New Drugs Targeting CGRP Offer Hope: American Academy of Neurology

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Role Of CGRP and Antagonists In Migraine Attack (1)

CGRP is critically implicated in the occurrence and unfolding or progress of a migraine attack. CGRP or Calcitonin gene-related peptide is a powerful protein/peptide containing a short chain of amino acid monomers. It plays a critical role in transmitting pain signals through the body in events such as migraines. It is also involved in the vasodilation, inflammation, immune-modulatory responses among others during migraine attack apart from increasing heart beat and altering sensory transmission.

CGRP is produced by the peripheral and central neurons of our central nervous system specifically around the spinal cord and the trigeminal ganglion. Prior to and during migraine episodes, the central and peripheral neurons release more CGRP. This is then mediated through CGRP receptors (CALCRL and RAMP1) found throughout the body. One way to prevent pain from occurring is to block the receptors that receive the CGRP protein using a chemical/drug. Such drugs are called CGRP antagonists or CGRP blockers.

In a post of March 28th, 2012 I had written (‘CGRP Blockers & SRAs – The New Faces In Research For Migraine Management’) on work being done on drugs that targeted CGRP receptors but were abandoned after Phase III trials due to adverse reaction found in some of the trial population. (2).

Currently, two studies showing work with calcitonin receptor blockers have moved into Phase II trials. This means that though positive outcomes have been had from these researches involving smaller populations, larger studies are required to clear the drug for sale or prescription.

Research 1:

This involves a prospective drug that aims to prevent migraine from starting rather than trying to stop attack from progressing once it has begun. The drug involves monoclonal antibodies or antibodies that are identical immune cells – clones of their unique parent cell. Such monoclonal antibodies are being directed at the CGRP to target the protein.

This research examined 163 migraineurs for a period of six months, who had migraine attacks ranging anything from 5 -14 days every month. In this time, they gave the population either a placebo or the drug under study called ALD403 without the migraineurs knowing what they were taking. Those who took the drug reported a 66% reduction in number of migraine days and in 12 weeks time reported to be migraine-free.

As per lead author Peter Goadsby, MD, PhD, of the UC San Francisco and a member of the American Academy of Neurology, “These results may potentially represent a new era in preventive therapy for migraine. Migraine remains poorly treated, and there are few effective and well tolerated treatments approved that prevent attacks from occurring.” (3)

Research 2:

This potential drug in injectable form too is a preventative rather than a mitigator of migraine condition and is based on monoclonal antibodies targeting CGRPs. In Phase II trials as well, the research studied 217 migraineurs who experienced anything from 4-17 days of migraine days every month.

The population being observed was also administered either a placebo or the drug under study called LY2951742 via the subcutaneous injection route, without being told which was which for a period of three months. Those who were receiving the real drug reported more than 4 days less of migraine days in a month. However, they also experienced more side-effects such as abdominal pain and upper respiratory tract infections.

As per Dr. David Dodick, MD, of Mayo Clinic Arizona in Phoenix and a member of the American Academy of Neurology, “We’re cautiously optimistic that a new era of mechanism-based migraine prevention is beginning. There is a huge treatment need for migraine — the third most common and seventh most disabling medical disorder in the world” (4)

SOURCES:

  1.  Image Credit: The Role of CGRP and its Antagonists in Migraine- Peripheral Actions of CGRP: Neurogenic Inflammation;  Flipper.diff.org; Web April 2014; http://bit.ly/PsCR7O
  2. CGRP Blockers & SRAs – The New Faces In Research For Migraine Management; Web April 2014; https://migrainingjenny.wordpress.com/2012/03/28/cgrp-blockers-sras-the-new-faces-in-research-for-migraine-management/
  3. New drugs offer hope for migraine prevention; ScienceDaily News; Web April 2014; http://www.sciencedaily.com/releases/2014/04/140422162048.htm
  4. Stopping Migraines Before They Start; DailyRx.com; Web April 2014; http://www.dailyrx.com/migraine-patients-had-fewer-attacks-monoclonal-antibody-treatment

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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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