What would be the difference in using Carnosine versus L-Carnosine regarding effectiveness and undisirable effects?
LongeCityAdvocacy & Research for Unlimited Lifespans
Carnosine, LEF, and Dr. E.K. Schandl
Started by
angelfire
, Jan 31 2006 03:09 AM
42 replies to this topic
#32
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Posted 18 February 2006 - 09:24 PM
Carnosine exists in either of two forms, or a mixture of the two. A product labeled as "carnosine" these days, is likely the L- form, though one can purchase D- from chemical companies, for approved, non-food, use, I would guess.
D- and L- (or R- and S-) are designations for chirality of the molecule -- each is the mirror image of the other. Stereoisomer is another term for this.
Any molecule that exists in chiral forms usually has one form that is biologically active, wrt a given biochemical frame of reference. Chiral mixtures can be produced easily during synthetic processes where an enzyme isn't used to control the reaction product, say. If this happens, a subsequent purification step can be used, to purify the form that's biologically active, and leave behind the form that is either inactive (benign wrt biological system it's being used in), or possibly active, but having potential as-yet-to-be-defined side-effects. Side effects would likely be concentration dependent, so taking small doses of a mixture might not be a problem, but unless large scale trials are done in humans, over long periods, one has little basis to assess the risk.
There have been cases of severe side effects associated with ingestion of the "wrong" (typically biologically uncommon or not found in nature) isomer.
D- and L- (or R- and S-) are designations for chirality of the molecule -- each is the mirror image of the other. Stereoisomer is another term for this.
Any molecule that exists in chiral forms usually has one form that is biologically active, wrt a given biochemical frame of reference. Chiral mixtures can be produced easily during synthetic processes where an enzyme isn't used to control the reaction product, say. If this happens, a subsequent purification step can be used, to purify the form that's biologically active, and leave behind the form that is either inactive (benign wrt biological system it's being used in), or possibly active, but having potential as-yet-to-be-defined side-effects. Side effects would likely be concentration dependent, so taking small doses of a mixture might not be a problem, but unless large scale trials are done in humans, over long periods, one has little basis to assess the risk.
There have been cases of severe side effects associated with ingestion of the "wrong" (typically biologically uncommon or not found in nature) isomer.
#33
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Posted 18 February 2006 - 09:31 PM
After I get some carnosine in bulk]
I've decided, as well, on an interim basis, to ingest the MEO as 3 caps in AM, and 1 cap in PM (12 hours later). Previously I'd been ingesting all 4 in AM. If I can define the risk more, I may go to 2+2, to get the same pharmacokinetic profile each 12 hours. With 3+1, I should get (though I can't be certain without more data) a gap in coverage between AM and PM dosing. I suspect, as noted in prior posts, that the slow, wide, symmetrical curve noted in the 200g meat ingestion study, reflects gastric emptying rate, and that uptake via small intestine will be faster and asymmetrical, similar to most pharmaceutical dosing, if done on empty stomach for both doses. This remains to be determined, though. Will keep all posted, should I drop like the proverbial fly.
#34
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Posted 19 February 2006 - 01:38 AM
OK, well thanks trh001.
I think it's a good point about a higher steady state than an even increasing concentration.
I think 1000mg a day in one dose (considering the breakdown) should be OK, especially with a 1 day/week break to prevent any long term build up...
That autism study above, does it say how the 800mg dose is spread (I probably missed it)?
So the issue I need to decide, when considering trh001 and funkodyssey, are whether it is better to maintain a constant level by splitting this dose for all the various carnosine-benefit reasons (say 4 * 250mg), or whether this may slightly mimic carnosinemia (as funkodyssey suggests) or not be as desireable in other ways...
Thanks.
I think it's a good point about a higher steady state than an even increasing concentration.
I think 1000mg a day in one dose (considering the breakdown) should be OK, especially with a 1 day/week break to prevent any long term build up...
That autism study above, does it say how the 800mg dose is spread (I probably missed it)?
