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        New Message Board Archives >> Medications, Treatments, Therapies 2004 >> Fresh Research - CGRP inhibitors for CH
        
(Message started by: floridian on Nov 25^th, 2003, 2:17pm)

Title: Fresh Research - CGRP inhibitors for CH
Post by floridian on Nov 25^th, 2003, 2:17pm

The title says migraine, but mentions clusters. CGRP is messed up in migraine and clusters. Triptans are thought of as acting on the serotonin system, but they also affect CGRP (calcitonin gene releasing peptide). CGRP inhibitors may be the next generation of meds for CH. CGRP is responsible for hot flashes - never thought a middle age man like me would get hot flashes, but the last two years the beast announced his departure with a hot flash. This article is 'new' on Pubmed, but I think I have seen its contents elsewhere. Second quoted article is on a Japanese herbal formula that stabilizes CGRP and reduces hot flashes. I have no idea what is in the kampo formula, what its side effects might be, or if there is any hope it would put a leash on the beast - but will research it further. ..

Quote:

Headache. 2003 Nov;43(10):1122-1125.

Edvinsson L. New therapeutic target in primary headaches-blocking the CGRP receptor. Expert Opin Ther Targets. 2003;7:377-383.

The primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. The associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP), but not other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches. Acute treatment with administration of a 5-HT(1B/1D) agonist (triptan) results in alleviation of the headache and normalisation of the CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small-molecule CGRP antagonists, which are predicted to have fewer cardiovascular side effects in comparison to the triptans. The initial pharmacological profile of such a group of compounds has recently been disclosed. These compounds have high selectivity for human CGRP receptors and are reportedly efficacious in the relief of acute attacks of migraine. Comment: My personal hunch is that CGRP antagonists may displace the triptans as the next therapeutic innovation in acute migraine treatment. DSM

Quote:

Maturitas. 2003 Jul 25;45(3):199-204.
Menopausal hot flash and calciotonin gene-related peptide; effect of Keishi-bukuryo-gan, a kampo medicine, related to plasma calciotonin gene-related peptide level.

Chen JT, Shiraki M. JT Chen Clinic, Sunbright Twin 3F, 2-46-1 Honcho, Nakano-Ku, Tokyo 164-0012, Japan.

OBJECTIVES: The purpose of this study is to investigate relationship of menopausal hot flash and calcitonin gene-related peptide (CGRP). Furthermore, this study evaluated the effect of the Japanese herbal (kampo) medicine Keishi-bukuryo-gan from the aspect of CGRP regulation. METHODS: Plasma CGRP and vasoactive intestinal peptide (VIP) levels were measured during hot flash and CGRP reactivity was studied by cold load test in subjects with/without hot flashes. The effect of Keishi-bukuryo-gan was assessed in comparison with plasma CGRP level. RESULTS: Only plasma CGRP but not VIP significantly elevated at the occurrence of hot flash (P=0.002). Stress by cold load significantly enhanced the over-secretion of CGRP in subjects with flash compared with those without flash (P=0.003) 3 min after the load. Keishi-bukuryo-gan decreased plasma CGRP level in subjects with hot flash. CONCLUSIONS: CGRP but not VIP was mainly related to the occurrence of hot flash. Keishi-bukuryo-gan, Japanese herbal medicine, improves hot flash possibly affecting plasma CGRP level.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by thomas on Nov 25^th, 2003, 2:19pm

Just curious - if it doesn't offend you, what is your educational background? You seem to be very bright.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by floridian on Nov 25^th, 2003, 2:44pm

My bachelors degree was biology related (started in physiological psychology, switched to plant and soil sciences, minor in microbiology). I worked two years in microbiology/veterinary pathology, where I picked up the habit of reading medical journals. I switched to the environmental/geographic field for subsequent degrees. Bright?? Dunno, But I do read fast, and have a good memory. I am also pissed off at having cluster headaches, so this is my way of dealing with it - in past years, I lurked on the board, hoped and prayed, and waited for it to go away. Now I am fighting back. When I am motivated and organized, I can do alot.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by thomas on Nov 25^th, 2003, 2:57pm

Thanks for picking up the sword. I'm glad you're on our side.

Title: Ingredients in Keishi-bukuryo-gan
Post by floridian on Nov 25^th, 2003, 2:57pm

The particular kampo formula mentioned contains the Poria fungus (Poria cocos) and cinnamon, among other ingredients.

