RespireRx Pharmaceuticals Inc (CE) (RSPI) 銘柄情報

There appears to be only one group currently investigating CX-929. The latest paper, which I had just posted, will be officially published Dec 15: Lorenzo Morè et al. Neuropharmacology Volume 261, 15 December 2024, 110110. RSPI has noticed and applied for a patent (posted below). In my view of the more than 2000 ampakines that Cortex/RespireRX have manufactured, CX-929 shows greatest potential of being a multibillion dollar molecule,,, but we will see.

I have a question. We can't find newer info on Cx929. I posted something regarding cx929 and it's need for MSK1. And a mention of BDNF I believe and their relationship. 
With Cx614 it seems that it may be a  better way due to the BDNF MSK1 relationship, thus no mention of Cx929 since 2020.I hope you understand what I mean or where I'm coming from.

Oncolytic Properties of Ampakines In Vitro

D Radin,R Purcell, A Lippa

Anticancer Research DOI: 10.21873/anticancres.12217

Abstract. Background/Aim: The 5-year survival rate of glioblastoma (GBM) is ~10%, demonstrating that a new therapeutic modality for this cancer is desperately needed. Complicating the search for such a modality is that most large molecules cannot pass through the blood brain barrier, so molecules demonstrating efficacy in vitro may not be useful in vivo because they never reach the brain. Recently, the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) was identified as an effective agent in targeting GBM in vitro and in vivo by agonizing AMPA-glutamate receptors (AMPARs), eliciting massive calcium influx and mitochondrial calcium overload and apoptosis. Materials and Methods: In the current study, we used a colorimetric cell viability assay to determine if we could enhance the oncolytic effect of FLX in vitro by pre treating cells with an AMPAR-positive allosteric modulator (Ampakine). Results: Our results demonstrated for the first time that concentrations of the Class I ampakine CX614, which increase AMPAR agonist binding affinity, possess oncolytic activity as a sole agent and synergistically reduce GBM viability when paired with FLX. FLX also demonstrates a dose dependent induction of apoptosis in cancer cells originating outside the CNS that overexpress calcium-permeable AMPARs. Likewise, CX614 inhibits cancer cell viability in a dose dependent fashion and its combination with FLX synergistically reduces cell viability. These effects of CX614 were not seen with the Class II ampakines, CX717 and CX1739. Conclusion: CX614 inhibits the growth of multiple cancers in vitro and bolsters the oncolytic activity of FLX in several cancers.

The holidays tend to be a great time of year for reflection.

The past, present and future that has led one to this point. It is curious that just recently the idea of finding accredited investors to finalize filing status and leave this EM "trading" market has been floated around. If truly this smallish level of funding and staying on the OTC pink market was important logically this would have been floated well in advance of monies for filings due. 9-10 months ago. And surely utilizing additional communications and updated presentation on their websites would have been an easier and cheap method to attract smallish funding. And most assuredly parlaying success with DOD funding a phase 2 clinical and the NIH highly regarding another candidate in preclinicals leading to clinical funding would have been company making awareness points...

If indeed the company is going to re-engage stakeholders lets hope it is done under the auspices of looking towards the future and leaving the ghosts of the past and present behind. These assets, their potential and all the efforts by individuals leading them to this point of clinicals deserve this. The patients who may benefit from these efforts deserve this chance. 2025 may be an exciting year here with the government funding multiple clinical trials and an OSA program that will only get more valuable as competitors and the industry advance on achiving the CPAP and developing therapeutic treatments. Enjoy the holiday season and wishing all investors here good luck in the new year.

https://synapse.patsnap.com/drug/8352d5be6aed4348805cfb3f7484d899

I'm a bit redundant - I believe CX-929 is RSPI's crown jewel in that not only does it appear to be effective (see my posts below), but it can be administered orally, A short half-life in vivo allows for controlled administration.

CX-929 - Drug Targets, Indications, Patents

CX-929: a AMPA receptor modulators Drug, Initially developed by RespireRx Pharmaceuticals, Inc., Now, its global highest R&D status is Pending

Yeah, I presume that anytime in Q1 2025 they may get news about beginning of the phase 2 SCI trial AND/OR news that NIH will grant funding for epilepsy trial. And OSA could get traction too.