So the issue I need to decide, when considering trh001 and funkodyssey, are whether it is better to maintain a constant level by splitting this dose for all the various carnosine-benefit reasons (say 4 * 250mg), or whether this may slightly mimic carnosinemia (as funkodyssey suggests) or not be as desireable in other ways...
Thanks.
#35
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Posted 19 February 2006 - 02:12 AM
My reasoning is that splitting it up into 4 doses throughout the day should still be fine because you've got ~9 hours between the last dose and the next morning dose. I am reasonably confident the body will bring carnosine levels back to baseline in less than 9 hours (at least with the 250-300mg doses we've been discussing).
If you took enough carnosine often enough to keep the enzyme that breaks down carnosine saturated 24/7, then carnosine levels would rise in a cumulative fashion every day and get out of control (if I understand correctly). So my proposed dosing scheme avoids that with the daily return to baseline while sleeping.
If you took enough carnosine often enough to keep the enzyme that breaks down carnosine saturated 24/7, then carnosine levels would rise in a cumulative fashion every day and get out of control (if I understand correctly). So my proposed dosing scheme avoids that with the daily return to baseline while sleeping.
#38
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Posted 25 February 2006 - 11:38 PM
In searching for more info on human dosing....
The paper below also discusses the role of beta-alanation of L-histadine (not L-alanine, beta-alanine) as a means keeping L-histidine reserved for use in a whole range of histidine containing peptides which are in fact more potent, in many assays, than L-carnosine. This suggests L-histidine may be a valuable supplement, given it's cheaper cost and ability to be synthesized into a spectrum of peptides related to carnosine.
Given the tone of the article: let's get this valuable class of compounds out of the "food supplement" stores, and into the clinic, is rather offensive, despite it being an accurate assessment of why clinical trials have not been done. They simultaniously cite it's mirad documented benefits in vivo and in vitro, yet scorn it's sale as an "anti-aging" supplement.
Authors suggest all literature, taken together since 1900, suggests safe in chronic doses as high as 100mg per day oral (no references specific to this, so not very helpful -- and does not mean it's unsafe at higher doses, obviously).
Suggest that carnosinase's role is to make L-histidine available for conversion into *other* carnosine-like peptides, so L-carnosine is in part a buffer peptide, keeping it in reserve for other uses, to avoid having L-histidine used up for other purposes.
Authors cite recent studies showing carnosine and it's family of peptides have efficacy against a new threat: ALE (advanced lipoxygenase end products) as well as AGE's. The former being amino acids reacting with organic peroxides (fat derived peroxides).
Authors suggest that carnosine and it's peptides are too valuable to be left in the public domain, as this prevents large scale clinical trials; they opine the lack of patentability, and the FDA refusal to take Carnosine (and acetyl-carnosine) off the "food supplement" listing, to allow pharmaceutical companies to patent it's use and restrict it to prescription.
They note that acetylated carnosine is the "hottest selling" carnsoine product on the market today, sold as "Brite Eyes, etc", and suggest that lack of medical progress in treating diseases will result from having this in the public domain, as no large scale studies will be done. They do cite small studies, and suggest physicians consider using this to treat cataracts.
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Curr Med Chem. 2005;12(20):2293-315. Related Articles, Links
Carnosine and carnosine-related antioxidants: a review.
Guiotto A, Calderan A, Ruzza P, Borin G.