Bai Shao / Peony (White) / 20%
Rou Gui / Cinnamon Bark / 20%
Tao Ren / Persica / 20%
Fu Ling / Poria / 20%
Mu Dan Pi (Su) / Moutan / 20%

Title: n it Re: Fresh Research - CGRP inhibitors for CH
Post by Paigelle on Nov 25^th, 2003, 3:28pm

I am with Thomas, I am glad you are on our side.

Having the CH does piss ya off! That is why I am armed with a folder full of information that I carry to the Dr with me every time I go.

It is amazing they can treat all of these illnesses, yet when it comes to CH they might as well hand over the prescription pads to us.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by bluesunshine on Nov 25^th, 2003, 10:45pm

Here's a collection of abstarcts about CGRP antagonists:

http://www.neurotransmitter.net/migrainecgrp.html

Another article named What Will the New Millennium Bring to the Migraine Sufferer?, talks about meds for migraine, but as you know, the trex was first developped for migraines...

http://www.achenet.org/articles/16.php

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by floridian on Nov 25^th, 2003, 11:45pm

Thanks for the links. The first link had a good collection of articles with a few connections I was unaware of.

The second article was interesting, but seemed very geared to patented medicines (at $50 to $100 per pop, I'd wager). Whatever works, works, but money is directing where people look. There are some non-patented molecules that act in some of the ways described in the article, e.g.,

Glutamate inhibitor - Magnesium, theanine (from tea)
NOS inhibitor - catechins (from tea), turmeric, wogonin (from skullcap)

Well, maybe being broke isn't so bad if you are pain free. I guess I'm just sensitive to the excessess of the system. I went in for a 1/2 hour appointment to the nutritionist today (learned a few things, but much was basic). Went to check out and looked at the paperwork - my $15 copay wasn't bad, but the insurance company was being billed $153!! $300 per hour for nutritional counseling!! I guess I picked the wrong profession.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by cleon on Nov 29^th, 2003, 5:46am

Floridian - with your knowledge and understanding you may be interested in something I was recently introduced to. To me it makes a lot of sense and I intend to follow it up in the New Year. Mineral deficiency it seems has much to do with the manufacture of serotonin and melatonin. Hair analysis seems the best way to determine one's mineral and trace element levels as these are stored in the body's tissue, not the blood (as compared to blood tests)
Very interesting reading - I found many sites with the info and the offers of analysis (for a fee of course).
Considering some of us have had success with CH & Magnesium, who know's?
Of course it is a complicated issue eg: too much copper depletes the zinc in one's system etc, etc.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by Medlengough on Nov 30^th, 2003, 9:34pm

Floridian,
How far away do you think we are from a CGRP antagonist actually being offered for civilian trial or is it possible to aquire it already? I know I've seen many different formulas and patent numbers mentioned, one in a govermental military report about its' effectiveness against eye pain caused by mustard gas exposure.
Another by a Japaese firm trying to isolate it from sardines.
Is the Keishi available in the US or the "poria cocos" fungi? I'd try either.
Medlengough

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by floridian on Dec 1^st, 2003, 9:39am

Medlengough,

Poria cocos grows in the US as well as Asia, and was used for food, especially in the colonial period. It is also known as tuckahoe or Indian Bread.

Peach pits contain chemicals that are converted to cyanide - the amounts are low, but there have been reports of problems with a few individuals that consumed large amounts. The same compounds are in apple seeds and almonds, I believe. Not sure if the peach pits are essential to the blend or not, but the cinnamon sounds better than the peach pits. Cinnamon does have some interesting effects on blood sugar and lipids, some bacteria and fungi, and is an anti-oxidant.

I don't know anything about the peony and moutan (tree-peony).

I did come across one source of a pre blended version of the formula, it can be found on the web, but it was marked for health care professionals only. I also don't want to promote or reccommend any brand on this website, especially when I have no experience with the product. You might be better off going to a practioner of TCM (traditional Chinese medicine) that has experience with the use of this. There is potential, but this is uncharted (atleast not on my charts).

