Our changing world - new drugs and treatments

[Umpalumpa]

What is going to be interesting over the next few years is the licensing of baclofen in France and then the trial of Arbaclofen. Also, there are ongoing studies in Pennsylvania on time released baclofen.

Please feel free to post about this amazing advance in the treatment of alcoholism on this thread.:heartbeat:

[neophyte]

im looking forward to see what comes out of Arbaclofen, baclofen is out of patent so no ones making money out of it, unfortunately it takes profits to bring good treatments to light, too bad i wont be able to order kgs on the cheap of this stuff from china when it comes available, since its under patent. and getting a prescription in australia, yeah even if we see 10 successful studies, its going to take at least 20 years before it gets prescribed here, they are so conservative with treating addiction with drugs here.

also where are good sources to find out what new studies are taking place on baclofen, naltrexone or other promising drugs? other addictions too.

[Umpalumpa]

I think the best person to ask that is TerryK. He has acccess to a data base. if you do a google search for baclofen studies you come up with NIH library papers and there are lists of blog posted papers and studies on the right of the page. Efficacy and Safety of Baclofen for Alcohol Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial

This is pretty good but you also get a list of scholarly articles at the top of any search result page.

I don't think we will hear much about Arbaclofen for a whle unless the trials are unsuccessful like they were for autism. It would have to go through the company's lawyers because of privacy issues, I would think.

EOMA has most of the good baclofen papers listed and I expect they will keep that updated.

[Umpalumpa]

I'm interested in the developing field of repurposing drugs such as baclofen, for alcoholism and now for Alzheimer's. It's interesting that baclofen research is spreading beyond just alcohol. I suppose the reason for it is that the theory behind alcoholism, that it is a neurological disorder, gives rise to the question of whether the medical profession now will have to look at neurological issues much more seriously and see whether they can be treated.

Here's an article on the use of baclaofen with acamprosate for Alzheimer's. It's interesting that these are both alcoholism medications:
Patent US8741886 - Baclofen and acamprosate based therapy of neurological disorders - Google Patents

We claim:
1. A method of treating Alzheimer's disease or a related disease selected from senile dementia of AD type (SDAT), mild cognitive impairment (MCI) and age-associated memory impairment (AAMI), comprising administering to a subject in need thereof a synergistic combination of baclofen and acamprosate, or pharmaceutically acceptable salts thereof, in an amount effective to treat said subject.
2. The method of claim 1, wherein baclofen and acamprosate are mixed with a pharmaceutically acceptable carrier or excipient.
3. The method of claim 1, wherein baclofen and acamprosate are formulated or administered together, separately or sequentially.
4. The method of claim 1, wherein baclofen and acamprosate are administered repeatedly to the subject.
5. The method of claim 1, wherein the synergistic combination of baclofen and acamprosate has a ratio of Acamprosate/Baclofen (W:W) between 0.1 and 1000.
6. The method of claim 1, wherein baclofen is administered at a dose of between 0.01 and 150 mg/day.
7. The method of claim 1, wherein acamprosate is administered at a dose of less than 400 mg/day.
8. The method of claim 1, wherein a calcium salt of acamprosate is used.
9. The method of claim 1, comprising administering to the subject:
baclofen and acamprosate,
baclofen and acamprosate and diethylcarbamazine,
baclofen and acamprosate and cinacalcet,
baclofen and acamprosate and sulfisoxazole,
baclofen and acamprosate and torasemide,
baclofen and acamprosate and ifenprodil,
baclofen and acamprosate and mexiletine,
baclofen and acamprosate and eplerenone,
baclofen and acamprosate and levosimendan,
baclofen and acamprosate and terbinafine, or
baclofen and acamprosate and leflunomide.
10. The method of claim 1, comprising administering to a subject a composition comprising:
baclofen, acamprosate and donepezil,
baclofen, acamprosate and rivastigmine, or
baclofen, acamprosate and memantine.
11. The method of claim 1, comprising administering to the subject baclofen and acamprosate as the only active agents.
12. A method for improving cognitive functions in a subject suffering from, predisposed to, or suspected to suffer from Alzheimer's disease, the method comprising administering to said subject a synergistic combination of baclofen and acamprosate, or pharmaceutically acceptable salts thereof in an amount effective to treat said subject.
13. A method for improving memory in a subject suffering from, predisposed to, or suspected to suffer from Alzheimer's disease, the method comprising administering to said subject a synergistic combination of baclofen and acamprosate, or pharmaceutically acceptable salts thereof in an amount effective to treat said subject.
14. The method of claim 1, wherein baclofen and acamprosate act synergistically in protecting neuronal or endothelial cells from Aβ toxicity in vitro.
15. The method of claim 1, wherein the subject is a human subject.
16. The method of claim 1, wherein said subject is a human subject having Alzheimer's disease.
17. The method of claim 1, said method comprising administering 0.01 to 150 mg/day of baclofen, or pharmaceutically acceptable salts thereof, and less than 400 mg/day of acamprosate, or pharmaceutically acceptable salts thereof, as the synergistic combination of baclofen and acamprosate to said subject.

