There have been posts here on the search for drugs that could be neuroprotective for people with Parkinson's. It's possible that there may be some drugs available now that can be used off-label to slow or stop the progression of PD. The drugs that I've come across are in the opioid receptor antagonist class and one of them is cough syrrup, Dextromethorphan, sold over the counter. Another is Naltrexone or low dose naltrexone which I have been taking for 28 months. My PD does not seem to be worse over that time but maybe that's because of the sinemet and not enough time has passed.
On the old forum, before it crashed and burned, there was a member, RLSmi, who said he was taking Simply Cough which has Dextromethorphan as it's active ingredient. I noticed that RLS has joined this forum. I saved his old post on the other site and re-posted below. Hope you don't mind RLS. I found it interesing and hopeful, if I lose my LDN source, I will probably be taking DM. If you see this post RLS, would like to know how you are doing and if you still see DM as a drug to stop or slow PD progression.
I have also posted research by Dr. Hong of the NIH on DM below. I also emailed him about LDN and he said it's worth taking but he's not sure about dosage.

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

Regards, Ashley

RLSmi
Braintalk 04/12/06
Join Date: Sep 2004
Posts: 93
Default *Attempting neuroprotection with DM*
------------------------------------------------------------------------
The third link Ashleyk listed in her post describes research on neuroprotection in a mouse model of PD using the drug Dextromethorphan (DM). DM is in the same class of drugs as naltrexone, which also has neuroprotective effects in the same system. Because DM is availablae over the counter, I have been taking it instead of naltrexone daily for more than a year at a dose of 5 mg, along with sinemet, amantadine and high-dose CoQ10. I am four years into my PD Dx, and I may still be in the sinimet honeymoon period, but my wife and I both think that something is keeping my symptoms from progressing.

At WPC I spoke with Dr. Jau-Shyong Hong, the senior author of the article mentioned above, after a presentation he made there on the role of glial cell inflammation in PD. His research group in North Carolina has been working on the mechanism of action of these drugs and the natural hormone dynorphin in neuroprotection. He was very interested in my story and we have been in communication about this several times since then. He hinted that there may be trials using DM for PD neuroprotection either planned or going on in other countries.

DM is most commonly used in cough medicines that also contain other active ingredients, and Dr. Hong was emphatic in specifying that any attempts at using it for neuroprotection should be with a preparation in which DM alone was the active ingredient. The preparation I am currently using is called Simply Cough. It is manufactured by McNeil Laboratories, who also make Children's Tylenol. When I described this process on this thread several months ago, someone added the precaution that DM should not be taken by someone also taking a MAO inhibitor.

Although I do not recommend that others start using DM, it seemed appropriate to post this information on this neuroprotection thread.
------------------------------------------------------------------------
/ Last edited by RLSmi : 04-13-2006 at 01:28 AM.

I have just now read your posting from yesterday.

Yes, I am still taking dextromethorphan in the form of the cough syrup "Simply Cough" each night before I turn in. The rest of my medication remains as it was when I described it earlier.

I am pleased to report that my symptoms do not seem to have progressed since starting this regimen. I am only 5 years into my diagnosis, though, and sinemet "honeymoons" have been known to last 10-15 years.

Perhaps the best indication of non-progression, or at least slowed progression, is the fact that my daily carbidopa/levodopa is only 2X50/200mg CR, plus one-half of a regular 25/100mg tablet for a morning "jump start."
CoQ10 is 900mg, amantadine 100mg, plus extra vitamin E and C, two multivitamins, Effexor and Welbutrin daily.

I have not heard directly from Dr. Hong lately, but have been keeping up with his scientific publications.

Last month, a former vice-president for research for Merck visited in our department. Since this man's special interest is neuroscience, I told him about my Dx and my use of DM. I described Hong's work to him, and showed a lot of interest in it and asked me for a copy of his latest publication in which he described similar supression of mouse midbrain inflammation by other recently discovered natural protein neurohormones and small fragments (peptides) derived from them.
I expect to eventually hear about clinical trials with DM in PD that may have already begun in Taiwan.

Robert

Hi Robert, good to hear from you and that you're doing ok with the DM. One question I had was how do you measure out your 5 mg dose of Simply Cough?
I also don't know how to determine if 28 mo's of 4.5 mg naltrexone daily, LDN, is keeping me from progressing except to continue with it and hope. I assume, I too am in the sinemet honeymoon. When I first started sinemet 24 mo's ago, the neuro had me at 3x 25/100 a day. Over a year ago, I have cut back to about 1x sinemet a day but I was also given 2x 0.25 Mirapex. Tremor was my main problem and that's gone. I would like to say I have not progressed because of LDN. I also take 200 mg of Q10, magnesium and am about to start Tumeric, all supplements that I've learned about on Braintalk.

