Aminoguanidine: TOXIC. QUIT. Human trial data.
Michael
Lots of folks are rightly interested in the drug,
aminoguanidine/pimegidine (ag). Many, many rodent studies show that
this stuff reduces AGE accumulation, & reduces complications (nerve
damage, nephropathy, retinopathy) in diabetic lab rodents. The
implication: by lowering our own AGE leves, ag might retard the
progress of a basic mechanism of aging, or at least the damage done by
same in at least some organs & tissues.
Of course, many people out there are not just following the research:
they're self-experimenting. WEll, to cut a long story short, I've now
discvered there are SERIOUS TOXICITY ISSUES WITH AMINOGUANIDINE WHICH
ARE UNDETECTABLE EXCEPT BY SPECIFIC TESTS NOT PART OF STANDARD
BLOODWORK.
QUIT.
We've known for some years that human ag trials are in the works, but
MEDLINE has had virtually nothing on the subject. It seems likely that
it'll WORK, tho' its short half-life & some debates over mechanism of
action do lead to questions.
But what of safety? Mostly, we're going on rumor. I suspect the most
well-known summary amongst life-extensionists is the following, from
LEF:
--------------------------------
http://www.lef.org/anti-aging/index2.htm#ami
When reports of toxicity were reported in a FDA-sanctioned human
clinical study conducted two years ago, The Life Extension Foundation
sought to ascertain what dose of aminoguanidine was causing toxic
reactions. The company conducting the studies, and the FDA, refused to
provide this information.
After two years of painstaking investigation, The Foundation has
learned
that when 300 mg of aminoguanidine where administered three times a
day
(900 mg/day) to diabetic patients, toxicity was noted. When the dose
was
lowered to 200 mg three times a day (600 mg/day), the signs of
toxicity
vanished. These results confirm The Foundation's previous
recommendations, based on extrapolations from the published
literature,
that healthy adults may consider taking 300 mg of aminoguanidine a day
(or every other day), while diabetics could consider a maximum dose of
600 mg a day. Semi-monthly CBC-chemistry blood tests should be
considered in order to protect against any unknown liver or kidney
toxicities.
======================
Some folks seem to have taken this as a green light for a 600 mg/day
dose. I do not. First, if toxicity is showing up at just half again
what's being taken, at the opening of controlled trials, that's at te
very least a pretty damned narrow therapeutic window. Second, contrary
to what many seem to believe, "mild flu-like symptoms" are NOT likely
to
mean upset stomach (which a true FLU rarely causes):
------------------------------
http://www.helioshealth.com/influenza/symptoms_diagnosis.html
Symptoms of an influenza infection include:
Fever
Muscle aches and pain
Headache
Fatigue
Dry cough
Sore throat
Runny nose.
Fever usually appears suddenly, and can alternate with chills.
Headache
is usually accompanied by pain around the eyes, and the whites of the
eyes can become reddened and irritated, with tearing and discharge.
Muscle aches are usually located in the back and legs.
A dry cough is often noticed in the early stages of flu, and can
progress to a "productive" cough and bronchitis - inflammation of the
bronchial passages to the lungs - lasting up to ten days. A lingering
sensation of weakness and fatigue can persist for weeks!
Children with the flu sometimes suffer from nausea, vomiting, and
diarrhea. The so-called "stomach flu" experienced by adults is NOT
related to influenza.
-------------------------------
Does a drug which causes a mild version of this sound like a safe drug
for home experimentation, even in the absence of symptoms?
In any case: isn't the whole situation rather odd? AG has been around
for MUCH longer than ALT-711, yet we're seeing proper publications
coming out on the latter, & news releases on human phase IIa trials.
Where the hell are the data from the studies the press was talking
about
in 1998? Indeed, Alteon's website declares that "Pimagedine, Alteon's
lead A.G.E. Formation Inhibitor, has completed a series of Phase
II/III
trials in which it demonstrated an ability to slow the progression of
kidney disease, retinopathy and cardiovascular disease in diabetic
patients." So where's teh publication?
If you hunt around on the web, you'll come across more direct reports
on
the ag trials, and they're somewhat more alarming than the common
understanding of the results to date -- indeed, not surprisingly, as
they're from later along, & thus chronic toxicity has had a chance to
set in:
-----------------------------
http://www.elis.sk/bll/00/full/bll1000a.pdf
"Aminoguanidine, the best prototype inhibitor of
AGEs formation in experimental models, inhibits the development of
retinopathy, nephropathy and neuropathy (100). {...} However, all
clinical studies with aminoguanidine (Pimagidine) in Europe and then
in
USA were stopped because its
toxicity."
====================
http://www.ndei.org/content/ndeipubs/issues/vol_4_no_1.asp
"One compound that reduces the level of tissue AGEs, aminoguanidine,
has
already undergone a clinical trial to determine if it could benefit
diabetic nephropathy and retinopathy. Unfortunately, this particular
drug proved too toxic to permit a safe long-term trial, but analogs
and
congeners of aminoguanidine are under development."
==================================
I finally got some REAL details. The ag study HAS been reporting
results
-- at conference meetings, presented as abstracts. It looks like,
having
abandoned the study, they aren't prioritizing publication.
Fortunately,
this review:
Singh R, Barden A, Mori T, Beilin L.
Advanced glycation end-products: a review.
Diabetologia. 2001 Feb;44(2):129-46. Review.
PMID: 11270668v
has the dope. (References & Table from the above will be posted
sometime
this week for those who want to dig further. I want to get this out
TONIGHT).
"A recent phase III trial using pimagedine has shown beneficial
affects[sic] on the progression of retinopathy and lipid
concentrations
{23}. In addition to the affects{sic} on diabetic nephopathy
progression
in optimally treated Type I diabetic subjects (Table 3) (22). The
reduction in retinopathy progression (95% had advanced retinopathy)
after 12 months of follow-up was significantly decreased only in the
high dose group (300 mg twice a day) compared iht the low dose (150 mg
twice a day) and placebo groups.
{Bear this carefully in mind thru'out what follows. when they say
"high
dose," they mean 600 mg/day. When they say "low dose," they mean 300
mg/day}.
"Both treatment groups showed, however,
statistically significant reductions in total cholesterol and LDL but
not HDL after 12 months of treatment. These observations were
independent of glycemic control with HbA1c values being comarable
between all groups."
"A small number of suubjects developed flu like symptoms and half
became
anemic. This ws also noted in placebo patients making it difficult to
ascribe this observation entirely to pimagedine therapy and could
depend
on the anemia of chroic disease, which culd occur with moderate renal
impairment. Early reports on the use of {ag} described, however, blood
picture changes resembling pernicious anemia (145)."
"Of greater concern was the development of anti-nuclear antibodies and
myeloperoxidase antinuclear cytoplasmic antibodies especially in the
high dose group, with three subjectsdeveloping crescentic
glomerulonephritis. One rescovered but two developed ESRD (24).
Generally lower dose therapy was well tolerated with a side effect
profile comparable to placebo."
"These results imply that patients using pimagedine require assessment
of full blood counts and autoimmune status before and during therapy.
Measures of vasculitic activity including {sed} rate, {C-RP}, and
urinary
sediment as well as physical examination. In addition {ag} is known to
inhibit diamine oxidase, which catalyses deamination of diamines such
as
histamine (145). This has the possibilit of raising histamine
concentrations wtih the attendant vascular and respiratory side
effects.
To date, there are no reports of {such} secondary to {ag} therapy."
"Although early studies using diabetic rats treated with {ag} have
recorded higher rates of pancreatic and renal neoplasms (25), there
are
no results so far on antibody generation. {AG} is, however, a
hydrazine
derivative as is hydralazine (26), which is itself associated with
antihistone and antinuclear cytoplasmic antibody production as well as
a
clinical situation similar to lupus (147). Although the mechanism for
autoantibody production as a result of hydrazine-hydrazie derivative
therapy is not known, ther is some evidence that it could involve
lympohocyte function associated with antigen-1 overexpression and
autoreactivity (148)."
"Based on the current phase III trial outcomes and considering the
side-effect profiles there is no greater benefit in taking the higher
dose of pimagedine. It is, hwever, not known how well the drug would
work in patients who are not optimally treated, if treatment should be
initiated at the time of diagnosis of diabetes or if a longer
follow-up
period would have separated outcome measures for the 2 treatment arms.
Similarly studies would need to be extended to {NIDDM}."
==================================
...Let alone to otherwise healthy people who have, as one of their
principle priorities in life, the desire to extend lifespan!