The fact that they have not positioned the company to be liquid for increasing the shareholder base and valuation of the company which would provide tons of resource flexibility. This is very suggestive of no concern to have the resources to continue to push forward. Coupled with insider equity related ownership…. Well there might just be Aces in their back pocket.

Somebody in the Great white north or who can buy on the EM could drive this up at anytime. My understanding of the trading on EM if two matching bid and ask is there it sells, could be wrong but if true someone could put a 100 shares up for .10 and someone could match it and we would be looking good. That would be a nice sight.

Hopefully RSPI gets a great XMAS present in the form of investor funding or a play by BP. Just a matter of time now .

Hopefully the news letter he will put out isnt a rehash of already known info , but is all new and with a direction and a plan in place. GLTA

RSPI's Margolis was unaware of CX929? I don't believe it.
 
MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF

Lorenzo Morè , Lucia Privitera , Marcia Lopes , J. Simon C. Arthur , Julie C. Lauterborn , Sonia A.L. Corrêa f, Bruno G. Frenguelli

Neuropharmacology Volume 261, 15 December 2024, 110110
https://doi.org/10.1016/j.neuropharm.2024.110110
Abstract
There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. However, what transduces the elevation of BDNF into long-lasting cognitive enhancement is not known. We have previously shown that MSK1, by virtue of its ability to regulate gene transcription, converts the elevation of BDNF associated with environmental enrichment into molecular, synaptic, cognitive and genomic adaptations that underlie enrichment-induced enhanced synaptic plasticity and learning and memory, a property that MSK1 retains across the lifespan. To establish whether MSK1 similarly converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies

MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF

Lorenzo Morè , Lucia Privitera , Marcia Lopes , J. Simon C. Arthur , Julie C. Lauterborn , Sonia A.L. Corrêa f, Bruno G. Frenguelli

NeuropharmacologyVolume 261, 15 December 2024, 110110
https://doi.org/10.1016/j.neuropharm.2024.110110
Abstract
There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. However, what transduces the elevation of BDNF into long-lasting cognitive enhancement is not known. We have previously shown that MSK1, by virtue of its ability to regulate gene transcription, converts the elevation of BDNF associated with environmental enrichment into molecular, synaptic, cognitive and genomic adaptations that underlie enrichment-induced enhanced synaptic plasticity and learning and memory, a property that MSK1 retains across the lifespan. To establish whether MSK1 similarly converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies

AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain

Fei Zeng, Qiaosheng Zhang, Yaling Liu, Guanghao Sun, Anna Li, Robert S. Talay & Jing Wang

Molecular Brain volume 14, Article number: 45 (2021) Cite this article

Abstract
The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.
CX546 (Tocris Bioscience, USA) was first suspended in dimethyl sulfoxide (DMSO) and then subsequently re-suspended in 0.9% saline (Hospira, USA) to a final concentration of 800 µM [39] for intra-NAc core infusions in naïve-, CFA-, SNI-treated rats. For intra-NAc core infusions, 0.5 µL of CX546 was locally infused to each side of the brain, while same volumes of 0.9% saline were applied in the control group. Rats were given at least 7 days to recover from cannula implantation before intracranial administrations and behavioral tests. All intra-NAc core infusions were performed 7 days after CFA (S.C.) injection or 14 days after SNI surgery. After the infusions, rats were given up to 15 min to rest before starting Hargreaves test, mechanical allodynia, cold allodynia, and two-chamber conditioned place preference assay (CPP).

Curious what happens to the shareprice while on EM as they begin to announce filings with SEC over 2 months?

Many here believe this would be sustaining multi-penny now if they were current with pipeline they have and clinical trials/events forthcoming. It seems like on EM with events forthcoming, that "experts" could consolidate share structure higher and higher and emerge as something institutional can control and take to next level absorbing any loose retail shares along the way...

They have to emerge sooner than later. Material events such as SCI phase 2 starting, NIH grant funding, OSA activities can really come anyday now and on top of that BP or other competitive financiers could make formal offers for some funding or acquisition of assets, etc.

Curious what they used the BOD member funds of $100k for when the 10-k was due....

Thanks for your input to us in-the-dark shareholders..

All this confirms is that the company is not looking for a simple convertible type note to get back off the EM. And really getting off the EM is surprisingly not a huge concern for them nor is valuing their assets properly currently. So now why would they take this position?

