--- In morelife@yahoogroups.com, "spboulet" <stephen@...> wrote:
>
> --- In morelife@yahoogroups.com, Ólafur Páll Ólafsson <olafurpall@>
> wrote:
>
> > For clarity and to prevent misunderstanding it would have been better
> > to have the above quote from the abstract within quote marks to
> > clearly separate it from the sentence you wrote below.
>
> I'll stay away from the advanced Yahoo editor next time.

So you used the advanced Yahoo editor, that explains it. According to
the groups policy the use of Rich Text is discouraged. Only text
messages are allowed in this group, thus your message must have been
converted from Rich Text to text resulting in loss of formatting. See
this quote taken from the "Group Policy" file under the file section
of the group (in the "Group Admin" folder).

"Third:
Because we want all messages to be readable as widely as possible,
*only text messages* will be accepted for this group. To ensure that,
we have selected the group management option that causes messages with
attachments to be rejected.
This option also causes all html messages to be converted to text.
Note that although Yahoo still allows posters to select Rich Text for
their message composition, since Rich Text requires html code, all
Rich Test formatting will be lost when the message appears in the
queue for posting. This will generally not only lose such formatting,
but will also cause the message to be so poorly formatted (all run
together) that a great deal of editing by the moderators will be
necessary. Therefore, DO NOT USE THE RICH-TEXT EDITOR."

> > There is need for more research in this area but in
> > general I do not think glycation of lipids is as harmful as that of
> > proteins.
>
> That seems to be the case from what I can tel.
>
> > > The next study however seems to be for protein glycation
> > > (http://pubmed.gov/17449494, August 2007:
> > > Streptozotocin (STZ)-induced diabetic rats were treated by oral
> > > administration of PLP or pyridoxamine (PM), another active form of
> > > vitamin B6, at a dose of 600 mg/kg/day for 16 weeks. ... PLP was
> > > superior to PM in inhibiting accumulation of AGEs, expression of
> > > TGF-beta1, type 1 collagen, and fibronectin, and the development of
> > > diabetic nephropathy.
> >
> > Now this is a study I had not seen before. I am surprised to see that
> > PLP was found to be superior to pyridoxamine in that study. Except for
> > this study, the only study of which I am aware that directly compares
> > PLP to pyridoxamine is this one: http://pmid.us/8602828 . That is an
> > in vitro study. In that study pyridoxamine was found to be the most
> > effective antiglycating compound followed by PLP, pyridoxal and
> > pyridoxine. Why PLP was found to be more effective than pyridoxamine
> > in the above study is difficult to say. There are reasons to suspect
> > this would not apply to humans.
> >
> > The absorption of phosphorylated forms of vitamin B6 generally starts
> > with hydrolysis by alkaline phosphatase in the digestive tract. PLP
> > thus will be hydrolized to pyridoxal before being absorbed. If this is
> > the case PLP should not be any more effective than pyridoxal as an
> > antiglycative agent when taken orally. However when very high doses
> > are taken some of the PLP may escape hydrolysis and be absorbed
> > intact. From the full text of http://pmid.us/479949 :
> >
> > "At physiological doses PLP is absorbed largely after hydrolysis to
> > PL, though a small percentage is absorbed without hydrolysis. This
> > direct absorption of PLP which is several fold slower than PL could be
> > important only at doses well above physiological level."
> >
> > Normally the majority of PLP will be hydrolized and absorbed as
> > pyridoxal but when high doses are taken some of it may be absorbed
> > intact. How high is difficult to say though but this may explain the
> > results of the above study since in that study a very high dose of PLP
> > was used. Most certainly some of it was absorbed intact without first
> > being hydrolized allowing PLP to provide beneficial antiglycating
> > protection.
>
> Perhaps there is a role for sublingual or bucchal P5P? It sounds like
> not much might be needed.

Yes this is a case where such administration might prove to be
beneficial. However I searched for and did not find any studies on
sublingual or buccal administration of PLP. I wouldn't count on much
of it being absorbed by such a route. I suggest waiting for further
research until it is determined exactly how effectively PLP is
absorbed by a sublingual or buccal route.