NB the talk re: antinuclear antibodies (ANA). This is serious shit,
folks. ANA is a marker for autoimmunity. It's a side effect of some
drugs that they CREATE unique autoimmune disorders, such as
drug-induced
autoimmune hepatitis or drug-induced "lupus" (which is not the same as
SLE per se). See, eg, the ugly case of teenage girls being given same
by
idiot docs who prescribe monocycline for acne:
http://bmj.com/cgi/content/full/312/7024/169?view=full&pmid=8563540
http://www.ama-assn.org/special/womh/library/readroom/arch99/ioi80305.htm
Note, specifically, that the review asserts "myeloperoxidase
antinuclear
cytoplasmic antibodies." I've had a hard time trying to figure out
exactly for what this tests: the exact phrase doesn't come up in my
searching. What DOES keep coming up is "Anti-neutrophil cytoplasmic
antibodies." Yes, of course, the nucleus iss not the same thing as a
neutrophil! But it seems t be the only thing that hooks in with a
myeloperoxidase cytoplasmic antibody. If so, anti-MPO is used "For
diagnosis and monitoring inflammatory activity in primary systemic
small
vessel vasculitides... Presence of anti-MPO antibodies is highly
specific for idiopathic and vasculitis-associated crescentic
glomerulonephritis, classic polyarteritis nodosa, Churg-Strauss
syndrome, and polyangiitis overlap syndrome without renal
involvement....{However,} Results of this assay are not diagnostic
proof
of the presence or absence of disease and should be used in
conjunction
with clinical findings and other serological tests." (
http://www.labcorp.com/datasets/labcorp/html/chapter/mono/se038900.htm
). Elsewhere, ANCA anti-MPO, or MPO ANA, are said to be a sign of
"Microscopic polyarteritis, Idiopathic crescentic necrotising
glomerulonephritis, Other small-vessel vasculitides, {or} Drug
reactions, eg. propylthiouracil (rare)."
"But," you say, "I'm very careful. I get my doc to order a CBC and a
liver profile every six months! Surely, s/he would have noted a
positive ANA."
S/he would've ... except ANA is NOT part of the standard liver
toxicity
profile. S/he would have to have SPECIFICALLY ordered it for you --
which s/he wouldn't have done without any reason to do so.
My advice:
If you're taking AG, QUIT.
Then immediately go convince a doctor you need an ANA test, because
you've been taking an unapproved drug which clinical trials have now
reported are causing elevated ANA and anti-MPO.
-Michael
--
End Corporate Rule: www.igc.org/trac/globalization/ and clean up the
physical ( www.greenpeace.org ) and mental ( www.adbusters.org )
environment!
"Spend the money, mobilize the scientists, and hunt down death like an
outlaw." -Alan Harrington. "If scientists don't play God, who will?"
-James Watson "Not even immortals can afford to waste time." -Mike
O'Gara
Tom Matthews
in sufficient quantity and it is the nature of the toxicity and the
dosages involved which is all important. There is very little in
Michael's long message below about which I was not aware and have not
written (though in less detail) and there are some important things
about the mechanism of action of aminoguanidine which are missing.
However, Michael has certainly done a valuable service in looking up a
full paper not available online, in summarizing the potential problems
of aminoguanidine and in, hopefully, convincing those people who are
taking more than 300 mg daily to lower their dosage and spread it out
over the day.
Michael wrote:
>
> All:
>
> Lots of folks are rightly interested in the drug,
> aminoguanidine/pimegidine (ag). Many, many rodent studies show that
> this stuff reduces AGE accumulation, & reduces complications (nerve
> damage, nephropathy, retinopathy) in diabetic lab rodents. The
> implication: by lowering our own AGE leves, ag might retard the
> progress of a basic mechanism of aging, or at least the damage done by
> same in at least some organs & tissues.
First, aminoguanidine will not reduce AGE levels. It will only reduce
the glycation rate and the rate at which AGE accumulates. Since the body
itself does slowly metabolize and eliminate AGEs, is it possible that if
we reduce the glycation rate sufficiently, then the AGE accumulation
rate will become less than the AGE breakdown rate and, thus, their total
amounts in the body (which cause harm) will decrease.
Second, aminoguanidine should only be one of an arsenal of methods to
reduce glycation rate and ultimately AGE accumulation (hopefully to a
negative value). One should never rely upon only one therapy to combat
any problem with health or aging.
> Of course, many people out there are not just following the research:
> they're self-experimenting. WEll, to cut a long story short, I've now
> discvered there are SERIOUS TOXICITY ISSUES WITH AMINOGUANIDINE WHICH
> ARE UNDETECTABLE EXCEPT BY SPECIFIC TESTS NOT PART OF STANDARD
> BLOODWORK.
>
> QUIT.
In a private email containing a copy of his post Michael also ordered me
to "QUIT", but since I don't take orders from anyone (who is not holding
a gun to my head), I simply ignored his imperative. :)
First, we need to know the nature of the "toxicity". Second, what
percentage of the experimental subjects were suffering such symptoms
versus what percentage of controls. Third, based on the nature of the
toxicity, the biochemistry of the drug and the patterns of those with
symptoms, is there something which can be done to reduce/eliminate the
likelihood of toxicity?
This was all an unnecessary aside about the definition of "flu"
symptoms. Why not simply describe the symptoms and forget what other
disease/disorder that they were erroneously stated as being like.
> -------------------------------
>
> Does a drug which causes a mild version of this sound like a safe drug
> for home experimentation, even in the absence of symptoms?
Lots of foods and other practices can cause upset stomach. It is the
nature of the cause and its systemic biochemical effects which is
important.
> In any case: isn't the whole situation rather odd? AG has been around
> for MUCH longer than ALT-711, yet we're seeing proper publications
> coming out on the latter, & news releases on human phase IIa trials.
> Where the hell are the data from the studies the press was talking
> about
> in 1998? Indeed, Alteon's website declares that "Pimagedine, Alteon's
> lead A.G.E. Formation Inhibitor, has completed a series of Phase
> II/III
> trials in which it demonstrated an ability to slow the progression of
> kidney disease, retinopathy and cardiovascular disease in diabetic
> patients." So where's teh publication?
This is all entirely reasonable. ALT-711 is an exclusively patented
substance which actually *breaks* AGEs (not merely reducing their
formation rate). Aminoguanidine has been around for decades. It is not
patentable and it is used extensively by diabetics in areas of the world
outside the US. If this were not so then it would not be so cheaply and
easily available from offshore purchasing sources and would not be mass
made by drug companies.
> If you hunt around on the web, you'll come across more direct reports
> on the ag trials, and they're somewhat more alarming than the common
> understanding of the results to date -- indeed, not surprisingly, as
> they're from later along, & thus chronic toxicity has had a chance to
> set in:
>
> -----------------------------
>
> http://www.elis.sk/bll/00/full/bll1000a.pdf
>
> "Aminoguanidine, the best prototype inhibitor of
> AGEs formation in experimental models, inhibits the development of
> retinopathy, nephropathy and neuropathy (100). {...} However, all
> clinical studies with aminoguanidine (Pimagidine) in Europe and then
> in USA were stopped because its toxicity."
>
> ====================
>
> http://www.ndei.org/content/ndeipubs/issues/vol_4_no_1.asp
>
> "One compound that reduces the level of tissue AGEs, aminoguanidine,
> has
> already undergone a clinical trial to determine if it could benefit
> diabetic nephropathy and retinopathy. Unfortunately, this particular
> drug proved too toxic to permit a safe long-term trial, but analogs
> and congeners of aminoguanidine are under development."
What neither of these quotes provide is information about the rate of
toxicty among those taking ag at different dosages and the biochemical
nature of this toxicity. If we search PubMed we find the following:
J Nutr Sci Vitaminol (Tokyo) 1995 Feb;41(1):43-50
Effects of aminoguanidine and pyridoxal phosphate on glycation reaction
of aspartate aminotransferase and serum albumin.
Okada M, Ayabe Y.
Faculty of Health and Living Sciences, Naruto University of Education,
Japan.
Effects of aminoguanidine (AG) on binding of glucose and pyridoxal
phosphate
(PLP) to albumin, and on glycation reaction of cytosolic aspartate
aminotransferase (cAST) were examined in an in vitro system. AG was
found to
inhibit not only glycation of albumin but binding of PLP to albumin,
indicating
that distribution of PLP into tissues is inhibited by AG. AG bound to
PLP
directly to produce a new compound, and in this manner AG inhibited cAST
activity. AG could also inhibit glycation of cAST and the extent of
inhibition
was varied with sugars used. It appears that, although AG is a useful
inhibitor
of glycation proteins, it may be toxic from the viewpoints of vitamin B6
as an
essential nutrient and also PLP-dependent enzymes.
PMID: 7616326
Some other papers, provide other enzymes which are inhibited to a
certain extent by ag all of which appear to be related to vitamin B6
biochemistry. Thus, the toxic effects of ag appear to be related to its
inhibition of vitamin B6 and the host of major biochemical pathways
which B6 influences. This is the reason that I have always warned people
that they should take extra B6 when taking ag.
In addition, if one is to judge by numbers, I can produce just as many
or more studies showing how aminoguanidane reduces some toxicity or or
other than that it causes it. Here is just a sample:
1: Eur J Pharmacol 2000 Sep 8;403(3):277-80
Inhibition of anti-Fas antibody-induced hepatitis by aminoguanidine in
mice.
Okamoto T, Okabe S.
Research Laboratories, Nippon Chemiphar Co., Ltd, 1-22 Hikokawato,
Saitama 341-0005, Misato, Japan. ncok...@green.ocn.ne.jp
Aminoguanidine is an inhibitor of inducible nitric oxide synthase (iNOS)
and is
of potential clinical usefulness. Treatment of mice with anti-Fas
antibodies
(150 &mgr;g/kg, i.v.) induced elevation of plasma alanine
aminotransferase
activity at 4 h and this elevation was inhibited by pretreatment of mice
with
aminoguanidine (3, 10 and 30 mg/kg, i.p.). The anti-Fas antibody-induced
elevation of caspase-3 activity was inhibited by aminoguanidine (30
mg/kg,
i.p.), but the addition of aminoguanidine to the cytosol up to 10(-4) M
did not
inhibit the caspase-3 activity in vitro. Thus, aminoguanidine prevents
anti-Fas
antibody-induced hepatitis by affecting the apoptotic pathway upstream
of
caspase-3 activation.
