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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Newly FDA-Approved Topamax For Migraines Raises Concerns Over Serious Side-Effects

Topamax

Recently-approved Topiramate For Adolescents Needs A Look Into Serious Side-Effects (1)

The Food and Drug Administration of USA recently (end of March 2014) approved the use of chemical topiramate in the 12 – 17 years of age group to prevent migraines. Topiramate is manufactured by drug corporation Janssen and sold under the name of Topamax. Such adolescents who report to a minimum of migraine episodes every month and have been given a clinical diagnosis of migraines in the last 6 months qualify for receiving a prescription of Topamax from their doctors to be used as a prophylactic medication.

Topamax originally came into the market in 1996 to treat seizures experienced in epileptic patients and was later also extended to manage other conditions such as need to reduce weight in obese and overweight patients.

However, the initial euphoria of being able to avail of the benefits of this drug are now subsiding with concerns that have been put forward by analysts from consulting firm GlobalData, on the severe side-effects Topamax comes with and those that have long been known to occur in adult patients. They are likely to be experienced by the adolescent migraining population as well and require a serious risk-benefit analysis before receiving a prescription.

Topamax is known to cause side-effects such as tiredness, dizziness, coordination problems, speech problems, changes in vision and sensory distortion.(2) In some cases it may cause sudden loss inn vision, memory problems, problems remembering words, brain fog, decline in cognitive condition and behavioral changes and the like.

As per GolbalData analyst Alvina To, “Migraine is experienced by both children and adults alike. For children in particular, these symptoms can affect school performance, social interactions and family life. The good news is that Topamax proved safe and well-tolerated in this patient group. But as with all anti-epileptic drugs, Topamax may also increase the risk of suicidal thoughts and behaviors in patients, as well as boosting the chances of cleft lip and/or cleft palate development in infants born to women who take the drug during pregnancy. It is therefore essential that all associated risks and benefits of Topamax are carefully assessed.” (3)

Randomized and placebo-controlled tests on Topiramate as well as trials on safety for this young age group was conducted on 103 patients who were diagnosed with migraines. In 72% of these patients, migraines were significantly reduced compared to 44% who took placebos.

Thus instructions have been given to neurologists to dispense a Medication Guide that spells out the safety and what to expect from the drug at time of giving a prescription. According to Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, “Adding dosing and safety information for the adolescent age group to the drug’s prescribing information will help to inform health care professionals and patients in making treatment choices.” (4)

Topamax tablets are available in potencies of 25 mg, 100mg and 200 mg.

SOURCES:

  1. Image Credits: Topamax; Pharma Agora; Web April 2014; http://www.pharma-agora.com/product/detail/1524-topamax-sprinkle-25mg; http://www.pharma-agora.com/product/detail/1524-topamax-sprinkle-25mg
  2. Topamax Side Effects Center; Rx List; Web April 2014; http://www.rxlist.com/topamax-side-effects-drug-center.htm
  3. Topamax safety concerns as a treatment for migraines in adolescents, despite recent FDA approval; The Pharma Letter; Web April 2014; http://www.thepharmaletter.com/article/topamax-safety-concerns-as-a-treatment-for-migraines-in-adolescents-despite-recent-fda-approval
  4. FDA approves Topamax for migraine prevention in adolescents; FDA News Release; Web April 2014; http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm391026.htm

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Corydalis Can Stub Pain Before Full-Blown Migraine Attack

corydalis

 

Corydalis (Chinese Poppy) Has The Power To Kill Migraine Pain (1)

Another natural alternative to stubbing migraine pain in the bud is the plant corydalis. It is also known as Chinese Poppy and is a popular analgesic used in the Chinese medicine system.