[Note: The reason that Olafur (and I also) keeps using the abbreviation PLP for
pyridoxal phosphate is because that has always been the official scientific
abbreviation used in all publications and texts. The abbreviation P5P is used
only by supplement suppliers in their articles and descriptions (perhaps because
the Merck Index uses the short name "Pyridoxal 5-Phosphate" for this molecule)
and is not as uniquely clearly related to pyridoxal as is PLP - for example
based on their structures, PMP (pyridoxamine phosphate) and PNP (pyridoxine
phosphate) could equally as well be called P5P. --Paul]

> > But I don't think this means PLP by an oral route is
> > superior to pyridoxamine for humans. The dose used in the above study
> > amounts to about 12g of PLP for a 70kg human. That is an extremely
> > large dose! To put it into perspective vitamin B6 generally causes
> > neurotoxicity at doses in excess of 1g per day in humans. There are
> > even reports of neurotoxicity from taking vitamin B6 in doses as low
> > as 100-300mg http://pmid.us/16320662 . For prevention 400mg per day of
> > vitamin B6 is about the most I would recommend to any adult human.
> > Thus as is so often the case this study has no applicability to
> > chronic human intakes of vitamin B6 for prevention.
> >
> > Furthermore pyridoxamine has several studies supporting it's efficacy
> > against glycation in both humans and animals while PLP has much fewer.
> > Newertheless this study does suggest that PLP may be superior to
> > pyridoxal as well as the commonly used pyridoxine when it comes to
> > antiglycative function particularly when high doses of PLP are taken.
> >
> > > Finally, in this study, http://pubmed.gov/18004515,
> > > Amino acids react with methylglyoxal to form advanced glycation end
> > > products. This reaction is known to produce free radicals. In this
> > > study, cleavage to plasmid DNA was induced by the glycation of
lysine
> > > with methylglyoxal in the presence of iron(III). This system was
found
> > > to produce superoxide as well as hydroxyl radicals. The abilities of
> > > various vitamins to prevent damage to plasmid DNA were evaluated.
> > > Pyridoxal-5-phosphate showed maximum protection, while pyridoxamine
> > > showed no protection. The protective abilities could be directly
> > > correlated to inhibition of production of hydroxyl and superoxide
> > > radicals. Pyridoxal-5-phosphate exhibited low radical scavenging
> ability
> > > as evaluated by its TEAC, but showed maximum protection probably by
> > > interfering in free radical production. Pyridoxamine did not inhibit
> > > free radical production.
> >
> > I am surprised by the results of the above study, particularly these
> > parts:
> > "The protective abilities could be directly correlated to inhibition
> > of production of hydroxyl and superoxide radicals. ... Pyridoxamine
> > did not inhibit free radical production."
> >
> > This is surprising in light of the fact that pyridoxamine has been
> > shown to be able to scavenge free radicals, including the hydroxyl
> > radical http://pmid.us/18374270 .
> >
> > This study suggests that under some conditions PLP may be superior to
> > pyridoxamine with respect to inhibiting glycation. But keep in mind
> > that this is an in vitro study. A large portion of the PLP taken
> > orally will generally be hydrolized to pyridoxal before being
absorbed.
> >
> > > Is there something I'm missing, or is P5P better at preventing AGE
> > > formation?
> >
> > Under some conditions yes pyridoxal-5-phosphate is better at
> > preventing AGE formation, while under some conditions pyridoxamine is
> > better. Overall however the evidence is strongly in favor of
> > pyridoxamine being the most effective antiglycative agent, at least by
> > an oral route. First of all because much of the PLP will be hydrolized
> > during digestion to pyridoxal whose antiglycating ability is much
> > poorer than that of pyridoxamine or PLP. Also because in general there
> > are far more in vivo studies supporting the effectiveness of
> > pyridoxamine in preventing AGE formation than there are for PLP.
> >
> > In conclusion among the B6 vitamers I think pyridoxamine is the best
> > orally administered antiglycative agent for humans. But the evidence
> > indicates that PLP, while not as effective as pyridoxamine, would be a
> > good choice over pyridoxine the form that not only appears to be the
> > least effective for glycation but unfortunately is the most common one
> > also in supplements.
> >
> > > Stephen
>
> Thank you very much for your reply. It's fortunate for us that you
> were in the middle of looking into this.
>
> You should also take a look at this post at imminst.org:
>
>
http://www.imminst.org/forum/index.php?showtopic=27493&view=findpost&p=297712