Some suggest fear of hostile takeover. I dont buy that one as there are plenty of things they could do to prevent that.

I think more logically. The assets are CLEARLY at a point where they need a huge infusion of support capital and not simply $150k. They have indicated as such in filings for years now. My guess is they have BP/Pharma Financiers at the table. It is illogical to think they don't. DOD funded phase 2, NIH likely funding phase 1 for epilepsy, OSA superior formulation... This is absolutely HUGE success and patent positioning on 3 platforms/paths!!!. Either BP or a pharma investing group is going to enter and make this a mid major pharma. It all fits. I am going to speculate 2025 will be transformative here.

Good luck to all and enjoy the holidays!

Happy Thanksgiving.

Pharmas have explosive potential especially one on the cusp and heading into clinicals. Next few years might be something special for this pipeline!

Here is what I got today from the investor group I posted awhile back and my reply . The reply he sent contains basically same info I posted awhile back that Jeff had talked about.
Hi XXXX,
Trust all is well.
I caught up with the company last week to press them on their SEC filings. Please find their response below
“With respect to getting current with our SEC filings, we would require approximately $150,000 and it would take approximately two month (subject to staff availability at our auditors) to catch up on the 31 Dec 2023 annual report and three quarterly reports. The $150K would be sufficient for us to complete timely (possibly on extension), the 31 Dec 2024 annual report.”
The company is cash-strapped, hence why it’s taking time to get their filings up to date. Would this be something you could potentially support if there was a meaningful equity component as an incentive?

Please let me know your thoughts.
Best Regards,
XXXX

Thanks I have been in talks with Jeff , I knew of the need for cash.

What I and other investors have concerns is with all the grants they have and positive results that they have released why no big invetsor or Big Pharm hasnt stepped in. The share structure that he was talking about to me just isnt enough to take more of a risk along with no gurantee they would come off EM and not return to it mid year. They could have gone a different direction than the EM , instead they went there, now they have no real way of trading to raise money. Many of us would have rather them have diluted a small amount of shares and stay on the OTC so it could have traded and build up the share price not collapse it on the EM. If we took the class shares he was talking about we would be stuck with shares that we would not be able to sell easily. I already have 15M shares at an average of .00098 and I am holding but to put in a 10k - 25k additional investment is not on my table.

Thanks for your response and have a great holiday season

It appears I that I am likely the only scientist contributing to this board. My failing is that I really don’t have much of a grasp of the nuances of the stock market. That said, here is what I believe will happen (best case scenario):
We all agree that RSPI has an extraordinary pipeline which appears unmatched by any publicly traded or private biotech. As a scientist I have been repeatedly blown away by many of the peer-reviewed published papers. I sure don’t understand much of the technology, but I understand the conclusions of these papers. My overall impression is that RSPI is on the cusp of an explosion in addressing many neurological issues. Also some ampakines have even been shown effective in preclinical trials for some forms of cancer, not only neurological.
RSPI’s silence has been intriguing. From my standpoint it appears that when they emerge from EM, it will be explosive! I just cannot believe that mega pharma has not been paying attention. Is it possible that the RSPI silence is due to multiple mega offers by mega pharma and RSPI is sorting them out?
If there isn’t some sort of exclusion of us shareholders, we WILL profit. I recall the “irrational exuberance” of the tech boom years ago of which I profited (and then got destroyed by Cortex). Could “irrational exuberance” happen with RSPI? Since that latest estimate that insiders hold (~ 50%) such a boom when RSPI can be publicly traded could fuel clinical trials.
I keep on thinking, “Gadzooks!!! Is it really possible we will see $1/share… $2… $3?” Now, wouldn’t that be mind-blowing?

Yeah nothing we can do but wait it out. Hopefully the year end shareholder letter has some juice in it to relive the excitement that was brewing in here before the drop off

Happy Thanksgiving to Everyone! Hoping for a better year ahead with RSPI!

Ah, there is too much at stake for reindeer games. It’s time for this to move forward unencumbered and see what these assets can become.

Lol good luck trying to get a conviction of them. I'm still bullish here but generally speaking 99.9 percent of time if a company goes off market they are not responsible for the loses share holders encur. Especially if they stated they have low finances like they have and gave us a update of going off market before it happened along with a disclaimer saying rentering depends on variety of uncontrollable variables. 

Nope we don't.

