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Old 04-13-2013, 06:32 PM
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Default ADX-71441 New Type of BACLOFEN -Just Received USA Patent

This is very exciting -From all that I have read, this will be a once daily dose of a drug that is very similar to BACLOFEN. I truly would appreciate the opportunity to participate in the human trials. This company ADDEX Pharm is located in Switzerland. Although this drug is will probably come first off-label for alcohol, I imagine it will take the alcoholism world by storm. Finally addressing some of the underlying issues of anxiety, etc related to al. Please google the drug name and see what you think. An excerpt from one article:

ADX71441 is a potent, selective, orally available small molecule that is brain penetrant and shows good pharmacokinetic properties for once-daily dosing. Addex GABA-BR PAM was studied in the transgenic CMT rat model which has 1.6-fold PMP22 overexpression (mRNA level) and exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimic findings in CMT1A patients. Nine week oral therapy of ADX71441 in CMT rats (5 weeks every other day at 10 mg/kg followed by 4 weeks at 5 mg/kg every day) down regulated PMP22 mRNA, reduced the amount of hypo-myelinated axons and increased compound muscle action potentials in peripheral nerves when compared to vehicle treated CMT rats. It also prevented grip strength loss in CMT rats compared to wild type rats.

"These data confirm previous observations obtained using a GABA-BR agonist and the GABAB1-/- mice (knock-out mice), which identified the importance of GABA-BR in the inhibition of the proliferation and in the reduction of the synthesis of specific myelin proteins, in particular PMP22" noted Sonia Poli, VP Non Clinical Development at Addex. "These and other data further reinforce the central role of GABA-BR in a broad range of important diseases and conditions, including spasticity, Fragile X, autism, pain, anxiety, obsessive-compulsive disorder, overactive bladder and alcohol binge drinking".
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Old 04-13-2013, 06:37 PM
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Default ADX-71441

Also, there are other articles and studies that state ADX71441 is "Superior" and far more reaching than Naltrexone. The other articles also speak of Bacfolen as if it might be a component of adx.
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Old 04-13-2013, 08:20 PM
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It is probably similar to Arbaclofen which is being trialed by Seaside and Roche Laboratories for autism. I think arbaclofen is futher along in getting FDA approval and some people are on it under a special licence. The issue seems to be that the baclofen molecule has a left and a right side and the left side causes side effects, hence, R Baclofen, the right side of the molecule. That is probably simplistic but you get the idea. It was inevitable this would happen although I suspect that at the rate baclofen is being taken up now it will become known as a treatment for alcoholism within the next year, before this drug hits the market. It will probably take a few years for it to be licensed and it will probably be more expensive. Arbaclofen is supposed to be 10 times as strong as baclofen so that would be why it is only a daily dose, and they will probably make it time released which baclofen isn't .

It makes me wonder. Novartis have now realized sales of baclofen are going through the roof, they could hardly have not noticed! I wonder if they will now move to improve the product by making it time released or address the side effects issues. Probably not...

I see that the ADX drug is mentioned for all sorts of issues. I still think the issue is going to be uptake by the public and medical profession. There is still a lot of resistance to the idea that alcoholism can be treated medically. Even if baclofen gets FDA approval for alcoholism, doctors don't study alcoholism at university and they don't treat it as an illness, and most alcoholics don't go to their doctor to ask for any pill.


I keep coming back to this issue. The real problem is public awareness. I have now heard back from my MSP:

Ken Macintosh MSP would like to thank you for taking the time to write on this issue. Ken clearly appreciates your frustration regarding this matter and he has therefore contacted the Health Minister for his views and comments. We will of course be back in touch as soon as we receive a response.

Regards


Marion Anderson
on behalf of Jim Murphy MP and Ken Macintosh MSP


I don't see any other way than to start putting pressure on people to educate doctors about this treatment. There is enough information out there already and baclofen can already be prescribed legallly. Ameisen keeps making this point as well. About 80% of cancer drugs are unlicensed and no one cares, they just prescribe them. The difference is that cancer is a "socially acceptable" way to die, whereas alcoholism isn't because the majority of people still consider it not to be an illness but, rather, a nasty and inconsiderate life style choice. That is why it is so important to get the medical information in front of decision makers in government and shame them by saying that the French government has now changed its position and doctors are now being told to prescribe baclofen.

