Replies to post #427 on RespireRx Pharmaceuticals Inc (RSPI)

[gfp927z]

Aiming, OT - Just in case you had any interest in Durect (the company providing the technology for Remoxy, and one of my recent stock picks for the long term), I found this article outlining some serious problems with the J+J Fentanyl patch (patients overdosing by placing too many patches too often). One of Durect's partnered programs is with Endo Pharma, for a smaller, longer acting Fentanyl patch (1/5 the size and lasting 7 days vrs 3 days). Of Durects's various programs, this is the 2nd most important to them (Remoxy is 3rd), so fallout from J+J's patch could possibly adversely affect Durect. I had a small position in Durect, but sold recently for other reasons (I figure it might continue consolidating lower after its big recent up move). Anyway, trouble with the J+J patch might also spell trouble for the Endo/Durect patch (the Durect version might present even more potential for misuse since it's smaller and more potent), so be extra wary if you're considering Durect. (That said, it'll probably double next week, since I sold my shares :o)



A Painkiller's Deadly Results


(Nov. 25) - There are new questions about whether the FDA has been too slow to take action on a pain-killing drug linked to more than 100 deaths and serious side effects.

CBS News correspondent Jerry Bowen reports the drug is Fentanyl, a powerful narcotic prescribed to millions of Americans.

It's the most popular pain patch on the market with four million prescriptions for Johnson & Johnson's Duragesic filled at pharmacies last year.

A patch that delivers Fentanyl – a narcotic many times more powerful than morphine to people suffering with chronic pain.

But the Los Angeles County Coroners Office reports a growing number of accidental over-doses by patients misusing the patch: 127 deaths over the last six years.

"They're not getting the relief that they want. Therefore they're slapping more patches on trying to get that instantaneous relief," says toxicologist Daniel Anderson. "What they don't realize is that most of these patches are to be applied over a three-day period."

Despite alerts from the L.A. County coroners lab as early as 2000, the FDA issued a health advisory just last July warning: "The directions for using the Fentanyl skin patch must be followed exactly to prevent death or other serious side effects from overdosing with Fentanyl."



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A Painkiller's Deadly Results
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It's a serious concern in Florida too where 115 deaths from Fentanyl poisoning were reported last year – most involving the patch.

Physicians say the problem is not the patch – but the patient – ignoring or not heeding warnings:

"When the physician first prescribes the patch to say, 'This isn't like candy, this isn't like one aspirin isn't working, I think I'll take a second one.' This is really potent medicine," says Dr. Lonnie Zeltzer, a pain management specialist

The patch underscores a broader issue regarding drug safety – the fact that neither the FDA nor the drug companies have a thorough system for monitoring the effects of a new medicine after it comes to market.

In this case, it's a deadly effect for patients who take far too much of a good thing in a desperate effort to ease their pain.



Copyright 2005, CBS Broadcasting Inc. All Rights Reserved.

[gfp927z]

Aiming, Concerning the calpain topic, one of my deepest fears would be that the 4 month delay in the 3 month animal tox studies might be due to toxic effects related to this calpain/spectrin phenomenon. However, a few weeks ago Neuro posted that he talked to Cortex, and it sounded like there wasn't anything to worry about - they apparently contracted out the 3 month animal tox studies, and the lab doing them has been slow, resulting in the delay.

The calpain phenomenon is a lingering gray area however, since there isn't much info available, and none of us Yahooers are really qualified to fully understand what info is available. In addition to being associated with the protein breakdown occuring after neurological trauma/damage/stress (as in stroke for example), calpain/spectrin elevation is also associated with Long Term Potentiation (LTP), which is the basis of normal memory formation - the process stimulated by Ampakines (as pointed out in Neuro's post and in the Lynch abstract). So the increase in calpain/spectrin activity from long term AMPA upregulation might not have anything to do with neural damage, but may merely be associated with the protein transformation / rebuilding which occurs during LTP.

The plot thickens however. The publication of the first calpain related paper last year created a stir on the Yahoo thread, prompting Neuro to contact Dr. Lynch and then post what he had learned (post 17204). Also, a YH poster (post 18096) said that he had asked Dr. Rogers about the calpain subject at the SHM, and apparently the author of that first paper had published it without first getting Dr. Lynch's OK, and Lynch and the author had a falling out as a result. Looking at the abstracts, Dr. Lynch seems to stress that elevation of calpain/spectrin is associated with normal LTP processes, while the other paper doesn't.

Anyway, things get even murkier, since we don't know definitively if the increase in calpain/spectrin activity is related to high or low impacts. The one calpian study uses CX-614 (a higher impact), but the abstract of the other study (Dr. Lynch's) indicates only that certain Ampakines increase calpain/spectrin activity, without specifying if they are high or low impact. Neuro's post after contacting Dr. Lynch indicates that the low impact CX-717 hadn't shown the deleterious effects one would expect from excessive calpian production. So the high impact CX-614 does significantly elevate calpain, while the low impact CX-717 doesn't.

Another abstract I found on glutamate toxicity / glutamate mediated cell death (implicated in many neurodegenerative diseases/injuries) outlines the process by which excess glutamte induces excitotoxicity, elevates calpain, thereby causing neuronal damage/apoptosis. We know that the high impact compounds developed so far generate varying degrees of excitotoxicity (calcium imbalance at the synapse), similar to the damaging glutamate toxicity seen after stroke. It's probably safe to say that a high impact compound that strongly induces excitotoxicity would very likely also induce calpain mediated neuronal damage eventually. The big question is whether this process might also occur after months/years of low impact dosing. Of course there hasn't been enough long term human data generated yet to answer this question. There has been some longer term dosing done in animals though, which may provide a clue. This would be a great question for the SHM.