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Spyder
I don't really know where to begin.
First, I made the point that many receptors and/or channels show pH-sensitivity in the context of what I clearly stated was my own opinion, not the consensus view, so it came with a disclaimer. As for the argument that NMDAR's pH-sensitivity is "not as great as you might think", in the context of a system as steeply nonlinear as the NMDAR, there is no such thing as a small difference.
Second, the notion of "established facts" to me seems a bit ridiculous. Aside from really basic biophysics, very little of what I learned 20 years ago still holds true (Dale's Principle, absence of neurogenesis in adults, etc...), and in the field of neural control of breathing, if you care to read the literature carefully and critically, there is really very little there that holds up to scrutiny. I don't think that my particular domain of knowledge is atypical, so this distinction between "established facts" and interesting hypotheses is perhaps more pernicious to the uninformed than minority opinions presented as minority opinions, since it leads people to believe that we have privileged knowledge. For my part, all my years toiling at this stuff has deepened my understanding of how little I know. Maybe that's just me.
Third you take my quote "however one interprets the lack of ampakinergic modulation of respiratory rhythm under ambient conditions, it can't really be interpreted as shedding light on ampakines' effect on central chemosensory neurons" out of context to make an erroneous point, since there is no lack of data regarding the point I was actually trying to make: under control conditions with eupneic breathing, chemosensory networks are inactive, since normocapnea, normoxia and physiological pH all prevail. This isn't an unproven countervailing hypthosesis. This is well-established. To argue that ampakines' effect on these quiescent neurons is going to be anything other than minimal is in fact the unproven countervailing hypothesis, and would be consistent with the notion that ampakines provoke seizures, which (at least in the case of low-impacts) is thankfully not the case.
You write: "Has it been established the Mu are found only in the chemosensory system as opposed to the rhythm generating circuits?" I never claimed this, and with all my skepticism, I can say with some certainty that this is likely false. Mu-opioid receptor agonsists directly target respiratory rhythm-generating constituents.
Read my posts or ignore them, please don't misread them, then mis-state their contents. There's enough confusion and stress here as it is.
Dick Dale, not Nick Dale.
Firstly,
>>While its true that NMDAr (and AMPAr actually) are somewhat pH sensitive,
I used this as an example, so as not to bring in other more physiologically relevant ph-sensitive conductances such as TASK
(J Neurosci. 2007 Dec 19;27(51):14049-58 TASK channels determine pH sensitivity in select respiratory neurons but do not contribute to central respiratory chemosensitivity.Mulkey DK, Talley EM, Stornetta RL, Siegel AR, West GH, Chen X, Sen N, Mistry AM, Guyenet PG, Bayliss DA.)
Although the finding of this paper would seem to exclude TASK channels in chemosensation, that is beside my point, which is that many channels that determine a neuron's biophysical response are pH-sensitive. In this context, the TASK channel is a better (but more obscure) example. There are plenty of others, particularly because the whole central acidosis response is mediated by the purinergic system (see Nick Dale's work). If pH changes affect the kinetics of subsets of channels/receptors in PBC neurons, then there is a direct pH effect on rhythm-generating circuits. The fact that this effect hasn't been described is because there is no well-defined class of cells that are identified as *the* critical constituents of the respiratory rhythm generator.
>>>You postulate that ampakine's effects on the chemosensory system would constitute a "generic upregulation of AMPAergic drives".
I may be wrong about this, but given that ampakines are allosteric modulators of AMPA receptors, this seemed reasonable.
Insofar as my description of ampakines' effect isn't wildly off, my point was that because central chemosensory neurons are opiate-sensitive (hence depressed by the fentanyl-like opioid), central chemosensory drive would likely be blunted. Because these neurons likely have AMPA receptors however, the allosteric modulation of these receptors by the ampakine might counteract the opioid-induced depression of these chemosensory neurons. Thus, the lack of an effect of ampakines on resting respiratory frequency is beside the point, because under ambient conditions, there is little chemosensory drive (the brain would be normoxic, normocapnic, and at the right pH). So however one interprets the lack of ampakinergic modulation of respiratory rhythm under ambient conditions, it can't really be interpreted as shedding light on ampakines' effect on central chemosensory neurons.
If you have somebody instrumented to measure breathing rate, why not acquire data throughout? I'm sure they will measure respiratory rate before cocktail administration, after, and during the rebreathing. What I don't know is whether they will disseminate these data in their announcement about the result of the trial.
It's been stated here that in addition to the response to rebreathing, opioid-induced changes in respiratory frequency would also be recorded. After the fact, this may give us some insight into how ampakines rescue the arousal response (if they do). If the opioids are administered in doses sufficient to slow respiratory rhythm, then ampakines can have a direct effect on the PBC, reversing the opioid-induced slowing. In the context of rebreathing, this would support the notion that ampakines rescue the arousal response both by direct effect on rhythmogenic networks (replicating Greer's data), and via chemosensory pathways (generic upregulation of ampaergic drive). So if the arousal response is restored, and if an opioid-induced slowing of respiratory frequency prior to rebreathing is observed, it's likely that ampakines were effective in restoring arousal via both mechanisms.
I don't foresee much of a jump in SP on good news, and even if there is, there will be major dips as people take their money off the table. I think SP will go towards $1.50 on good news, not much higher. The bigger jump will come on partnership news.