Dr. Hong and his people at the NIH seem to have come across a class of drugs such as DM and naloxone that, used at very low doses, seem to slow or stop disease causing neuroinflamation. Their work is done with mice and they are able to quickly determine the effects of these drugs. The problem with PD is that the disease is variable so how would they do clinical trials on people? Even if these drugs are shown to really work, it will be years before they are released. The big drug companies would have to spend millions in research and trials on simple drugs that exist now with their patents expired. There's no money in it for them. That's why I am not waiting, DM and LDN are known and relativly safe with few side effects. Since DM cough syrrup is available over the counter, I thought if people are interested, I would post Dr. Hong's research on opioid recetptor atagonists and they could go from there.
Ashley


http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

Mechanistic studies indicated that the neuroprotective effect of DM is mediated through the inhibition of microglia over-activation (18) . In the course of attempting to determine DM’s action site, we realized that the inhibitory effect of DM on the production of superoxide mimicked the effect of dynorphins at femtomolar concentrations (19) . This comparison led us to study the neuroprotective effect of DM at femtomolar concentrations. In this paper, we report the extremely unusual and exciting finding that femtomolar concentrations of DM exert an effect as efficient as micromolar concentrations of DM in protecting dopaminergic neurons against LPS-induced damage. We have elucidated the underlying mechanism for this femtomolar acting compound’s neuroprotective effect. DM has been used clinically for decades with a proven safety record and it is a small molecule that can be administered orally, suggesting that DM is an ideal remedy for long-term usage for neurodegenerative diseases. In view of the lack of therapeutic agents that can halt the progression of PD, our findings may provide a novel therapy for these neurodegenerative diseases.

and the other substances Hong's group have been testing at such low concentrations is a total mystery to me. I am not aware of any precedent for the known opioid receptors one would expect to be involved to be responsive to any drug or natural ligand in the femtomolar concentration range. This is thousands of times lower than observed with other opioid effects.

They have clearly demonstrated that the critical enzyme that is inhibited is the NADPH oxidase of microglial cells. This is a complex intracellular enzyme which uses a one-electron transfer to molecular oxygen to generate the superoxide ions released when lipopolysaccharide (LPS) activates the process through a cell-surface LPS receptor. This system is part of the intrinsic immune system in the brain which serves to kill invading microorganisms that have LPS in the structure of their cell wall.

Somehow, these femtomolar-effective molecules are interfering with this process. Invoking an ordinary ligand-receptor equilibrium to achieve this at such low concentrations makes a physical chemist squirm and a medicinal chemist start thinking "homeopathy." The apparent dissociation energy in such a reaction is more typical of a stable covalent bond.

I would be interested to see if the activity of the enzyme in these microglial cell cultures returns after medium containing the drug was replaced with drug-free medium. I may give the good doctor a call on that next week!

Sorry to bore you folks with this, but writing it out it has helped me to see this phenomenon from a different angle.

Robert

Well ya got a central nervous system senior research scientist (chemist) in the crowd somewhere around here, I don't know who he is, but he's a bit forgetfull these days. (he's a bit daft and has a difficult time doing things like erasing his own posts, because his fingers keep hitting the wrong buttons when he's all dyskinetic ).
I don't think one has to get quite into the explanations for DEX as has been stated. DEX is the mirror image of LEVOMORPHAN, which is a narcotic mu agonist.

"Dextromethorphan crosses the blood-brain barrier, and the following pharmacological actions have been reported:

NMDA glutamatergic receptor antagonist
Dopamine reuptake inhibitor[3]
σ1 and σ2 receptor agonist (Zhou & Musacchio, 1991)
α3β4 nicotinic receptor antagonist[4]
Serotonin reuptake inhibitor[5]"

