The MJF Foundation has issued a "Dyskinesia Challenge 2013"...you'll see that N is not particularly high on their priorities or expectations.
The Dyskinesia Challenge 2012 program seeks proposals focused on identifying and validating novel and innovative targets that will complement current MJFF efforts in the discovery and development of dyskinesia therapies.
Current MJFF therapeutic development efforts focus on the following:
Serotonergic system: in order to control its inappropriate dopamine release, using partial 5-HT1A/1B agonists
Overactive glutamatergic system: with an antagonist of mGluR5 or with a selective activation of mGluR4
Enhanced MAP kinase signaling pathway: with inhibitors of RasGRF1
Nicotinic receptor subtypes: with selective ligands of the nicotinic acetylcholine receptors
Altered opioidergic neurotransmission: using mu opioid receptor antagonists
For the Dyskinesia Challenge RFA, MJFF is particularly interested in pre-clinical studies revealing new pathways, other than the above described targets already being thoroughly explored with MJFF support.
N works on the serotonergic and glutaminergic pathways though the main one for N is likely to be glutaminergic but that is the NMDA receptor rather than the mGluR4 receptor (metabotropic) targeted.
If interested look for their youtube videos Dyskinesia: Hope on the Horizon and The Parkinson's Minute: A Promising Target to Treat Dyskinesia
Also look at Addex Therapeutics and google mGluR5
To Ray - I can't reply directly.
Amantadine has been proven to improve LID - that's a fact. Amantadine is known to be inadequate beyond mild benefit - this I knew. Dopamine agonists and leveling out L-dopa dosing are also strategies used but are also frequently INADEQUATE. The fact is, it's an area of tremendous need and that is all your Harrison's excerpt tells us.
You want to say you knew I was referring to the study when I said I was "hopeful" and that "there is substantial evidence that it will be successful" but then claim your "shot in the dark" response referred to FDA approval? When the only lead-in was my quote about "it will be successful"? In a thread I started that was overall somewhat negative on DMQ for LID? When every PII drug is a long shot? When FDA approval is not even needed for use?
This review article from 2010 indicates Amantadine may not be effective for LID and that its effect may be due to other neurotransmitters like acetylcholine and that animal studies do not predict success in LID. This is an excerpt from page 2 of the Medscape article:
Following the hypothesis that pulsatile stimulation of dopaminergic receptors may induce an upregulation of NMDA receptors expressed on the same striatal GABAergic neurons favoring dyskinesia,[76,77] the possible antidyskinetic effects of a variety of NMDA glutamatergic receptor antagonists have been investigated in the last decades. Among these drugs, amantadine was the most studied. Amantadine is a noncompetitive NMDA-receptor antagonist (an open-channel blocker) demonstrated to decrease dyskinesia and improve motor complications in PD patients, when administered adjunctively with L-Dopa. Amantadine minimizes the dyskinetic effects of an acute L-Dopa/carbidopa challenge in PD patients on chronic L-Dopa treatment,[78,79] and several clinical trials have reported the efficacy of amantadine in reducing severity and duration of LIDs, without worsening PD motor symptoms.[80–82] On the other hand, it has also been documented that the anti-LID effects of amantadine are not long-lasting, since they may progressively diminish after 3–8 months. Moreover, a Cochrane analysis was unable to definitively establish the safety and efficacy of amantadine for LID treatment, owing to a lack of evidence verified in the examined clinical trials. The potential antidyskinetic role of numerous NMDA, as well as non-NMDA receptor antagonists have been largely investigated in animal models of PD, where a reduction of dyskinesias was found using various drugs, including ramacemide,[85,86] NMDA-receptor NR2B-subunit antagonists, talampanel, and others.[89–91] Unfortunately, clinical trials have failed to reproduce in PD patients the positive antidyskinetic results obtained from animal studies. In this regard, Cenci warned clearly that NR2B antagonists had no effect on LID and in some cases even worsened LID in animal models. She clarified in several papers how the dysregulation of DA release and clearance resulted in maladaptive neuroplasticity, sustaining abnormal patterns of movement;[4,66,91,92] in other words, Cenci suggested that postsynaptic alterations should not be accepted as the sole key player.
Not surprisingly, according to a double-blind, crossover study, even memantine (an open-channel blocker at NMDA-binding sites) which is able to cross the blood–brain barrier much more effectively than amantadine, did not affect LID, despite initial original enthusiasm due to preclinical data carried out in animal models. On the other hand, memantine has become a front-runner for the treatment of dementia, and further investigations on the effect of this drug in PD would be welcome.