All in all, if I were sitting on the sidelines, I would wait for the news, particularly because it is unlikely to be unambiguous, and even more particularly, because if the news is bad, you've just thrown away the money.
The odds I give it is 60%. By "good enough" I mean satisfying points 1-3 of Aiming's post.
I don't think that cor is in a position to raise capital via share dilution or borrowing. They will have to do a deal, on whatever terms their data will support.
I'm not sure I understand your question.
As a general preface to what follows, I should state that I don't fully subscribe to the hypothesis that the PBC is *the* rhythm-generator for breathing. The reasons why are too long to go into here, also, you won't find many people who ascribe to my view. So what I'll try to do is put aside my opinions, and attempt an answer within the conventional conception of how respiratory regulation works.
The PBC is thought of as a dedicated circuit, modulated by afferent feedback, including chemosensory drive, originating from the retrotrapezoid nucleus, the raphe, and others (central chemoreception) and the carotid body (peripheral). So within this simplified view, the answer is no. the effect of hypercapnea on PBC would be indirect, mediated by these other chemosensory structures, and these structures would increase tonic drive to PBC. Even within this conventional view, it should be stressed that there are few channels that are impervious to pH swings (hypercapnea is accompanied by acidosis). An example is the NMDA receptor, whose kinetics change with pH, and there are many others, so there should be some chemosensitivity to the PBC, even though people don't think of it as playing a role in chemosensation. If you're having a hard time following this, it's not because it is conceptually difficult, but rather because it is a bit incoherent, that's one of the characteristics of consensus views.
My view is that there are multiple paths to respiratory rhythmogenesis within the brainstem and within the PBC. These functionally similar, mechanistically distinct circuits are interdigitated, talk to each other, recieve differential inputs from different afferent sources, respond differently to these sources, and have markedly different "intrinsic" responses to hypercapnea/acidosis. So within my framework, there is much more room for a direct effect of chemo drive on rhythmogenic circuits, and also a blurring of the distinction between chemosensory and rhythmogenic networks.
Athero,
Perversely, the CO2 rebreathing protocol is the perfect experiment for the sleep apnea indication, since the physiological consequence of sleep apnea is hypercapnea, and the apnea ends because of an arousal response that disrupts sleep but restores airway patency. There isn't much that pharmacology can do for the mechanical cause of OSA (typically fatty tissue causes airway collapse), but the RD study will establish whether ampakines can upregulate a depressed chemosensory arousal response. This is relevant to OSA because over time OSA sufferers desensitize to hypercapnea, and then they really have troubles.
Aside from the issue of whether ampakines can rescue a depressed (or desensitized) chemosensory pathway, there is the issue of whether the effective ampakine dosage disrupts sleep. Maybe they'll take ampakines at night to fend off OSA-induced hypercapnea, and then take it during the day to fend off the sleepiness incurred because of ampakine-induced insomnia. These people generally don't get a very good night's sleep anyway, because they stop breathing (and then wake up) in REM so their sleep cycles are totally disrupted.
I'm glad you're not. I agree about my timing, and hope that when the dust settles none of this will matter. If you're not pumping the stock, and nakedmouse isn't around to trash it, maybe this is a sign that people have better things to do than fleece long-suffering micro-cap biotech investors.
Let's hope this thing goes well.
There are reasons to be cheerful, however:
1. We know that rodents and humans both slow, then stop their breathing in response to opiates. We also know that the effects of ampakines is generic, upregulating the most common receptor (AMPA) mediating excitatory neurotransmission. Finally, there's good data supporting the notion that networks are highly concerved across the vertebrate lineage (opiates' common effect on respiratory rhythm is one piece of evidence). Thus, based on what we currently know, RD seems to be a good indication for ampakines.
2. The fact that Richter's animals overcame RD, but the human subjects trial failed cannot be interpreted as evidence that the human trial design was flawed, since a different drug was used in humans, and when the drug used in humans was used in rodents, the animal study failed as well (thanks to GFP for pointing this out). Thus it seems likely that the human trial failed because of the drug, leaving us completely in the dark about eventual problems with the rebreathing protocol. There are certainly problems with the rebreathing protocol, because both central and peripheral chemoreceptors are opiate-sensitive, but the earlier study says nothing about how serious these problems are.
On another issue: thanks to haysaw for getting that old "davey" post. It's interesting that someone trying to push up cor's share-price to increase his profits in a shorting play gets a better reception here than the nakedmouse types who try to scare people off.
Because of the very low share-price, and because of the relatively low volumes traded in this stock, it seems to me that there is a real possibility of downward manipulation of the share-price on ambiguous news to create the market perception that the trial was a failure. My guess is that on anything less than unambiguously good news, and the resulting heavy trading volume, people who are shorting this stock may attempt to crater it.
>>1) It doesn't have to be all or none. The rat data illustrates the pretty-much complete elimination of analgesia by naloxone. Even if Ampakines reduce that slightly (to take the raw numbers from this rat study and use them as an example of what it could--I emphasize could--look like) 15% or so--rescuing a patient from RD and keeping 85% of the analgesia is a whole lot better than losing all of it. And I suspect it would still show up as at least a solid trend in this human study.