In the January 28th show of Dr. Oz Show, the doctor said that corydalis is both natural and a cheap option to treat migraine pains. In addition, corydalis does not come with any side effects! He suggests a dosage of 3 – 9 grams (six capsules) of twice or thrice a day would help treat chronic and migraine pains. (2)

As per acupuncturist Dr. Hsu corydalis contains very potent pain killing chemical called dehydrocorybulbine (DHCB) which is known to thwart pains from migraines, menstrual cramps, back pain and rheumatism. Corydalis works by causing the release of dopamine into our bloodstream thus giving us a feeling of well-being. However, it is not addictive in nature as is common with chemicals that work the central nervous system.

Research has also been conducted by the University of California when the scientists were searching for compounds in corydalis that seemed likely to function in a manner similar to morphine.

As per lead researcher at the University Olivier Civelli, “We landed on DHCB but rapidly found that it acts not through the morphine receptor but through other receptors, in particular one that binds dopamine.” Some of the earlier studies have indicated that the dopamine D2 receptor plays a critical role in pain sensations. (3)

SOURCES

  1. Image Credit: Corydalis; Medical Daily; Web February 2014; http://bit.ly/1nGMHAq
  2. Dr. Oz details natural painkillers to relieve migraines and back pain; Examiner.com; Web February 2014; http://www.examiner.com/article/dr-oz-details-natural-painkillers-to-relieve-migraines-and-back-pain
  3. Traditional Chinese medicine proves effective for chronic pain; Tracktec.in; Web February 2014; http://www.tracktec.in/2014/01/traditional-chinese-medicine-proves-effective-for-chronic-pain.html

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Candesartan Gives Migraineurs New Hope: Study

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Candesartan seems to reduce incidences of migraines just as well as Propranolol (1)

Hope comes for migraineurs via a new study conducted by St. Olavs Hospital in Trondheim, Norway and the Norwegian University of Science and Technology. Migraine patients who have been prescribed propranolol, (a popular beta-blocker that also doubles up to reduce the number and severity of migraine episodes) as a migraine prophylactic but get no relief from taking it can now breathe a sigh of relief as the study demonstrates that chemical candesartan proves as if not more effective for migraine prophylaxis.

Though the theory of candesartan working as an effective migraine prophylactic had been propounded more than a decade ago, it has been proved only now that the drug actually works. In the study, the placebo administered showed a 20% ‘feel-better’ on patients but administering of candesartan exhibited an additional 20-30% patients’ ‘feel-better’. (2)

Candesartan is a blocker of the angiotensin II receptor. Angiotensin is a peptide hormone that constricts blood vessels causing the blood pressure to rise and the heart to pump blood harder. Blocking receptors that receive angiotensin hormone helps relax/dilate the blood vessels thereby lowering blood pressure and easing the heartbeat. (3)

The study which examined 72 migraineurs who had migraines at least twice every month, was a triple blind test in which neither neither patients nor doctors nor those who analyzed the results knew whether the patients had been given placebo or real medicine. The patients used each treatment (candesartan, propranolol or placebo) for 12 weeks, and also underwent four weeks before start and between the treatment periods without any medication at all. Thus every patient was part of the study for almost a year.

According to Professor Lars Jacob Stovner, leader of Norwegian National Headache Centre, “This gives doctors more possibilities and we can help more people.” (4)

Common side effects of candesartan are: dizziness, fatigue, abdominal discomfort, headache and reduced renal functions.

Atacand (AstraZeneca), Cipsartan (Cipla) are some popular brand names under which Candesartan is sold. Propranolol on the other hand is sold under the brand names Inderal, Inderal LA, InnoPran etc.

