Eukarion, BUk Institute, Euk-8 & Euk-134
Greg Watson
Whets known about Eukarion, the Buck Institute, Euk-8 & Euk-134?
A Medline search on either of the synthetic Anti-Oxidants turns up some very
interesting papers.
Is this another sleeper like Alteon & their ALT-711?
Eukarion are the folks which did the 50% extension of max LS in nematodes:
http://www.eukarion.com/Press%20Releases/p8_31_00.html
========================
Good Health & Long Life,
Greg Watson,
http://www.ozemail.com.au/~gowatson
gowa...@asiaonline.net.au
Aubrey de Grey
Greg Watson wrote:
> What's known about Eukarion, the Buck Institute, Euk-8 & Euk-134?
The EUK compounds have unprecedentedly high superoxide dismutase
activity for small molecules, and they also have considerable catalase
activity due to the unique redox activity of manganese (it can exhibit
valencies of 2, 3 or 5). Also, unlike some other SOD mimetics, they
cross the blood-brain barrier. Simon Melov at the Buck is the main
researcher on them in academia right now: he was the first author on
the nematode study you cite, and he's currently testing the compounds
for lifespan extension in mice. Unlike ALT-711, as I understand it
there are no significant problems in terms of patent robustness, so it
needn't be long before serious money gets put behind human trials. On
the other hand, there is the ubiquitous problem of aging not being
classified as a disease, which means that a particular clinical effect
(say, retardation of dementia) would have to be both identified and
demonstrated. That may be the main short-term barrier to commercial
exploitation. Eukarion clearly know this, however, as shown by their
current emphasis on animal models of neurodegenerative diseases; when
more in vivo work is published it will move them forward fast, I suspect.
See http://www.eukarion.com/publications.html for a complete list of
the relevant publications.
Aubrey de Grey
Peter H. Proctor
>From: ag...@mole.bio.cam.ac.uk (Aubrey de Grey)
>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>Date: 26 Feb 2001 13:28:03 GMT
>Greg Watson wrote:
>> What's known about Eukarion, the Buck Institute, Euk-8 & Euk-134?
>The EUK compounds have unprecedentedly high superoxide dismutase
>activity for small molecules, and they also have considerable catalase
>activity due to the unique redox activity of manganese (it can exhibit
>valencies of 2, 3 or 5). Also, unlike some other SOD mimetics, they
>cross the blood-brain barrier. Simon Melov at the Buck is the main
>researcher on them in academia right now: he was the first author on
>the nematode study you cite, and he's currently testing the compounds
>for lifespan extension in mice. snip....
There may be a problem with these compounds getting thru the FDA,
except for acute indications and/or forms that do not cross the blood-brain
barrier. This is that chronic exposure to manganous salts induces manganism
in humans. This generally presents as a combination of parkinsonism with a
psychosis.
Here is the rub-- you can't show this effect of manganese easily in
rodent models, so nontoxicity in them may not mean much. It seems to
require substantial amounts of brain melanin, which binds and concentrates
manganese. Few animals have this--- primates and horses are all that come
to mind. And yes, horses can get manganism, if memory serves. The
issue may be whether neuromelanin can snatch manganese from the salen
complex, which I suspect is the case....
Dr P
Peter H. Proctor
>From: ppro...@proctorgamble.com (Peter H. Proctor)
>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
> There may be a problem with these compounds getting thru the FDA,
>except for acute indications and/or forms that do not cross the blood-brain
>barrier. This is that chronic exposure to manganous salts induces manganism
>in humans. This generally presents as a combination of parkinsonism with a
>psychosis.
> Here is the rub-- you can't show this effect of manganese easily in
>rodent models, so nontoxicity in them may not mean much. It seems to
>require substantial amounts of brain melanin, which binds and concentrates
>manganese.
Here is a review article.
Neurotoxicology 1984 Spring;5(1):13-35
Manganese and extrapyramidal disorders (a critical review and tribute to Dr.
George C. Cotzias).
Barbeau A
" In this essay we first review the important contributions of Dr. George
Cotziasto the understanding of chronic manganese intoxication and of manganese
metabolism in man and animals. We also indicate the original contribution of Dr.
