/j.archger.2015.06.020. PMID 26169182. RESULTS: A total of seven randomized controlled trials were included, in which 147 older adults received HMB intervention and 140 were assigned to control groups. The meta-analysis showed greater muscle mass gain in the intervention groups compared with the control groups (standard mean difference=0.352kg; 95% confidence interval: 0.11, 0.594; Z value=2.85; P=0.004). There were no significant fat mass changes between intervention and control groups (standard mean difference=-0.08kg; 95% confidence interval: -0.32, 0.159; Z value=0.66; P=0.511).
    CONCLUSION: Beta-hydroxy-beta-methylbutyrate supplementation contributed to preservation of muscle mass in older adults. HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors. Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults.
  7. ^ Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. S2CID 45124293.
    3.6 Beta-Hydroxy-Beta-Methylbutyrate
    HMB is a metabolite of the amino acid leucine and is a precursor to cholesterol. ... A 2013 NCAA survey study reported a 0.2 % rate of use among all student athletes [13]. However, it appears that HMB is increasingly being added to many training regimens [88]. ... There are several proposed mechanisms by which HMB acts. One of the primary mechanisms involves the up-regulation of the mechanistic target of rapamycin/ p70S6K signaling pathway, which promotes protein synthesis and muscle hypertrophy [89].
    Other studies have focused on the anti-catabolic effects of HMB. Smith et al. [90] demonstrated that HMB preserved lean body mass and decreased proteolysis through the down-regulation of the increased expression of certain components of the ubiquitin–proteasome proteolytic pathway. Some studies have examined HMB and its effect on muscle by measuring markers of muscle breakdown. Wilson et al. [91] demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al. [92] showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. ... Despite differences in these studies, it does appear that HMB overall enhances muscular hypertrophy, strength, and power. In fact, the International Society for Sports Nutrition, in a position statement, writes that HMB can be used to enhance recovery by reducing skeletal muscle damage after exercise in athletically trained and untrained people. The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97]. Further, chronic consumption of HMB appears safe [97]. ... Currently, HMB is available as an over-the-counter supplement. The drug is not tested for nor banned by any sporting organization.
  8. ^ Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention" (PDF). Mol. Aspects Med. 50: 56–87. doi:10.1016/j.mam.2016.04.006. PMID 27106402. S2CID 29717535. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30–50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people.
  9. ^ Kim JS, Khamoui AV, Jo E, Park BS, Lee WJ (October 2013). "β-Hydroxy-β-methylbutyrate as a countermeasure for cancer cachexia: a cellular and molecular rationale". Anticancer Agents Med. Chem. 13 (8): 1188–1196. doi:10.2174/18715206113139990321. PMID 23919746.
  10. ^ Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Crit. Rev. Food Sci. Nutr. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID 24279396. S2CID 22657268. Creatine, carnitine, HMB, and taurine are reported to delay the onset of fatigue, improve exercise performance, and body strength. HMB helps in increasing fat-free mass and reduce exercise induced muscle injury. ... [Need full text for more detail]
  11. ^ Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708. PMID 27187465. Given the role of leucine as the master dietary regulator of muscle protein turnover, the ingestion of protein sources enriched with this essential amino acid, or its metabolite β-hydroxy β-methylbutyrate, is thought to offer the greatest benefit in terms of preservation of muscle mass and function in old age. ... Recently, it has been demonstrated that β-hydroxy β-methylbutyrate (HMB)—an amino acid metabolite of leucine—is able to stimulate protein synthesis and improve muscle strength and body composition in older adults [67]. ...
    6.2. Nutritional Supplementation with HMB
    HMB is an active leucine metabolite which activates the mTOR signaling pathway in muscle. Following its absorption, dietary leucine is converted into α-ketoisocaproate (KIC), which is further metabolized into either isovaleryl-CoA or HMB. Under normal conditions, the majority of KIC is converted into isovaleryl-CoA, while only approximately 5% of leucine is metabolized to HMB. This implies that, in order to reach pharmacological levels of HMB, this compound needs to be administered directly, rather than via increasing leucine dosage. It has recently been suggested that HMB may be used to protect or restore muscle mass in older persons with reduced lean body mass [74].
    HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68]. The daily administration of a nutritional mixture including HMB (2 g), arginine (5 g), and lysine (1.5 g) for 12 weeks was shown to improve physical performance, muscle strength, fat-free mass and protein synthesis in sedentary older women [74]. More recently, Deutz and colleagues [13]—in a multicenter, randomized, placebo-controlled, double-blind trial—demonstrated that the early administration (within 72 h of hospitalization) of a nutrient-dense oral nutritional supplement containing high concentrations of protein and HMB was associated with decreased post-discharge mortality and improved nutritional status in malnourished older adults [13].
  12. ^ Mullin GE (February 2014). "Nutrition supplements for athletes: potential application to malnutrition". Nutr. Clin. Pract. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID 24336486.
  13. ^ "3-Hydroxyisovaleric acid". Human Metabolome Database. 11 February 2016. Retrieved 25 May 2016.
  14. ^ a b Phillips SM (July 2015). "Nutritional supplements in support of resistance exercise to counter age-related sarcopenia". Adv. Nutr. 6 (4): 452–460. doi:10.3945/an.115.008367. PMC 4496741. PMID 26178029.
  15. ^ Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). J. Physiol. (Lond.). 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. Retrieved 27 May 2016.
  16. ^ Szcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T (June 2015). "Dietary supplementation of β-hydroxy-β-methylbutyrate in animals - a review". J Anim Physiol Anim Nutr (Berl). 99 (3): 405–417. doi:10.1111/jpn.12234. PMID 25099672. Retrieved 1 June 2016. Cholesterol is a major component of the cell membrane, and sarcolemma is the one that relies mainly on de novo synthesis of cholesterol. This is important under stressful conditions when muscle cells may lack the capacity to produce adequate amounts of the cholesterol that is essential to proper functioning of cell membranes. Many biochemical studies have shown that HMB may be a precursor of cholesterol synthesis (Bachhawat et al., 1955; Bloch et al., 1954; Coon et al., 1955; Adamson and Greenberg, 1955; Gey et al., 1957). According to pertinent literature, HMB carbon is incorporated into cholesterol. Therefore, increased intramuscular HMB concentrations may provide readily available substrate for the cholesterol synthesis that is needed to form and stabilize the sarcolemma. ... In theory, HMB use as a precursor to cholesterol could aid in stabilizing muscle cell membranes; however, this has not been confirmed by research studies.
  17. ^ Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708. PMID 27187465. HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68]. ... More recently, Deutz and colleagues [13]—in a multicenter, randomized, placebo-controlled, double-blind trial—demonstrated that the early administration (within 72 h of hospitalization) of a nutrient-dense oral nutritional supplement containing high concentrations of protein and HMB was associated with decreased post-discharge mortality and improved nutritional status in malnourished older adults [13].
  18. ^ a b c d e f g h Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (June 2016). "Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease". J. Am. Med. Dir. Assoc. 17 (9): 789–96. doi:10.1016/j.jamda.2016.04.019. PMID 27324808. Studies suggest dietary protein and leucine or its metabolite b-hydroxy b-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. ... These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia.65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84 A growing body of evidence suggests HMB may help slow, or even reverse, the muscle loss experienced in sarcopenia and improve measures of muscle strength.44, 65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84 However, dietary leucine does not provide a large amount of HMB: only a small portion, as little as 5%, of catabolized leucine is metabolized into HMB.85 Thus, although dietary leucine itself can lead to a modest stimulation of protein synthesis by producing a small amount of HMB, direct ingestion of HMB more potently affects such signaling, resulting in demonstrable muscle mass accretion.71, 80 Indeed, a vast number of studies have found that supplementation of HMB to the diet may reverse some of the muscle loss seen in sarcopenia and in hypercatabolic disease.65, 72, 83, 86, 87 The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation.68 ...
    Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB.     {{cite journal}}: External link in |quote= (help)
  19. ^ Rahman A, Wilund K, Fitschen PJ, Jeejeebhoy K, Agarwala R, Drover JW, Mourtzakis M (July 2014). "Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation?". JPEN J. Parenter. Enteral Nutr. 38 (5): 567–575. doi:10.1177/0148607113502545. PMID 24072740. More than 20 publications in humans have demonstrated benefit with HMB supplementation associated with increased lean body mass without fat gain, improved markers of muscle strength, and decreased onset of muscle soreness with training and reduced markers of muscle damage.5,29