PMID: 10973630
2: Life Sci 2000;66(3):265-70
Protective effect of aminoguanidine, a nitric oxide synthase inhibitor,
against carbon tetrachloride induced hepatotoxicity in mice.
Al-Shabanah OA, Alam K, Nagi MN, Al-Rikabi AC, Al-Bekairi AM.
Department of Pharmacology, College of Pharmacy, King Saud University,
Saudi Arabia. shab...@ksu.edu.sa
The present study was undertaken to evaluate the effect of
aminoguanidine (AG)
on carbon tetrachloride (CCl4)-induced hepatotoxicity. Treatment of mice
with
CCl4 (20 microl/kg, i.p.) resulted in damage to centrilobular regions of
the
liver, increase in serum aminotransferase and rise in lipid peroxides
level 24
hours after CCl4 administration. Pretreatment of mice with AG (50 mg/kg,
i.p.)
30 minutes before CCl4 was found to protect mice from the CCl4-induced
hepatic
toxicity. This protection was evident from the significant reduction in
serum
aminotransferase, inhibition of lipid peroxidation and prevention of
CCl4-induced hepatic necrosis revealed by histopathology.
Aminoguanidine, a
relatively specific inhibitor of inducible nitric oxide synthase, did
not
inhibit the in vitro lipid peroxidation. Taken together, these data
suggest a
potential role of nitric oxide as an important mediator of CCl4-induced
hepatotoxicity.
PMID: 10666002
3: Diabetes 1999 Jun;48(6):1308-15
Dietary glycotoxins: inhibition of reactive products by aminoguanidine
facilitates renal clearance and reduces tissue sequestration.
He C, Sabol J, Mitsuhashi T, Vlassara H.
Mount Sinai School of Medicine, New York, New York 10029, USA.
Evidence indicates that the metabolic turnover of food-derived reactive
orally
absorbed advanced glycation end products (AGEs) or glycotoxins (GTs) is
delayed,
possibly contributing to the tissue damage induced by endogenous AGEs,
especially in patients with diabetes and kidney disease. The aim of this
study
was to explore whether pharmacologic inhibition of dietary AGE
bioreactivity by
aminoguanidine (AG) can improve turnover and renal excretion of these
substances. Normal Sprague-Dawley rats were fed single-labeled
[14C]AGE-ovalbumin, double-labeled [14C-125I]AGE-ovalbumin, or control
125I-labeled ovalbumin diet plus free [14C]glucose, with or without AG
(0.2% in
water). [14C]AGE- and 125I-labeled peptide-associated radioactivity (RA)
were
compared with AGE immunoreactivity (by enzyme-linked immunosorbent
assay) in
tissues, serum, and 72-h urine samples. The effect of AG on dietary AGE
bioreactivity was assessed by monitoring the inhibition of covalent
complex
formation between fibronectin (FN) peptide fragments and serum
components, after
a meal of labeled dietary AGE with or without AG. The radiolabeled AGE
diet
produced serum absorption and urinary excretion peaks kinetically
distinct from
those of free [14C]glucose or [125I]ovalbumin. Some 26% of the orally
absorbed
AGE-ovalbumin was excreted in the urine, whereas after AG treatment,
urinary
excre-tion of dietary AGEs increased markedly (to >50% of absorbed).
More than
60% of tissue-bound RA was found covalently deposited in kidneys and
liver,
whereas after treatment with AG, tissue AGE deposits were reduced to
<15% of the
amount found in untreated AGE-fed controls. Sera enriched for dietary
GTs formed
covalently linked complexes with FN, a process completely inhibitable by
AG
cotreatment. Amelioration of dietary GT bioreactivity by AG improves
renal
elimination and prevents tissue deposition of food GTs. This may afford
a novel
and potentially protective use of AG against excessive tissue AGE
toxicity in
diabetic patients with renal disease.
PMID: 10342821
4: Crit Care Med 1998 May;26(5):905-11
Aminoguanidine attenuates endotoxin-induced acute lung injury in
rabbits.
Mikawa K, Nishina K, Tamada M, Takao Y, Maekawa N, Obara H.
Department of Anaesthesiology, Kobe University School of Medicine,
Japan.
OBJECTIVE: To assess the effect of aminoguanidine, a selective inducible
nitric
oxide synthase inhibitor, on endotoxin-induced acute lung injury in
rabbits.
DESIGN: Prospective, blinded, controlled laboratory study. SETTING:
University
research laboratory. SUBJECTS: Twenty-eight male rabbits. INTERVENTIONS:
The
animals were randomly assigned to receive one of four treatments (n = 7
for each
group): infusion of saline only (S-S group), infusion of saline and
aminoguanidine (S-AG group), infusion of Escherichia coli endotoxin (5
mg/kg
over 60 mins) (E-S group), and infusion of endotoxin and aminoguanidine
(E-AG
group). Fifteen minutes before infusion of endotoxin (E-S and E-AG
groups) or
saline (S-S and S-AG groups), the animals received an intravenous
injection of 1
mg/kg of aminoguanidine (S-AG and E-AG groups) or saline (S-S and E-S
groups).
The same dose of aminoguanidine or saline was given 1 hr after the end
of
endotoxin or saline infusion. The lungs of the rabbits were ventilated
with 40%
oxygen. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, peripheral
leukocyte
counts, and PaO2 were recorded during the ventilation period (6 hrs).
After
these observations were made, lung mechanics, cell fraction of
bronchoalveolar
lavage fluid, and concentrations of thromboxane A2 and prostacyclin
metabolites
in bronchoalveolar lavage fluid were determined. The wet weight/dry
weight ratio
of the lung and albumin concentrations in bronchoalveolar lavage fluid
were
analyzed as indices of pulmonary edema. Endotoxin decreased the lung
compliance
and PaO2 and increased the wet weight/dry weight ratio, neutrophil
counts, and
albumin concentrations in bronchoalveolar lavage fluid. The
bronchoalveolar
lavage fluid concentrations of thromboxane B2 in bronchoalveolar lavage
fluid
were increased by infusion of endotoxin. Aminoguanidine attenuated these
changes. Endotoxin caused extensive morphologic lung damage, which was
lessened
by aminoguanidine. CONCLUSIONS: Aminoguanidine given intravenously
before and
after endotoxin attenuated endotoxin-induced lung injury in rabbits.
These
findings suggest that inducible nitric oxide synthase inhibition may be
useful
in the treatment of endotoxin-induced lung injury. However, further
studies are
required to determine the optimal dosage of aminoguanidine, when the
inhibitor
is given alone as therapy after lung injury.
PMID: 9590321
That is certainly beneficial. However, with an already very low total
and LDL and a relatively high HDL, I have seen no further changes.
> "A small number of suubjects developed flu like symptoms and half
> became
> anemic. This ws also noted in placebo patients making it difficult to
> ascribe this observation entirely to pimagedine therapy and could
> depend
> on the anemia of chroic disease, which culd occur with moderate renal
> impairment. Early reports on the use of {ag} described, however, blood
> picture changes resembling pernicious anemia (145)."
Note the researchers doing these experiments are rarely practicing MD's
and this is likley the reason for the mix-up in the definition of the
term "flu-like". Note also that (mycrocytic) anemia is a secondary
result of vitamin B6 deficiency. At 300 mg of ag daily for several years
now, I have never seen any such symptoms, but then I always made sure to
take extra B6.
> "Of greater concern was the development of anti-nuclear antibodies and
> myeloperoxidase antinuclear cytoplasmic antibodies especially in the
> high dose group, with three subjectsdeveloping crescentic
> glomerulonephritis. One rescovered but two developed ESRD (24).
> Generally lower dose therapy was well tolerated with a side effect
> profile comparable to placebo."
I have never taken more than the lower dosage and have never had any
symptoms or blood tests indicating kidney problems, but then I also take
several other kidney strengthening supplements and I never take
acetaminophen which is far more dangerous for the kidneys than any other
non-prescription drug and most prescription ones too.
> "These results imply that patients using pimagedine require assessment
> of full blood counts and autoimmune status before and during therapy.
> Measures of vasculitic activity including {sed} rate, {C-RP}, and
> urinary
> sediment as well as physical examination. In addition {ag} is known to
> inhibit diamine oxidase, which catalyses deamination of diamines such
> as histamine (145). This has the possibilit of raising histamine
> concentrations wtih the attendant vascular and respiratory side
> effects.
> To date, there are no reports of {such} secondary to {ag} therapy."
This effect on histamine could be a problem if high histamine generating
foods are consumed, but again only if one is taking insufficient vitamin
B6, the inhibition of which is the reason for this inhibitory effect of
ag on the diamine oxidase enzyme.
Crit Rev Toxicol 1986;17(2):91-128
Histamine food poisoning: toxicology and clinical aspects.
Taylor SL.