Cleon,

I am aware of hair testing for minerals, and know it can be of some value, especially for heavy metals. But different minerals go to different parts of the body, and I don't think that there is one single test that gives full insight to the nutrient status of a person. Most testing labs look at the plasma or serum levels of nutrients, which is sometimes useful, but can also be very different from the levels inside the cells. In some cases, hair testing can be confounded by grooming practices (selenium or zinc shampoo for dandruf, lead or other minerals to color the hair, etc). I worked a little with soil testing, and one frustration is that many minerals exist in different forms - the solvents used to dissolve one form might not dissolve another, or a mineral might be present, but not available because of pH, or some other factor. I have also seen people pushing hair testing as THE way to figure out a persons health. Too simple. I would include hair testing as one tool, but I don't know all the strengths and limitations of that tool. But interesting to consider - may come in handy.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by LSUnut on Dec 1^st, 2003, 1:00pm

CGRP antagonists have become a very hot topic in relation to headache research. This is an abstract I was privy to at the most recent ACS meeting in New York this past September.
Quote:

Bibliographic Information

Synthesis and evaluation of novel small-molecule CGRP antagonists. Zartman, C. Blair; Bell, Ian M.; Gallicchio, Steven N.; Graham, Samuel L.; Kane, Stefanie A.; Leonard, Yvonne M.; Mallee, John; Miller-Stein, Cynthia; Rutledge, Ruth; Salvatore, Christopher; Vacca, Joseph P.; Wallace, Audrey; Williams, Theresa M. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA. Abstracts of Papers, 226th ACS National Meeting, New York, NY, United States, September 7-11, 2003 (2003), MEDI-166. Publisher: American Chemical Society, Washington, D. C CODEN: 69EKY9 Conference; Meeting Abstract written in English. AN 2003:634774 CAPLUS

Abstract

Calcitonin Gene-Related Peptide (CGRP) is a 37-amino acid neuropeptide which is widely distributed in various tissues including the CNS. CGRP-contg. nerves are closely assocd. with blood vessels and CGRP's most pronounced effect is vasodilation. This vasodilatory effect and the elevated levels of CGRP assocd. with migraine headache attacks initiated the investigation of antagonists of the CGRP receptor as a possible treatment for migraine and pain. Recently, Boehringer Ingelheim reported the first selective small mol. CGRP antagonist for the human CGRP receptor. This compd. has entered human clin. trials as an iv agent for the treatment of migraine. Our project team is attempting to identify an orally bioavailable CGRP antagonist and a structurally novel non-peptide lead was identified from screening. Extensive SAR studies defined the key pharmacophoric elements and provided insight into the bioactive conformation. These compds. are competitive with CGRP but, in contrast to other non-peptide antagonists, their activity is affected by the presence of divalent cations. Ultimately, optimization of this series produced a low mol. wt. CGRP receptor antagonist with excellent pharmacokinetic properties in both rat and dog.

The first possible small-molecule therapeutic agent to which this article refers by Boehringer Ingelheim is known as BIBN4096BS. It is in clinical trials by IV injection, but an alternative inhaled formulation is also in the works. As you can tell by the authors of this abstract (Merck Pharmaceuticals), all of the big Pharma's are hot on the trail of new headache medicines due to the huge revenue generated by all of the prescrition triptans that most of us, unfortunately have to take. The impending problems with this new series of potential drug candidates is that they are petidomimetics (they have to look similar to the CGRP peptide), meaning many of the most active compounds contain peptide bonds, which the body, unfortunately, likes to cleave when taken orally and passed through the liver. This is why the new candidate, BIBN4096BS, is being tested by IV. If it passes all of the toxicity testing and phases 1-3 of the clinical trials, we could see it come to market within the next 5-7 years (cross your fingers). Unfortunately, the first orally available CGRP antagonists probably won't make it to market for at least ten years :(, because the research is just beginning to take shape. FYI, potential CGRP antagonists may also help with more than just headaches. There has been some speculation that CGRP and its mediators play a key role in the inflammatory response of the gut and gastric acid release (colitis and peptic ulcer disease). There have been many reports showing an increase in both of these disorders in people who suffer from migraines and clusters. ;)

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by CJohnson on Dec 19^th, 2003, 4:56pm

Interestingly, capsaicin is a potent stimulator of CGRP release.