Thanks, I just read over that thread. BTW I am not a member of
imminst.org for reasons I've already made clear but I do sometimes
read the message boards there, mainly the supplement and lifestyle
sections.

> I've brought up some of the commentary you made over there. I hope
> that is OK -- I don't want to step on anyone's toes.

That is fine. Anything I post here you can post elsewhere. The only
thing I ask for is that you link to the original post.

> In his post
> there, Michael argues that P5P is the better anti-glycation agent, but
> that pyridoxamine has better safety data behind it.

I agree with this last, that pyridoxamine has better safety data
behind it, but not with his conclusion that PLP is a better
anti-glycation agent. For rats taking extremely high doses of PLP it
may be a better anti-glycation agent but for humans taking reasonable
doses of it I think pyridoxamine is better.

Reading over his post there are two major points he makes which I want
to address. The first one is this:

"IAC, the key point for me is not the ultimate answer to this
particular issue, but the outcome on actual health parameters. (4) is
an in vivo study showing that P5P lowers AGE/ALE even more than
pyridoxamine, and leads to better health outcomes; ther is no
equivalent data for pyridoxine, and until someone does a comparative
study with a B6 arm showing that it performs as well or better, the
take-home message is to take P5P."

I disagree with his conclusion above. Here he is referring to
http://pmid.us/17449494 , the study you posted and I previously
criticized for using extremely high doses of PLP, doses that are so
high that the results of that study can not be extrapolated to humans
taking reasonable doses of pyridoxamine. Another point he makes is
this one:

"Moreover, high-dose B6 has been reported to cause a reversible
neuropathy, which has not been reported (as I would assume that it
would be) for quite high dose P5P in the pharma trials ((6) and its
Phase II precursor), which may also somehow involve the
pharmacokinetics or pharmacodynamics;"

Here he refers to http://pmid.us/18381567 a human study on the
efficacy and safety of PLP. The full text of that study is free
through pubmed. As seen in the full text 1519 patients were given
250mg per day of a drug containing pyridoxal 5-phosphate monohydrate.
On a molar basis this is equivalent to about 235mg per day of PLP. I
don't think the fact that no reports of neurotoxicity were reported in
this study means PLP is any safer than pyridoxamine. In this respect
it is important to mention that most of the reports of neurotxicity
resulting from high intakes of vitamin B6 involved ingestion of
pyridoxine the most common form of vitamin B6 in supplements. In the
case of pyridoxine, neurotoxicity doesn't usually occur except at
doses a good bit higher than 235mg per day http://pmid.us/16320662 .
In addition research suggests that pyridoxal, pyridoxamine and PLP are
all less toxic than pyridoxine http://pmid.us/15558839 . In light of
this, the fact that PLP in doses equivalent to 235mg of PLP daily did
not cause signs of neurotoxicity in the study above is not surprising
at all and is not suggestive of PLP being any safer than pyridoxamine.

> On the whole I'm
> leaning back more to PM, but am curious about bypassing hydrolisis
of P5P.

Except for sublingual or buccal administration, the effectiveness of
which is not known in the case of PLP, I am not aware of any
reasonable way to get PLP to be absorbed without first being
hydrolized. Ingesting high amounts of phosphate along with the PLP to
saturate intestinal alkaline phosphatase could work (this was done in
some of the rat studies) but that would be unhealthy for other reasons.

[Note: In the case of PLP, hydrolysis (literally - "breaking apart by the
addition of water") is the removal of the phosphate group from the molecule to
leave pyridoxal (PL). --Paul]