I agree completely. This is why I don't think it's entirely accurate to describe this as a binary event. Of course, the outcome could be binary: a rescuing of the arousal response without any effect on analgesia. My hunch is that the outcome will be somewhere in between, and thus the way that the market responds to the news will depend on how close it is to either an unambiguous positive or negative result, and how effectively cor highlights the positive aspects and provides context for the negative aspects of the study.
>>2) The relationship between glutamatergic activity and analgesia is not consistent and marked. For example, memantine, a NMDA-antagonist (which thus reduces glutamatergic activation) has been tried in a number of neuropathic pain trials, with mixed data in Phase II, failure in Phase III. Thus reducing glutamate activation in pain states has not been a clear means of decreasing pain, thus I suspect that modestly upregulating glutamatergic activation (in this case allosterically)is not going to be aignificantly proalgesic.
I don't think you can infer much from a clinical trial that impacts NMDA rather than AMPA receptors. These different classes of receptors have very different functional roles, and the fact that they are both activated by glutamate shouldn't lead one to lump them together.
First off, I don't take your post badly. I understand where you're coming from, and agree that at this late hour, all the issues I raise are pretty much beside the point. I hope that my misgivings are misplaced, since I also have a big chunk of money in cor.
The timing of my comments may be too late for those of us who are already heavily invested, but they may help someone thinking of investing in this stock get a better understanding about some of the ambiguities surrounding this trial. For my part, I'm trying to do one thing that is always available in a bad situation: learn. I post my comments here to get feedback from people who are more familiar with this sector, who have a clinical background, or who are knowledgeable about investing generally, areas where I know little. I don't think anything I write here has any impact on cor's share-price. That is entirely dependent on the outcome of a clinical trial that's already completed, so I don't feel that what I'm doing is harming our investment.
I hope I'm wrong. GFP gave reasons as to why I'm likely wrong, and I'm fine with that. As much as anything else, I see this as a place where we can educate each other, and there are plenty of MDs and people with a strong science background here who are capable of poking holes in my logic or in the facts I present. Being told that somebody at cortex said I was wrong isn't very compelling though.
Unless they've gotten access to the data, they don't know and we don't know. We're all in the dark.
This board looses its utility if we all sing the same song. There are plenty of people here who have robust confidence in cor, and nobody tells them not to give newbies a false sense of security or expectations. Insofar as this bulletin board has unrealistically raised people's expectations, I think considerably more harm has been done by that than by my scaring people.
I'm an investor because I am excited about the possibilities of ampakines in the treatment of neurodegenerative diseases (in the first instance). I care about the people ampakines could help, about my wallet, and in distant third place, about cor. I am pretty sure that's exactly how the people who work at cor have their priorities (with "cor" replaced by "shareholder").
That's true. Rats are used as animal models for pain research, so their sensitivity/response characteristics must be pretty similar. At some ampakine concentration, however, I'd expect to see a loss of analgesia. It's not as though the pathway modulated by opioids is insensitive to ampakines.
Neurons in the pain pathway are excited by a pain stimulus. Opioids reduce the excitability of constituents of this transmission pathway, causing the signal not to be transmitted. By upregulating the efficacy of glutamatergic transmission, so long as there is some tonic excitatory drive converging on neurons depressed by opioids, then by increasing the gain of that excitatory glutamatergic signal, the opioid-induced reduction in excitability will be itself reduced.
Sorry about the double negatives. What it boils down to is that the state of a neuron is determined by the voltage difference across its membrane. If that value is very negative, action potentials, which are used to propagate signals from neuron to neuron, will not occur. Glutamate tends to move the voltage difference to less negative values, increasing the likelihood of an action potential, while opioids hold neurons at more negative values. All this happens via the opening and/or closing of channels through which charge-carrying ions flow, and the voltage difference reflects the integration of all these fluxes. The point is that increasing the gain of glutamatergic drive is generally going to have the same effect as decreasing opioid-induced depression.
I don't think this will be a binary event. I think the story will be mixed, thus subject to interpretation.
Because of the opioid-sensitivity of both the peripheral and central chemoreceptor pathways, I foresee that cx-717 will show efficacy only at higher doses. At these higher doses there may be partial loss of analgesia.
It's not clear to me the extent to which ampakine's effect on opioid-induced respiratory slowing will be quantified or tested for, but that's where I think there may be an effect at lower doses.
In light of this, I expect at best a small bump up, to ~$1.10, which will leave cor in need of a partnership, since dilutive financing will not be worth it at that share price. If the ambiguous data are interpreted negatively by the market, I expect the SP to fall into the high 0.50s. Then we have to hope that the BP people will be better able to interpret the study than the market will have.
OT Are you talking about the Tillman case?
I wouldn't be surprised if this Slate article moves us past the 0.95 resistance Jerry writes about.
I've attached the Defense Research and Engineering doc cited in the Slate article:
link:
http://fas.org/irp/agency/dod/jason/human.pdf
3.3.1 Ampakines
The neurostimulators listed in Table 1 increase the concentration of neurotransmitters,
thus increasing the ease of creating an action potential. A
more controlled response is possible if instead the action of the neuroreceptors
is modulated to create a stronger response to a normal physiological level
of neurotransmitter. One approach to modulation of the glutamate neuroreceptors
uses a class of simple chemical compounds called ampakines. These
53
molecules alter the conductivity of AMPA receptors by, in effect, modifying
their structural conformation when glutamate is docked on the AMPA,
as illustrated in Figure 3.5. The chemical (patch) and electrical (synapses)
responses as a function of time are shown in the lower panel of the figure,
with the normal response as the upper curves and the ampakine-modified
response in the lower curves.
