Searching,

You seem to have a way of mis-stating other people's positions regularly. The problem with IPLEX is that it was hyped up with very subjective hearsay which then leads others to shell out very large amounts of money to try it. You've heard the hype and repeated it on this thread with your comment about "more than 50% have been helped", which is clearly not a supportable statement based on the actual data from Italy. I have stated many times on other threads that if people want to try IPLEX, they should be allowed to. What I object to was that PALS were enticed to believe "it was it".

Your attempt to equate the molecule with such hype falls way short. ALS-TDI has not claimed any efficacy for this molecule in ALS. They have not offered it for sale to any PALS. What they are doing is following standard practices in getting the molecule into trials which take years. I for one am interested but not thrilled or excited. Its a long procedure with only some chance of ultimate success.


Jomoco,

I will state once again that I am not a scientist. I really don't know what will treat ALS. I have stated before my doubts that conventional technology would be able to solve ALS. However, I really don't know. The reason that I have supported ALS-TDI's efforts in the past to look for a small molecule had only to do with the time factor for me out of self-interest. It may not be possible. The analogy I have used before is the Apollo moon program. If in 1861, Lincoln would have announced the intent of the United States to land a man on the moon, it could not have been done in 10 years. There could have been some pretty good papers written about how it could ultimately be done. But in the 1860s there was not the existing technology to do it in just about every field, computers, rockets, radio, cryogenics, and so on. They didn't have the tools to do it until about 100 years later when Kennedy made the challenge.

Such could be the case today with small molecule drugs and ALS. However, I don't have time to wait so I hope that the answer can be obtained with the tools at hand. Otherwise, its just not that exciting for me.

Fixing the heart with stemcells.

http://www.cbsnews.com/stories/2009/06/29/eveningnews/main5123569.shtml

Logic based, high yield, cell based therapy.

jomoco

So now you are claiming that instead of looking at the complete set of patients of the Italy trial, you choose to use the reference of one Italian doctor who is claiming that out of his 22 patients, more than 50% are better. Yet you can't reference the comments or the doctor and claim that it is "on the INSMED" site. Please....

Interesting to hear that out of the current patients. I'm sorry to hear that out of the 16 patients that started 3 months ago that 3 have died or withdrawn. That's nearly a 20% reduction in 3 months and what I would expect for the normal course of the disease.

It’s great that you’re using percentage figures to sensationalize your thoughts, just for the record I know of one of the three that pulled out of Iplex. As they received the green light placed the order, unfortunately the patient passed away while waiting for Iplex. Now that’s a 33% reduction in your death/failure stat on Iplex. Wonder if we dug into it some more what we will find into why the other two bailed out. Then again since when did I start digging into facts hey? Then again according to you and your analysis in the US there is only a 20% failure rate in Iplex means that 80% are benefiting that beats my “doctored” 50%.
Let’s see what was that you said a few posts ago “Any objective analysis of a treatment of ALS would not rely on a few weeks of data. Anyone that is objective wouldn't do it.” I suppose 3 months assuming everybody started at exactly the same which is being realistic (that’s sarcasm) is “what I would expect for the normal course of the disease” would take to come to a complete scientific conclusion to the efficiency of a drug/treatment. Who said it takes years of up to 70 trials until an accurate conclusion to the efficiency of a treatment can be determined thus allowing release to the general public? Surely this can be achieved in a max of 3 months can it not??

Ahh Wyne you’ve missed your calling as a politician.
We both do definitely agree that:
“In the end no-one cares a whit whether it works in a mouse or not. They care about whether it works in a human.”

P.S. Luv the sarcasm in your posts really gives me a giggle LOL Hope I’ve been able to maintain that..
P.P.S. Debie looks like you answered the other two....damn 100% debunc on Wayne's failure analysis of Iplex, so that means it's 100% effective!!!