Histamine poisoning can result from the ingestion of food containing
unusually
high levels of histamine. Fish are most commonly involved in incidents
of
histamine poisoning, although cheese has also been implicated on
occasion. The
historic involvement of tuna and mackerel in histamine poisoning led to
the
longtime usage of the term, scombroid fish poisoning, to describe this
food-borne illness. Histamine poisoning is characterized by a short
incubation
period, a short duration, and symptoms resembling those associated with
allergic
reactions. The evidence supporting the role of histamine as the
causative agent
is compelling. The efficacy of antihistamine therapy, the allergic-like
symptomology, and the finding of high levels of histamine in the
implicated food
suggest strongly that histamine is the causative agent. However,
histamine
ingested with spoiled fish appears to be much more toxic than histamine
ingested
in an aqueous solution. The presence of potentiators of histamine
toxicity in
the spoiled fish may account for this difference in toxicity. Several
potentiators including other putrefactive amines such as putrescine and
cadaverine have been identified. Pharmacologic potentiators may also
exist;
aminoguanidine and isoniazid are examples. The mechanism of action of
these
potentiators appears to be the inhibition of intestinal
histamine-metabolizing
enzymes. This enzyme inhibition causes a decrease in histamine
detoxification in
the intestinal mucosa and results in increased intestinal uptake and
urinary
excretion of unmetabolized histamine.
Publication Types:
Review
PMID: 3530640
Agents Actions 1981 Apr;11(1-2):20-7
Putrescine metabolism and the study of diamine oxidase activity in vivo.
Sourkes TL, Missala K.
The catabolism of 14C-putrescine (1,4-tetramethylene-diamine) to labeled
CO2 in
small laboratory animals has been studied extensively in order to
establish the
influence of nutritional, endocrine and other factors on this process.
Special
attention has been paid to treatments that are known to affect the
activity of
diamine oxidase (DAO, histaminase, EC, 1.4.3.6), a copper-containing
enzyme
characteristically inhibited by semicarbazide. Thus, copper-deficient
rats
metabolize putrescine more slowly than their controls. Antimalarial
drugs that
inhibit histamine N-methyltransferase also inhibit putrescine catabolism
in vivo
and DAO activity in vitro. Adrenalectomized rats metabolize the diamine
at a
reduced rate, a result consistent with the previously demonstrated
decrease of
DAO in the tissues of several species of animal. There is no effect on
the rate
of catabolism of putrescine when thyroid state is altered. Heparin (up
to 15,000
U/kg), which releases DAO from the small (0.1 mg/kg), intestine, and
aminoguanidine (0.1 mg/kg), which inhibits the enzyme powerfully, both
cause
decreased rates of catabolism of the diamine in rats. The
putrescine-catabolizing ability returns with a half-time of recovery of
15-18 h,
corresponding to the estimates of SHAFF and BEAVEN [36] for recovery of
intestinal DAO activity following administration of heparin or
cycloheximide.
Together with out other results this suggests that what is being
measured by
putrescine catabolism depends to a significant extent on the activity of
DAO in
vitro.
Publication Types:
Review
PMID: 6787849
> "Although early studies using diabetic rats treated with {ag} have
> recorded higher rates of pancreatic and renal neoplasms (25),
Megadoses on rats with almost anything causes increased neoplasms of one
form or another! So what else is new?
> there are no results so far on antibody generation. {AG} is, however,
> a hydrazine derivative as is hydralazine (26), which is itself
> associated with antihistone and antinuclear cytoplasmic antibody
> production as well as a
> clinical situation similar to lupus (147). Although the mechanism for
> autoantibody production as a result of hydrazine-hydrazie derivative
> therapy is not known, ther is some evidence that it could involve
> lympohocyte function associated with antigen-1 overexpression and
> autoreactivity (148)."
>
> "Based on the current phase III trial outcomes and considering the
> side-effect profiles there is no greater benefit in taking the higher
> dose of pimagedine. It is, hwever, not known how well the drug would
> work in patients who are not optimally treated, if treatment should be
> initiated at the time of diagnosis of diabetes or if a longer
> follow-up
> period would have separated outcome measures for the 2 treatment arms.
> Similarly studies would need to be extended to {NIDDM}."
>
> ==================================
>
> ...Let alone to otherwise healthy people who have, as one of their
> principle priorities in life, the desire to extend lifespan!
But at the low dose of 150 mg bid, with appropriate extra B6,
aminoguanidine may reasonably be added to ones arsenal of life extension
therapies, *none of which*, I may remind you have to date been proven to
work for humans.
> NB the talk re: antinuclear antibodies (ANA). This is serious shit,
> folks. ANA is a marker for autoimmunity. It's a side effect of some
> drugs that they CREATE unique autoimmune disorders, such as
> drug-induced
> autoimmune hepatitis or drug-induced "lupus" (which is not the same as
> SLE per se). See, eg, the ugly case of teenage girls being given same
> by
> idiot docs who prescribe monocycline for acne:
>
> http://bmj.com/cgi/content/full/312/7024/169?view=full&pmid=8563540
>
> http://www.ama-assn.org/special/womh/library/readroom/arch99/ioi80305.htm
>
> http://www.google.com/search?q=cache:lZcNWC6jiys:www.ajcp.com/goldstein1000ar.html++Minocycline-Related+Autoimmune+Hepatitis+Case+Series+and+Literature+Review+&hl=en
>
> Note, specifically, that the review asserts "myeloperoxidase
> antinuclear
> cytoplasmic antibodies." I've had a hard time trying to figure out
> exactly for what this tests: the exact phrase doesn't come up in my
> searching. What DOES keep coming up is "Anti-neutrophil cytoplasmic
> antibodies." Yes, of course, the nucleus iss not the same thing as a
> neutrophil! But it seems t be the only thing that hooks in with a
> myeloperoxidase cytoplasmic antibody.
Myeloperoxidase is merely a special name for peroxidase produced by
polymorphonuclear leukocytes. It is concerned with the bactericidal
action of these cells. It was so named because it was originally
isolated from the blood of myeloid leukemia patients. Peroxidase is a
hemoprotein enzyme which catalyses the oxidation of various chemicals by
hydrogen peroxide to convert it to water.
Frankly, I do not think that either Michael or I (or possibly even the
review authors) are competent to assess the full meaning of this without
a lot more depth of knowledge and research.
--Tom
Tom Matthews
The LIFE EXTENSION FOUNDATION - http://lef.org
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***
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Michael
I (Michael Rae) wrote:
>I've now discvered there are SERIOUS TOXICITY ISSUES WITH
AMINOGUANIDINE
>WHICH ARE UNDETECTABLE EXCEPT BY SPECIFIC TESTS NOT PART OF
>STANDARD BLOODWORK.
>
>QUIT.
Tom said: "In a private email containing a copy of his post Michael
also ordered me to "QUIT", but since I don't take orders from anyone
(who is not holding a gun to my head), I simply ignored his
imperative. :)"
First, I should note that my "QUIT" was more due to screaming panic &
concern than paternalism, as one screams out "STOP" when one sees
someone (no matter how intelligent & self-responsible) stepping out in
front of an oncoming truck while momentarily looking another way.
Please read this instead as I concluded:
>My advice:
>
>If you're taking AG, QUIT.
>
>Then immediately go convince a doctor you need an ANA test,
>because you've been taking an unapproved drug which clinical trials
>have now reported are causing elevated ANA and anti-MPO.
Second, I did not, in fact, specifically order you (Tom) to quit -- I
just forwarded you (personally) the (public) post, because I happen to
know that you, personally, are taking it, and (please take this in the
quite sincere & non-condescending spirit in which it is intended) I
was -- and am -- accordingly gravely concerned for you.
I can understand that you would feel that I was ordering you to quit,
and I apologize. As an independent thinker & actor in life, it's
understandable that you would react negatively to any such perception.
I fear, however, that this reaction may have clouded your judgement on
this issue: I confess to thinking that it is quite unreasonable for
anyone who does not have advanced IDDM to continue on w/AG in the
light of the present data.
I do respect your judgement, as well as a person's right to make up
hir own mind even if hir judgement is poor, but I appeal to you, Tom,
for your own sake & for the sake of many who put much weight into your
stated opinions, to re-read the original, taking into consideration
what follows, and reconsider your use of AG & your endorsement (tho' I
recognize that you're careful to insist that others, too, form their
own judgement on such matters) of its use in otherwise healthy folks.
Let me start by finishing my previous post, with the quantitative data
on side effects & benefits on (AGE-dependent) retinopathy (for which
disease they were running the trial). Relevant sections of Table 3 (it
improves blood lipids, but few will care):
Placebo 300 mg/day 600
mg/day
----------------------------------------------------------------------------
Retinopathy progression (%) 16 11 (P=0.0112) 8
(p=0.044)
Flu-like illness with reversible
liver fun functioin tests 5 11 13
Anemia (%) 33 50 40
Induction of ANA 29 39 53
Induction of MPO-ANCA 22 31 55
-------------------------------------------------------------------------
Now, note that AG did not have significant effects on retinopathy at
the lower dose. This may be irrelevant because a low dose might be
sufficient to inhibit AGE beneficially in folks who are otherwise
healthy & thus have less stress & healthier AGE-detoxing mechanisms,
but it may also be read as indicating that such a dose would be even
less likely to benefit healthy folks, either: an antioxidant which
doesn't help a person with extreme oxidative stress is unlikely to
help those with "normal" levels, eg.
>::Before we begin here, let me remind everyone that everything is
>"toxic" in sufficient quantity and it is the nature of
>the toxicity and the dosages involved which is all important.::
I agree. The relativity of the term does not render it meaningless,
however. Vitamin C is not absolutely safe, and AG is not a catalyst of
universal cataclysm; I believe, however, that the evidence is clear
enough that the risks of AG in healthy folk (& probably even in IDDM
patients) far outweigh the benefits, from the available data.