Figure 3.5: Mechanisms for actions of ampakines. Upper row: glutamine
present in the synaptic channel binds to the AMPA neuroreceptors, causing
a structural change that opens a channel through the cell membrane. If
the synaptic concentration of glutamate decreases, unbinding occurs and the
channel closes (deactivation). If the concentration of glutamate remains high
for a long time, a second conformational change occurs, closing the channel
(desensitization). Lower row: Ampakine binds cooperatively with glutamate
and increases the time constants for both deactivation and desensitization.
The graphs show the chemical and electrical responses to short and long gluatamate
exposures (indicated by red bars) for normal AMPA action (upper
curves), and ampakine-modified AMPA action (lower curves).
54
There are many consequences of enhancing the activity, magnitude of
voltage response, and time course of response at AMPA receptors, as shown
in Figure 3.6. Every biochemical action is linked by feedback and regulatory
Figure 3.6: Interconnected biochemical cycles. Ampakine-induced increase
in AMPA activity directly affects NMDA response in admitting calcium ions.
Increased Ca2+ concentration increase subsequent AMPA response (path 2),
and cause long-term changes in the effectiveness and number of AMPA receptors
(paths 3A and 3B). Path 3A involves changes in the cytoplasmic region
near AMPA. Path 3b involves gene-signaling pathways including the CREB
transcription factors. Figure from reference [36].
networks (only a few of the network paths for the glutamate system are shown
in Figure 3.6. [36, 37, 39] For ampakine-mediated AMPA response, there
are cooperative effects from the increased Ca2+ flow through the NDMA
receptors, and the subsequent production of messengers that signal changes
in gene expression. Responses in the form of increased protein production
(e.g. additional AMPA) can occur on the time scale of minutes, and new
synapse formation can occur on the time scale of tens of hours.
55
3.3.2 Effects of ampakines on cognition
Both the biochemical effects of ampakines and their effects on performance
of cognitive tasks have been tested extensively [36, 38, 40]. Direct
confirmation of improvements in LTP and modification of biochemical pathways
have been demonstrated. Both rats and primates have been subject
to behavioral tests to evaluate the correlated effects of ampakines on performance,
with tests including subjects of various ages, and subjects with
disease-induced impairment of cognition. Of particular interest for possible
uses in non-disease related human peformance modification have been studies
on healthy young adults. One example, involving cognitive tests for Rhesus
moneys, is illustrated in Figure 3.7. The upper panel illustrates the test, in
which first an image is shown, such as the one to the left, then after a certain
delay a group of images (2 to 6 images) is shown, such as the group to the
right, from which the subject selects the matching image. The center panel
shows a comparison of the response for monkeys without (left) and with
(right) ampakine treatment. There is a clear improvement in performance,
correlated with changes in fMRI patterns, when the monkeys were treated
with ampakines. The performance gain was
The potential of using ampakines to ameliorate the effects of sleep deprivation
was also tested, as shown in the lower panel of Figure 3.7. Comparison
of the Normal Alert and Sleep Deprived results to the right shows decrements
in performance after 30-36 hours without sleep. The decrements are most
severe in the tasks that the monkeys were originally best at (e.g., short time
delays). Repeating the tasks with sleep-deprived monkeys that had been
administered ampakines, as shown in the lower right, restored performance
to levels comparable to or better than those for well-rested monkeys without
ampakine treatment. This preliminary result is unsurprising, given that
stimulants such as amphetamines and modafinil, that enhance neurotransmission,
are known to be effective for combating the effects of sleep deficit.
If the amapkines prove useable for extended periods without adverse side
56
Figure 3.7: A delayed match-to-sample test is illustrated in the top row.
The first image is shown, and then after a time delay, a group (2 through 6
images) of images is shown. The subjects score is simply the number of times
that the correct image is chosen. Center row: average performance results
for 9 monkeys each performing 150-300 selections per session. Left and right
graphs show results with and without administration of ampakine. Bottom
row: results for monkeys subjected to 30-36 hours of sleep deprivation before
tests.
57
effects, it is likely that they will also find application in chronic fatigue syndrome.
3.3.3 Continuing development of neuromodulators
Many medical treatments are under development that use the strategy
of modulating the neuroreceptor response or regulatory network [36, 38], as
shown in Table 3. While the drug development and approval process is being
carried out for medical conditions such as ADHD and Alzheimer’s disease,
the correlated potential of these drugs for improving normal cognition is well
recognized. As with the stimulants listed in Table 2, there is certain to be
extensive off-label use and experimentation with these drugs when they are
approved for prescription use.
Table 3: Modulator Drugs Under Development.