Only thing we know is they have had excuses for not filing and choosing the EM trading status this stock currently resides in. Which my opinion helps nobody.

We know they have a phase 2 for SCI funded, starting when?
We know they hired consultants to handle grant funding for the gabakine for epilepsy, that is probably a Q1 NIH determination and then who knows when they would begin phase 1 trials.
We know they have had the OSA program set-up in Australia for awhile and have been silent for a year now about it.

Outside of those items, there is shockingly no other updated communication or presentation of the company. As you put it, in self imposed hibernation.

LT - Do we really know what the current status is, other than RSPI has a helluva potential?

That is the thing. In the filings, the CEO and BOD member and other insiders have provided cash/loans to the company with warrants and preferred shares in return that is all tied to the success of the company.

The current status doesn't help any stakeholder nor the assets to advance smoothly.

If the CEO is not getting stock out of EM, it is a legal issue that is open for lawsuits. CEO is responsible for the financial value of a stock which ultimately affects shareholders

Yeah, the last 6 months feels like they have been beholden to something. Waiting.

The pipeline appears so close to breaking out and getting the ball rolling on multiple clinical fronts. This can be exciting for all stakeholders including those patients who may benefit from solutions to their unmet needs.

Yes sooner would be great but that's the best answere he's giving at this point

Never has to be EOY. IMO, all stakeholders, shareholders, collaborators and potential resources, etc should be given a decent understanding of the status and strategies for developing the assets based upon stakeholder funds and time equity.

Part of a duty of executives working for a public company is to engage all stakeholders and keep updated and information refreshed as time and milestones are eclipsed.

Hopefully this aberration of time will be a distant memory soon and focus on progress and potential can be forefront.

It's called an EOY Shareholder letter for a reason, they just need to follow thru.

Who knows when that will be. There was no timeline given.  Oh well.  Just get current so I can have more! 

University of Florida
College of Public Health & Health Professions

Spotlight on spinal cord injury research
September 25, 2024
“We are investigating the concept that modest exposure to intermittent periods of low oxygen, or acute intermittent hypoxia, elicits forms of neuroplasticity in the motor nerve cells that drive diaphragm contractions and breathing,” Mitchell said. “In close collaboration with other BREATHE investigators, we explore how these acute intermittent hypoxia protocols combine with traditional rehabilitation, the impact of combining intermittent hypoxia with a class of drugs known as the ampakines, and the impact of delivery with sub-acute versus chronic spinal cord injury. Our findings inspire the next clinical trials in humans living with chronic spinal cord injury.”

I am optimistic. I think many share the same sentiment here. It is a head scratcher for sure, but regardless of the complaints about communication and presentation and whatever you want to call this trading exchange, etc which I think all is very fair criticism investors should have. The science approach has been very smart in how they have developed the assets on not much funding and to get several of them in position for clinicals going in with superior profiles to current standards of care. No success is guaranteed but odds are greatly improved.

Be a great way to start the new year!

That would be wonderful news and hopefully set the stage for a prosperous 2025 for all.

DOD funding an SCI phase 2 that will possibly lead into ADHD clinicals
KRM-ll-81 with a superior preclinical profile as a strong candidate for NIH funded clinicals for epilepsy and pain
OSA new formulation of dronabinol with a logical approach and likely superior performance potential progressing to pk/later stage clinicals

Each platform individually is potentially company making. All 3 under one umbrella is really quite amazing and more reflective of pipelines of NASDAQ pharmas.

These assets truly have the potential to be transformative to the respective medical indications and unmet needs of patients. IMO, it is long past time that someone gives this girl a chance and takes her to the ball and watch her shine.

Yea let's see if he follows thru.

Thats good a shareholder Letter


I been asking bout a year end Shareholder letter and this is Jeff's response....How bout a year end shareholders letter to keep hope alive?

Show quoted text

We are planning to issue a letter to shareholders and other stakeholders.

As long as RSPI is in hibernation (i.e., EM) mode it will not happen. As soon as they emerge, hopefully January, will we see daylight at the end of the tunnel (I love mixing metaphors). Contrary to all you guys, I still believe CX929, by virtue of effect and oral administration, will be an additional jewel (if there isn't a patent issue).

I been asking bout a year end Shareholder letter and this is Jeff's response....How bout a year end shareholders letter to keep hope alive?