Institute of Biomolecular Chemistry of CNR - Padova Unit, Italy. andrea.guiotto@unipd.it
First isolated and characterized in 1900 by Gulewitsch, carnosine (beta-alanyl-L-hystidine) is a dipeptide commonly present in mammalian tissue, and in particular in skeletal muscle cells; it is responsible for a variety of activities related to the detoxification of the body from free radical species and the by-products of membrane lipids peroxidation, but recent studies have shown that this small molecule also has membrane-protecting activity, proton buffering capacity, formation of complexes with transition metals, and regulation of macrophage function. It has been proposed that carnosine could act as a natural scavenger of dangerous reactive aldehydes from the degradative oxidative pathway of endogenous molecules such as sugars, polyunsaturated fatty acids (PUFAs) and proteins. In particular, it has been recently demonstrated that carnosine is a potent and selective scavenger of alpha,beta-unsaturated aldehydes, typical by-products of membrane lipids peroxidation and considered second messengers of the oxidative stress, and inhibits aldehyde-induced protein-protein and DNA-protein cross-linking in neurodegenerative disorders such as Alzheimer's disease, in cardiovascular ischemic damage, in inflammatory diseases. The research for new and more potent scavengers for HNE and other alpha,beta-unsaturated aldehydes has produced a consistent variety of carnosine analogs, and the present review will resume, through the scientific literature and the international patents, the most recent developments in this field.
Publication Types:
Review
PMID: 16181134 [PubMed - indexed for MEDLINE]
The paper below also discusses the role of beta-alanation of L-histadine (not L-alanine, beta-alanine) as a means keeping L-histidine reserved for use in a whole range of histidine containing peptides which are in fact more potent, in many assays, than L-carnosine. This suggests L-histidine may be a valuable supplement, given it's cheaper cost and ability to be synthesized into a spectrum of peptides related to carnosine.
Given the tone of the article: let's get this valuable class of compounds out of the "food supplement" stores, and into the clinic, is rather offensive, despite it being an accurate assessment of why clinical trials have not been done. They simultaniously cite it's mirad documented benefits in vivo and in vitro, yet scorn it's sale as an "anti-aging" supplement.
Authors suggest all literature, taken together since 1900, suggests safe in chronic doses as high as 100mg per day oral (no references specific to this, so not very helpful -- and does not mean it's unsafe at higher doses, obviously).
Suggest that carnosinase's role is to make L-histidine available for conversion into *other* carnosine-like peptides, so L-carnosine is in part a buffer peptide, keeping it in reserve for other uses, to avoid having L-histidine used up for other purposes.
Authors cite recent studies showing carnosine and it's family of peptides have efficacy against a new threat: ALE (advanced lipoxygenase end products) as well as AGE's. The former being amino acids reacting with organic peroxides (fat derived peroxides).
Authors suggest that carnosine and it's peptides are too valuable to be left in the public domain, as this prevents large scale clinical trials; they opine the lack of patentability, and the FDA refusal to take Carnosine (and acetyl-carnosine) off the "food supplement" listing, to allow pharmaceutical companies to patent it's use and restrict it to prescription.
They note that acetylated carnosine is the "hottest selling" carnsoine product on the market today, sold as "Brite Eyes, etc", and suggest that lack of medical progress in treating diseases will result from having this in the public domain, as no large scale studies will be done. They do cite small studies, and suggest physicians consider using this to treat cataracts.
-------------
Curr Med Chem. 2005;12(20):2293-315. Related Articles, Links
Carnosine and carnosine-related antioxidants: a review.
Guiotto A, Calderan A, Ruzza P, Borin G.
Institute of Biomolecular Chemistry of CNR - Padova Unit, Italy. andrea.guiotto@unipd.it
First isolated and characterized in 1900 by Gulewitsch, carnosine (beta-alanyl-L-hystidine) is a dipeptide commonly present in mammalian tissue, and in particular in skeletal muscle cells; it is responsible for a variety of activities related to the detoxification of the body from free radical species and the by-products of membrane lipids peroxidation, but recent studies have shown that this small molecule also has membrane-protecting activity, proton buffering capacity, formation of complexes with transition metals, and regulation of macrophage function. It has been proposed that carnosine could act as a natural scavenger of dangerous reactive aldehydes from the degradative oxidative pathway of endogenous molecules such as sugars, polyunsaturated fatty acids (PUFAs) and proteins. In particular, it has been recently demonstrated that carnosine is a potent and selective scavenger of alpha,beta-unsaturated aldehydes, typical by-products of membrane lipids peroxidation and considered second messengers of the oxidative stress, and inhibits aldehyde-induced protein-protein and DNA-protein cross-linking in neurodegenerative disorders such as Alzheimer's disease, in cardiovascular ischemic damage, in inflammatory diseases. The research for new and more potent scavengers for HNE and other alpha,beta-unsaturated aldehydes has produced a consistent variety of carnosine analogs, and the present review will resume, through the scientific literature and the international patents, the most recent developments in this field.