>Many, many rodent studies show that {ag} reduces AGE
>accumulation, & reduces complications (nerve damage, nephropathy,
retinopathy) in diabetic
>lab rodents. The implication: by lowering our own AGE leves,
>ag might retard the progress of a basic mechanism of
>aging, or at least the damage done by same in
>at least some organs & tissues.
>
>::First, aminoguanidine will not reduce AGE levels.
By this, I take it that you mean that AG will not reverse existing
AGE. That wasn't what I meant: I only meant that it would reduce the
level a person would accumulate over time, relative to the level the
same person would have if s/he had not taken the drug. Tho' I see that
the sentence in isolation could be read as you did, I would have
thought that my meaning would have been clear in context, as I started
out by saying that "this stuff reduces AGE accumulation," & not (eg)
"this stuff cleaves AGE crosslinks,"etc.
Also, I recently posted a detailed discussion of AG's mechanims of
action, in part in response to a question from you (Tom), which I
think would make it pretty clear to anyone that I do understand that
the stuff reduces AGE formation, not reverses existing AGE:
http://groups.google.com/groups?hl=en&safe=off&ic=1&th=224de02911dd4154,1
... but from the above, & from your immediately following comment, I
take it you must've missed it. Apologies for the confusion.
::> It will only reduce
>the glycation rate::
Actually, as I noted in the op cit post, AG does not reduce the
glycation rate per se (ie. the attachment of glucose to proteins) to
any significant degree in vivo. In vitro, it reduces several steps in
the AGE-formation process, including glycation, but from its lack of
effect on HbA1C in both rodents (see op cit) & humans (as reported in
the trials summarized in this post), it's clear that in vivo AG's
anti-GLYCATION effects are negligible. It's widely accepted that AG's
AGE-accumulation-reduction effects are due to (a) scavenging of
reactive dicarbonyls, & probably (b) preserving renal function via
iNOS suppression, thus allowing for greater renal clearance & hence
less buildup over time. See the post for more details & refs.
:: > and the rate at which AGE accumulates. ::
As noted above, this latter is what I meant. I don't mention all of
this just to quibble: it's mechanistically & practically important to
distinguish late-stage inhibitors like AG & pyridoxamine from
early-stage inhibitors like pyruvate.
>::First, we need to know the nature of the "toxicity".::
Agreed. I believe that my original post addressed this: induction of
ANA and what (I now see clearly, from Table 3, which I somehow failed
to re-read in posting) specifically MPO-ANCA -- ie markers of
autoimmunity, elevated in various drug-induced autoimmune syndromes,
incl some known to be induced by close relatives of AG & one which
actually did manifest in a portion of the patients, despite the
relative brevity of the trials.
Tom, you often counsel people younger than yourself not even to take
more than very mild supplement doses, & to restrict themselves to a
healthy, mild-CR diet & exercise. I think it's reasonable to say that
this goes well beyond anything ever reported for any supplement
program a typical LEF Forum participant who you've counselled to skip
starting has been endeavoring upon. I take it that you will at least
agree that, while each person must weigh the risks for hirself, AG
does not appear to be a reasonable tradeoff for relatively young,
healthy folk?
:: > Second,
>what percentage of the experimental subjects were suffering such
symptoms
>versus what percentage of controls.::
See above. It's surprising, of course, that so many controls exhibited
these problems, but the levels to me are clearly outside the realm of
acceptability for otherwise healthy life-extensionists.
:: >Third, based on the nature
>of the toxicity, the biochemistry of the drug and the
>patterns of those with symptoms, is there something which can
>be done to reduce/eliminate the likelihood of toxicity?::
More on this below.
>
>Second, contrary to what many seem to believe, "mild flu-like
symptoms"
>are NOT likely to mean upset stomach (which a true
>FLU rarely causes):
>
>------------------------------
>
>Symptoms of an influenza infection include: Fever, Muscle aches and
pain,
> Headache, Fatigue, Dry cough, Sore throat, Runny nose.
>
>Fever usually appears suddenly, and can alternate with chills.
Headache
>is usually accompanied by pain around the eyes, and the whites
>of the eyes can become reddened and irritated, with tearing and
discharge.
>Muscle aches are usually located in the back and legs.
>
>A dry cough is often noticed in the early stages of flu, and can
>progress to a "productive" cough and bronchitis - inflammation of the
>bronchial passages to the lungs - lasting up to ten days.
>A lingering sensation of weakness and fatigue can persist for weeks!
>
>Children with the flu sometimes suffer from nausea, vomiting, and
>diarrhea. The so-called "stomach flu" experienced by adults is NOT
>related to influenza.
>
>::This was all an unnecessary aside about the definition of "flu"
>symptoms. Why not simply describe the symptoms and forget what
>other disease/disorder that they were erroneously stated as being
like.::
I was doing just that: from this comment, & that which follows below,
I take it that you misunderstood my point, here:
{Elsewhere}:
>::Note the researchers doing these experiments are rarely practicing
MD's
> and this is likley the reason for the mix-up in the
>definition of the term "flu-like".::
As the authors are MDs in the Dept of Medicine at the U of Western
Australia & the W Australian Heart Research Institute (as are nearly
all the investigators i nthe cited trial(s)) say "flu-like," I believe
that we should take them literally: they almost certainly mean (I put
it to you) that > 1 AG user in 10 (more than twice as many as taking
placebo, despite being relatively advanced IDDM patients) experienced
Fever, Muscle aches and pain, Headache, Fatigue, Dry cough, Sore
throat, & Runny nose -- not that they reported nausea.
>
>Does a drug which causes a mild version of this sound
>like a safe drug
>for home experimentation, even in the absence of symptoms?
>
>::Lots of foods and other practices can cause upset stomach. It
>is the nature of the cause and its systemic biochemical
>effects which is important.::
This comment further suggests to me that you missed the point of my
comments, above (whether or not you now agree with them, having
understood what I meant). I am pretty confident that, as medical
people, these people did NOT mean nausea (whic of course people get
from any number of things over & above placebo), but actual FLU-LIKE
symptoms.
>-----------------------------
>
>http://www.elis.sk/bll/00/full/bll1000a.pdf
>However, all clinical studies with aminoguanidine (Pimagidine) in
Europe and
>then in USA were stopped because its toxicity."
>
>====================
>
>http://www.ndei.org/content/ndeipubs/issues/vol_4_no_1.asp
>
> "Unfortunately, this particular drug proved
>too toxic to permit a safe long-term trial, but
>analogs and congeners of aminoguanidine are under development."
>
>::What neither of these quotes provide is information about the rate
>of toxicty among those taking ag at different dosages and
>the biochemical nature of this toxicity.
Again, see above. But also, even if we didn't have this data, the fact
that trials were shut down over toxicity issues, in people whose
immediate survival (as opposed to long, long-term health, as in most
life-extensionists) is not at stake, is enough to say to me that this
drug is a bad bet. NB that Alteon (who, in an unforgivable lack of
proper disclosure to both investors & those who are (from their POV)
illegitimately pirating 'their' drug (NB that they DO have use-patents
on the stuff for AGE complication in vivo) are announcing AG's success
in lipids & retinopathy, but toxicity sufficient to lead to the
shutting down of trials, such tht it is unlikely to ever come to
market!) is now seemingly starting over again, with drugs like
ALT-946:
Forbes JM, Soulis T, Thallas V, Panagiotopoulos S, Long DM, Vasan S,
Wagle D,
Jerums G, Cooper ME.
Renoprotective effects of a novel inhibitor of advanced glycation.
Diabetologia. 2001 Jan;44(1):108-14.
PMID: 11206401
The full text is careful to say that "ALT-946 is also a poor inhibitor
of {NOS} with fewer toxic side effects than AG (unpublished results)."
I believe that Alteon may also be behind 2,3-DAP.
> :: If we search PubMed
>we find the following:
>
>J Nutr Sci Vitaminol (Tokyo) 1995 Feb;41(1):43-50
>Effects of aminoguanidine and pyridoxal phosphate on glycation
reaction of aspartate
>aminotransferase and serum albumin.
>Okada M, Ayabe Y. ::
>
>::Some other papers, provide other enzymes which are inhibited to a
>certain extent by ag all of which appear to be
>related to vitamin B6 biochemistry. Thus, the toxic effects of
>ag appear to be related to its inhibition of vitamin
>B6 and the host of major biochemical pathways which B6
>influences. This is the reason that I have always warned
>people that they should take extra B6 when taking ag.::
I think that making sure one gets extra B6 when taking AG is wise
advice, but without very clear evidence that B6 depletion is
responsible for the ANA induction, I don't think it's reasonable to
assume that such is the origin. NB the specific comment of Singh et al
that "there are no results so far on antibody generation" in rodents.
>
>
>In addition, if one is to judge by numbers, I can
>produce just as many or more studies showing how aminoguanidane
>reduces some toxicity or or other than that it causes
>it. Here is just a sample:
>
Well, I don't think many life extensionists are routinely exposing
themselves to anti-Fas antibody, CCL4, or injected endotoxin. If they
are, they have much more significant changes in lifestyle to make than
supplements, CR, exercise, or AG :). & while glycotoxins (& endogenous
AGE formation, of course) are certainly bad things, neither
caramelized duck nor even mild hyperglycemia are going to induce
biochemical signs of autoimmune disorders after a few months.
I really don't think that the possible benefits balance the evident
risks; apparently, the investigators in this/these trial(s) don't even
think it's worth it for IDDM patients.
Each, of course, must choose for hirself. I again apologize for giving
the (false) impression that I believed otherwise.