Wayne,
I acknowledge what you say and accept everything you say in reference to the questionable source of my comments and yes I am unable to produce documents names etc but the reasons for this I have previously stated and all I can do is point you to the Insmed site which has given you the data you quoted. I can add that the Dr I mentioned is not singularly overlooking the 22 but part of the team that is treating and maintaining these patients.
I at no stage indicated anything regarding the 16 patients that are in the US that was misleading. I quoted that of the 16, 3 had either died or stopped using Iplex, you jumped to the conclusion that they had all died as a failure of Iplex to halt or cure them, please do not use me as an excuse for your misinterpretation or assumptions, no faulty misleading facts there.
Although you have repeatedly seized on one point you have at every point ignored or overseen the mass of information presented to you, all you seemed to be is focused on one point of clarification that was not made clear to you by me. I at no stage quoted that from the 160+ Italian patients 50% saw benefit, when you yourself clearly know, so to do all who have been following the stream of information on this and other threads, do not be so "blinkers on" just to benefit your arguments.
Regardless of where we both sit regarding the possible benefits of Iplex we are both unanimous in wanting a form of treatment and cure today not tomorrow but now. We both agree on the importance of having put forward candidates for trial that will not waste time and money and realize the importance of accurate, clear, factual information. Where we differ greatly is in the strong unquestionable belief that all that ALSTDI do is bulletproof and infallible. Although appreciative and grateful for all they have done, I cannot stand and blindly back whatever ALSTDI say and do, nor should I accept anything they or their representative’s say without question and scrutiny. Nor will I sit back and accept the blaze attitude portrayed due to the unimportance of value my comments may be deemed by some, I have an opinion and will present it after all that’s what forums are, a vehicle for discussion exploring different opinions and presenting clear precise answers that will not be misinterpreted.
At the end of the day we are all hopefully pointed towards the same target of a world without ALS and nothing else will do.

Not criticising or even commenting on the specifics of the debate, but going back to the original comment, this thread appears to me to be about the necessity for justification supporting a statement made. I also struggle a bit with the nay sayer response that knocks a treatment, thought or potential solution without actually providing the evidence. History has shown this to be a poor approach to science. I acknowledge that sometimes some will have a great deal more knowledge and hence its fair that they will assume others "already know" the answer, but the purpose of these great threads is to share and spread valid information. Validating comments is a good way of doing this.

just my tcw

More importantly - I've been off line for a while and haven't seen anything more on the elusive molecule. What happened to it? When is further information going to be released, or have I lost the info somewhere?

Mark

I'm not sure they didn't find some benefit in SOME people who were manifesting problems.
There is a hypothesis lithium reflects the fatty acid content of the brain and IF .. you personally .. are not manifesting the problems of fatty acid content of the brain in RELATION to your ALS then the lithium may not reflect any recovery in YOU.

"Some researchers believe that one effect of Lithium carbonate, the
standard pharmaceutical treatment for bipolar depression, is the
promotion of increased acetylcholine activity in the brain."

New Insights Into The Mechanism Of Action Of Antipsychotic Drugs
Main Category: Schizophrenia
Also Included In: Pharma Industry / Biotech Industry
Article Date: 11 Mar 2009 - 2:00 PDT

Vanda Pharmaceuticals Inc. (Nasdaq: VNDA) reports the publication in
Schizophrenia Research, the official journal of the Schizophrenia
International Research Society, of a manuscript entitled "Common
effect of antipsychotics on the biosynthesis and regulation of fatty
acids and cholesterol supports a key role of lipid homeostasis in
schizophrenia" (1).


This publication highlights the discovery of a major effect of
antipsychotics that sheds new light on how these drugs work. Vanda
researchers analyzed the mechanism of action of 18 antipsychotics at
the molecular level and discovered that they regulate specific genes
that control the production and transport of lipids. These findings
suggest that antipsychotic drugs may alter the fluidity of cell
membranes of neurons, which could result in changes in neuronal
connectivity. The antipsychotics tested included Vanda's antipsychotic
iloperidone, currently under review by the U.S. Food and Drug
Administration (FDA) for the treatment of schizophrenia.


"This exciting discovery demonstrates Vanda's commitment in
understanding the molecular mechanism of drugs with a goal of
improving therapeutic solutions for patients" said Mihael H.
Polymeropoulos, MD, Vanda's Chief Executive Officer.


(1) Polymeropoulos M.H. et al., "Common effect of antipsychotics on
the biosynthesis and regulation of fatty acids and cholesterol
supports a key role of lipid homeostasis in schizophrenia." Schizophr
Res. 2009 Mar; 108(1-3):134-42.


About Vanda Pharmaceuticals Inc:


Vanda Pharmaceuticals Inc. is a biopharmaceutical company focused on
the development and commercialization of clinical-stage product
candidates for central nervous system disorders. For more on Vanda
Pharmaceuticals Inc., please visit http://www.vandapharma.com.


CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS


Various statements in this release are "forward-looking statements"
under the securities laws. Words such as, but not limited to,
"believe," "expect," "anticipate," "estimate," "intend," "plan,"
"targets," "likely," "will," "would," and "could," and similar
expressions or words, identify forward-looking statements. Forward-
looking statements are based upon current expectations that involve
risks, changes in circumstances, assumptions and uncertainties. Vanda
is at an early stage of development and may not ever have any products
that generate significant revenue. Important factors that could cause
actual results to differ materially from those reflected in the
company's forward-looking statements include, among others: delays in
the completion of Vanda's clinical trials; a failure of Vanda's
product candidates to be demonstrably safe and effective; Vanda's
failure to obtain regulatory approval for its products or to comply
with ongoing regulatory requirements; a lack of acceptance of Vanda's
product candidates in the marketplace, or a failure to become or
remain profitable; Vanda's inability to obtain the capital necessary
to fund its research and development activities; Vanda's failure to
identify or obtain rights to new product candidates; Vanda's failure
to develop or obtain sales, marketing and distribution resources and
expertise or to otherwise manage its growth; a loss of any of Vanda's
key scientists or management personnel; losses incurred from product
liability claims made against Vanda; a loss of rights to develop and
commercialize Vanda's products under its license and sublicense
agreements and other factors that are described in the "Risk Factors"
section (Part II, Item 1A) of Vanda's quarterly report on Form 10-Q
for the quarter ended September 30, 2008 (File No. 000-51863). In
addition to the risks described above and in Part II, Item 1A of
Vanda's quarterly report on Form 10-Q, other unknown or unpredictable
factors also could affect Vanda's results. There can be no assurance
that the actual results or developments anticipated by Vanda will be
realized or, even if substantially realized, that they will have the
expected consequences to, or effects on, Vanda. Therefore, no
assurance can be given that the outcomes stated in such forward-
looking statements and estimates will be achieved.


All written and verbal forward-looking statements attributable to
Vanda or any person acting on its behalf are expressly qualified in
their entirety by the cautionary statements contained or referred to
herein. Vanda cautions investors not to rely too heavily on the
forward-looking statements Vanda makes or that are made on its behalf.
The information in this release is provided only as of the date of
this release, and Vanda undertakes no obligation, and specifically
declines any obligation, to update or revise publicly any forward-
looking statements, whether as a result of new information, future
events or otherwise.


Vanda Pharmaceuticals Inc.
http://www.vandapharma.com

---

Herbivore Hypothesis
http://sites.google.com/site/herbivorehypothesis/age-related-iron-accumulation

In man consumption of choline increases in levels in the
serum and cerebrospinal fluid; its administration is an
effective way of treating tardive dyskinesia.

Sooo .. if iron CAUSES this and iron 'fries' lecithin .. ?
IS it the lack of the lecithin which causes the tardive / pain .. ?
When nifediprine or other iron chelators are used the tardive is relieved.

Lecithin is recommended as a BETTER method of choline supplementation
due to its ability to produce a 5 times increase of choline and a
retention time
of 3 times as many hours.


Lecithin consumption raises serum-free-choline levels.
Lancet 1977 Jul 9;2(8028):68-9
Wurtman RJ, Hirsch MJ, Growdon JH.


Consumption of choline by rats sequentially increases
serum-choline, brain-choline, and brain-acetylcholine
concentrations.
In man consumption of choline increases in levels in the
serum and cerebrospinal fluid; its administration is an
effective way of treating tardive dyskinesia.
We found that oral lecithin is considerably more effective in
raising human serum-choline levels than an equivalent quantity
of choline chloride.
30 minutes after ingestion of choline chloride (2-3 g free base),
serum- choline levels rose by 86% and returned to normal values
within 4 hours; 1 hour after lecithin ingestion, these levels rose
by 265% and remained significantly raised for 12 hours.
Lecithin may therefore be the method of choice for accelerating
acetylcholine synthesis by increasing the availability of choline,
its precursor in the blood.


"Tracey's paper in the December 2002 issue of Nature presented
evidence that this cholinergic antiinflammatory pathway is mediated
by acetylcholine.
He showed that cholinergic signals inhibit inflammation.
That the vagus nerve connects the immune system directly to the
brain has led to a critical understanding of how the nervous system
modulates immune responses.
This finding also provides hope that stimulating the vagus nerve or
the use of cholinergic agonists could be used to treat inflammatory
disease.
Tracey also discussed the cholinergic anti-inflammatory pathway
and the implications for treating disease in a paper published in
2007 in the Journal of Clinical Investigation."