Name Biochemical Action Approval Status
Ampakines Modulate AMPA glutamate
receptors, enhance LTP
Phase IIB studies
Phosphodiesterase
inhibitors
Improve CREB activation of protein
synthesis, enhance LTP
Phase IIA studies
Bryostatin Protein kinase C activator, enhances
protein synthesis and LTP
Approved as cancer
treatment, under clinical
trials for memory function
It is not at all clear that vast improvements in normal cognition will
be achieved with these drugs, and unexpected consequences may well occur
when off-label (or illegal) uses of these drugs are explored. The proposals
for intervening at the cellular induction stage of enhancement or decrement
of synaptic conduction strengths involves at least two broad assumptions.
First, the detailed connection between actions at the cellular level on one or
a few neurons and the manifestation of these actions through a complex network
of neurons to functional behavior is conjectural. Neither the anatomical
58
nor the electrophysiological details of the network are known, much less understood.
How the network responds to differing inputs, possibly learning
signals, possibly threats from predators, possibly signals indicating pleasure,
is not understood either.
Secondly, the application of neuromodulators, such as ampakine and the
others mentioned, are broad through the brain and thus are not targeted to
specific brain regions—not yet anyway. Since the reports quoted by Lynch
in themselves show that different regions of cortex respond differently to the
same neuromodulators, the overall implications of any type of neuromodulator
is far from being known.
To adopt an optimistic view, however, it is quite possible that these
issues will be resolved with finer and finer detail by experimentation correlating
detailed investigations of the biochemical interconnections, brain-area
response and cognitive response. As with most things one wishes to know
about complex networks, even many much simpler than our brain, the techniques
for comprehending these networks are not well developed, and the path
ahead is itself complex, and probably long. On a shorter timescale, however,
it is virtually certain that empirical experimentation will occur using drugs
approved for medical applications. Such experimentation will reveal risks,
such as unexpected side affects, and also will reveal the range of human performance
modification (good or ill) that can be achieved with the present
imperfect understanding. The potential for adversarial threats arriving from
such developments will be discussed in the following section.
What do you thinkk of scstocks' argument about the weakness of cor now? He's using a different TA metric, and what he says makes sense.
How do you weigh these two conflicting ways of looking at the same stock?
PS. Have you been following the comedy regarding proposed temporary restrictions on naked short selling of financial stocks only?
This isn't necessarily a good thing, because with the very steep dose/response curve associated with this powerful an opioid, it may be harder to hit a "sweet spot", where you get RD without inducing apnea.
I think at this stage, both a basic researcher and a clinician are equally important: Greer has expertise on the relevance the animal model to the human at the level of pharmacology and the functional anatomy, but a clinician with a good understanding of RD would be able to determine what respiratory responses to expect at a given opiate dose, particularly the trajectory to steady state and steady-state duration. Somebody who has familiarity with opiates in a clinical setting would have a better understanding than someone who works primarily with brainstem slices.
I wrote that I thought it was very likely that they are doing plethysmography in this trial. It seems to me that if they are looking at respiratory rate during rebreathing, they have to be doing plethysmography.
>>we're also measuring more straightforward respiratory parameters, like pre and post-respiratory rates.
I very much hope that's going to be quantified, since opiates slow breathing before stopping it, and to my mind, reduction of opioid-induced respiratory slowing is a better indicator of ampakine efficacy in reversing RD than the rebreathing data, for reasons I've beaten to death.
>>Would the reason this technique wasn't also used in our human studies due to its impracticality (a large enclosed breathing box), it's not being available,
Plethysmography is routinely carried out in humans, and I'd be surprised if it wasn't carried out here.
>>From what I've been able to find, barbiturate works via both increasing GABA pathway activity (GABA pathways being CNS inhibitory), and reducing AMPA pathway activity (AMPA pathways being CNS stimulatory). So it sounds like the mechanism for barbiturate RD could be significantly different than that of opioids.
You're right, it is a different mechanism for RD, but the beauty part wrt ampakines, is that it doesn't matter, since the effect of ampakines is a generic upregulation of excitatory transmission via more powerful glutamatergic modulation of AMPA receptors. I think Neuro is right, the difference in RD mechanism shouldn't matter.
>> This being in contrast to simpler/more easily seen endpoints, like changes in the rate of breathing, or the complete cessation of breathing, etc.
At the dosages given there should be a statistically significant difference in pre- and post-opioid breathing rates. To my mind, this means that a comparison should be possible between ampakine+opioid, and just opioid subjects. This for me is the more meaningful measure.
>>They weren't able to use BIMU8 in the human study, so they used another 5HT4 agonist called Mosapride,... It showed no effect in the human RD study, and also bombed in the concurrent animal RD study they ran.
The fact that the matching Mosapride animal study failed renders the 5-HT study unintelligible, since it suggests that Mosapride was the problem, and leaves unanswered the more important questions about the role of species differences and inappropriate trial design.
Despite the futility of that human subject trial, I hope cor did a rodent trial that matched the design of the human trial, using BIMU8 as well as ampakines. If BIMU8 failed in rescuing the arousal response, and the ampakines succeeded, that would be a positive sign. Furthermore, if BIMU8 succeeded, given that mosapride failed in the matching animal study, it would leave open the possibility that a 5-HT 4 agonist might be an alternative mechanism for reversing RD, which might warrant an adjustment in cor's partnering strategy, since another BP might bring forward a competing drug.
>>Neuro, Wouldn't it figure that Greer gave considerable input to Cortex, concerning his opinion on the viability of the German trial design?