>
>Singh R, Barden A, Mori T, Beilin L.
>Advanced glycation end-products: a review.
>Diabetologia. 2001 Feb;44(2):129-46. Review.
>PMID: 11270668v
>
>has the dope. (References & Table from the above will be
>posted sometime this week for those who want to dig
>further. I want to get this out TONIGHT).
Here are teh promised references, for those who want to dig further:
{22} Appel G, Bolton K, Freedman B et al.
Pimagedine lowers total urinary protein and slows progression of overt
diabetic nephopathy in patients with type I diabetes.
J Am Soc Nephrol. 1999;10:153A.
{23} Raskin P, Caltran D, William M et al.
Pimagedine reduces progression of retinopathy and lowers lipid
concentrations in patients with type I diabetes.
J Am Soc Nephrol. 1999;10:179A.
{24} Whittier F, Spinowitz B, Wuerth JP et al.
Pimagedine safety profile in patients with Type I diabetes.
J Am Soc Nephrol. 1999;10:184A.
{25} Boel E, Selmer J, Flodgaard HJ, Jensen T.
Diabetic late complications: will aldose reductase inhibitors or
inhibitors of advanced glycosylation end-product formation hold
promise?
J Diabetes Complications. 1995;9:104-29.
{145} Nilsson BO.
Biological effects of aminoguanidine: an update.
Inflamm Res. 1999 Oct;48(10):509-15. Review.
PMID: 10563466
{146} Goodwin DC, Aust SD, Grover TA.
Free radicals produced during the oxidation of hydrazines by
hypochlorous acid.
Chem Res Toxicol. 1996 Dec;9(8):1333-9.
PMID: 8951237
{147} Tervaert JW, Mulder AH, Kallenberg CG.
Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA): clinical
significance and relation to antibodies against myeloid lysosomal
enzymes.
Adv Exp Med Biol. 1993;336:253-6.
PMID: 8296614
148. Yung R, Chang S, Hemati N, Johnson K, Richardson B.
Mechanisms of drug-induced lupus. IV. Comparison of procainamide and
hydralazine
with analogs in vitro and in vivo.
Arthritis Rheum. 1997 Aug;40(8):1436-43.
PMID: 9259423
>"A recent phase III trial using pimagedine has shown beneficial
affects[sic]
>on the progression of retinopathy and lipid concentrations {23}. In
>addition to the affects{sic} on diabetic nephopathy progression in
optimally
>treated Type I diabetic subjects (Table 3) (22). The reduction
>in retinopathy progression (95% had advanced retinopathy) after 12
months
>of follow-up was significantly decreased only in the high dose
>group (300 mg twice a day) compared iht the low
>dose (150 mg twice a day) and placebo groups.
>
>{Bear this carefully in mind thru'out what follows. when they say
>"high dose," they mean 600 mg/day. When they say "low
>dose," they mean 300 mg/day}.
>
>"These observations were independent of glycemic control with HbA1c
values
>being comarable between all groups."
>
>"A small number of suubjects developed flu like symptoms and half
>became anemic."
>
>"Of greater concern was the development of anti-nuclear antibodies
and
> myeloperoxidase antinuclear cytoplasmic antibodies especially in the high
> dose group, with three subjectsdeveloping crescentic glomerulonephritis.
> One rescovered but two developed ESRD (24). Generally lower dose therapy
> was well tolerated with a side effect profile comparable to placebo."
But also, NB, no statistically significant effect on retinopathy.
>
>::I have never taken more than the lower dosage and have
>never had any symptoms or blood tests indicating kidney problems,
>but then I also take several other kidney strengthening supplements
>and I never take acetaminophen which is far more dangerous
>for the kidneys than any other non-prescription drug and most
>prescription ones too.::
But have you had ANA tests done? This is the greater concern to both
me & to Singh et al. Unless you specifically requested same, or your
doc took it upon hirself to order them, I greatly doubt you'd have
such data. Also (& I point this out to Forum readers; you (Tom) are of
course fully aware f this), your single, anecdotal case is not in any
way equivalent in evidence to the results of controlled trials, & (as
you note) you're an exceptional case anyway because of your overall
lifestyle.
Again, as I noted,
>NB the talk re: antinuclear antibodies (ANA). This is serious shit,
>folks. ANA is a marker for autoimmunity. It's a side
>effect of some drugs that they CREATE unique autoimmune disorders,
>such as drug-induced autoimmune hepatitis or drug-induced "lupus"
(which is
>not the same as SLE per se). See, eg, the
>ugly case of teenage girls being given same by idiot
>docs who prescribe monocycline for acne:
>
>http://bmj.com/cgi/content/full/312/7024/169?view=full&pmid=8563540
>
>http://www.ama-assn.org/special/womh/library/readroom/arch99/ioi80305.htm
>
>http://www.google.com/search?q=cache:lZcNWC6jiys:www.ajcp.com/goldstein1000ar.html
Minocycline-Related Autoimmune Hepatitis Case Series and Literature
Review &hl=en
...
> anti-MPO is used "For diagnosis and monitoring inflammatory activity
>in primary systemic small vessel vasculitides... Presence of anti-MPO
> antibodies is highly specific for idiopathic and vasculitis-associated
> crescentic glomerulonephritis, classic polyarteritis nodosa, Churg-Strauss
> syndrome, and polyangiitis overlap syndrome without renal
>involvement....{However,} Results of this assay are not diagnostic
proof of
>the presence or absence of disease and should be used
>in conjunction with clinical findings and other serological tests."
(http://www.labcorp.com/datasets/labcorp/html/chapter/mono/se038900.htm).
>Elsewhere, ANCA anti-MPO, or MPO ANA, are said to be
>a sign of "Microscopic polyarteritis, Idiopathic crescentic
necrotising glomerulonephritis, Other
>small-vessel vasculitides, {or} Drug reactions, eg. propylthiouracil
(rare)."
Here is the abstract of (148), cited by Singh et al:
Adv Exp Med Biol 1993;336:253-6
Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA): clinical
significance and relation to antibodies against myeloid lysosomal
enzymes.
Tervaert JW, Mulder AH, Kallenberg CG.
Department of Clinical Immunology, University Hospital Groningen, The
Netherlands.
In a prospective study of 27 months duration p-ANCA were found in 120
patients. 35% of these patients had vasculitis and/or
glomerulonephritis. 28% of the p-ANCA positive sera reacted with
myeloid lysosomal enzymes.
PMID: 8296614
>
>"These results imply that patients using pimagedine require
assessment of full
>blood counts and autoimmune status before and during therapy.
Measures
>of vasculitic activity including {sed} rate, {C-RP}, and urinary
sediment
>as well as physical examination. In addition {ag} is known
>to inhibit diamine oxidase, which catalyses deamination of diamines
such
>as histamine (145). This has the possibility of raising histamine
>concentrations with the attendant vascular and respiratory side
effects. To
>date, there are no reports of {such} secondary to {ag}
>therapy."
>
>::This effect on histamine could be a problem if high histamine
>generating foods are consumed, but again only if one is
>taking insufficient vitamin B6 the inhibition of which is the
>reason for this inhibitory effect of ag on the diamine
>oxidase enzyme. {Tom here cites Agents Actions 1981 Apr;11(1-2):20-7
} ::
I don't believe that your reading of this is FULLY correct. DAO
activity depends directly on its carbonyl group; I therefore believe
that AG DIRECTLY inhibits DAO. NB this paper's finding that, while DAO
activity does appear to be B6-dependent, "There does not appear to be
an important interaction between the effects of the deficiency and
those stemming from treatment of the animals with the diamine oxidase
inhibitor aminoguanidine."
Can J Biochem 1978 Jun;56(6):470-3
Role of pyridoxine in the metabolism of putrescine in the rat.
Sourkes TL, Missala K.
1. The ability of rats to metabolize radioactive putrescine to 14CO2
in vivo has been studied. 2. Animals made deficient in pyridoxine
exhibit a significantly lower rate of catabolism of the diamine. 3.
There does not appear to be an important interaction between the
effects of the deficiency and those stemming from treatment of the
animals with the diamine oxidase inhibitor aminoguanidine. 4. These
results favour the concept of a role of pyridoxal cofactor in the
metabolism of diamines, presumably at the diamine oxidase stage.
PMID: 96921
Likewise, the full text of
Nilsson BO.
Biological effects of aminoguanidine: an update.
Inflamm Res. 1999 Oct;48(10):509-15. Review.
PMID: 10563466
... says that "Tamura et al show that inhibition by {AG} is composed
of at least two phases and that {AG} not only inhibits the enzyme but
inactivates it. However, we still lack the exact mechanism ..."
(a) Again, my big concern is ANA & the implications thereof, & (b)
remember that many of us are taking large amounts of carnosien, which
carnosinase is (mostly) breaking down into histidine & thence in part
histamine ...
>
>there are no results so far on antibody generation. {AG} is,
>however, a hydrazine derivative as is hydralazine (26), which is
>itself associated with antihistone and antinuclear cytoplasmic
antibody production as
>well as a clinical situation similar to lupus (147). Although
>the mechanism for autoantibody production as a result of
hydrazine-hydrazie
>derivative therapy is not known, ther is some evidence that
>it could involve lympohocyte function associated with antigen-1
overexpression and
>autoreactivity (148)."