[Umpalumpa]

cont'd

FIELD OF THE INVENTION
The present invention relates to combinations and methods for the treatment of neurological diseases and disorders. More specifically, the present invention relates to novel combinatorial therapy of neurological disorders, based on Baclofen and Acamprosate combination.

BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is the prototypic cortical dementia characterized by memory deficit together with dysphasia (language disorder in which there is an impairment of speech and of comprehension of speech), dyspraxia (disability to coordinate and perform certain purposeful movements and gestures in the absence of motor or sensory impairments) and agnosia (ability to recognize objects, persons, sounds, shapes, or smells) attributable to involvement of the cortical association areas. Special symptoms such as spastic paraparesis (weakness affecting the lower extremities) can also be involved (1-4).

Incidence of Alzheimer disease increases dramatically with the age. AD is at present the most common cause of dementia. It is clinically characterized by a global decline of cognitive function that progresses slowly and leaves end-stage patients bound to bed, incontinent and dependent on custodial care. Death occurs, on average, 9 years after diagnosis (5).

The incidence rate of AD increases dramatically with age. United Nation population projections estimate that the number of people older than 80 years will approach 370 million by the year 2050. Currently, it is estimated that 50% of people older than age 85 years are afflicted with AD. Therefore, more than 100 million people worldwide will suffer from dementia in 50 years. The vast number of people requiring constant care and other services will severely affect medical, monetary and human resources (6).

Memory impairment is the early feature of the disease and involves episodic memory (memory for day-today events). Semantic memory (memory for verbal and visual meaning) is involved later in the disease. By contrast, working memory (short-term memory involving structures and processes used for temporarily storing and manipulating information) and procedural memory (unconscious memory that is long-term memory of skills and procedure) are preserved until late. As the disease progresses, the additional features of language impairment, visual perceptual and spatial deficits, agnosias and apraxias emerge.

The classic picture of Alzheimer's disease is sufficiently characteristic to allow identification in approximately 80% of cases (7). Nevertheless, clinical heterogeneity does occur and not only is this important for clinical management but provides further implication of specific medication treatments for functionally different forms (8).

The pathological hallmark of AD includes amyloid plaques containing beta-amyloid (Abeta), neurofibrillary tangles (NFT) containing Tau and neuronal and synaptic dysfunction and loss (9-11). For the last decade, two major hypotheses on the cause of AD have been proposed: the “amyloid cascade hypothesis”, which states that the neurodegenerative process is a series of events triggered by the abnormal processing of the Amyloid Precursor Protein (APP) (12), and the “neuronal cytoskeletal degeneration hypothesis” (13), which proposes that cytoskeletal changes are the triggering events. The most widely accepted theory explaining AD progression remains the amyloid cascade hypothesis (14-16) and AD researchers have mainly focused on determining the mechanisms underlying the toxicity associated with Abeta proteins. Microvascular permeability and remodeling, aberrant angiogenesis and blood brain barrier breakdown have been identified as key events contributing to the APP toxicity in the amyloid cascade (17). On contrary, Tau protein has received much less attention from the pharmaceutical industry than amyloid, because of both fundamental and practical concerns. Moreover, synaptic density change is the pathological lesion that best correlates with cognitive impairment than the two others. Studies have revealed that the amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the GABAergic terminals (11). Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system. Under pathological conditions, its abnormal accumulation in the synaptic cleft leads to glutamate receptors overactivation (18). Abnormal accumulation of glutamate in synaptic cleft leads to the overactivation of glutamate receptors that results in pathological processes and finally in neuronal cell death. This process, named excitotoxicity, is commonly observed in neuronal tissues during acute and chronic neurological disorders.