In addition, other clinical studies have investigated the potential efficacy of different agents affecting glutamatergic transmission, and not just NMDA-mediated conductance. However, trials with riluzole and lamotrigine, both presynaptic glutamate-release inhibitors, produced inconclusive results.[96,97]
Finally, decades of experimental studies have outlined the roles of metabotropic glutamate receptors (mGluRs) in shaping BG electrophysiology and synaptic plasticity. Some promising data indicate the type 5 mGluR as an emerging target for LID treatment (a positive proof-of-concept clinical trial with a mGluR5 antagonist has already been carried out).
Nevertheless, despite the restrictions previously reported above, amantadine is so far the sole NMDA-receptor antagonist currently used as antidyskinetic drug in advanced PD patients, this raises the question of whether such an effect could be due to the other pharmacological actions of the drug, such as anticholinergic effects, inhibition of DA reuptake and enhancement of DA release.
Even if the results of clinical trials have failed to demonstrate convincing anti-LID effects of antiglutamatergic compounds, the NMDA-receptor complex gives rise to considerable attention based on a great body of evidence that an excessive excitatory NMDA activation may be a possible mechanism of neurodegeneration. Thus, NMDA-receptor antagonists are still of great interest in terms of the pathogenesis of motor complications or for potential neuroprotective strategies in PD.
Adenosine A2A-receptor Antagonists Since adenosine A2a receptors are localized in the BG and are widely expressed on the spiny neurons in the striatopallidal pathway, where there are localized DA D2 receptors, the strict functional interaction between these two receptor types has been considered as an important factor in the development of PD motor complications and dyskinesias. In PD, enhanced GABA release in the external globus pallidus through activation of adenosine A2a receptors, has been hypothesized to contribute to the overactivity of the indirect striatopallidal pathway. Thus, it has been proposed that adenosine A2a antagonists may improve parkinsonian symptoms and counteract L-Dopa motor complications, reducing overactive firing in striatal neurons bearing D2 receptors. Conflicting reports on istradefylline (KW-6002) have been demonstrated, with results suggesting that it was either capable of diminishing LIDs in a primate model of PD,[98,99] or had no intrinsic antidyskinetic efficacy in the rat model. Recent placebo-controlled clinical trials with istradefylline performed in fluctuating L-Dopa-treated PD patients, showed an improvement in patients' OFF time without increasing dyskinesias.[101,102] However, to date, the antiparkinsonian and antidyskinetic effects of this drug have not been long-established across clinical trials.
5-HT1A Receptor Agonists Different 5-HT-receptor subtypes, including 5-HT1A, 5-HT1B and 5-HT2A receptors are largely expressed in the striatum. Sarizotan is a selective 5-HT1A-receptor agonist with high affinity to D3–D4 receptors that, by acting on 5-HT1A autoreceptors, may modulate (reduce) the release of 5-HT and DA."
I never said the study in LID should not be done.
Yes, by "shot in the dark" I meant eventual FDA approval. And, yes,when one says there is good evidence to think a Nuedexta study for LID will be successful would have to mean there is good reason to hope the drug will eventually be shown to be effective enough to get FDA approval. But there isn't.
My point is there is not "good evidence" to think the Nuedexta study for LID will be successful and the whole endeavor IS a "shot in the dark". I'm not saying the LID study isn't a shot worth taking (like I think the agitation in dementia study does not even have the prerequisite study in non-PBA neurologic patients done and therefore should not even be done now). But it is a shot in the dark.
I hadn't taken it to the next thought that off-label use can occur prior to approval. I was thinking about the odds of FDA approval from this point, even before the first Phase 2 study results are available.
But even off-label use prior to approval does not occur after the first small Phase 2 study. It would probably take a successful Phase 3 study. We have not seen appreciable off-label use for pain even with a successful Phase 3 study for diabetic neuropathic pain (albeit at a higher dose) and the subset of MS neuropathic pain patients of a previous Phase 3 PBA study as well as the subset of MS neuropathic pain patients in the STAR study.
So yes, I meant all of what I said in my previous post.
I don't think you have appreciated my point about amantadine not being effective often for LID.
If a drug is not often effective or not very effective, it is illogical to think some other drug that MIGHT work throught the same transmitters MAYBE in the same part of the brain that amantadine works in , will work better.
And what if the possible mild effectiveness of amantadine is mediated through acetycholine and not through other neurotransmitters? (See the article below).
Don't you see how many possibly incorrect assumptions have to be made when extrapolating from a neurotransmitter effect to clinical effectiveness for a neurologic condition?