Publication Types:
Review
PMID: 16181134 [PubMed - indexed for MEDLINE]
#39
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Posted 25 February 2006 - 11:47 PM
Note: wrt this paper above (PMID 16181134) I only have PDF vs. "full text", so can't copy/paste: let me know if you'd like specific quotes.
Still hunting for more info on dosing. As noted, L-histidine deserved some attention as a supplement, if only because it seems to be the basis for interconversion into a spectrum of related peptides, of which carnosine is only one.
A secondary issue: if L-carnosine, and related peptides were to ever leave the shelves under patent (unlikely, but you never know) the would be no precedent to patent L-histidine, so access to this would remain.
Finally, given the cost of L-carnosine relative to L-Histidine, and given the theory held by some (will have to print out and read this in more detail and follow up on specific references in the paper) that L-histidine is the central point of synthesis of a broader functionality via a family of peptides, I may try and cut costs by supplementing more L-histidine, and less L-carnosine. We'll see. Once again, dosing and coverage wrt all these peptides is probably hopelessly lacking in literature.
Still hunting for more info on dosing. As noted, L-histidine deserved some attention as a supplement, if only because it seems to be the basis for interconversion into a spectrum of related peptides, of which carnosine is only one.
A secondary issue: if L-carnosine, and related peptides were to ever leave the shelves under patent (unlikely, but you never know) the would be no precedent to patent L-histidine, so access to this would remain.
Finally, given the cost of L-carnosine relative to L-Histidine, and given the theory held by some (will have to print out and read this in more detail and follow up on specific references in the paper) that L-histidine is the central point of synthesis of a broader functionality via a family of peptides, I may try and cut costs by supplementing more L-histidine, and less L-carnosine. We'll see. Once again, dosing and coverage wrt all these peptides is probably hopelessly lacking in literature.
#40
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Posted 27 February 2006 - 04:22 AM
Unfortunately I don't have access to paper electronically, otherwise we might have some additional dosing data. There are a few observations in the abstract, however, that may be interesting to some, notably...
"Highest carnosinase activities were observed in those subjects who regularly underwent physical training.
Given the evidence for carnosine acting as a reservoir of L-his, releasing L-his when needed for interconversion through a spectrum of L-his peptides with different functionalities similar to carnosine, one wonders if the high level of carnosinase seen in those subjects noted above was an adaptive response to oxidative stress during exercise.
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J Physiol. 1991 Aug;439:411-22. Related Articles, Links
Intestinal absorption of the intact peptide carnosine in man, and comparison with intestinal permeability to lactulose.
Gardner ML, Illingworth KM, Kelleher J, Wood D.
Department of Biomedical Sciences, University of Bradford.
1. Healthy humans ingested the dipeptide carnosine (L-beta-alanyl-L-histidine). Their plasma levels and urinary outputs of carnosine and beta-alanine were monitored over the following 5 h. 2. Large amounts of intact carnosine (up to 14% of the ingested dose) were recovered in the urine over the 5 h after ingestion. However, carnosine was undetectable in the plasma unless precautions were taken to inhibit blood carnosinase activity ex vivo during and after blood collection. 3. The amount of carnosine recovered in urine varied substantially between subjects. It correlated negatively with carnosinase enzymic activity in the plasma. Highest carnosinase activities were observed in those subjects who regularly underwent physical training. 4. Urinary recovery of the disaccharide lactulose also varied considerably between subjects, but was substantially lower than that of carnosine. There was no significant correlation between the recoveries of carnosine and lactulose. 5. When lactulose was ingested with a hypertonic solution, the urinary recovery of lactulose was generally increased. When carnosine was ingested with a hypertonic solution, the urinary recovery of carnosine was reduced: hence the paracellular route probably is not dominant for absorption of intact carnosine. 6. Intact carnosine must have crossed the intestine to an extent much greater than hitherto recognized. Rapid post-absorptive hydrolysis is a severe obstacle to quantification of intact peptide absorption.
