CGRP Blockers & SRAs – The New Faces In Research For Migraine Management

CGRP stands for Calcitonin Gene-Related Peptide. It is a calcitonin group compound made up of polymers of amino acid monomers. CGRP is manufactured in the human body in the nerve cells (neurons) of the central nervous system and the peripheral nervous system.

Research – New Migraine drugs In The Pipeline (1)

So what is the function of CGRP? Of the many functions, CGRP is a powerful vasodilator and it contributes significantly in the transmission of pain message through the body. It is also believed to play a critical role in cardiovascular homeostasis as well as in processing noxious stimuli that has the potential to damage the tissues of the heart.

The development of drugs which are essentially CGRP receptor antagonist is in the pipeline aimed at helping migraineurs the world over cull the pain of their migraine episodes. How does the CGRP receptor antagonist do this? It has been observed that during the onset of a migraine attack, CGRP binds to CGRP receptors and activates these receptors which then transmit pain signals. CGRP receptor antagonist prevents the CGRP from binding on to CGRP receptors thus circumventing the transmission of pain signals causing migraine pain.

Telecagepant was such a CGRP receptor antagonist drug developed by Merck & Co. and was undergoing Phase III clinical trials but the trials were abandoned after identification of two patients with significant elevations in serum transaminases indicating liver damage. However, similar drugs without such side-effects are now being designed. CGRP receptor blockers also significantly reduce nausea and are more desirable in total benefit than triptans. As per Peter Goadsby, MD, PhD, director of UCSF’s Headache Center, “So this is a way for it to be effective and adds a safety bonus to the patients and it seems to be better tolerated.” (2)

There is another approach to drug design and development aimed at reducing the misery of migraineurs and it comes from the side of serotonin activity. In this class, one investigational drug of note is Lasmiditan thought of by Eli Lilly & Co and being designed to treat acute migraine by CoLucid Pharmaceuticals. These drugs are technically serotonin receptor agonists and selectively bind to the 5-HT1F receptor subtype. Unlike triptans these drugs do not constrict the heart vessels and have lesser side-effects. Trials have shown that administration of this drug reduced migraines to almost nothing within a two-hour period in almost 60% of the patients also tackling nausea and photophobia beautifully. The drug is expected to be ready by 2014. As per Dr. Goadsby, “Lasmiditan is now that finished its phase two studies and clearly works. It does not have the same sort of liver effects as its predecessors and will move on into phase three. That is again for acute migraine treatment. So it is a safe and totally different action than what we currently have.” (2)

 

SOURCES:

  1. Image by Ponsulak; Freedigitalphotos.net; March 2012; http://www.freedigitalphotos.net/images/view_photog.php?photogid=1983
  2. Cutting Edge Treatments For Migraines: More Than Just A Headache; Ivanhoe.com; March 2012; http://www.ivanhoe.com/channels/p_channelstory.cfm?storyid=29106&channelid=CHAN-100018

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Brahmari Pranayama and Serotonin Benefits for Migraineurs

Brahmari

The Brahmari Pranayama – An Effective Technique To Stave Off Migraines (1)

This Pranayama imitates the sound of a humming bee during it’s exhaling phase. It thus channelizes breathing through a vibrating state. The Brahmari Pranayama is the most efffective of all the Pranayamas chalked out for migraineurs.

The Benefits:

  • The brahmari cures post delivery and menstrual migraines through higher serotonin release pre-menstruation,
  • It is extremely useful for Alzheimer patients and those with heart conditions,
  • The Brahmari also balances blood sugar and hormone secretion,
  • It’s practice increases the rate of metabolism and calms the mind,
  • It is proven to improve memory and concentration.

Here’s how you do it:

  1. Sit on a mat on an even floor (Preferably in Vajra Asana or Sukha Asana).
  2. Close your glottis partially as you inhale through both nostrils, making a snoring sound.
  3. Exhale slowly emitting the buzzing sound of a humming bee.
  4. Humming while exhaling allows you to spin out your breath and make a longer exhalation.
  5. Repeat the process 5 – 10 times.

Personally, I recommend The Art of Living Foundation’s Basic Course where they teach you how to do the different Pranayama with precision. The Foundation’s chapters have presence in almost all the countries of the world and in all major cities. You may visit their website to www.artofliving.org to find out the location of their branch in your locality. Another trusted source would be to watch and follow or buy the DVDs of Baba Ramdev. His instructions are articulate and make them easy to follow. Information and YouTube demonstrations of asana and Pranayama are available on his website www.baba-ramdev.info.

Remember, any Pranayama done wrongly has the potential to be dangerous. It is recommended that you learn Pranayama through a qualified Yoga instructor.

As with aerobic exercises, benefits can be enjoyed with consistency. As with homeopathic medications, benefits are more forthcoming with regularity in timing of practice. In addition, as with aerobics and homeopathic programs a sensible diet, lean on fat, moderate on complex carbohydrates, high on high fibre, protein and water, along with a good dose of patience brings sustained results. As with all Pranayamas, they are best done on an empty stomach in the morning or evening.

