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        New Message Board Archives >> Medications, Treatments, Therapies 2005 >> fresh research - more on CGRP inhibitors. 
        
(Message started by: floridian on May 5^th, 2005, 8:08pm)

Title: fresh research - more on CGRP inhibitors.
Post by floridian on May 5^th, 2005, 8:08pm

More progress on the CGRP inhibitor known as BIBN4096BS. 66% effective as an abortive when given orally (better than oral sumatriptan) , and it seems to also act as a preventive. Side effects seem to be minor at this point.

Quote:

CNS Drug Rev. 2005 Spring;11(1):69-76.

Clinical Data on the CGRP Antagonist BIBN4096BS for Treatment of Migraine Attacks.

Edvinsson L. Department of Internal Medicine, University Hospital, S-221 85 Lund, Sweden. lars.edvinsson@med.lu.se.

Basal studies have shown that calcitonin gene-related peptide (CGRP) is a major sensory neuronal messenger in the trigeminovascular system, the pathway conveying intracranial pain. In migraine and cluster headache attacks, CGRP is released in parallel with the pain and successful treatment of the attacks abort both the associated pain and the CGRP release. The search for a potent small molecule CGRP antagonist has been successful and such an agent has been tested in preclinical and clinical studies. The aim of the present study was to examine current knowledge on the clinical pharmacology of systemic BIBN4096BS, which has been shown in man to abort acute migraine attacks as well or better than oral sumatriptan. BIBN4096BS is a specific and potent CGRP receptor antagonist in humans. In safety and tolerability studies the substance is well tolerated with no or only mild side effects. In acute migraine attacks the overall response was 66% with the drug and 27% with placebo. A difference as compared to placebo was seen at 30 min; the response was still rising at 4 h suggesting a long duration of action. At 24 h the pain-free rate was better than that with triptans, suggesting a lower grade of rebound and perhaps even a prophylactic possibility.

More on CGRP at med-owl.com:
http://www.med-owl.com/clusterheadaches/tiki-index.php?page=CGRP

Title: Re: fresh research - more on CGRP inhibitors.
Post by Lizzie2 on May 5^th, 2005, 8:24pm

YAYyyyyyyyyy...

Now would they hurry up and get them into a Phase I trial over here? I'll sign up! Just tell me how!!!

Lizzie

Title: Re: fresh research - more on CGRP inhibitors.
Post by TxBasslady on May 6^th, 2005, 1:11am

Floridian...

You amaze me !!!

I hope you know...how much we appreciate you.

You're a walkin' medical book! 8)

I wish I had just 1/2 the patience you have...and twice the knowledge! :-*

Much love to you, sweetie!

Jean

Title: Re: fresh research - more on CGRP inhibitors.
Post by Giovanni on May 6^th, 2005, 9:36am

That Floridian is our resident guru!!! ;;D

What herb in particular can one purchase to try this out?

Pill or liquid form?

John

Title: Re: fresh research - more on CGRP inhibitors.
Post by Bob P on May 6^th, 2005, 9:39am

And there you have it. Fungi in a pill. Hope they move quickly in research and development.

Here's a little ditty on CGRP:

http://www.pahlow.net/temp/CGRP.mht

Interesting that CGRP release is mediated by calcium levels - verapamil?

Title: Re: fresh research - more on CGRP inhibitors.
Post by ozzy on May 6^th, 2005, 1:33pm

Bob,

might want to change the extension from "mht" to "htm"

Otherwise it's just raw html

Ozzy

Title: Re: fresh research - more on CGRP inhibitors.
Post by Flash on May 6^th, 2005, 1:33pm

It would not surprise me to learn that hallucinogenic drugs such as psilocybin, LSD, and LSA are potent CGRP inhibitors.

Title: Re: fresh research - more on CGRP inhibitors.
Post by Bob P on May 6^th, 2005, 1:42pm

Hmmmmm. Interesting Ozzy. I saved the file as a web page archive (.mht) when I stole it from the web site. That way all the images are contained in the file.

I changed the extension to .htm and uploaded it. http://www.pahlow.net/temp/CGRP.htm It comes up but none of the graphics are there, naturally. Hopefully you can get the jist of the text of the article though.

Funny because the .mth page comes up just fine in my browser.

Title: Re: fresh research - more on CGRP inhibitors.
Post by ozzy on May 6^th, 2005, 2:01pm

After further research, it seems it's one of those Micro$oft proprietary file format.

My Firefox browser can't see it. When I save a page, it saves it in native html format.

Ozzy

Title: Re: fresh research - more on CGRP inhibitors.
Post by Bob P on May 6^th, 2005, 2:08pm

Opened it with Firefox and see what you mean. Never knew that before.