Greer isn't a clinician. Without a deep practical understanding of, and first-hand experience with, RD in a clinical setting, I think his basic research background would not have made him the best person to talk with regarding human subjects trial design.
Not questioning the competence of cor management begs the question of why, with the extraordinary IP they posess, they are one binary event away from going out of business.
The purpose of this kind of a website is to drill into a company's strategy, so that collectively we can make informed decisions. I make no apologies for that.
Again, what you are focussing on in your response is whether or not cor did "due dilligence" prior to initiating the human subjects trials. I can't know what they did or didn't do, and I'll take it on faith that they plunked some rats in a plethysmograph, gave them some fentanyl, varied PCO2, and looked at what happened. It's not hard to do, and it's an obvious experiment.
What I can state unequivocally is that the rebreathing protocol used in the human subjects trials is a lousy way to test for reversal of opiate-induced RD, since both the carotid body and central chemosensory pathways are opiate-sensitive. I'm not saying that it would be easy to come up with a better experimental protocol, but I find it hard to believe that this is the best that can be done.
I have a certain amount of faith in people's willingness to be thorough when their livelihoods are in play, but that faith doesn't do much to calm my jitters about the real problems associated with this trial.
If you can't say anything relevant about the points I raise, don't duck the issue by questioning my competence. Predicating boorishness with "with all due respect" and/or following it with "just kidding" doesn't make it less boorish.
Have you ever met anyone who isn't guilty of negligence and stupidity at some point, about something?
Leaving aside the issue of whether or not they did the animal trials that matched the human trials, I consider the trial design a terrible one: both central and peripheral chemosensory pathways are subject to endogenous opiate modulation, so a negative result may just as well be due to failure of chemosensory drive transmission as to failure of central rhythmogenic networks.
I consider it facile to argue that there is no other experiment that can be done in humans to test for efficacy in RD. This is tantamount to the argument that it makes sense to look for the keys under the lamp-post because the light there is better.
You're right, they don't owe me anything, but in light of the disappointments and dilutions that shareholders have endured over the past 18 moths, transparency and reassurance is something cor management can afford to offer.
As to why I'm holding cor: short answer, because I am guilty of fatal negligence and terminal stupidity. I have a cost basis average of about $2, and hate to write off the loss. My error was not in betting on cor, but in the size of the bet.
If I'm pissing some of you off, I apologize. I feel that the issues I raise are legitimate, and as someone who spends too much time reading posts on this board, I know that they haven't been raised. Insofar as I owe this community anything, it is to discuss issues that are relevant to what is happening with this company. My fondest hope is that this trial goes well, because even if I wanted to, with the trading volume we're seeing, I'd have difficulty unloading 10K shares above 0.80.
Nothing would make me happier than to have them insult me personally. I want to believe that they've done the preparatory work, and have animal data matching the human study.
What I don't get is why there is so little transparency about this. I wrote Stoll a brief note asking him if matching animal trials had been carried out. He didn't need to respond in detail, but I don't see why he couldn't have written something along the lines of "these issues have occurred to us, and went into the planning of the human subjects trials". I don't need the details, since common sense would dictate that a negative outcome in an animal study would have precluded work in humans.
I raise these issues here precisely because I would like answers. I've put my money behind this company, and I feel that I have a right to know. This information does not provide competitors with information that they can use against cor, since only cor has actually completed the human subjects trials.
True, and I don't have a hell of a lot invested in that claim. It's my opinion, and my opinion is of little interest.
What matters here is that, because both peripheral and central chemoreceptive networks are opiate-sensitive, the experimental design of this study is flawed. We can get a negative result because of disruption of chemosensory feedback before it even gets to the rhythmogenic networks upregulated by ampakines. If these networks don't get the signal there won't be an arousal response.
Because of the broad spectrum of AMPA receptor-expressing cells, ampakine-induced upregulation may restore the arousal response, thus, we may get a positive result anyway.
They told us about Greer's work. Every presentation that I can recall presented animal data, some of it directly pertinent to upcoming human-subjects trials (primate sleep deprivation work).
Ignore my posts. I'm giving you abstracts, and my thinking on the subject, you can do with it whatever you want.
The takehome here is that the carotid body, the primary sensor of hypercapnea, is sensitive to opiates. The rebreathing protocol will be considerably more likely to give a negative result if the carotid body is not activated by hypercapnea. I'm still plowing through the literature, but find no evidence of AMPAergic modulation of carotid body function, but there is good evidence of ampaergic transmission in the nucleus tractus solitarii, the first synapse in this pathway.
Central chemosensory pathways are also opiate sensitive:
Naloxone application to the ventrolateral medulla enhances the respiratory response to inspired carbon dioxide.
Trouth CO, Bada FJ, Pan Y, Holloway JA, Millis RM, Bernard DG.
Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, D.C. 20059.
Previous studies have shown that systemic administration of the opiate antagonist naloxone potentiates the ventilatory response to inspired carbon dioxide. The present study was designed to localize the site of action of naloxone for increasing the respiratory chemosensitivity to inhaled carbon dioxide (CO2) in cats. Naloxone applied topically to the caudal chemosensitive area on the ventral medullary surface (VMS) during hypercapnic breathing produced a 75% greater increase in minute ventilation than hypercapnic breathing alone. Furthermore, hypercapnic breathing produced a 200% increase in neuronal activity of VMS chemosensitive cells; this was further increased 120% by naloxone. It is concluded that naloxone increases the sensitivity of neurons in the caudal respiratory chemosensitive area of cats to hypercapnia, and that endogenous opiates may act as modulators at VMS chemosensitive sites during hypercapnic breathing.