[Umpalumpa]

It is becoming evident that excitotoxicity is involved in the pathogenesis of multiple disorders of various etiology such as: spinal cord injury, stroke, traumatic brain injury, hearing loss, alcoholism and alcohol withdrawal, alcoholic neuropathy, or neuropathic pain as well as neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, and Huntington's disease (19-21). The development of efficient treatment for these diseases remains major public health issues due to their incidence as well as lack of curative treatments.

Two kinds of medication are used for improving or slowing down symptoms of AD which lay on some acetylcholinesterase modulators and blockers of NMDA glutamate receptors (26-27).

NMDAR antagonists that target various sites of this receptor have been tested to counteract excitotoxicity. Uncompetitive NMDAR antagonists target the ion channel pore thus reducing the calcium entry into postsynaptic neurons. Some of them reached the approval status. As an example, Memantine is currently approved in moderate to severe Alzheimer's disease. It is clinically tested in other indications that include a component of excitotoxicity such as alcohol dependence (phase II), amyotrophic lateral sclerosis (phase III), dementia associated with Parkinson (Phase II), epilepsy, Huntington's disease (phase IV), multiple sclerosis (phase IV), Parkinson's disease (phase IV) and traumatic brain injury (phase IV). This molecule is however of limited benefit to most Alzheimer's disease patients, because it has only modest symptomatic effects. Another approach in limiting excitotoxicity consists in inhibiting the presynaptic release of glutamate. Riluzole, currently approved in amyotrophic lateral sclerosis, showed encouraging results in ischemia and traumatic brain injury models (22-25). It is at present tested in phase II trials in early multiple sclerosis, Parkinson's disease (does not show any better results than placebo) as well as spinal cord injury. In 1995, the drug reached orphan drug status for the treatment of amyotrophic lateral sclerosis and in 1996 for the treatment of Huntington's disease. The use of NMDA receptor antagonists such as memantine, felbamate, acamprosate and MRZ 2/579 for treating depression has also been suggested in US2010076075.

WO2009133128, WO2009133141, WO2009133142 and WO2011054759 disclose drug combinations for use in the treatment of AD.

Despite active research in this area, there is still a need for alternative or improved efficient therapies for neurological disorders and, in particular, neurological disorders which are related to glutamate and/or amyloid beta toxicity. The present invention provides new treatments for such neurological diseases of the central nervous system (CNS) and the peripheral nervous system (PNS).

SUMMARY OF INVENTION
It is an object of the present invention to provide new therapeutic methods and compositions for treating neurological disorders. More particularly, the invention relates to compositions and methods for treating neurological disorders related to glutamate and/or amyloid beta toxicity, based on a combination of Baclofen and Acamprosate.

The invention stems, inter alia, from the unexpected discovery, by the inventors, that the combination of Baclofen and Acamprosate provides substantial and unexpected benefit to patients with Alzheimer's disease. Moreover, the inventors have surprisingly discovered that this combination provides substantial and unexpected protection of neuronal cells against various injuries encountered in neurological disorders including glutamate toxicity. Thus, this combination of Baclofen and Acamprosate constitutes an efficient treatment for patients suffering from, predisposed to, or suspected to suffer from neurological disorders.

An object of this invention therefore relates to compositions comprising a combination Baclofen and Acamprosate, for use in the treatment of a neurological disorder, particularly AD and related disorders, Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD), neuropathies (for instance neuropathic pain or alcoholic neuropathy), alcoholism or alcohol withdrawal, Huntington's disease (HD) and spinal cord injury.

The composition of the invention may contain Baclofen and Acamprosate as the only active ingredients. Alternatively, the compositions may comprise additional active ingredient(s). In this regard, a further object of this invention relates to a composition comprising a combination of Baclofen, Acamprosate, and at least one third compound selected from Sulfisoxazole, Methimazole, Prilocalne, Dyphylline, Quinacrine, Carbenoxolone, Aminocaproic acid, Cabergoline, Diethylcarbamazine, Cinacalcet, Cinnarizine, Eplerenone, Fenoldopam, Leflunomide, Levosimendan, Sulodexide, Terbinafine, Zonisamide, Etomidate, Phenformin, Trimetazidine, Mexiletine, Ifenprodil, Moxifloxacin, Bromocriptine or Torasemide, for use in the treatment of neurological disorders in a subject in need thereof.