What I find so amazing is this idea that it is somehow ok to sit back and say, gee, in a couple of years there might be FDA approval, or NICE approval. It ignores the fact that doctors can and should prescribe baclofen now, are negligent if they haven't kept up their research in the area of alcoholism treatment and the government bodies charged with informing the public and medical profession about new formulations and indications of drugs are letting everyone down by not keeping abreast of the medical developments in alcoholism treatment and not advising doctors now that there is a prescribing guide available and lots of results from actual use of the drug.

Last edited by Otter; 04-13-2013 at 08:23 PM..
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Old 04-13-2013, 09:38 PM
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Here is a link to a press release which Addex put out last Fall:

Addex Therapeutics : Addex Reports ADX71441 Reduces Alcohol Intake in a Preclinical Model of Alcohol Binge Drinking

Here is a link to the press release announcing the issuance of the US patent in January:

Addex Therapeutics : Addex Announces Issuance of a Broad US Composition of Matter Patent for ADX71441
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With profound appreciation to Dr Olivier Ameisen for his brilliant insight and courageous determination

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Old 04-13-2013, 09:42 PM
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Quote:
Originally Posted by Otter View Post
It is probably similar to Arbaclofen which is being trialed by Seaside and Roche Laboratories for autism.
Actually, it's probably a little different than Arbaclofen Placarbil: ADX71441 sounds like it is a Positive Allosteric Modulator of the GABAb receptor - It increases the functioning of endogenous GABA at the GABAb receptor site. Arbaclofen is a pro-drug of the therapeutically active enantiomer of baclofen, which acts like GABA at the GABAb site itself.

I've brought up PAMs on MWO before, from Dr Ameisen: I will no longer post on MWO! :

CGP7930: a positive allosteric modulator of the... [CNS Drug Rev. 2007] - PubMed - NCBI

CGP7930: a positive allosteric modulator of the GABAB receptor

Adams CL, Lawrence AJ. Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, Australia.

Abstract CGP7930 (3-(3',5'-Di-tert-butyl-4'-hydroxy)phenyl-2,2-dimethylpropanol) is a positive allosteric modulator of the metabotropic GABAB receptor. CGP7930 has been found to modulate the GABAB receptor in the open, or high affinity, state increasing agonist affinity for the receptor and signal transduction efficacy following agonist stimulation. The GABAB heteromeric subunit B2, involved in signal transduction but not ligand binding, seems to be the site of action of CGP7930 and similar allosteric modulators. When administered alone in naïve animals, CGP7930 acts as an anxiolytic in rodents without other overt behavioral effects and has also been demonstrated to reduce self-administration of nicotine, cocaine, or alcohol in rodents, suggesting that "fine tuning" of the GABAB receptor by positive allosteric modulators may be able to regulate abuse of these drugs. Baclofen, the GABAB agonist, is currently finding use in treating addiction and various other disorders, but this can result in off-target effects and tolerance. CGP7930 when co-administered with baclofen enhances its potency, which could in theory minimize deleterious effects. Further study of CGP7930 is required, but this compound, and others like it, holds potential in a clinical setting.


MID: 17894647 [PubMed - indexed for MEDLINE]

and Otter, you'll get a kick out of this (although the website I got it from seems a bit dubious and "spammy.") But don't think that I'm trying to encourage you here......

from http://www.gabafacts.com/:

Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, has reported a positive Proof of Concept for its lead GABA-B receptor (GABA-BR) positive allosteric modulator (PAM) compound, ADX71441, in a validated pre-clinical model of Charcot-Marie-Tooth 1A (CMT1A).

CMT1A is a rare (1:5,000) hereditary motor and sensory demyelinating peripheral neuropathy (also known as Hereditary Motor and Sensory Neuropathy, HMSN) which is caused by an intrachromosomal duplication and consecutive toxic overexpression of the PMP22 gene on chromosome 17. In other words, CMT1A keeps PMP22 in check, and this new compound tells us when CMT1A is malfunctioning.

CMT1A is one of the most common inherited peripheral nerve-related disorders which is passed down through families in an autosomal dominant fashion. CMT1A disease becomes evident in young adulthood and slowly progresses with distally pronounced muscle weakness and numbness. Pain can range from mild to severe. The disease can be highly debilitating with wheel chair-boundness and is often accompanied by severe cases of neurological pain. There is no known cure for this incapacitating disease.

“We are very excited about the promising results obtained with the Addex GABA-BR PAM candidate,” said Professor Michael Sereda, of the Max-Planck Institute of Experimental Medicine, Göttingen, Germany, in whose laboratories the study was performed.

“Current CMT1A therapies are primarily symptomatic such as physiotherapy and only focus on the manifestations of the disease, while the data obtained with the Addex compound seem to suggest that positive modulation of GABA-B receptor could lower toxic PMP22 over expression and potentially delay the progression of the disease and offer a unique therapeutic opportunity for CMT1A patients.