SOURCE:

  1. In Touch Yoga Byron Bay; Web December 2013; http://www.google.com/imgres?sa=X&espv=210&es_sm=93&biw=1280&bih=708&tbm=isch&tbnid=4Z_R3L98-9N17M:&imgrefurl=http://www.intouchyogabyronbay.com/newsletter-article-2-just-being/p/82&docid=AFVdzisGtonBFM&imgurl=http://www.intouchyogabyronbay.com/media/images/content/detail/N_and_H_Aug_Sept_07_014-text446.jpg&w=1000&h=750&ei=8VapUs7ZFsa_ywOTjIHIDA&zoom=1&ved=1t:3588,r:53,s:0,i:251&iact=rc&page=3&tbnh=177&tbnw=236&start=45&ndsp=23&tx=91&ty=89

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How Exercises Help Migraineurs At Multiple Levels

Any exercise induces the body’s pituitary gland to release endorphins. There are 4 different types of endorphins – alpha, beta, gamma and sigma. It is found that during prolonged exercise sessions, acidosis of the blood occurs, which is indicated by decrease in the blood flow and oxygen to the muscle tissues. This triggers the release of beta-endorphins, as a response to tackle the anticipated pain or stress. These beta-endorphins have analgesic properties and raise the bar for the body in tackling migraine pains.

 

Similarly, another polypeptide, the enkephalin, is released by the thalamus of the brain during periods of exercise. They have the specific capacity to block the neurotransmitter, Substance P, which is notorious in triggering migraines. Catecholamines are another substance, which is released in short periods of exerting exercises. They raise the density and secretion of serotonin mildly and help counter migraine pains to some extent.

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Excellent Exercises For Migraineurs

Hi,

For over a month now, I have been covering technical areas of migraine condition to increase our understanding of the internal dynamics of this neurological disease.   Today’s post will encompass what we can do in terms of physical activities and exercises to keep the migraine beast best tamed- i.e. we will look at the external dynamics which is within our control. Remember, our aim should be to:

a. Increase levels of Serotonin

b. Increase levels of the pain-fighting Endorphin

c. Increase levels of Dopamine

 All repetitive movements raise serotonin levels. This includes chewing, massages and the like, though the elevation in serotonin levels through such activities is marginal and ephemeral.

Significant increase in serotonin combined with endorphin and dopamine levels occur at the time of any activity that involves continuous or continual exertion for a certain period of time – a minimum of 20 minutes. If you can incorporate repetitive movements to such an exercise sessions, it would augment the effect of serotonin and endorphin. Let’s look at the activities that can give such benefits:

1. Brisk Walking

2. Jogging

3. Running

4. Weight training

5. Cycling – outdoors and stationary

6. Swimming

7. Dancing

8. Stretching

9. Yoga

10. Pilates

11. Aerobics – Step, Circuit training etc

12. Kickboxing

13. Any Sport

14. Gym activities – treadmills, elliptical, rowing machines, push-ups etc

15. Any other activity that causes you to exert for 20 minutes at one go (with possible rest periods built in)

If you have never done exertive physical activities before or have led a sedate life, it is advisable to keep your exercise routine to 30 minutes every other day. If you do not have the luxury of working out 30-minutes in a single go, break it up. You can fit in lots of 10 minutes thrice in a day. It all adds up.

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Serotonin and Neurological Afflictions

Hi,

Last week we saw how eating a tryptophan-rich diet didn’ t necessarily translate into increased serotonin levels in the brain unless backed by adequate Vitamin B3, B6 and complex carbohydrates. It however, did place one a better chance at getting a serotonin boost.

Studies have established some links to a defecient state of brain serotonin with other neurological afflictions besides migraines, such as alcoholism, depression, suicidal tendencies, PTSD, obsessive compulsive disorders, generalised anxiety disorders and social phobia to name a few.

We may experience low brain serotonin levels due to a variety of reasons:

1. Low levels of production of brain serotonin.

2. Less number of serotonin receptors in our brain region

3. High reuptake rate of serotonin back from the synapse into the presynaptic neurons, and

4. Defeciency in tryptophan levels in our body.

There is a new and fifth interesting dimension that has cropped up – that of the serotonin transporter gene (SERT). To relay a message, a neuron releases serotonin into the synapse or the gap between two neurons from where their dendrites begin. Once the message is relayed to the next neuron, the released serotonin in the synapse is collected and transported back to the pre-synaptic neuron by the SERT. SERTS are monoamine proteins. It has been found that when there are changes in the SERT metabolism, neurological afflictions begin.

It is also now being thought that the gene (called SLC6A4 – Solute Carrier family 6, member 4) that encodes the SERT can be mutated and result in changing the functions of SERT.

The area (aka promotor) in the gene SLC6A4 which synthesises RNA under the instrucions from DNA, contains polymorphism – some long repeats (16 repeats of a sequence) and some short repeats (14 repeats of a sequence). Shorter repeats obviously enable lesser coding in them and thus when we have a pair of short repeats we get an increase in the risks of developing disorder states.