This is actually good news: central chemosensory pathways are parallel to the carotid body pathway, so even if the carotid body is effectively shut down, this pathway (because its constituents are less homogeneous, and therefore very likely include neurons expressing AMPA receptors) will likely be upregulated by ampakines, perhaps counteracting the effect of opiates.
It should be stressed that hypercapnea is perhaps the strongest stimulus to respiration, so as long as one of these pathways are functional there should be some response.
Again, don't shoot the messenger.
Again, closing the barn door after the horse has left, here's an old abstract that nails down opiate regulation of carotid body chemoreception (the fast pathway mediating response to elevated CO2):
J Appl Physiol. 1981 Dec;51(6):1533-8.
Effects of naloxone on carotid body chemoreception and ventilation in the cat.
Pokorski M, Lahiri S.
The effects of intravenous injection of naloxone (0.4 mg.kg-1), an opiate antagonist, on the responses of carotid body chemoreceptor discharge and ventilation to steady-state levels of hypoxia and hypercapnia were investigated in 12 anesthesized cats. After naloxone, carotid chemoreceptor response to hypoxia (PaO2 60--30 Torr) was enhanced, a finding that suggested that the endogenous enkephalin-like peptide present in the carotid body inhibits carotid chemoreceptors. This reasoning is supported by the observation that close intra-arterial injection of met-enkephalin inhibits carotid chemoreceptors and that the effect is blocked by naloxone. After naloxone, ventilation was stimulated even in the absence of a significant stimulation of carotid chemoreceptors during hyperoxia, indicating that ventilation is normally suppressed by endogenous opiates in the central nervous system, an effect disinhibited by naloxone. Also, the ventilatory effect of the peripheral chemoreceptor input was augmented after naloxone.
Although this experiment looked at response to hypoxia, the carotid body is also the primary mediator of hypercapnea-induced respiratory drive:
The carotid chemoreceptors are a major determinant of ventilatory CO2 sensitivity and of PaCO2 during eupneic breathing.
Forster HV, Martino P, Hodges M, Krause K, Bonis J, Davis S, Pan L.
Medical College of Wisconsin, Physiology, USA. bforster@mcw.edu
Both carotid and intracranial chemoreceptors are critical to a normal ventilatory CO2-H+ chemosensitivity. At low levels of hypercapnia, the carotid contribution is probably greater than the central contribution but, at high levels, the intracranial chemoreceptors are dominant. The carotid chemoreceptors are also critical to maintaining a stable and normal eupneic PaCO2, but lesion-induced attenuation of intracranial CO2-H+ chemosensitivity does not consistently alter eupneic PaCO2. A major unanswered question is why do intracranial chemoreceptors in carotid body denervation (CBD) animals tolerate an acidosis during eupnea which prior to CBD elicits a marked increase in breathing.
The more I think about this, the more I think they just went ahead with the human-subjects trials. I don't think they did the matching study in rodents, because if they had and the result was positive, they certainly would have disseminated the news, and I don't think they are devious or stupid to the point of getting negative results in the rodent, and then going ahead with what would likely be a futile human-subjects trial.
Whether they failed to do the matching rodent trial because they didn't think of it, or because they looked at the cash time-line, and decided that it wasn't doable is irrelevant. We're flying by the seat of our pants here.
I think there is a good chance that we will get positive results, simply because AMPA receptors are so ubiquitous, and as a result, high doses of cx-717 are going to upregulate all circuits, making the patency of a CO2-induced arousal response more likely. Let's just hope that the effective dose doesn't induce seizures, and better yet, doesn't adversely impact analgesia.
The big difference between this trial and the 5-HT agonist that was tested in a matching human-subjects trial is that in the earlier study, they took a "silver bullet" approach, targeting a 5-HT receptor subtype expressed in respiratory rhythm-generating circuits, and not necessarily anywhere else in the pathway mediating the arousal response. By contrast here, by upregulating AMPA receptors, you are increasing synaptic efficacy in a very broad cross-section of neurons. It's more like a bucket of cold water over somebody's head.
>>>Why are you assuming that Varney, Stoll, and Tran are idiots who would not have thought of this as well?
I'm not assuming anything. I'm glad you agree that they'd be idiots if they hadn't done this.
If they had carried out matching studies in rodents though, it's not clear to me why they would have withheld the results of such a study, assuming the results were positive.
I also fully understand why Stoll didn't answer the email.
I am quite nervous about this whole thing. I wrote Stoll asking if any animal studies had been carried out that more closely matched the trial design (i.e., measuring reversal of RD using hypercapnea as an arousal stimulus to a opioid-sedated rodent). He hasn't responded, and I don't expect him to. My fear is that the trial will produce a negative result despite the fact that ampakines are in fact effective against respiratory depression, because I am not convinced that the rebreathing protocol is equivalent to opioid-induced respiratory depression.