ADX71441 is a potent, selective, orally available small molecule that is brain penetrant and shows good pharmacokinetic properties for once-daily dosing. Addex GABA-BR PAM was studied in the transgenic CMT rat model which has 1.6-fold PMP22 over expression (mRNA level) and exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimic findings in CMT1A patients.

Nine week oral therapy of ADX71441 in CMT rats (five weeks every other day at 10 mg/kg followed by 4 weeks at 5 mg/kg every day) down regulated PMP22 mRNA, reduced the amount of hypo-myelinated axons and increased compound muscle action potentials in peripheral nerves when compared to vehicle treated CMT rats. It also prevented grip strength loss in CMT rats compared to wild type rats.

“These data confirm previous observations obtained using a GABA-BR agonist and the GABAB1-/- mice (knock-out mice), which identified the importance of GABA-BR in the inhibition of the proliferation and in the reduction of the synthesis of specific myelin proteins, in particular PMP22,” said Sonia Poli, VP Non Clinical Development at Addex.

“These and other data further reinforce the central role of GABA-BR in a broad range of important diseases and conditions, including spasticity, Fragile X, autism, pain, anxiety, obsessive-compulsive disorder, overactive bladder and alcohol binge drinking.”

“We are rapidly advancing ADX71441 into clinical development. Phase I clinical testing with this compound is planned for the first half of this year, initially for the treatment of spasticity associated with multiple sclerosis (MS),” said Graham Dixon, CSO at Addex. “These data are very encouraging as they indicate that the compound may also have a therapeutic benefit in treatment of patients with this debilitating rare disease.”

-tk

Last edited by terryk; 04-13-2013 at 09:50 PM..
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Old 04-14-2013, 05:10 AM
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Good morning (just waking up in Ireland)

Here is a popular science link from 2010 to using a derivative of baclofen for treating anxiety in autism (or Fragile X related type, in any case)

New Version of an Old Drug Could Treat Autism (and Addiction Too) | TIME.com

it includes a bit on right and left-hand molecule that Otter refers to above:

“”…….Like many drugs, baclofen contains two types of its main molecule, which are mirror images of each other. Often, one is an active ingredient, while the other is not. STX209, also known as arbaclofen, contains only the “right-handed” molecule of baclofen, the drug’s active component. …, STX209 is about 10 times more potent than baclofen. ……””

Regarding public education, I have also been reading the following which I found to be good (you can probably access via Google Scholar…):

• Chick, J., & Nutt, D. J. (2012). Substitution therapy for alcoholism: time for a reappraisal?. Journal of Psychopharmacology, 26(2), 205-212.
• Nutt, D. J., Lingford-Hughes, A., & Chick, J. (2012). Through a glass darkly: can we improve clarity about mechanism and aims of medications in drug and alcohol treatments?. Journal of Psychopharmacology, 26(2), 199-204.
• Ameisen, O. (2012). Suppressing addiction using high-dose baclofen, rather than perpetuating it using substitution therapy. Journal of Psychopharmacology,26(7), 1042-1043.

The last one is by Dr Ameisen arguing that suppression rather than substitution is the goal. Whichever the belief, it is really great to see the debate in progress.

- joan
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Old 04-15-2013, 02:11 AM
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Thumbs up Spot-On Otter

Quote:
Originally Posted by Otter View Post
It is probably similar to Arbaclofen which is being trialed by Seaside and Roche Laboratories for autism. I think arbaclofen is futher along in getting FDA approval and some people are on it under a special licence. The issue seems to be that the baclofen molecule has a left and a right side and the left side causes side effects, hence, R Baclofen, the right side of the molecule. That is probably simplistic but you get the idea. It was inevitable this would happen although I suspect that at the rate baclofen is being taken up now it will become known as a treatment for alcoholism within the next year, before this drug hits the market. It will probably take a few years for it to be licensed and it will probably be more expensive. Arbaclofen is supposed to be 10 times as strong as baclofen so that would be why it is only a daily dose, and they will probably make it time released which baclofen isn't .

It makes me wonder. Novartis have now realized sales of baclofen are going through the roof, they could hardly have not noticed! I wonder if they will now move to improve the product by making it time released or address the side effects issues. Probably not...

I see that the ADX drug is mentioned for all sorts of issues. I still think the issue is going to be uptake by the public and medical profession. There is still a lot of resistance to the idea that alcoholism can be treated medically. Even if baclofen gets FDA approval for alcoholism, doctors don't study alcoholism at university and they don't treat it as an illness, and most alcoholics don't go to their doctor to ask for any pill.