Pharmacological stimulation of the cholinergic
antiinflammatory pathway.
Mar 18, 2002
Thomas R Bernik,Steven G Friedman,
Mahendar Ochani,Robert DiRaimo,
Luis Ulloa,Huan Yang,Samridhi Sudan,
Christopher J Czura,Svetlana M Ivanova,
Kevin J Tracey
Efferent activity in the vagus nerve can prevent
endotoxin-induced shock by attenuating tumor
necrosis factor (TNF) synthesis.
Termed the "cholinergic antiinflammatory pathway,"
inhibition of TNF synthesis is dependent on nicotinic
alpha-bungarotoxin-sensitive acetylcholine receptors
on macrophages.
Vagus nerve firing is also stimulated by CNI-1493 ,
a tetravalent guanylhydrazone molecule that inhibits
systemic inflammation.
Here, we studied the effects of pharmacological and
electrical stimulation of the intact vagus nerve in adult
male Lewis rats subjected to endotoxin-induced shock
to determine whether intact vagus nerve signaling is
required for the antiinflammatory action of CNI-1493 .
CNI-1493 administered via the intracerebroventricular
route was 100,000-fold more effective in suppressing
endotoxin-induced TNF release and shock as compared
with intravenous dosing.
Surgical or chemical vagotomy rendered animals
sensitive to TNF release and shock, despite treatment
with CNI-1493 , indicating that an intact cholinergic
antiinflammatory pathway is required for
antiinflammatory efficacy in vivo.
Electrical stimulation of either the right or left intact
vagus nerve conferred significant protection against
endotoxin-induced shock, and specifically attenuated
serum and myocardial TNF, but not pulmonary TNF
synthesis, as compared with sham-operated animals.
Together, these results indicate that stimulation of the
cholinergic antiinflammatory pathway by either
pharmacological or electrical methods can attenuate
the systemic inflammatory response to
endotoxin-induced shock.


---------------


Iron modulates neuroleptic-induced effects related to the
dopaminergic
system.


Ben-Shachar D, Livne E, Spanier I, Zuk R, Youdim MB
Department of Pharmacology, B. Rappaport Faculty of Medicine,
Technion
Haifa,
Israel.


Long-term neuroleptic medication to schizophrenic patients is often
associated
with extrapyramidal side effects, of which tardive dyskinesia is the
most
severe. The mechanism by which neuroleptics induce these side effects
is
unclear. The dopaminergic system is the main target with which the
neuroleptics
interact in the brain. Intact dopaminergic function is dependent on
normal
iron
metabolism. Thus, the relationship between iron and the neuroleptics
may
elucidate some new aspects of their mechanism of action. Indeed,
peripheral
iron status plays a crucial role in neuroleptic-induced dopamine
supersensitivity. Moreover, neuroleptics such as haloperidol and
chlorpromazine, alter the blood brain barrier (BBB) of the rat and
enhance
the
normally restricted iron transport into the brain. Increased brain
iron
levels
may be related to the toxic effects of these drugs since clozapine,
an
atypical
neuroleptic with a low incidence of extrapyramidal side effects,
prohibits
iron
uptake into the brain but causes sedimentation of iron in brain blood
vessels.
The demonstration that peripheral iron concentrations affect
neuroleptic-induced dopamine receptor supersensitivity as well as
iron
transport into the brain may have therapeutic significance. In
addition, the
different potentials of typical and atypical neuroleptics to increase
iron
transport into the brain may be related to the severity of the side
effects
they induce and to the pathophysiology of tardive dyskinesia.


Publication Types:


Review
Review, tutorial


Quercetin .. an iron binder has been shown to have significant
results /
reduction of incidence of tardive in the animal model ..


Neuropharmacology. 2003 Jun;44(8):1100-6. Related Articles, Links
Quercetin, a bioflavonoid, attenuates haloperidol-induced orofacial
dyskinesia.
Naidu PS, Singh A, Kulkarni SK.
Pharmacology Division, University Institute of Pharmaceutical
Sciences, Panjab
University, -160014, Chandigarh, India.