John Donaldson to the mechanism of the neurotoxicity of manganese. In a
secondphase, the author challenges the tenet that Parkinson's disease is a
form of chronic manganese intoxication and that manganism is an experimental
model forParkinson's disease. Clinical, pathological, experimental and
biochemical evidence are brought to bear on this argument. Thirdly the author
proposes that the necessary event to the so-called "depigmentation" of the
substantia nigraand subsequent bradykinetic "low dopamine" syndrome is an
early enhancedturnover of dopamine. Manganese intoxication is only one of
the factors which may serve as a trigger to this event. Many others are also
listed. In opposition to current views, who look for causal factors in
Parkinson's disease along the pathways for melanogenesis, the author thus
proposes a novel hypothesis which envisions a variety of transient "trigger
factors" acting at the dopamine synapse to increase dopamine turnover. In
turn, this increased synthesis of dopamine favours the production of large
quantities of free radicals within the cell bodies in the substantia nigra,
eventually overflowing the scavenging capacity of neuromelanin and their
protective barrier, and causing cell death.The resulting decreased pool of
dopamine-producing cells leads to aself-perpetuating situation of ever
increasing demand on the remaining cells,and "progression" of the disease.
Finally the author stresses the fact thatgenetic factors may play a role in an
individual's susceptibility to such triggers. Again defective manganese
transport, metabolism or binding are only some of the mechanisms possibly
underlying such genetic predisposition toinduced basal ganglia disorders.
Further studies relating to manganese in these disorders and particularly in
Parkinson's disease should focus not on the"intoxication" part of the overload
and its striatopallidal consequences, but on the intimate mechanism of
destabilization of the homeostatic regulator inneuromelanin bearing cells,
even after the exposure period."
Dr P
Peter H. Proctor
J Neural Transm Park Dis Dement Sect 1993;5(3):203-13
Total and paramagnetic metals in human substantia nigra and its neuromelanin.
Zecca L, Swartz HM
Istituto Tecnologie Biomediche Avanzate, CNR, Milano, Italy.
A number of hypotheses on the etiology of Parkinson's disease and other CNS
disorders postulate a role of metal ions and/or neuromelanin. As part of an
investigation of the interactions between neuromelanin and metal ions, we have
studied the amount and type of metal ions in human neuromelanin in intact
substantia nigra and in isolated neuromelanin using electron paramagnetic
resonance (EPR), snip....
" The studies of substantia nigra with TXRF indicated the presence of
substantial amounts of iron, zinc, lead, copper, manganese, and titanium at
concentrationsup to 4 times greater than those of non-pigmented brain tissue
(basis pedunculi). The concentrations of metal ions in isolated neuromelanin
were 5-260 times higher than in substantia nigra. snip.. These results
are consistent with the hypotheses that postulate a role of metal ions in
promoting oxidative reactions in pigmented neurons.
Dr P
serge zdanovich
sod's are going into human trials this year. Looks promising. Toxicity? This is Mn3 there talking
about.
Peter H. Proctor
>From: serge zdanovich <se...@chem.bu.edu>
>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>We had Bernard Malfroy, founder and ceo of Eukarion by for a two hour talk
>friday. The Euk Mn sod's are going into human trials this year. Looks
>promising. Toxicity? This is Mn3 there talking about.
In article <3A9B0A3D...@chem.bu.edu> serge zdanovich <se...@chem.bu.edu> writes:
>From: serge zdanovich <se...@chem.bu.edu>
>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>Date: Mon, 26 Feb 2001 21:00:29 -0500
>We had Bernard Malfroy, founder and ceo of Eukarion by for a two hour talk
>friday. The Euk Mn sod's are going into human trials this year. Looks
promising. Toxicity? This is Mn3 there talking about.
How easily is this reduced to Mn2 ? And how strongly is the Mn3 bound ? The
reduced forms are allegedly the most toxic. Mn makes me a bit nervous---
copper and iron overloads are also assiciated with similar neurologic
symptoms, but iron and copper miners don't get these diseases, manganese
miners do. The real problems are
1) the variability of response in animal models. It is difficult to know if
your animal model will translate to the human situation.
2) The time it takes to see toxicity. A year or more in some primates, if
memory serves....
3) Melanin-binding. Like Mn, low dose MTPT doesn't seem to cause
Parkinson's in species which lack visible neuromelanin either. Melanin
concentrates these agents in the dopaminergic cell bodies of the Pars
compacta. BTW, if you want to see a picture of these, go to
www.drproctor.com/crcpap2.htm (he says with his usual modesty).
Also, even in Rhesus ( much less rodents) , the anatomical and
clinical picture is very different from humans. For example, unlike humans,
there is not a lot of damage to the substantia nigra and monkeys don't respond
to levodopa, which humans with manganism do.. So you never know. I'll let
you guys try it first, for at least a year or two...<G>....
Acta Pharmacol Toxicol (Copenh) 1984 Aug;55(2):133-8
Melanin affinity of manganese.