Seppi333 (Insert 2¢) 20:36, 29 April 2016 (UTC)

Thanks for posting those sources! I cannot believe how crappy that 2013 review is. Disturbing. Am going to open a discussion at WT:MED about it. Jytdog (talk) 18:16, 30 April 2016 (UTC)
@Jytdog: I've only read (mostly) through half of these, but it appears that the reviews that describe HMB's effects in general (i.e., not solely in the context of a pharmacotherapy for sarcopenia/muscle wasting) - [1][2] - draw the same or even stronger conclusions about its effects in humans compared to the ISSN review. I'll probably end up relying on the newer reviews for supporting statements about clinical effects, so using this source to independently support such statements won't be an issue.
Also, I'm considering taking this article to FA status since its primary clinical/therapeutic effect is unique and improving the article won't be too much work compared to other drug articles that I've worked on; there's only a handful of reviews and a few database refs from which to collate information on the compound, so finding all the relevant information to satisfy the comprehensiveness criterion won't be difficult (researching/revising amphetamine for FA took over a year; this would probably take ~1 month). With that in mind, if you have any feedback on the other sources or any other suggestions, I'd be interested to hear it. Seppi333 (Insert 2¢) 16:51, 20 May 2016 (UTC)

@Jytdog: Hey, sorry to bother you again with this request, but would you be willing to send me these 5 reviews?[3][4][5][6][7] They're paywalled and I don't have access. I'd really appreciate it. Seppi333 (Insert 2¢) 22:28, 23 May 2016 (UTC)

I sent them all except PMID 23919746 which my library doesn't get. Jytdog (talk) 00:30, 24 May 2016 (UTC)
 Thank you very much! I appreciate it. Hopefully I can get that last one from WP:RX. Seppi333 (Insert 2¢) 05:08, 24 May 2016 (UTC)

December 2016

  • Review of HMB's effects on skeletal muscle, pharmacodynamics, and pharmacokinetics from January 2016[8]
  • Systematic review on supplements for cachexia from 2016[9]

Seppi333 (Insert 2¢) 19:15, 5 December 2016 (UTC)

References

  1. ^ Cite error: The named reference Molecular Aspects of Medicine 2016 review was invoked but never defined (see the help page).
  2. ^ Cite error: The named reference PEDs in sports 2015 review was invoked but never defined (see the help page).
  3. ^ Cite error: The named reference HMB for cancer cachexia 2013 review was invoked but never defined (see the help page).
  4. ^ Cite error: The named reference Effects of amino acid derivatives 2015 review was invoked but never defined (see the help page).
  5. ^ Cite error: The named reference Nutrition supplements for athletes 2014 review was invoked but never defined (see the help page).
  6. ^ Duan Y, Li F, Li Y, Tang Y, Kong X, Feng Z, Anthony TG, Watford M, Hou Y, Wu G, Yin Y (January 2016). "The role of leucine and its metabolites in protein and energy metabolism". Amino Acids. 48 (1): 41–51. doi:10.1007/s00726-015-2067-1. PMID 26255285. S2CID 254080284.
  7. ^ Mochamat, Cuhls H, Marinova M, Kaasa S, Stieber C, Conrad R, Radbruch L, Mücke M (July 2016). "A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project". Journal of Cachexia, Sarcopenia and Muscle. 8 (1): 25–39. doi:10.1002/jcsm.12127. PMC 5326814. PMID 27897391.

Recent preclinical research

  • Covers HMB's effects on protein synthesis in brain cells, neurite outgrowth, and age-related dendritic remodeling in the brain of various nonhuman animals:
    • Evidence that HMB is a (non-protein small molecule) neurotrophic factor in the brain of nonhuman animals (mice - in vitro/rats - in vivo)[1][2]
    • Increases protein synthesis in the mouse brain (in vitro) and pig brain (in vivo)[1][3]

Seppi333 (Insert 2¢) 03:19, 28 May 2016 (UTC)