"J Neural Transm. 2010 March; 117(3): 293–299.
Published online 2010 February 4. doi: 10.1007/s00702-010-0371-1
Effects of amantadine on circulating neurotransmitters in healthy subjects
Fuad Lechin,1,2,4 Bertha van der Dijs,1,2 Betty Pardey-Maldonado,1 Jairo E. Rivera,1 Scarlet Baez,2 and Marcel E. Lechin3
Considering that glutamatergic axons innervate the C1(Ad) medullary nuclei, which are responsible for the excitation of the peripheral adrenal glands, we decided to investigate catecholamines (noradrenaline, adrenaline and dopamine) plus indolamines (plasma serotonin and platelet serotonin) at the blood level, before and after a small oral dose of amantadine, a selective NMDA antagonist. We found that the drug provoked a selective enhancement of noradrenaline plus a minimization of adrenaline, dopamine, plasma serotonin and platelet serotonin circulating levels. Significant enhancement of diastolic blood pressure plus reduction of systolic blood pressure and heart rate paralleled the circulating parameter changes. The above findings allow us to postulate that the drug was able to enhance the peripheral neural sympathetic activity. Minimization of both adrenal sympathetic and parasympathetic activities was also registered after the amantadine challenge. The above findings supported the postulation that this drug should be a powerful therapeutic tool for treating diseases affected by adrenal sympathetic hyperactivity.
Adrenal glands secrete adrenaline (Ad) (80%) + noradrenaline (NA) and dopamine (DA) (20%), approximately. Sympathetic nerves release NA (80–90%) plus DA. Both branches of the peripheral sympathetic activity may act in association or dissociation (Young et al. 1984), in accordance with the physiological and/or pathophysiological circumstances. At the central nervous system level, the C1(Ad) rostral ventral lateral (RVL) medullary nuclei and the A5(NA) pontomedullary nucleus are responsible for these two branches of the peripheral autonomic nervous system (ANS), respectively (Bazil and Gordon 1993; Byrum and Guyenet 1987; Guyenet 1984; Li et al. 1992; Loewy and Haxhiu 1993; Morrison et al. 1991; Strack et al. 1989; Woodruff et al. 1986). Both CNS structures interchange inhibitory axons. Adrenaline released from C1-axons inhibits A5(NA) neurons by acting at alpha-2 post-synaptic receptors, whereas NA released from A5(NA) axons inhibits the adrenergic nuclei by acting at alpha-2 inhibitory receptors located at these latter (Li et al. 1992; Strack et al. 1989; Woodruff et al. 1986).
Amantadine, a glutamate (NMDA) antagonist is considered as an anti-Parkinson agent because it might attenuate the glutamatergic + acetylcholinergic over the dopaminergic predominance at the striatal level (Bibbiani et al. 2005). However, considering that glutamate axons innervate and excite the RVL medullary nuclei, responsible for the adrenal sympathetic activity, by acting at NMDA receptors (Bazil and Gordon 1993; Hand et al. 1997; Morrison et al. 1991), we decided to #$%$ circulating neurotransmitters before and after an oral dose of the drug."
Great leg work Onlyfacts. Thank you for bringing the topic to our attention, it has turned out to be an informative week.
As I see it the wording on the web site would be just right for Avanir to consider submitting an application.
“The Dyskinesia Challenge 2012 ( I think that 2012 is a typing error, on the web site the title reads 2013) program seeks proposals focused on identifying and validating novel and innovative targets that will complement current MJFF efforts in the discovery and development of dyskinesia therapies”
By the way, I watched the video, thank you for steering me in that direction.
Is it just me or do you also feel things are beginning to progress and move along more freely now. May be something to do with in the past when we did not have so much to go on. I’m going to sneak off and have a recap on the Avanir presentation slides.
Thanks for this and all of your analysis on the mechanisms/expectations of N. I suspect some zealous long posters here might try to critique you for being "negative", but I prefer a complete picture. Thank you for taking the time to help us educate ourselves.
The Michael J. Fox Foundation has provided a substantial grant to study N's effectiveness in reducing levodopa induced dyskensias. The pharmacology of the NDMA receptor is complex and not completely characterized in terms of specific mechanisms of action. Simplistic statements regarding those actions can be misleading. There are many theoretical reasons it may be very helpful, but that is the question that is being asked through the process of a carefully designed clinical study. Let's wait and see what the study determines. Hopefully, it will provide another tool to help people.
Sentiment: Strong Buy