Title: Re: fresh research - more on CGRP inhibitors.
Post by floridian on May 6^th, 2005, 6:59pm

on 05/06/05 at 13:33:18, Flash wrote:

It would not surprise me to learn that hallucinogenic drugs such as psilocybin, LSD, and LSA are potent CGRP inhibitors.

Looks like you are right, Flash. This says that the CGRP and 5-ht2a genes tend to be expressed in the same cells, and that inflammation that leads to increased CGRP also increases 5-ht2a gene expression/receptors. All of which is consistent with the idea that a potent 5-ht2a mimic (clusterbuster) leads to tolerance and long term reduction of the very receptors it initially stimulates.

Quote:

Pain. 2002 Sep;99(1-2):133-43.

5-HT2A receptor subtype in the peripheral branch of sensory fibers is involved in the potentiation of inflammatory pain in rats.

Okamoto K, Imbe H, Morikawa Y, Itoh M, Sekimoto M, Nemoto K, Senba E.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City 641-8509, Japan.

One of the major serotonin (5-HT) receptor subtypes expressed in the rat dorsal root ganglion (DRG) neurons is the 5-HT2A receptor. We have previously shown that 5-HT2A receptors in the peripheral sensory terminals are responsible for 5-HT-induced pain and hyperalgesia. In the present study, we characterized neurons expressing 5-HT2A receptors in the rat DRG neurons by means of in situ hybridization, immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and behavioral tests. In situ hybridization on consecutive sections revealed that 5-HT2A receptor mRNA is colocalized with calcitonin-gene related peptide (CGRP) mRNA (100/104; 96.2%) but not with c-Ret mRNA (1/115; 0.9%). Signals for 5-HT2A receptor mRNA were found in 9.4 +/- 2.2% of normal DRG (L5) neurons, most of which were small to medium in size. Four days of complete Freund's adjuvant-induced inflammation of the hindpaw doubled the incidence of 5-HT2A receptor mRNA-expressing neurons to 19.3 +/- 2.8%. The level of 5-HT2A receptor mRNA in DRGs of normal and various pathological conditions was then determined by RT-PCR. The level was up-regulated by peripheral inflammation, but not by axotomy or chronic constriction of the peripheral nerve. Systemic administration of 5-HT2A receptor antagonist (Sarpogrelate HCI) produced analgesic effects on thermal hyperalgesia caused by peripheral inflammation, but failed to attenuate thermal hyperalgesia in chronic constriction injury model. These findings suggest that 5-HT2A receptors are mainly expressed in CGRP-synthesizing small DRG neurons and may be involved in the potentiation of inflammatory pain in the periphery.

Title: Re: fresh research - more on CGRP inhibitors.
Post by JJA on May 6^th, 2005, 8:44pm

Wow,
Nice find.

So cells with down-regulated 5-ht2a receptors would be less active (or inactive) and therefore release less CGRP? Now there's a hypothesis.

Thanks Floridian and Flash.

Jesse

Title: Re: fresh research - more on CGRP inhibitors.
Post by Flash on May 16^th, 2005, 11:31am

I emailed this information to Dr Sewell, the neurologist at Harvard who is working on the MAPS clinical trials for testing the efficacy of LSD and Psilocybin for treating cluster headaches. Here is his reply:

"CGRP has been attracting considerable interest lately because it appears that levels rise and fall in the bloodstream in parallel with the pain, providing the first objective measurement of pain and treatment efficacy. Interestingly enough, recent evidence from rats (Okamoto K, Imbe H, Morikawa Y, Itoh M, Sekimoto M, Nemoto K, et al. 5-HT2A receptor subtype in the peripheral branch of sensory fibers is involved in the potentiation of inflammatory pain in rats. Pain 2002;99(1-2):133-143.) shows that the neurons that synthesize CGRP in the dorsal root gangion are also the ones that express the serotonin 2A receptor that’s responsible for psilocybin and LSD’s psychedelic effect. That’s the only link I’ve been able to find so far.

It has some interesting implications, though. One question yet to be answered is whether or not the mechanism by which psychedelics treat cluster headaches is related to the psychedelic effect, or whether that’s just an unnecessary byproduct. I’ve been proceeding under the assumption that it’s the latter, since people don’t actually need to “trip” to treat their headaches. On the other hand, if it is CGRP-related through the mediation of serotonin 2A neurons, then it’s likely a dose effect, and a subhallucinogenic dose should work for everyone."

So my (mis)interpretation of this is that while it is a long shot, perhaps the psychedelic effect of the hallucinogenic drugs is what makes them work, and that they might also be just as effective at a subhallucinogenic level. Sounds familiar!