References

  1. ^ a b Salto R, Vílchez JD, Girón MD, Cabrera E, Campos N, Manzano M, Rueda R, López-Pedrosa JM (August 2015). "β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells". PLOS ONE. 10 (8): e0135614. Bibcode:2015PLoSO..1035614S. doi:10.1371/journal.pone.0135614. PMC 4534402. PMID 26267903. In conclusion, we have shown for the first time that HMB promoted neurite outgrowth through PI3K/Akt and ERK1/2 signaling pathways in Neuro2a cells. Its effect in neuron differentiation is concomitant with higher levels of glucose transporters, the activation of mTOR by mTORC2 and consequently an increase in protein synthesis. Moreover, HMB is involved in promoting MEF2 activity and expression of members of this family of transcriptional factors. We believe that HMB may have great potential as [a neurotrophic] factor promoting neuron differentiation and plasticity. Our results indicated a novel effect of HMB on neurite outgrowth and call to further studies to reveal its positive influences on cognitive outcomes.
  2. ^ Kao M, Columbus DA, Suryawan A, Steinhoff-Wagner J, Hernandez-Garcia A, Nguyen HV, Fiorotto ML, Davis TA (May 2016). "Enteral β-Hydroxy-β-Methylbutyrate Supplementation Increases Protein Synthesis in Skeletal Muscle of Neonatal Pigs". Am. J. Physiol. Endocrinol. Metab. 310 (11): E1072–84. doi:10.1152/ajpendo.00520.2015. PMC 4935142. PMID 27143558. The fractional rates of protein synthesis in the brain were greater in the piglets supplemented with HMB 40 and 80 or fed the HP diet compared to feeding the LP diet alone or the fasting condition (P < 0.05, Fig. 5, G).

mTOR signaling cascades

Leaving this here for personal reference.

  • Has a detailed mTOR signaling cascade diagram[1]
  • Discusses and includes a diagram of signaling cascades involved in MPS/MPB[2] hosted here temporarily

Seppi333 (Insert 2¢) 08:51, 1 June 2016 (UTC) Updated 00:42, 27 August 2016 (UTC)

References

  1. ^ Lipton JO, Sahin M (October 2014). "The neurology of mTOR". Neuron. 84 (2): 275–291. doi:10.1016/j.neuron.2014.09.034. PMC 4223653. PMID 25374355.
    Figure 2: The mTOR Signaling Pathway
  2. ^ Anthony TG (July 2016). "Mechanisms of protein balance in skeletal muscle". Domest. Anim. Endocrinol. 56 Suppl (Suppl): S23 – S32. doi:10.1016/j.domaniend.2016.02.012. PMC 4926040. PMID 27345321.

Should be able to write a comprehensive biosynthesis/metabolism section using these 5 refs:

  1. [1] (covers α-KIC → HMB reaction)
  2. [2] (covers most of the metabolic pathway; has another diagram)
  3. [3] (covers HMB-CoA → HMB)
  4. [4] (covers most of the metabolic pathway; includes the same metabolic pathway graphic as the ISSN review)
  5. ISSN review - PMID 23374455 (review with the article's current metabolic pathway graphic)

Seppi333 (Insert 2¢) 00:10, 7 June 2016 (UTC)

References

  1. ^ a b "Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction". MetaCyc. SRI International. 20 August 2012. Retrieved 6 June 2016.
  2. ^ a b Kohlmeier M (2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 9780123877840. Figure 8.57: Metabolism of L-leucine {{cite book}}: External link in |quote= (help)
  3. ^ Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". J. Nutr. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457. PMID 21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.
For Nergaal's review
WADA and NCAA refs
  • allowed by WADA and the NCAA[1] plus Added
  • WADA banned substances list[2] plus Added
Physical/Chemical properties and classification refs

References

  1. ^ Rippe JM (2013). "Beta-Hydroxy beta-methylbutyrate". Lifestyle Medicine (2nd ed.). CRC Press. p. 724. ISBN 9781439845448. Retrieved 15 August 2016.
  2. ^ "List of Prohibited Substances and Methods: By Substance". World Anti-Doping Agency. 2016. Retrieved 15 August 2016.
  3. ^ "3-hydroxyisovaleric acid". Chemical Entities of Biological Interest. European Bioinformatics Institute. 23 October 2015. Retrieved 20 August 2016.
  4. ^ "3-hydroxyisovalerate". Chemical Entities of Biological Interest. European Bioinformatics Institute. 16 September 2014. Retrieved 20 August 2016.
For Jytdog's review
Primary clinical research involving Juven (3 g HMB + 14 g arginine + 14 g glutamine)
  • PMID 11975938 - 2002 trial of Juven for cancer cachexia
  • PMID 12192323 - 2002 trial examining the effect of Juven on collagen deposition
  • PMID 17215743 - 2007 trial examining the effects of Juven in critically ill trauma patients.
  • PMID 18293016 - 2008 Phase 3 clinical trial of Juven w/o exercise for cancer cachexia
  • PMID 26420181 - 2015 trial of Juven for postoperative recovery of quadriceps muscle strength after total knee arthroplasty
  • PMID 26306566 - 2016 trial with Juven examining the effect on vascular endothelial function in older adults after 6 months