>
>"Based on the current phase III trial outcomes and considering the
>side-effect profiles there is no greater benefit in taking the
>higher dose of pimagedine. It is, however, not known how
>well the drug would work in patients who are not
>optimally treated, if treatment should be initiated at the time
>of diagnosis of diabetes or if a longer follow-up period
>would have separated outcome measures for the 2 treatment arms.
>Similarly studies would need to be extended to {NIDDM}."
>
>==================================
>
>...Let alone to otherwise healthy people who have, as one of
>their principle priorities in life, the desire to extend lifespan!
>
>
>::But at the low dose of 150 mg bid, with appropriate
>extra B6, aminoguanidine may reasonably be added to ones arsenal
>of life extension therapies, *none of which*, I may remind
>you have to date been proven to work for humans.::
>
Efficacy-wise, no; but we do have a pretty good reason to believe that
orthomolecules, many herbs, CR, exercise, & even many drugs are much
safer than AG appears to be. Again, IMHO it's pretty clear that the
risks (on which we have some data) cost outweigh the (presently
speculative in the healthy) benefits.
-Michael
Tom Matthews
>
> All:
>
> I (Michael Rae) wrote:
[snip]
> Let me start by finishing my previous post, with the quantitative data
> on side effects & benefits on (AGE-dependent) retinopathy (for which
> disease they were running the trial). Relevant sections of Table 3 (it
> improves blood lipids, but few will care):
>
> Placebo 300 mg/day 600
> mg/day
> ----------------------------------------------------------------------------
> Retinopathy progression (%) 16 11 (P=0.0112) 8
> (p=0.044)
>
> Flu-like illness with reversible
> liver fun functioin tests 5 11 13
>
> Anemia (%) 33 50 40
>
> Induction of ANA 29 39 53
>
> Induction of MPO-ANCA 22 31 55
>
> -------------------------------------------------------------------------
>
> Now, note that AG did not have significant effects on retinopathy at
> the lower dose.
Michael, I think that you read far too much "rigor" and "absolutivity"
into these measures of statistical significance. They are merely that:
measures of the likelihood that some deviation is chance or (directly or
indirectly) causally connected. Thus, IMO, it is inaccurate and biased
to imply, as you did, that there is a "black and white" differenct
between the effects of the two dosages on retinopathy progression as if
the higher dose has "some" effect and the lower dose has "none". Looking
at the figures, it would be far more accurate, IMO, to say that "from
the data of this experiment 300 mg/day did not have as much benefit for
retinopathy as did 600 mg/day".
> This may be irrelevant because a low dose might be
> sufficient to inhibit AGE beneficially in folks who are otherwise
> healthy & thus have less stress & healthier AGE-detoxing mechanisms,
Especially, as I have stated, if one is taking the ag only as an adjunct
to many other anti-AGE therapies, from the point of view that "many
little benefits many still add up to a lot, yet small damage from any of
them may easily be repairable".
> but it may also be read as indicating that such a dose would be even
> less likely to benefit healthy folks, either: an antioxidant which
> doesn't help a person with extreme oxidative stress is unlikely to
> help those with "normal" levels, eg.
Yes, I admit that the opposite to what I have stated above may also be
true, that: "The effects of many little benefits may be dissipated among
one another and may amount to nothing while the harm of them all may add
and do significant damage." However, again IMO based on my knowledge of
the body's ability to deal effectively with many small toxic effects
over a lifetime, I think that the former is more likely to be true. And
that is what I am counting on.
> >Before we begin here, let me remind everyone that everything is
> >"toxic" in sufficient quantity and it is the nature of
> >the toxicity and the dosages involved which is all important.
>
> I agree. The relativity of the term does not render it meaningless,
> however.
But it does mean that using "toxic" in a subject line or a lead-in
paragraph *before* fully defining its meaning in the current context is
not an unbiased or responsible action.
> Vitamin C is not absolutely safe, and AG is not a catalyst of
> universal cataclysm;
It is good to have that established and acknowledged up front. Note that
wrt to AG, it is in opposition to the subject line which you chose for
this thread!
> I believe, however, that the evidence is clear
> enough that the risks of AG in healthy folk (& probably even in IDDM
> patients) far outweigh the benefits, from the available data.
And, as I have stated, *I* neither believe nor think that that is so
when one takes small quantities of AG as part of an overall anti-AGE
strategy, and guards against its potentially harmful effects.
> >Many, many rodent studies show that {ag} reduces AGE
> >accumulation, & reduces complications (nerve damage, nephropathy,
> retinopathy) in diabetic
> >lab rodents. The implication: by lowering our own AGE leves,
> >ag might retard the progress of a basic mechanism of
> >aging, or at least the damage done by same in
> >at least some organs & tissues.
> >
> >First, aminoguanidine will not reduce AGE levels.
>
> By this, I take it that you mean that AG will not reverse existing
> AGE. That wasn't what I meant: I only meant that it would reduce the
> level a person would accumulate over time, relative to the level the
> same person would have if s/he had not taken the drug. Tho' I see that
> the sentence in isolation could be read as you did,
Yes, and that is why I wanted to make it clearer. Even so AG, per se,
can *not* cause any of the *reduction*! It is the body which may cause
reduction by eliminating AGE faster than it is being produced *if* AG
and other therapies are used to lower the rate of production! When you
keep talking about AG "reducing" AGE, you constantly mislead thinking
and obfuscate the real mechanism of action of what is happening.
> I would have
> thought that my meaning would have been clear in context, as I started
> out by saying that "this stuff reduces AGE accumulation,"
It would be far clearer to say the AG "lowers the rate of AGE
formation". Whether it "reduces AGE accumulation" or not is related to a
whole host of other factors involving production rate and elimination
rate. It is not directly and only related to AG.
> & not (eg) "this stuff cleaves AGE crosslinks,"etc.
Only then would it be correct to say unequivocally that it "reduces AGE
accumulation", although I suppose that, technically, even that could be
incorrect if it at the same time happened to increase the production
rate.
> Also, I recently posted a detailed discussion of AG's mechanims of
> action, in part in response to a question from you (Tom),
BTW, it was a rhetorical question.
> which I
> think would make it pretty clear to anyone that I do understand that
> the stuff reduces AGE formation, not reverses existing AGE:
>
> http://groups.google.com/groups?hl=en&safe=off&ic=1&th=224de02911dd4154,1
>
> ... but from the above, & from your immediately following comment, I
> take it you must've missed it. Apologies for the confusion.
No need to apologize. It is your (unintentional, I am sure) inaccurate
and sometimes mislead word phrasing to which I take exception. In your
zeal to report your findings and your viewpoint you go overboard in your
portrayal of the situation. I fully understand because I have had to
guard against the same all my life and I am sure that I still
unintentionally often do it too.
> > It will only reduce the glycation rate
>
> Actually, as I noted in the op cit post, AG does not reduce the
> glycation rate per se (ie. the attachment of glucose to proteins) to
> any significant degree in vivo. In vitro, it reduces several steps in
> the AGE-formation process, including glycation, but from its lack of
> effect on HbA1C in both rodents (see op cit) & humans (as reported in
> the trials summarized in this post), it's clear that in vivo AG's
> anti-GLYCATION effects are negligible.
Actually, I don't think that it is totally clear from the research done.
HbA1c is not the only thing or even the most important thing which can
be glycated. It is simply the easiest to measure. Such studies as the
following are what I use for my conclusions.
Anal Biochem 1994 Feb 1;216(2):305-12
Determination of glycation crosslinking by the sugar-dependent
incorporation of (14C)lysine into protein.
Prabhakaram M, Ortwerth BJ.
Mason Institute of Ophthalmology, University of Missouri, Columbia
65212.
A simple, quantitative assay has been established to determine the
glycation-dependent crosslinking ability of any sugar by measuring the
incorporation of (14C)-lysine into protein. The assay was shown to be
both
sugar-dependent and protein-dependent and was completely inhibited by
sodium
cyanoborohydride, 2-aminoguanidine, and semicarbazide. A typical 1.0-ml
reaction
mixture contained 5 mg lysozyme, 20 mumol threose, and 5 microCi of
(14C)lysine
and exhibited an incorporation of 8 x 10(5) cpm (1.6 nmol of lysine)
after 7
days of incubation. A comparison of the crosslinking ability of a
variety of
sugars showed glyceraldehyde and dihydroxyacetone to be twice as active
as
erythrose and threose and eight times more reactive than ribose. Little
or no
crosslinking could be demonstrated with three different hexoses as well
as their
phosphorylated derivatives. The dicarbonyl sugars 3-deoxyglucosone and
xylosone
were at least as effective as ribose in crosslinking, as were the
oxidation
products of ascorbic acid. Several amine-containing compounds were
tested as
inhibitors of crosslinking; however, 2-aminoguanidine was the most
effective.
The rate of synthesis of Lys-Lys, Lys-Arg, and Lys-His crosslinks was
determined
by measuring the incorporation of (14C)lysine into specific amino acid
homopolymers. The relative incorporation was polylysine > polyarginine >
polyhistidine with threose, but polyarginine > polyhistidine >
polylysine with
dehydroascorbic acid, suggesting a different crosslinking mechanism for
these two compounds.
PMID: 8179185
> It's widely accepted that AG's
> AGE-accumulation-reduction effects are due to (a) scavenging of
> reactive dicarbonyls, & probably (b) preserving renal function via
> iNOS suppression, thus allowing for greater renal clearance & hence
> less buildup over time. See the post for more details & refs.