I keep coming back to this issue. The real problem is public awareness. I have now heard back from my MSP:

Ken Macintosh MSP would like to thank you for taking the time to write on this issue. Ken clearly appreciates your frustration regarding this matter and he has therefore contacted the Health Minister for his views and comments. We will of course be back in touch as soon as we receive a response.

Regards


Marion Anderson
on behalf of Jim Murphy MP and Ken Macintosh MSP


I don't see any other way than to start putting pressure on people to educate doctors about this treatment. There is enough information out there already and baclofen can already be prescribed legallly. Ameisen keeps making this point as well. About 80% of cancer drugs are unlicensed and no one cares, they just prescribe them. The difference is that cancer is a "socially acceptable" way to die, whereas alcoholism isn't because the majority of people still consider it not to be an illness but, rather, a nasty and inconsiderate life style choice. That is why it is so important to get the medical information in front of decision makers in government and shame them by saying that the French government has now changed its position and doctors are now being told to prescribe baclofen.

What I find so amazing is this idea that it is somehow ok to sit back and say, gee, in a couple of years there might be FDA approval, or NICE approval. It ignores the fact that doctors can and should prescribe baclofen now, are negligent if they haven't kept up their research in the area of alcoholism treatment and the government bodies charged with informing the public and medical profession about new formulations and indications of drugs are letting everyone down by not keeping abreast of the medical developments in alcoholism treatment and not advising doctors now that there is a prescribing guide available and lots of results from actual use of the drug.
Otter, thanks for your comments. Just dang, how many more lives must be lost to addiction/alcoholism relative to "life style choice/moral judgment" population? Just imagine how many more would be dead without the internet and access to information. And wow, you put into words my exact frustrations relative to the FDA/Doctors/Governing bodies. And by the way, I don't give one rats ass if the FDA approves or disapproves a particular medication relative to alcoholism recovery. I will try to improve my odds at recovery with any legitimate semi-trialed medication or method. God only knows, I have tried almost every imaginable way possible to date to quit drinking. And what much more do I have to lose before I lose my life? ***Bacfolen is my most successful attempt at recovery/reinvention so far.*** And my bac has been a direct result of this site as well as your bacusa site*** And last thing Otter, it is my belief that if they could develop a drug or brain restructuring cure for alcoholism tomorrow morning, it would take years (even decades) before it would reach the population majority. I am just thankful to you MWO folks who have kept up the valuable work in getting the word out and helping those of us who have received the gift of desperation.
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Old 04-15-2013, 01:45 PM
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Well thanks all for those articles.

It's certainly great news!
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Old 05-03-2013, 02:49 PM
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Default Dr. Olivier Ameisen -Updates

I was not sure if this has already been posted, so after translating and copying, here is the paste:

End of 2004, Professor Olivier Ameisen published in the scientific press the therapeutic success of baclofen at high doses over his addiction to alcohol. In 2008, he published the last glass, which popularized this discovery. Since then, several scientific publications have reported the positive effects of this treatment on large cohorts of patients, while the results obtained by other therapeutic methods are considerably lower.

Two trials in double blind placebo are underway to demonstrate the effects of baclofen at high doses with the highest level of evidence in alcohol dependence. During this time, considering that in France 100 people die prematurely every day because of alcohol. Alcohol is also the origin of many dramas, road, domestic violence, passages to cbta auto accidents or hetero-agressifs. It is a large-scale social scourge which affects not only alcohol-dependent patients but also their entourage. While there is a drug that could help a large proportion of the alcohol-dependent patients, public authorities demonstrate of procrastination and hinder the provision of treatment for all those who needed. The national food safety agency must authorize a temporary recommendation to use (RTU) as soon as possible pending the authorization for placing on the market.
It must put an end as quickly as possible to this delay to the serious consequences for patients who are sensitive to baclofen!

Sponsorship Committee
President: Pr Didier Sicard, former president of the national ethics Advisory Committee
Coordination: Pr Bernard Granger
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Old 05-25-2013, 08:38 AM
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thanks everybody for this thread and this links ;-)

All of us knows that the main bad sides of Baclofen are finally just the ES and the difficulty on having a fix protocol for quantity,time... posology in general.

I always was thinking that a Baclofen 2.0 ;-) would be definitevely the best and the only cure for alcoholism...

I will inform myself about this new ADX71441 and even about the interesitng subject of Arbaclofen (right side).

I will post here my findings!

have good day
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