Lyden A, Larsson BS, Lindquist NG
The melanin affinity of manganese was studied in vitro using melanin isolated
from beef eyes or human hair, and synthetic dopamine melanin, which is known to
be structurally similar to the melanin present in the pigmented nerve cells in
the human substantia nigra. In addition, the uptake of manganese in melanin
containing tissues in vitro and in vivo was studied by whole body
autoradiography. Manganese was bound to beef eye, human hair and synthetic
dopamine melanin, and was taken up in pigmented tissues in mice and a monkey.
Long-time exposure to manganese may cause a chronic extrapyramidal disorder. It
is suggested that manganese, due to its neurotoxicity, may cause lesions in
pigment containing neurones in the substantia nigra secondary to its
accumulation on the neuromelanin.
and
Neurotoxicology 1999 Apr-Jun;20(2-3):415-32
Animal models of manganese's neurotoxicity.
Newland MC
Department of Psychology, Auburn University, AL 36849, USA.
Manganese's neurotoxicity continues to present a puzzling array of differences
across individuals and across published reports in the profile of effects seen
in humans and nonhuman species, but some of the sources of individual
variability are becoming clear from studies of animals.. snip.... Manganese
produces a constellation of neurotoxic signs whose appearance and detection
are influenced by dose and exposure rate. Despite investigations of
manganese'sneurotoxicity in animals over a wide range of exposure levels, a
NOAEL has not been identified.
Dr P
Nelson J. Navarro
"Greg Watson" <gowa...@asiaonline.net.au> wrote in message
news:1bhm6.6$eF1.1...@news.interact.net.au...
> Hi All,
>
> Whets known about Eukarion, the Buck Institute, Euk-8 & Euk-134?
>
> A Medline search on either of the synthetic Anti-Oxidants turns up some
very
> interesting papers.
>
> Is this another sleeper like Alteon & their ALT-711?
>
> Eukarion are the folks which did the 50% extension of max LS in nematodes:
>
> http://www.eukarion.com/Press%20Releases/p8_31_00.html
>
Where did you see a 50% increase in maximum life span? The abstract, if the
below is the correct one, only mentions an extension of mean life span
(which other antioxidants e.g. tocotrienols, have also been shown to do).
Science 2000 Sep 1;289(5484):1567-9 Related Articles, Books, LinkOut
Extension of life-span with superoxide dismutase/catalase mimetics.
Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC,
Malfroy B, Doctrow SR, Lithgow GJ
Buck Institute for Age Research, Novato, CA 94949, USA.
We tested the theory that reactive oxygen species cause aging. We augmented
the natural antioxidant systems of Caenorhabditis elegans with small
synthetic superoxide dismutase/catalase mimetics. Treatment of wild-type
worms increased their mean life-span by a mean of 44 percent, and treatment
of prematurely aging worms resulted in normalization of their life-span (a
67 percent increase). It appears that oxidative stress is a major
determinant of life-span and that it can be counteracted by pharmacological
intervention.
PMID: 10968795
Regards,
Nelson Navarro
Greg Watson
news:ABFm6.8614$wf.22...@news1.epix.net...
>
> Where did you see a 50% increase in maximum life span? The abstract, if
the
> below is the correct one, only mentions an extension of mean life span
> (which other antioxidants e.g. tocotrienols, have also been shown to do).
Hi Nelson,
I don't have the full papers but I was referring to earlier comments from
Aubrey on the worm study:
===============
From: Aubrey de Grey (ag...@mole.bio.cam.ac.uk)
Subject: Re: _Science_ Paper: 'Anti-age' drug found
Newsgroups: sci.life-extension
Date: 2000-09-01 05:23:02 PST
Michael Rae wrote:
> The premise that this is news doesn't appear justified: per the piece,
> the study only showed increased AVERAGE ls.
The effect on maximum lifespan is indeed rather curiously understated,
but it's there all right -- see Table 1 and Figure 1.
Aubrey de Grey
==================
From: Aubrey de Grey (ag...@mole.bio.cam.ac.uk)
Subject: Re: _Science_ Paper: 'Anti-age' drug found
Newsgroups: sci.life-extension
Date: 2000-09-05 08:41:41 PST
Peter Proctor wrote:
> This study starting with young adult mice produced more extension.
>
> Biochem Biophys Res Commun 1995 Jun 26;211(3):847-9
And moreover, though the abstract doesn't say so, the extension was
just as strong with respect to maximum lifespan as mean. The caveat,
which is of course why this can't be counted as a confirmation of the
Cutler study, is that this experiment was not done on wild-type mice.