As it will be further disclosed in the present application, the compounds in a combinatorial therapy of the invention may be administered simultaneously, separately, sequentially and/or repeatedly to the subject.

The invention also relates to any pharmaceutical composition per se comprising a combination of at least two compounds as defined above.

The compositions of the invention typically further comprise one or several pharmaceutically acceptable excipients or carriers. Also, the compounds as used in the present invention may be in the form of a salt, hydrate, ester, ether, acid, amide, racemate, or isomer. They may also be in the form of sustained-release formulations. Prodrugs or derivatives of the compounds may be used as well.

In a preferred embodiment, the compound is used as such or in the form a salt, hydrate, ester, ether or sustained release form thereof. A particularly preferred salt for use in the present invention is Acamprosate calcium.

In another preferred embodiment, a prodrug or derivative is used.

A further object of this invention is a method of preparing a pharmaceutical composition, the method comprising mixing Baclofen and Acamprosate, in a pharmaceutically acceptable excipient or carrier.

Another object of this invention relates to a method for treating a neurological disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising administering to said subject an effective amount of a combination of the invention.

A further object of this invention relates to a method for treating Alzheimer or a related disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising administering to said subject an effective amount of a combination of the invention.

A preferred object of this invention relates to a method for treating a neurological disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising simultaneously, separately or sequentially administering to said subject an effective amount of Baclofen and Acamprosate.

A more preferred object of this invention relates to a method for treating Alzheimer or a related disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising simultaneously, separately or sequentially administering to said subject an effective amount of Baclofen and Acamprosate.

The invention may be used for treating a neurological disorder in any mammalian subject, preferably in any human subject, at any stage of the disease. As will be disclosed in the examples, the compositions of the invention are able to ameliorate the pathological condition of said subjects.

[neophyte]

great, so potentially i can avoid alzheimer's, by taking high dose baclofen, it just keeps getting better!

[Umpalumpa]

It seems very promising. I wish we had a friendly neurologist to help us understand this.

What I have noticed is that the illnesses which seem to be treatable with baclofen are those which have similar symptoms. Alcoholics develop memory problems, like in Alzheimers. Alcoholics suffer from the "shakes" and Baclofen is used to treat multiple sclerosis which is characterized by nervous tremors. There is a common denominator here of an underlying neurological disorder. I think what has happened over the years is that the use of psychiatry and psychology has meant we have overlooked neurological disorders.

[Umpalumpa]

A google search shows this is now a becoming very well known

New Ideas for Alzheimer's Treatment: What's on Offer in 2015 ...

https://www.alzforum.org/news/.../new-ideas-alzheimers-treatment-whats-offer-2015

Dec 22, 2014 - Series - Clinical Trials on Alzheimer's Disease 2014: ... calcium, used to treat alcohol dependency, and the muscle relaxer baclofen, approved for spasticity. ... Acamprosate is an analog of the neurotransmitter GABA, while ...
Patent EP2560631A2 - Baclofen and acamprosate based therapy of ...
Patent EP256631A2 - Baclofen and acamprosate based therapy of neurogical disorders - Google Patents
Feb 27, 2013 - A composition comprising Baclofen and Acamprosate for use in the treatment of ... Alzheimer's disease (AD) is the prototypic cortical dementia ...
Combination of acamprosate and baclofen as a promising therapeutic ...
National Center for Biotechnology Information › Journal List › Scientific Reports
Nov 6, 2015 - Combination of acamprosate and baclofen as a promising ... data as well as the substantial overlap between Alzheimer's disease (AD) and PD ...
Combining two repurposed drugs as a promising approach for ... - NCBI
Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy. - PubMed - NCBI
by I Chumakov - 2015 - Cited by 8 - Related articles
Jan 8, 2015 - Alzheimer disease (AD) represents a major medical problem where ... of two approved drugs - acamprosate and baclofen - synergistically ...
Alzheimer's & Dementia Weekly: Combine Baclofen & Acamprosate ...
Alzheimer's & Dementia Weekly: Combine Baclofen & Acamprosate and You Get A Promising Alzheimer's Treatment
Jan 11, 2015 - Combine Baclofen & Acamprosate and You Get A Promising ... two re-purposed drugs, they came up with a promising Alzheimer's therapy.
Multi-drug approach could be way to treat Alzheimer's, study suggests ...
https://www.washingtonpost.com/...al...4-aabd-d0b93ff...
Jan 8, 2015 - It was combined with baclofen, a medication that has been used for ... One of the approved drugs, acamprosate calcium, decreases levels of ...
Acamprosate/baclofen - AdisInsight
adisinsight.springer.com/drugs/800040823
Acamprosate/baclofen is in phase II development in France for the treatment of Alzheimer's disease, and in phase I development for the treatment of amyotrophic ...
Pilot Study Assessing the Effects of PXT00864 in Patients With Mild ...