Show quoted text

We are planning to issue a letter to shareholders and other stakeholders.

 

Interesting...

Communication and Presentation should never be overlooked as it is critical to supporting and establishing a resource structure for success.

Whenever the powers at be choose to re-engage all stakeholders, I hope there is a plan to address the shortcomings.

Ah yes, the alure of pharmaceutical investing...

RSPI can be much much more explosive as it is "trading" on this "expert" market as a penny stock and has not even established a baseline valuation for these assets, whereas that example you provide of PSTX being acquired by Roche, PSTX was already established on Nasdaq where institutional and support investors were maintaining a roughly 200 million valuation on their assets before todays announcement of 1-1.5 billion acquisition pending milestone payments.

Another example of why the shares are held very tightly here as the potential in 3 different platforms is massive and undiscovered by deep pockets, yet.... or maybe the explanation is that it has been discovered...

Makes the current situation all the more ridiculous. Today's "expert market" valuation for the entirety of RSPI's assets is under 1 million dollars. SMH and LOL....

Interesting about PSTX:

Halper Sadeh LLC, an investor rights law firm, is investigating whether the sale of Poseida Therapeutics, Inc. (NASDAQ: PSTX) to Roche Holdings, Inc. for $9.00 per share in cash, plus a non-tradeable contingent value right to receive certain contingent payments of up to an aggregate of $4.00 per share in cash upon achievement of specific milestones, is fair to Poseida shareholders.
The investigation concerns whether Poseida and its board of directors violated the federal securities laws and/or breached their fiduciary duties to shareholders by failing to, among other things: (1) obtain the best possible consideration for Poseida shareholders; (2) determine whether Roche is underpaying for Poseida; and (3) disclose all material information necessary for Poseida shareholders to adequately assess and value the merger consideration.

Someday ...

we will have a day like today in PSTX. Keep the dream alive!

Yes but is it necessary for low impact ampakines that do not have toxicity issues and already have been in human trials?

It is a requirement for the OSA program to deliver a more soluble formulation for consistency and ability to extend the release for duration of effect.

This has not been reported on explicitly, but throughout the literature on ampakines the molecule delivery, targeting, etc has been a recurring, and pervasive problem. I commented on this before here, it’s a rather technical detail, a bit esoteric, but it’s a key factor in getting positive allosteric modulators to tweak a ubiquitous transmembrane receptor/ion channel like the AMPAr’s. Because they are the single most numerous neurotransmitter receptors in neurons, binding glutamate, the number one signaling molecule in essentially all known nervous systems, be it lab animals or people.

Such that seeking ways to calibrate action on AMPAr’s is an OBVIOUS lead into getting a whole zoo of forgotten candidate molecules to become relevant again. AND develop therapeutics on a trigger-happy switch in brains whereas most naturally occuring ligands tend to be violent, lethal poisons. This is Arnold Lippa’s gambit, he’s been grinding this all along.

Do the low impact ampakines need lipid nano particles to achieve end points with minimal side effects?

Maybe archived high impact ampakines could be revived with improved delivery system to reduce side effects ?

The nano particles are needed for solubility and extended release for dronabinol, I am not sure that would be requirement with the ampakines.

The whole point of the lipid nanoparticles is to support the ampakine program, and resolve their constitutive problem with delivery and targeting. Dronabinol is just a means to that end.

I suppose maybe if delivery systems were improved, like with lipid nanoparticles, past impediments of molecules as such could be overcome.

My opinion though is that RSPI has already advanced 3 platforms/candidates to clinical stage and all 3 could be billion dollar treatments in the end... There isnt much room in the fire pit for any more irons...

No No No.... Specific brain target area for CX929. Thanks for a good laugh

A patent for an anatomical location in the brain would be something so obscene and scary it hurts my brain to think about it.

Well... I wonder about that. There is the patent for the molecule, which apparently has expired. How about a patent for the target part of the brain, which until recently hadn't been discovered? Or application? CX929 can be administered orally. For the preclinical trials (rats), it was with 10% honey in drinking water (a thesis posted here a while ago). Even though CX929 is a high impact molecule, oral administration and effect appears to make it a viable molecule for clinical trials. Does the oral administration of CX929 make that process patentable? If the effect of CX929 in rats is also in humans, that seem to me to make it a billion-dollar molecule.