Chronic treatment with neuroleptics leads to the development of
abnormal
orofacial movements described as vacuous chewing movements (VCMs) in
rats.
Vacuous chewing movements in rodents are widely accepted as one of the
animal
models of tardive dyskinesia. Oxidative stress and the products of
lipid
peroxidation are implicated in the pathophysiology of various
neurological
disorders including tardive dyskinesia. In the present study chronic
haloperidol (1.0 mg kg(-1) for 21 days) treatment induced vacuous
chewing
movements and tongue protrusions in rats. Co-administration of
quercetin, a
bioflavonoid, dose dependently (25-100 mg kg(-1)) reduced haloperidol-
induced
vacuous chewing movements and tongue protrusions. Biochemical analysis
revealed
that chronic haloperidol treatment induces lipid peroxidation and
decreases the
glutathione (GSH) levels in the forebrains of rats. The antioxidant
defense
enzymes, superoxide dismutase (SOD) and catalase were also decreased
due to
chronic haloperidol treatment. Co-administration of quercetin (25-100
mg
kg(-1)) significantly reduced the lipid peroxidation and restored the
decreased
glutathione levels in these animals. Further quercetin (50-100 mg
kg(-1)) also
reversed the haloperidol-induced decrease in forebrain SOD and
catalase levels
in rats. The major findings of the present study suggested that
oxidative
stress plays a significant role in neuroleptic-induced orofacial
dyskinesia and
quercetin co-administration reverses these behavioral and biochemical
changes.
Quercetin, a naturally occurring bioflavonoid could prove to be a
useful agent
in neuroleptic-induced orofacial dyskinesia.
PMID: 12763102

---

Herbivore Hypothesis
http://sites.google.com/site/herbivorehypothesis/age-related-iron-accumulation

>>Only trying to save some grief and money <<

I think the last time they found a drug which they were going to use they let it be used by a lottery and at a very high cost .. ?
Like I said the .. tardive .. study .. seems not to have even been spoken to on this board.
It seems tardive seems to have been spoken to though on this board many times ..
Sooo one might assume tardive is a pertinent thread for this board and as I have shown the study shows the iron seems to cause the tardive.

Iron **modulates neuroleptic-induced effects** related to the
dopaminergic system.


Ben-Shachar D, Livne E, Spanier I, Zuk R, Youdim MB
Department of Pharmacology, B. Rappaport Faculty of Medicine,
Technion
Haifa,
Israel.


Long-term neuroleptic medication to schizophrenic patients is often
associated with extrapyramidal side effects, of which tardive dyskinesia
is the most severe.
The mechanism by which neuroleptics induce these side effects
is unclear.
The dopaminergic system is the main target with which the
neuroleptics interact in the brain.
Intact dopaminergic function is dependent on
normal iron metabolism.
Thus, the relationship between iron and the neuroleptics
may elucidate some new aspects of their mechanism of action.
Indeed, peripheral iron status plays a crucial role in
neuroleptic-induced dopamine supersensitivity.
Moreover, neuroleptics such as haloperidol and
chlorpromazine, alter the blood brain barrier (BBB) of the rat and
enhance the normally restricted iron transport into the brain.
Increased brain iron levels may be related to the toxic effects of
these drugs since clozapine, an atypical neuroleptic with a low incidence
of extrapyramidal side effects, prohibits iron uptake into the brain but
causes sedimentation of iron in brain blood vessels.
The demonstration that peripheral iron concentrations affect
neuroleptic-induced dopamine receptor supersensitivity as well as
iron transport into the brain may have therapeutic significance.
In addition, the different potentials of typical and atypical neuroleptics
to increase iron transport into the brain may be related to the severity
of the side effects they induce and to the pathophysiology of tardive
dyskinesia.

---

Herbivore Hypothesis
http://sites.google.com/site/herbivorehypothesis/age-related-iron-accumulation

Ron, don't disagree with anything in your response. In fact my neuro offered to put me on Lithium 4 months after the Italian paper came out. I turned him down at that point, because I'd done more research than him and could see no efficacy in the results they published, but could see likely damaging effects on my liver. A small band of us are currently exploring stem cell options, given the advances made over the past 18 months. When we have raised our findings on various forums we get a mixed response. Often we're not making statements based on our own opinions, we're actually posting information (much the same as this site does very well) so that others may be able to dig further than us and come up with further validation, whether positive or negative. What's not useful is the simple "you're wrong" statements. No for a moment suggesting that you're doing this, just making the point that responses to postings that generate successively better data is really what I'm looking for.

There will always be folks with long time experience and newbies like me, but i think the "newbie" factor is a bit irrelevant - in business I've been doing technical research for 30 years, so the fact that the topic now happens to be ALS makes no difference to me and most others. I have great sympathy for those who see any statement of hope as a cure, but I don't believe most of us react that way. We move with caution and research the facts. Having others add to any information that we discover is what ultimately validates (or not) our findings. This is a much better site than most for these types of discussions and certainly provides better quality research. I value the input from those of you with a solid platform of information, but I will always look for facts in any postings and ignore those that merely offer personal perspectives without backup. This isn't a personal criticism, just a general commentary on postings.