https://clinicaltrials.gov/ct2/show/NCT02361424

Dec 19, 2014 - ... of several doses of PXT00864 (new fixed combination of acamprosate and baclofen at low dose) in patients with mild Alzheimer Disease.
BACLOFEN AND ACAMPROSATE BASED THERAPY OF ... - Patents

https://www.patentsencyclopedia.com/app/20140378440

Dec 25, 2014 - A method of treating Alzheimer's disease or a related disease selected from ... The method of claim 1, wherein baclofen and acamprosate ...
Baclofen Info on Twitter: "NEW Combining #baclofen + #acamprosate ...

https://twitter.com/baclofenews/status/553562887298777088

Jan 9, 2015 - baclofenews's profile · Baclofen Info · @baclofenews · Baclofen Info .... NEW Combining #baclofen + #acamprosate for Alzheimer's disease ...

[Umpalumpa]

I think this shows the approach that should be taken with respect to alcoholism. If someone comes up with a drug which works because it treats a newly discovered/understood neurological disorder, then you have to look at the neurological disorder and see what other medications can be added to the mix to treat that disorder. In the course of this, you may find other manifestations of this disorder which are called something else, Alzheimer's, or autism, for instance.

I find Ibogaine to be the least likely solution to this. It's a plant extract so what are the chances that it has been "designed" naturally and accidentally to work on the human brain in a way which is just by chance going to cure alcoholism? Zero.

What Ibogaine does, like other naturally occurring substances, is that it sends you off into a day long hallucinatory trip. During that time you stop taking your drug of choice because you can't take it. It may also have some effect on neurotransmitters. However, if it hasn't changed the structure of the brain, and you still have anxiety craving, then I would think all you have done is given yourself a break from the addictive cycle. I think this is borne out by the reports on the rehab centers, that they give you Ibogaine, and then dose you up on diazapam for a few days, which is just a standard alcohol/drug detox so it's impossible from that to say whether Ibogaine is treating the addiction or the diazapam

[neophyte]

Umpa, there is definitely something in ibogaine, one mechanism of action where it acts as a KOR-opioid agonist which upregulates dopamine receptors in the nucleus encumbers. the same thing which happens when taking baclofen and abstaining from alcohol. this has an anti craving effect. ill post later with all my findings, but basically ibogaine cant be used because of all the other activity it has in the brain, i think drugs targeting this receptor hold some promise if one were to develop it.

[Umpalumpa]

Yes, I picked up the it has a similar mechanism to baclofen and that it had some effect, but as you point out, it has other effects, which is going to be likely given that it is a plant extract and not "designed for purpose". I still find that the reports suggest that it has some immediate effect on this receptor "cleans it out" I think someone says, so that with heroin, the addiction suddenly clears up, but then they dose up with diazepam, probably to prevent withdrawal. And, then the addiction seems to click back in again pretty quickly. With heroin you have to look at the social background. I have known hundreds of heroin addicts and they get their drugs with money from crime. One in a thousand would be able to pay for this treatment. It is so fringe it is hardly worth discussing.

If Carl was genuine he would just put his garbage on the Medical Research thread and not try to bludgeon anyone who uses baclofen. We are just being made victims of his ego massaging.