Aubrey de Grey
joe record
Aubrey de Grey wrote:
> Greg Watson wrote:
>
> > What's known about Eukarion, the Buck Institute, Euk-8 & Euk-134?
>
> The EUK compounds have unprecedentedly high superoxide dismutase
> activity for small molecules, and they also have considerable catalase
> activity due to the unique redox activity of manganese (it can exhibit
> valencies of 2, 3 or 5). Also, unlike some other SOD mimetics, they
> cross the blood-brain barrier. Simon Melov at the Buck is the main
> researcher on them in academia right now: he was the first author on
> the nematode study you cite, and he's currently testing the compounds
> for lifespan extension in mice. Unlike ALT-711, as I understand it
> there are no significant problems in terms of patent robustness, so it
> needn't be long before serious money gets put behind human trials. On
> the other hand, there is the ubiquitous problem of aging not being
> classified as a disease, which means that a particular clinical effect
> (say, retardation of dementia) would have to be both identified and
> demonstrated. That may be the main short-term barrier to commercial
> exploitation.
i very much doubt it. potentially there is a nice little category nestling in
( and a colossal income to be derived from )....'benign senescent disorder'
a rationalization of the advancing fluffy-mindedness we all have - since that
strange episode at the bus stop near winchester or morden or wimbledon or
wherever it was that this became more or less apparent than that etc etc
> Eukarion clearly know this, however, as shown by their
> current emphasis on animal models of neurodegenerative diseases; when
> more in vivo work is published it will move them forward fast, I suspect.
>
> See http://www.eukarion.com/publications.html for a complete list of
> the relevant publications.
just watch 'em shove it when they get a green light.....trouble is ..with new
lamps for old...that the hype is so much more thrilling than the effects of
an "heroic remedy".....if you like - cocaine so much more pursuasive than
coca cola,
& coca cola so much less inspiring than water. and so we retch into our
futures:
so stimulating......if it is! otherwise check out....the stunts of the cunts
in the punts that were fuckin' em.
......hummmm....somewhat opaque for such a gentle fellow as you who maintains
clarity/and the pole star of reason.....still dear aub. - you can get that!
peace and chips bruvver!....joe.
>
>
> Aubrey de Grey
serge zdanovich
Not very reactive in this case of the molecular configurations. (I'll look for the notes)
Toxicity was highlighted and discounted by the speaker. Most of the studies seemed to be
focused on sod knockout mice/hamster/rat brain tissue. Any volunteers?
Peter H. Proctor
>From: serge zdanovich <se...@chem.bu.edu>
>Not very reactive in this case of the molecular configurations.
If it is an ionic bond, it can be broken, especially when you get
something like neuromelanin, which has a high manganese affinity. Also,
you can't depend on the oxidation state. Typically, such transition-series
metals undergo easy reduction-oxidation because spin-orbit coupling
facilitates "forbidden" transitions.. This is why they are the active sites
of redox enzymes such as SODs. But it is also why they can catalyze
autooxidations.
BTW, I have a US patent which includes claims for Mn-containing SODs
as hair-growth stimulators. I have been following this area for a while..
> (I'll look for the notes)Toxicity was highlighted and discounted by the
>speaker.
Did they do primate studies ? And did they do them for long enough ?
Again, manganese toxicity in rodents is much less because they do not have
visible brain melanin. BTW, all this likely doesn't matter for acute
indications such as stroke.
Dr P
Serge Zdanovich
applications, reperfusion. ok Same problem with Cnzn SODs, for example, may lead to ALS
in invididuals who can't handle them. Also problably highly dose dependent. But these are
mimics... They are probably building on Monsanto's and your earlier work, patentable and
possibly improved.
Lou Pagnucco
model for human neuro-degenerative diseases was bioengineered.
If I recall correctly, this species' neurons are essentially the same
as human neurons.
Would this be a good way to determine potential toxicity?
Regards,
Lou Pagnucco
Peter H. Proctor wrote in message ...
Martin E. Lewitt
Peter H. Proctor <ppro...@proctorgamble.com> wrote:
>In article <3A9C4684...@chem.bu.edu> serge zdanovich <se...@chem.bu.edu> writes:
>>From: serge zdanovich <se...@chem.bu.edu>
>>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>>Date: Tue, 27 Feb 2001 19:29:56 -0500
>
>>Not very reactive in this case of the molecular configurations.
>
> If it is an ionic bond, it can be broken, especially when you get
>something like neuromelanin, which has a high manganese affinity. Also,
>you can't depend on the oxidation state. Typically, such transition-series
>metals undergo easy reduction-oxidation because spin-orbit coupling
>facilitates "forbidden" transitions.. This is why they are the active sites
>of redox enzymes such as SODs. But it is also why they can catalyze
>autooxidations.