Now this gets back to a discussion that we had awhile back where, I believe it was fiona who asked something about low dose Naltrexone (which is a dopamine antagonist). During this discussion, this medicinal chemist (wish I could remember his name! ) started a line about his believing that narcotic agonists, and antagonists bear a superficial resemblance to Apomorphine, where, if you look at that molecules structure has the dopamine structure "buried" in what we would call a lipophilic molecule, and lipophilic molecules are often brain penetrable, so they have "CNS effects". Nearly all narcotics of the "phenanthrene" class have the dopamine structure embedded within them, and have "extra structural details" that allow the molecule increased lipophilicity ("fat loving", increased solubility in fatty tissue) which is a property involved in passive blood brain barrier penetration of a molecule, since the brain is literally all fat no muscle.
So, these types of molecules get into the brain, wheras dopamine itself can't. The fact that the dopamine structure is preserved in the larger molecule, is unquestionable to say that these molecules could have dopaminergic effects. I noticed it from Oxycontin. Therapeutic doses allowed me to cut my sinemet intake by half. And now, using Apomorphine, a molecule devoid of narcotic properties, but still retaining the dopamine structure within the molecule, and the most potent dopamine agonist known; the user suggests that in the phenanthrene like molecular structure, there lies the next best chance at creating the next "best D agonist", one with no emetic effects, a long half life, orally active, easy on the liver enzymes, and most of all, being a blockbuster antiparkinson drug.
HOwever, we're not there yet and we don't even know if anybody is working on it; most of the pharma companies bowing to the supremecy of Dopa. Many pharm companies that had active D agonist projects just stopped pouring money into this area. IN fact, CNS D agonism is considered a liability as far as receptor binding profiles of new "ethical" drug discovery.
In a nutty shell, Dextromethorphan may be a simple weak D agonist, a molecule whose properties as far as they relate to an antiparkinsons drug which have not been optimized.
That's how an old school pharmaceutical discovery science would at first look at the reported phenomenon that is reported for this molecule. Femtomolar uncharacterized enzyme inhibitory effects is a good reason not to pour money into it's further investigation, but relate it to apomorphine's receptor binding profile, and dopamine structure similarities itself and you might get a few "experts" to give it some more thought. THat would be nice, but will it, or is it happening? Your guesses are as good as this guy I seem to know, what's his name, damn, I forget!
By the way, will somebody just open the door and let us out of here!

Hi, I've updated this old post on dextromethorphan (cough syrrup). I sort of changed the the subject on the BBB post which I didn't mean to do.
In the BBB thread, Steve disscuses his interesting improvements after being on dextromethorphan, DM, for only a few weeks. At first I thought his observations were a placebo effect of the DM. I then recalled a report on DM that I had read and went back to look at it and this report noted that DM can cause dopamine release. It's interesting and should be read by anyone thinking of using DM long term. It was written, I believe, on the concern that DM can be used at high doses to get high. Anyway, there are some interesting points in this long report (para 3.2, 3.3, 3.4). I suspect Steves improvements may be due to the DM creating more dopamine and maybe the DM is also being neuroprotective. This is territory where we should be careful. Try to get all the info you can if you intend to go DM longterm. DM cough syrrup has been around a few decades?, it's currious that Steves improvements have not been noted by the medical profession (or have they?).
If you read the research done by Dr. Hong, Head of Pharmacology at the NIH, he has observed that DM used at very low doses in rodents can be neuroprotective.
Ashley

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

<3.2> What are the side effects and risks of chronic DXM use?

Prolonged, regular use of DXM has some definite risks. The
most common is mania; this has been reported in people who used large
amounts of DXM (especially to self-medicate depression) (1-3). Some
research has linked sigma receptors to schizophrenia (46-49), and
chronic use of NMDA antagonists has been shown to upregulate
(increase) dopamine receptors (50). This could theoretically mean
that DXM could trigger schizophrenia in susceptible individuals,
although nobody knows for sure. DXM could also decrease immune
function due to sigma activity (51). One thing that is known is that
neither DXM nor PCP nor ketamine cause any change in PCP or sigma
receptors.
Another possible effect of long-term DXM use is neurotoxicity.
This has not been observed, but would be consistent with DXM's
hypothesized ability to induce 5HT and dopamine release (52). Such
neurotoxicity would probably be restricted to 5HT (serotonin) neurons,
and be similar to the neurotoxicity resulting from use of MDMA
(ecstasy). Note that no animal studies have ever demonstrated this.
Chronic use of NMDA antagonists seems to modify alcohol
tolerance; this is based mostly on anecdotal evidence and theory, but
it appears to be a very real phenomenon. If true, then it is
important to note that the GABA receptor effects of alcohol may NOT be
changed; in practical terms, you might be a lot drunker than you feel,
and this could possibly lead to alcohol poisoning. Be careful, and
limit yourself to as little alcohol as possible when using DXM. A
recent paper supports the ability of DXM to affect alcohol tolerance
(53).


Reason to believe DM could work at very low doses:
Dr Hong, Head of Pharmacology, NIH

Findings from our research not only reveal an extremely unusual and interesting femtomolar acting compound, but also raise a new concept of using "ultra-low" concentrations of drugs for future therapeutic interventions for inflammation-related diseases. Although whether these in vitro findings can be substantiated in animal studies and eventually tested in clinical trials remain to be studied, the obvious advantages of this low-dose therapy, including the much reduced side effects warrants serious consideration of this approach. To obtain a preliminary glimpse, we have recently observed in an animal study that 100 million-fold lower than the regular dose of DM was effective in reducing the plasma level of alanine aminotransferas (ALT) in LPS/D-galactosamine-induced liver damage (unpublished observations). It is very surprising to learn that DM in such low concentrations is still effective to possess anti-inflammatory effect. However, in view of its potent inhibitory effect on the flavo-containing enzyme (PHOX) we have studied, which is one of the contributors of proinflammatory factors, may explain its potent anti-inflammatory potency and justify further studies of DM or its analogs using different animal models of inflammation.