"The cloned capsaicin receptor, also known as vanilloid receptor subtype 1 (VR1) receptor, has been demonstrated to be an integral membrane protein with homology to a family of putative store-operated calcium channels. The VR1 receptor is activated not only by capsaicin but also by noxious heat and protons, and therefore it is suggested as a molecular integrator of chemical and physical stimuli that elicit pain. In the present study, indirect immunofluorescence detected a small number of neurons that are VR1 receptor immunoreactive (ir) (171 versus 1038 or 16% of all neuronal cell bodies) in the human trigeminal ganglion (TG). In addition, RT-PCR confirmed the presence of VR1 mRNA in the human TG. It has been hypothesized that TG neuronal cell bodies are the source of capsaicin-stimulated release of calcitonin gene-related peptide (CGRP), and hence co-localization experiments were performed. Around 10% of the VR1 receptor-ir is expressed on neurons that contain CGRP-ir (ten among 74) in the human TG, indicating that capsaicin may act through the VR1 receptor to modulate the release of CGRP and in turn to modulate pain. We observed that 8% of the VR1 receptor-ir neuronal cell bodies contain substance P-ir and 5% nitric oxide synthase. Capsaicin can release nitric oxide, CGRP and substance P from sensory nerves and contribute to central sensitization."

http://arc.cs.odu.edu:8080/dp9/getrecord/oai_dc/lu-research.lub.lu.se/oai:lu-research.lub.lu.se:11184

PFDANs
-Curtis

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by floridian on Dec 19^th, 2003, 5:14pm

In the short run, capsaicin stimulates Substance P nerves (causing burning pain), but after a time, it depletes those nerves of Substance P.

Quote:

The first exposure to capsaicin intensely activates these neurons in both senses (orthodromic: pain sensation; antidromic: local reddening, oedema etc.). After the first exposure, the neurons become insensitive to all further stimulation (including capsaicin itself).

Drugs. 1997 Jun;53(6):909-14.
Peppers and pain. The promise of capsaicin.
Fusco BM, Giacovazzo M. Department of Clinical Medicine, University La Sapienza, Rome, Italy. bmfusco@mbox.vol.it

Quote:

The VR1 receptor is activated not only by capsaicin but also by noxious heat and protons

Clusterheads know that heat can be a trigger - but did you know that acids are proton donors?? Could a simple antacid like sodium bicarbonate help? I doubt that all clusterheads have unusually acid blood (that would be too easy to spot), but maybe low buffer capacity is a factor. (??) Magnesium has specific calcium channel blocking effects, but it is also an anti-acid.

Title: Re: Fresh Research - CGRP inhibitors for CH
Post by floridian on Feb 6^th, 2004, 10:11am

I met with a person who practices Chinese herbology a few weeks ago, and got a formula similar to the one described above. Got if for my wife (having hot flashes from thyroid and female disruption) and took it myself (out of cycle, but wanted to see how my body tolerated it). Neither of us were taking any prescription medicines, and nutritional supplements were limited to a multivitamin, vitamin C (500 mg/day) and vitamin E (400 IU/day).

The formula was composed of equal parts of:
Peony (White)
Cinnamon Twig
Poria
Moutan (tree peony)
Dong Quai / Angelica
Licorice

One ounce of each herb, boiled in water for an hour, yielding about a gallon. Took it for a week - 1/2 cup morning and evening.

I didn't feel any side effects, though my nagging cold symptoms improved. Hot flashes in spouse decreased, and she reported better sleep/more vivid dreams. Not a double blind controlled study for either use, but both consistent with traditional uses of these herbs.

The licorice contains compounds that have prednisone/aldosterone like effects. Short term/moderate use not a problem - long term or high dose can increase water retention, blood pressure, etc.

Both Angelica and Peony have calcium channel blocking activity - not a good idea to mix this with verapamil or other calcium channel blockers. In theory, the amount of calcium channel blockers may be much lower than from verapamil. It could hypothetically act in a way that is milder than verapamil, causing fewer side effects. But that isn't known - it could also increase verapamil's activity in an additive or synergistic manner, which would not be good. (Calcium channel blockers like verapamil are a leading cause of prescription related hospitalization and death - why take a chance?)

I tried a different formula a while ago for anxiety - it had lots of Poria (hoelen), which is a diuretic. That formula dehydrated me and I got very thirsty regarldess of how much I drank. At one ounce poria per gallon/1 cup tea per day, these side effects were not noticed.

One ounce of herb to a gallon of water equates to about 0.25 grams of herb per ounce of tea. So the licorice from a cup per day would be about 2 grams (and it was very sweet from the glycrrhizin). 2 grams licorice per day is not a problem in the short term, but could be a problem for long term. Dropping to 1/2 ounce licorice after a week or two, or eliminating licorice every other week probably better.