Wouldn't the metabolites and mode of excretion tell us something, such
as is there unaccounted for manganese? If these compounds do hold onto
their manganese, then either they leave the body with it, or they or
their metabolites, with their firmly gripped manganese, accumulate in
the body. Since they do get past the blood/brain barrier, there is
also the question of whether any metabolites are produced there and
whether they can get back out WITH the manganese. Perhaps there
is a chelator they can be paired with, which would assure negative
manganese "balance" within the brain. -- Martin
--
Personal, not work info: Martin E. Lewitt My opinions are
Domain: lew...@swcp.com P.O. Box 729 my own, not my
Hm phone: (505) 281-3248 Sandia Park, NM 87047-0729 employer's.
Peter H. Proctor
>From: "Lou Pagnucco" <pagn...@oeonline.com>
>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>I believe that yesterday I read a report that a new mouse
>model for human neuro-degenerative diseases was bioengineered.
>If I recall correctly, this species' neurons are essentially the same
>as human neurons.
>Would this be a good way to determine potential toxicity?
Only if the neurones are pigmented. This seems to be the key to the
difference in manganese toxicity between humans and otherwise valid animal
models. This is also true for other agents that induce parkinsons-like
symptoms in humans, BTW. The problem is that neuromelanin binds
and concentrates such compounds.
Dr P
>Regards,
>Lou Pagnucco
>Peter H. Proctor wrote in message ...
>>In article <3A9C4684...@chem.bu.edu> serge zdanovich
><se...@chem.bu.edu> writes:
>>>From: serge zdanovich <se...@chem.bu.edu>
>>>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>>>Date: Tue, 27 Feb 2001 19:29:56 -0500
>>
>>>Not very reactive in this case of the molecular configurations.
>>
>> If it is an ionic bond, it can be broken, especially when you get
>>something like neuromelanin, which has a high manganese affinity. Also,
>>you can't depend on the oxidation state. Typically, such
>transition-series metals undergo easy reduction-oxidation because spin-orbit
coupling>>facilitates "forbidden" transitions.. This is why they are the
active>sites of redox enzymes such as SODs. But it is also why they can
catalyze>>autooxidations.
>
>>
Peter H. Proctor
>From: lew...@swcp.com (Martin E. Lewitt)
>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>In article <DD32168DC94566B9.257B096A...@lp.airnews.net>,
>Peter H. Proctor <ppro...@proctorgamble.com> wrote:
>>In article <3A9C4684...@chem.bu.edu> serge zdanovich <se...@chem.bu.edu>
>writes:
>>>From: serge zdanovich <se...@chem.bu.edu>
>>>Subject: Re: Eukarion, BUk Institute, Euk-8 & Euk-134
>>>Date: Tue, 27 Feb 2001 19:29:56 -0500
>>
>>>Not very reactive in this case of the molecular configurations.
>>
>> If it is an ionic bond, it can be broken, especially when you get
>>something like neuromelanin, which has a high manganese affinity. Also,
>>you can't depend on the oxidation state. Typically, such transition-series
>>metals undergo easy reduction-oxidation because spin-orbit coupling
>>facilitates "forbidden" transitions.. This is why they are the active sites
>>of redox enzymes such as SODs. But it is also why they can catalyze
>>autooxidations.
>Wouldn't the metabolites and mode of excretion tell us something, such
>as is there unaccounted for manganese?
The problem is that the actual amount of neuromelanin ( and thus bound
manganse ) is small. Nueromelanin is primarily concentrated in very
specific areas. These are the pars compacta of the substantia nigra ("black
stuff" ) as well as the locus ceruleus ( "blue spot" ). It is the
pigmented eurons of the substantia nigra that die off in parkinsons and
manganese poisoning.
If these compounds do hold onto>their manganese, then either they leave the
body with it, or they or>their metabolites, with their firmly gripped
manganese, accumulate in>the body.
Manganses does accumulate, but mostly by melanin-binding.
Since they do get past the blood/brain
barrier, there is>also the question of whether any metabolites are produced
there and>whether they can get back out WITH the manganese. Perhaps there
>is a chelator they can be paired with, which would assure negative
>manganese "balance" within the brain.
Could be. In fact, chelating agents are used to treat hemochomatosis
(iron) and Wilsons disease (copper), both of this are assciated with
parkinsonian-like sysmptoms and accumulation of their respecitve
transition-series metal in neuromelanin. Iron accumulation in particular
has been associated with parkinson't disease itself.
Dr P