SOURCES

  1. Image Credit: Cipsartan-16 (Candesartan Cilexetil Tablets 16 mg) from Cipla; pharmacywebstore.com; Web January 2014; http://bit.ly/1aqwpIO
  2. New Hope for Migraine Sufferers; ScienceDaily.com; Web January 2014; http://sciencedaily.com/releases/2014/01/140113104841.htm
  3. Angiotensin II receptor blockers; Diseases and Conditions; Mayo Clinic; Web January 2014; http://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/angiotensin-ii-receptor-blockers/art-20045009
  4. University of Science And Technology – News’ Web January 2014; http://www.ntnu.edu/news/2014/migraine-help

For more details of the study, please visit:

A Comparative Study Of Candesartan Versus Propranolol For Migraine Prophylaxis: A Randomised, Triple-Blind, Placebo-Controlled, Double Cross-Over Study; Sage Journals – Cephalagia; Web January 2014; http://cep.sagepub.com/content/early/2013/12/11/0333102413515348

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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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New Rapid Relief Migraine Drug from MAPP Inc Issued U.S Patent

The US Patent and Trademark Office has issued MAP Pharmaceutical Inc’s new drug under the banner, “Method of Therapeutic Administration of DHE to Enable Rapid Relief of Migraine while Minimizing Side Effect Profile.”

Pulmonary Administration DHE from MAPP Issued Patent (1)

The drug’s primary ingredient DHE or Dihydroergotamine is MAPP’s proprietary formulation. The novelty of this new formulation is that it has proved to have rapid efficacy in curbing migraine pain but minimizes the adverse effects that other migraine formulations have.

To be able to achieve quick distribution, metabolization and excretion of the drug, the DHE drug involves pulmonary administration or inhalation of the drug. This is advantageous as the results are almost instantaneous because the drug does not undergo a ‘first-pass effect’ and is absorbed almost entirely into the general blood circulation through the lungs.

The drug has been named LEVADEX® is an orally inhaled investigational drug administered using the Company’s proprietary TEMPO® inhaler for the potential acute treatment of migraine in adults and targets the pharmacokinetic profiles described in this patent. DHE is a drug that is currently available in other dosage forms to treat migraine. (2)

SOURCES:

  1. Image from Ambro; Freedigitalphotos.net; February 2012; http://www.freedigitalphotos.net/images/view_photog.php?photogid=1499
  2. MAP Pharmaceuticals, Inc. (MAPP) Issued Additional U.S. Patent for Methods of Achieving Rapid Treatment of Migraine Based Upon Pharmacokinetic Profile; BioSpace; Febraury 2012; http://www.biospace.com/news_story.aspx?StoryID=250731&full=1

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What the Migraineurs Should Know About The Triptan Drugs

(Source: http://tinyurl.com/l332mz )

Triptans are the relatively new weaponry in the scientists’ arsenal in migraine management and treatment. They work at the neurochemical (serotonin receptor) level. Triptans are not painkillers. All the Triptan drugs act at the wall of the blood vessels (especially cranial/dural blood vessels) and cause their constriction (or narrowing) called vasoconstriction, thus offsetting the swelling that causes the pain. It is also effective in alleviating some of the other symptoms of migraine attack such as sensitivity to light and sound. It acts towards stimulating the release of serotonin in the bloodstream.

Triptan range of medication includes chemicals Frovatriptan, Naratriptan, Eletriptan, Sumatriptan, Almotriptan and Rizatriptan. They should however, never be mixed with ergotamine drugs or any other drug stated in the drug literature or by the doctor. In addition, they are not to be taken in conjunction with any anti-depressant that is known to increase serotonin levels. Neither are they indicated for use by hemiplegic and basilar artery migraineurs.

All of these medications have similar possible side effects such as those of dizziness, fatigue, tingling sensations on skin, dryness of mouth, hot flashes, chest pain or tightness, sensitivity to temperatures, joint pains, coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation, serotonin syndrome etc.

Triptan drugs are available at pharmacies on showing a doctor’s prescription due to the potential side effects, which may be serious in nature. Some Triptan drugs work faster than the others do. Some others work for longer hours, some have only one set of side effects, and the other Triptans may have another set. This makes it imperative for you to consult your doctor before taking these medications. The doctor will make a decision on a case-to-case basis depending on your migraine frequency, intensity, duration, medical history (especially those of heart, diabetes and hypertension etc).

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