Very promising, actually. Been around fifty ears. Lot of recreational freelancers taking up o fifty times the normal dose without noticing bad effects. Lasts up to eight to twelve hours. Makes your dopamine go farther so hopefully yo can cut back on the darned stuff.

I, for one, am going to give it a trial once I give my mao inhibitor a couple of weeks to clear out.

As to the lack of research, may I suggest that when the patent expired that there was no reason to put money into competeing with the new wonder drug levodopa.

I will dutifully report on my experience.

#%%^!@@ ...Ground Control to Major Tom...)))*^&&%
$$)*%@@# Houston, we have a problem. Tom forgot the munchies...




From wikipedia (so take with one grain of salt):

At therapeutic doses, the drug acts centrally to elevate the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract, and metabolizes within 15 to 60 minutes of ingestion. The duration of action after oral administration is approximately three to eight hours for dextromethorphan-hydrobromide, and ten to twelve hours for dextromethorphan-polistrirex. Because administration of DXM can trigger a histamine release (an allergic reaction), its use in atopic children is very limited.

The average dosage necessary for effective antitussive therapy is between 10 mg and 30 mg. The time to re-dose depends on the specific preparation being used.


Side-effects of dextromethorphan use can include body rash/itching, nausea as well as other gastrointestinal disturbances, drowsiness, dizziness, excitation, vomiting, blurred vision, dilated pupils, sweating, fever, hypertension, shallow respiration, urinary retention, and increases in heart rate, blood pressure, and body temperature.[5]

Dextromethorphan can also produce psychological dependence due to its potential for recreational use, but does not produce physical addiction, according to the WHO committee on Drug Dependence.

Dextromethorphan, when combined with guaifenesin, an expectorant used in many preparations, is likely to cause nausea and vomiting when the combination is taken at recreational doses.

Dextromethorphan should not be taken with any of the following:

* monoamine oxidase inhibitors (MAOIs)[5]
* selective serotonin reuptake inhibitors (SSRIs)[5]
* CNS depressant drugs and substances, including alcohol, antihistamines, and psychotropics, will have a cumulative CNS depressant effect if taken with dextromethorphan.[5]


Dextromethorphan was first patented with U.S. Patent 2,676,177 .<1954>

The FDA approved dextromethorphan for over-the-counter sale as a cough suppressant in 1958. This filled the need for a cough suppressant lacking the sedative side-effects, stronger potential for abuse, and physically addictive properties of codeine phosphate, the most widely-used cough medication at the time (now prescription-only in the United States).[11] As with most cough suppressants, studies show that dextromethorphan's effectiveness is highly debatable.[2] See also: Cough medicine controversy

During the 1960s and 1970s, DXM became available in an over-the-counter tablet form by the brand name Romilar. It was put on the shelves in hopes of cutting down on codeine cough remedies. In 1973, Romilar was taken off the shelves after a burst in sales due to common recreational use. It was then replaced by cough syrup, in an attempt to cut down on recreational usage.[11]

More recently (around 2000) gel capsule forms began reappearing in the form of Robitussin CoughGels as well as several generic forms of that preparation.

It still has not been scientifically proven that ANY compound known exhibits "neuroprotective" properties IN VIVO. There are compounds on the market that are in use with the blessing of the FDA for use in alzheimers disease, but their effects are mainly attributed to their anticholinergic activity. We worked for years barking up the "neuroprotective" tree and found that all we ever came up with just showed certain human cell lines aged a bit slower in media treated with some of the compounds we had made. Nothing that the FDA would buy, so we dropped all research in this area.
But I would never discourage any researcher from keeping on trying, and maybe, just maybe something will come up in the future. And just as a footnote, "neuroprotective" agents are all the rage in Japan, where rules for allowing drugs on the market are more lax. In other words you can claim neuroprotection without ever proving it, as long as your compound is pretty well "dead" as far as having any other possibly detrimental physiological effects.

I cant hardly tell what you folks are talking about.. ..All I can say is that Ive consistantly felt alot better symptomatically than I have in approx 2 years..with the exception of today because I have a wicked stomach bug going on..uggghh!..got a case of the watery runs etc..not fun.. ..feverish..So when I feel better I will make a list of the changes in symptoms

I happened to research Rasagiline, and with my very limited education on chemistry I got the notion that it does something similar to DM in the dopamine reuptake inhibitor dept..Am I on the right track here or am I out in left field with that assuption?