So though SSRIs and beta blockers may help migraineurs as well as those suffering from insomnia, depression, PTSD and other anxiety disorders, their efficacy will not be the same between 2 persons with the same condition. Those predisposed to neurological and psychological conditions due to the presence of 2 short versions of the gene will be less benefitted than those with other variations (2 long or 1 long and 1 short).

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Why eating tryptophan-rich foods may not increase brain serotonin

Hi,

I will continue on the note of last week.  Tryptophan, as I said earlier, is one of the 14 essential amino acids (building blocks of proteins) we need to get through food. (Examples of  other essential amino acids are Tyrosine, Phenylanine, Valine, Leucine, Isoleucine, Taurine, Glutamine, Alanine and Asparagnine etc)  

Tryptophan is especially essential for migraineurs as they form the raw material for serotonin – the key player in migraine occurence and prevention. Unlike most of the other essential amino acids, tryptophan has large molecular structure (as shown in my last post). Such large molecules are not allowed through the blood-brain barrier.  

We must understand that tryptophan is required in only trace quantities by the body. The RDA value for it is set at 0.2 grams. Our meals on an average provide us anything between 1 to 1.5 grams every day. Yet only a small fraction of it reaches our brain where it is needed most. Let us see how the scarce tryptophan can play truant in the various stages of it’s metabolisation:

Stage #1: Tryptophan is first broken down by the enzyme Tryptophan Hydroxylase with the help of Vitamin B3 (or Niacinamide) into 5HTP. Here is Catch #1: It might so happen that you are deficient in Vitamin B3, which will spin into action a whole new string of events in the body. When the liver encounters the dietary tryptophan in the absence of adequate levels of Vitamin B3, it will use the scarce tryptophan to manufacture Vitamin B3. It does so at a very steep ratio of  60mg of tryptophan to produce 1mg of Vitamin B3!!

Stage # 2: Here, another enzyme called Decarboxylase converts 5HTP to 5HT with the help of Vitamin B6. Catch # 2: In the liver, tryptophan is metabolised using the enzyme tryptophan pyrrolase. However, if you are even mildly deficient in Vitamin B6, this tryptophan will be converted to toxic metabolites such as hydroxikynurenine, xanthurenic acid and hydroxyanthranilic acid, by the liver. 

Now assuming that tryptophan was successfully converted to the 5HT compound without being lost as Vitamin B3 or toxin metabolites or both, it now faces competition with 5 other amino acids (tyrosine, valine, leucine, isoleucine and phenylanine) to reach the blood-brain barrier. 5HT is carried to the barrier through carbohydrate transport molecules. What can be done at this stage, is to make more carbohydrate available so that the chances of tryptophan transportation increase. A migraineur’s preference should be a mild increase in the intake of complex carbs (wholemeal grains, cereals, lentils, pulses etc). This makes free buses available to carry the tryptophan to the brain.

Crossing the blood brain barrier and reaching the Central Nervous System, 5HT is converted to serotonin. 

Doctors prescribe 5HTP supplements as they have better chances to convert to serotonin than tryptophan supplements. It is generally also prescribed with a low dose of Vitamin B3 and B6. The indicative doses are generally in the range of 1 -3 grams of tryptophan, 100 mg of B3 and 25 mg of Vitamin B6.  Consult your doctor before taking them.

Next week I shall touch upon the importance of serotonin and how it helps alleviate symptoms of disturbed sleep, depression etc in migraineurs.

Until then, take care.

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Calcium’s Control on Serotonin Channels

Hi,

Much as Magnesium’s role in migraine management has been spoken about, Calcium has almost always figured as an also-ran. But Calcium intake, it’s effective metabolisation and absorption are just as important as Magnesium balance in your food.

Calcium is known to have anti-spasmodic action, which helps alleviate headaches and migraines. However, studies have shown that when calcium is administered along with Vitamin D, it reduces the frequency of migraines in a considerable number of patients .

Recent studies have also concluded that abnormalities in the channels within the cells that transport calcium, magnesium, sodium and potassium contribute to the onset of migraines. The calcium channels are known to regulate the release of serotonin. With impaired functioning of the channels, serotonin may not be effectively released or may be released in low quantities. This would contribute towards migraine occurrences.

For Reader’s Interest – a related link: http://mcb.berkeley.edu/labs/zucker/PDFs/Wang_Neuron21,155.pdf

The RDA for Calcium in women of the age group 18- 50 is approximately 1000 mg and between 1000-1300 mg for pregnant and lactating women. For post-menopausal women the RDA is set at about 1500 mg.
Calcium absorption reduces with aging and is dependent on a variety of factors such as genetics, availability of Vitamin D, intake of Vitamin C among others.

However, any supplement or drug should be had with consultation with your physician. Self-medication is a dangerous practice and can have fatal outcomes.

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