Okay, my simplication error. By "glycation rate", I simply meant the
rate of formation of all the "bad" things which begins with glycation. I
will try to be more accurate in future (if you will :-) so that you
don't have to pick so many nits.
> > and the rate at which AGE accumulates.
>
> As noted above, this latter is what I meant. I don't mention all of
> this just to quibble: it's mechanistically & practically important to
> distinguish late-stage inhibitors like AG & pyridoxamine from
> early-stage inhibitors like pyruvate.
I agree. I was merely summing them together for simplicity. It was your
phrasing "reduces AGE accumulation" which I found to be highly
misleading.
> >First, we need to know the nature of the "toxicity".
>
> Agreed. I believe that my original post addressed this: induction of
> ANA and what (I now see clearly, from Table 3, which I somehow failed
> to re-read in posting) specifically MPO-ANCA -- ie markers of
> autoimmunity, elevated in various drug-induced autoimmune syndromes,
> incl some known to be induced by close relatives of AG & one which
> actually did manifest in a portion of the patients, despite the
> relative brevity of the trials.
It would be much less misleading and distorting to not use the "scare"
word "TOXIC" until you defined the specific and limited nature of the
toxicity.
> Tom, you often counsel people younger than yourself not even to take
> more than very mild supplement doses, & to restrict themselves to a
> healthy, mild-CR diet & exercise. I think it's reasonable to say that
> this goes well beyond anything ever reported for any supplement
> program a typical LEF Forum participant who you've counselled to skip
> starting has been endeavoring upon. I take it that you will at least
> agree that, while each person must weigh the risks for hirself, AG
> does not appear to be a reasonable tradeoff for relatively young,
> healthy folk?
Of course. I never said it was. Anyone under 50 should be taking damned
few xenobiotics. AG, in particular is "on the edge" of reasonableness,
IMO, and I would not counsel anyone under 50 to take it. However, once
you start getting older the trade-offs to prevent decline get more
severe in their calculation.
Yes, I accept that I should have made that clear. OTOH, you were telling
everyone "its TOXIC!! so QUIT" without regard to such need/age
tradeoffs.
> > Second,
> > what percentage of the experimental subjects were suffering such
> > symptoms versus what percentage of controls.
>
> See above. It's surprising, of course, that so many controls exhibited
> these problems, but the levels to me are clearly outside the realm of
> acceptability for otherwise healthy life-extensionists.
But because so many controls had the same problems, I would maintain the
whole experiment is suspect.
For example, it could mean that there was some *essential* cause for the
autoimmunity markers, anemia, etc. in all experimental subjects which
was merely *promoted* by aminoguanidine. And if that *essential* cause
(from whatever) were not present, the ag would not have produced any of
these problems at all!
It would then still be correct to be concerned with the capability of ag
to *promote* such problems in those who had a tendency to them, but it
would be incorrect to state that it *causes* such problems in otherwise
fully healthy and safeguarded people.
> >Third, based on the nature
> >of the toxicity, the biochemistry of the drug and the
> >patterns of those with symptoms, is there something which can
> >be done to reduce/eliminate the likelihood of toxicity?
>
> More on this below.
Since from your reply, I am now completely confused concerning the
portions of you message about flu-like symptoms and the proper meaning
of "flu", I have snipped it all out.
> >http://www.elis.sk/bll/00/full/bll1000a.pdf
>
> >However, all clinical studies with aminoguanidine (Pimagidine) in
> >Europe and then in USA were stopped because its toxicity."
> >
> >====================
> >
> >http://www.ndei.org/content/ndeipubs/issues/vol_4_no_1.asp
> >
> > "Unfortunately, this particular drug proved
> >too toxic to permit a safe long-term trial, but
> >analogs and congeners of aminoguanidine are under development."
> >
> >What neither of these quotes provide is information about the rate
> >of toxicty among those taking ag at different dosages and
> >the biochemical nature of this toxicity.
>
> Again, see above. But also, even if we didn't have this data, the fact
> that trials were shut down over toxicity issues, in people whose
> immediate survival (as opposed to long, long-term health, as in most
> life-extensionists) is not at stake, is enough to say to me that this
> drug is a bad bet.
Not necessarily, since most of these trials are single drug/nutrient
trials. Definitely, taking ag requires taking more B6 than the RDA
amount at the very least.
[Snip stuff on Alteon and ALT-496]
> >If we search PubMed we find the following:
> >
> >J Nutr Sci Vitaminol (Tokyo) 1995 Feb;41(1):43-50
> >Effects of aminoguanidine and pyridoxal phosphate on glycation
> >reaction of aspartate aminotransferase and serum albumin.
> >Okada M, Ayabe Y.
> >
> >Some other papers, provide other enzymes which are inhibited to a
> >certain extent by ag all of which appear to be
> >related to vitamin B6 biochemistry. Thus, the toxic effects of
> >ag appear to be related to its inhibition of vitamin
> >B6 and the host of major biochemical pathways which B6
> >influences. This is the reason that I have always warned
> >people that they should take extra B6 when taking ag.
>
> I think that making sure one gets extra B6 when taking AG is wise
> advice, but without very clear evidence that B6 depletion is
> responsible for the ANA induction, I don't think it's reasonable to
> assume that such is the origin.
By my reasoning above, it is also not reasonable to assume that AG
"initiated" any such induction.
> NB the specific comment of Singh et al
> that "there are no results so far on antibody generation" in rodents.
Perhaps because the factor(s) responsible for those effects in the
placebo group above were also not present in the rodent experiments (see
my reasoning above).
> >In addition, if one is to judge by numbers, I can
> >produce just as many or more studies showing how aminoguanidane
> >reduces some toxicity or or other than that it causes
> >it. Here is just a sample:
> Well, I don't think many life extensionists are routinely exposing
> themselves to anti-Fas antibody, CCL4, or injected endotoxin.
But they are (as is everyone else) exposing themselves to small amounts
of a host of similarly acting toxins from food and the environment.
> If they
> are, they have much more significant changes in lifestyle to make than
> supplements, CR, exercise, or AG :). & while glycotoxins (& endogenous
> AGE formation, of course) are certainly bad things, neither
> caramelized duck nor even mild hyperglycemia are going to induce
> biochemical signs of autoimmune disorders after a few months.
>
> I really don't think that the possible benefits balance the evident
> risks;
Obviously, for someone over 50 who is knowledgeably safeguarding, I do.
> apparently, the investigators in this/these trial(s) don't even
> think it's worth it for IDDM patients.
The investigators are establishment scientists, who, when they work in
the US, will generally not endorse anything which has not passed FDA
trials, even though if you talk to them privately you will find that
they (as with many nutrition knowledgeable physicians) take many such
things themselves.
> Each, of course, must choose for hirself. I again apologize for giving
> the (false) impression that I believed otherwise.
> >"These results imply that patients using pimagedine require
You may be right. Seeing it again now, I accept that I read the next
abstract below incorrectly (although they give absolutely no explanation
for the statement that you quoted and 3) seems to me to be inconsistent
with 4)).
Still, I am not so sure that you (and they) are correct about this
potential side effect of AG or the result not being related to AG's
inhibition of B6. My biochemical pathways book shows that histamine is
catabolized both by diamine oxidase (producing ammonia) requiring
copper, FAD and pyridoxal phospate as cofactors, and by histamine
methyltransferase which abtains is methyl group from SAM. As we all know
B6 is also needed to keep adequate SAM supplies high enough.
Thus, both histamine pathways of degradation are B6 dependent (as is its
production from histidine) and might be indirectly inhibited by AG's
effects on B6.
Furthermore, upon closer examination, the biochemistry the biochemistry
of histamine metabolism is sufficiently different than that of
putrescine metabolism as not be related regarding any interactions
between AG and B6.
> Can J Biochem 1978 Jun;56(6):470-3
> Role of pyridoxine in the metabolism of putrescine in the rat.
> Sourkes TL, Missala K.
>
> 1. The ability of rats to metabolize radioactive putrescine to 14CO2
> in vivo has been studied. 2. Animals made deficient in pyridoxine
> exhibit a significantly lower rate of catabolism of the diamine. 3.
> There does not appear to be an important interaction between the
> effects of the deficiency and those stemming from treatment of the
> animals with the diamine oxidase inhibitor aminoguanidine. 4. These
> results favour the concept of a role of pyridoxal cofactor in the
> metabolism of diamines, presumably at the diamine oxidase stage.
> PMID: 96921
>
> Likewise, the full text of
>
> Nilsson BO.
> Biological effects of aminoguanidine: an update.
> Inflamm Res. 1999 Oct;48(10):509-15. Review.
> PMID: 10563466
>
> ... says that "Tamura et al show that inhibition by {AG} is composed
> of at least two phases and that {AG} not only inhibits the enzyme but
> inactivates it. However, we still lack the exact mechanism ..."
>
> (a) Again, my big concern is ANA & the implications thereof, & (b)
> remember that many of us are taking large amounts of carnosien, which
> carnosinase is (mostly) breaking down into histidine & thence in part
> histamine ...
Again, anecdotally, I have seen no effects related to excess histamine
since starting to take 1267 mg of carnosine daily several months ago.
Once again "safer" is relative to age/need, care, testing, knowledge and
taking of side effect antidotes.
My preference is a small load high spread shotgun approach covering all
bases.
> Again, IMHO it's pretty clear that the
> risks (on which we have some data) cost outweigh the (presently
> speculative in the healthy) benefits.
Obviously, for myself at least, I disagree.
--Tom Matthews