PMID: 1910085 [PubMed - indexed for MEDLINE]
"Highest carnosinase activities were observed in those subjects who regularly underwent physical training.
Given the evidence for carnosine acting as a reservoir of L-his, releasing L-his when needed for interconversion through a spectrum of L-his peptides with different functionalities similar to carnosine, one wonders if the high level of carnosinase seen in those subjects noted above was an adaptive response to oxidative stress during exercise.
-----------------
J Physiol. 1991 Aug;439:411-22. Related Articles, Links
Intestinal absorption of the intact peptide carnosine in man, and comparison with intestinal permeability to lactulose.
Gardner ML, Illingworth KM, Kelleher J, Wood D.
Department of Biomedical Sciences, University of Bradford.
1. Healthy humans ingested the dipeptide carnosine (L-beta-alanyl-L-histidine). Their plasma levels and urinary outputs of carnosine and beta-alanine were monitored over the following 5 h. 2. Large amounts of intact carnosine (up to 14% of the ingested dose) were recovered in the urine over the 5 h after ingestion. However, carnosine was undetectable in the plasma unless precautions were taken to inhibit blood carnosinase activity ex vivo during and after blood collection. 3. The amount of carnosine recovered in urine varied substantially between subjects. It correlated negatively with carnosinase enzymic activity in the plasma. Highest carnosinase activities were observed in those subjects who regularly underwent physical training. 4. Urinary recovery of the disaccharide lactulose also varied considerably between subjects, but was substantially lower than that of carnosine. There was no significant correlation between the recoveries of carnosine and lactulose. 5. When lactulose was ingested with a hypertonic solution, the urinary recovery of lactulose was generally increased. When carnosine was ingested with a hypertonic solution, the urinary recovery of carnosine was reduced: hence the paracellular route probably is not dominant for absorption of intact carnosine. 6. Intact carnosine must have crossed the intestine to an extent much greater than hitherto recognized. Rapid post-absorptive hydrolysis is a severe obstacle to quantification of intact peptide absorption.
PMID: 1910085 [PubMed - indexed for MEDLINE]
#43
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Posted 07 May 2006 - 05:05 PM
In a PDF that was posted on this forum, on carnosine, it was stated that a human equivalent dosage of 500mg a day was insufficient to change carnosine levels in muscles, heart, or liver of rats.
It was also stated that benefits consistently emerged at the dose equivalent of 950mg a day for a person of 70kg.
Maynard LM, Boissonneault GA, Chow CK, Bruckner GG.
Free Full Text High levels of dietary carnosine are associated with increased concentrations of carnosine and histidine in rat soleus muscle.
J Nutr. 2001 Feb;131(2):287-90.
PMID: 11160547
Chan WK, Decker EA, Chow CK, Boissonneault GA.
Effect of dietary carnosine on plasma and tissue antioxidant concentrations and on lipid oxidation in rat skeletal muscle.
Lipids. 1994 Jul;29(7):461-6.
PMID: 7968266
It was also stated that benefits consistently emerged at the dose equivalent of 950mg a day for a person of 70kg.
Maynard LM, Boissonneault GA, Chow CK, Bruckner GG.
Free Full Text High levels of dietary carnosine are associated with increased concentrations of carnosine and histidine in rat soleus muscle.
J Nutr. 2001 Feb;131(2):287-90.
PMID: 11160547
Chan WK, Decker EA, Chow CK, Boissonneault GA.
Effect of dietary carnosine on plasma and tissue antioxidant concentrations and on lipid oxidation in rat skeletal muscle.
Lipids. 1994 Jul;29(7):461-6.
PMID: 7968266
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