Of course, RD would lead to hypercapnea, but it doesn't follow that inducing hypercapnea is equivalent to RD. Ampakines would likely prevent RD in the first place.
I would be reassured if there were some data from rodents that came from a study that matched the one being carried out in humans. This should have been done in advance of the human subjects trials. If it wasn't I'd consider it a pretty serious error in management. They don't have any margin of error, and it would have been preferable to develop a protocol that works in rodents, even at the cost of delaying the human subjects trials.
I agree with your point that cx-717 will not obliterate analgesia the way that naloxone does. I am also not questioning the efficacy of cx-717 in restoring breathing following opioid-induced RD.
Rather, my point is that Greer's data may not be all that relevant to the human subject trials here. He depressed breathing by administering opioids at doses that are unacceptably high for human studies, so the clinical trial uses an arousal response to elevated CO2 as a surrogate, since this response is depressed at lower dosages of opioids. The arousal response elicited by elevated CO2 involves both respiratory rhythmogenic networks and (peripheral and central) chemosensory pathways, thus it is possible that a reduced arousal response might just as well be due to opioid's effects on the sensory pathway as on the rhythmogenic network. This may be the best possible human subjects trial possible given safety issues, but I think it is a pretty crummy experiment.
My concern is that it could fail for stupid reasons, and if it works, my hunch is that it works not so much by targeting rhythmogenic networks, than by targeting chemosensory pathways. Transmission along these pathways would be restored via the mechanism described in the last post (i.e. upregulation of tonic/phasic glutamatergic drive on opioid-depressed chemosensory neurons).
Because this is a less than ideal experiment, any efficacy at any dosage, regardless of analgesia should motivate BP to partner.
A caveat to all this: I don't know that chemosensory neurons are opioid-sensitive. If they aren't then all this is useless worry.
I'm not suggesting that the ampakine interact with the opioid receptor, rather that the cell depressed by opioids likely also has AMPAergic glutamate receptors, and is receiving tonic/phasic drive from other neurons. So long as this glutamatergic drive is facilitated, the opioid-induced depression will be reduced.
Aiming (gfp)
Insofar as the loss of an arousal response is due to disruption of sensory drive to rhythmogenic networks (my working pessimistic assumption), my thinking is that the threshold for chemosensory transmission upregulation is higher than the threshold for rhythmogenic network rescue, at a dosage level where cx-717 is likely to have non-specific upregulatory effects on any pathway mediated by glutamatergic transmission. If this notion of nonspecific effects is correct, then pain pathways may also be upregulated.
I'm in part playing devil's advocate, and would be delighted to be told that I'm wrong.
I've written Stoll for clarification on this issue. We'll see if he responds.
My jitters were laid out in a post to GFP. Neuro thinks that cor did a rodent study in-house that accurately matched the human study design. If they did that, great, although (in the event of positive data)it's not clear why they kept it confidential.
I'm not sure that there will be a run-up prior to the announcement. At the trading levels seen here, it would be difficult to unload a substantial number of shares without cratering sp.
Here's a prediction: the cx-717 dosages sufficient to rescue the arousal response will also impact analgesia. The dosages necessary to rescue respiratory rhythmogenesis will be lower.
GFP thanks for the link. Your points are all well-taken, but while the difference in compound may have been the problem in Richter's study, it's also possible that a false ocmparison is being made here.
In the rodent model, an opioid dose sufficient to depress respiratory frequency is given. In the human trials, the effect of opioids is to depress an arousal response. This could be because of the opioid's effect on respiratory rhythm-generating networks, or via depression of chemosensory feedback. If the latter is the case, then for Richter, the study was a false negative: the respiratory rhythm generating networks were being rescued by the 5-ht agonist, but the chemosensory drive wasn't reaching the respiratory rhythm generating networks.
I mention all this because it would have been straight-forward to do high CO2 (hypercapnea) manipulations in the in vivo rodent under opiates with and without cx-717. If this were done, the human study could have been conducted with a better understanding of what effective dosages might be, or even if there was any reason to expect that the study would work.
Ready, fire, aim.
Based on the trading volume we've been seeing, it's not clear to me that you'll see an opportunity to sell at those prices before the RD trial outcome is disclosed. Afterwards, in the event of a positive outcome, $1.20 may be low; in the event of a negative outcome, it'll likely be in the .30s
I want to go back and look at the original Richter animal trials that motivated the failed human subjects trials that matched the ones used here with cx-717. If his data were as good as Greer's, we may be in trouble. The more I think about the trial design, the less happy I am about this whole thing. My best hope is that the 5-HT agonist Richter used was more of a "silver bullet" approach, specifically targeting rhythmogenic networks. Here what is being tested is the efficacy of chemosensory feedback in eliciting an arousal response.
The slim advantage that cor may have is that cx-717 is a generic upregulator, as likely to rescue chemosensory transmission as respiratory rhythmogenesis. The flip-side to this is that at dosages effective in rescuing chemosensation, you may also have loss of analgesia. I'll take that, because what we're really trying to do here is get a positive outcome in a trial that only tangentially tests efficacy for the condition supposedly under study.
All this ruminating is too late anyway. At the volumes being traded here, I'd be lucky to be able to unload 20K shares prior to release of the results.
We're in God-protects-idiots territory here. I wish I had more faith in wishful thinking.