Reviews covering clinical trials with Juven

HMB mixed with other molecules in chronic diseases

Interesting results were observed during cancer, notably, patients with advanced (stage IV) cancer receiving a HMB/ ARG/GLN supplement gained 0.95 ± 0.66 kg of BM in 4 weeks and a change in body composition (FFM increase of 1.12 ± 0.68 kg). The FFM increase was maintained over the 24 weeks (May et al. 2002). Human immunodeficiency virus (HIV)-infected patients gained 3.0 ± 0.5 kg of BM after 8 weeks of HMB/ARG/GLN supplementation, mainly FFM (2.55 ± 0.75 kg). HMB/ARG/GLN supplementation also improved immune status, measured by increasing CD3 and CD8 cells and decreasing the HIV viral load. The HMB/ARG/GLN-supplemented group presented an increased BUN concentration due to higher nitrogen intake and trends towards lower triglyceride levels, higher protein and higher hemoglobin levels not due to treatment (Clark et al. 2000). Regarding haemoglobin, the magnitude of the response to HMB/ARG/GLN was more apparent in cancer patients compared to HIV patients and healthy volunteers. These results show that HMB/ARG/GLN can be safely used to treat AIDS- and cancer-related muscle wasting (Rathmacher et al. 2004). Berk et al. (2008) showed a strong trend towards higher FFM and BM in HMB/ARG/GLN-supplemented patients but they did not adequately test the ability of HMB/ARG/GLN to reverse or prevent cancer cachexia because most of patients did not complete the study. It was also demonstrated that both placebo and experimental amino acid mixtures significantly increased FFM, total body protein, arms and legs lean mass, and measures of physical function in rheumatoid arthritis patients but HMB/ARG/GLN supplementation was not superior to placebo in reversing rheumatoid cachexia (Marcora et al. 2005). No influence of HMB/ARG/GLN administration on the decrease in BM, body mass index (BMI), FFM and resting metabolic rate (RMR) after laparoscopic gastric bypass (LGB) was observed. Therefore, there was no potential preservation of FFM (Clements et al. 2011; Breitman et al. 2011). In addition, no effects on the early postoperative incretins after LGB, negative influence on insulin sensitivity, and degree of inflammatory markers after HMB/ARG/GLN administration were measured (Breitman et al. 2011).

— PMID 24057808 / #cite_note-Systematic_review_December_2013-5

For Nergaal+Axl's reviews (History section content)

Metabolic Technologies, Inc. (MTI) is a small research and development company located in the Iowa State University Research Park in Ames, Iowa, with current sales just under $2 million annually. MTI was founded in 1990 with the vision of developing and marketing naturally derived products that enhance health, performance, and well-being. ...

Developed Products: The first commercial product developed was HMB® or β-hydroxy-β-methylbutyrate. This naturally occurring leucine metabolite has become a standard bearer in the sports nutrition market by having superior efficacy and safety data available. HMB is now protected under several patents. HMB is currently sold as a calcium salt, CaHMB.

The second commercial product MTI developed was Juven®. Juven® is a combination of arginine, glutamine, and HMB. Clinical studies showed that this product enhanced maintenance and restoration of muscle mass in both AIDS and cancer patients. In 2003, the rights to market Juven® were acquired by Abbott Nutrition. Abbott Nutrition currently markets Juven® for AIDS, cancer-cachexia, and wound healing.

Although not commercially developed yet, a third product, Re-Vigor®, was researched and designed by MTI. Re-Vigor® is a combination of arginine, lysine, and HMB, and is intended to slow down muscle wasting in the elderly. In 2008, the rights to this product were acquired by Abbott Nutrition. ...

As previously stated, MTI has been successful in transitioning HMB from an “exercise commodity” to that used by medical nutritional products (Juven® and Abound®-- Abbott Nutritional Laboratories).
— The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011

References

  1. ^ "The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011" (PDF). University of Iowa. pp. 13–16. Retrieved 1 September 2016.

Seppi333 (Insert 2¢) 00:55, 25 August 2016 (UTC)

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