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The CGRP Receptor and Migraines.
A video review from Eli Lilly. Venture 17 has no economic relationship with Eli Lilly. This video is for educational purposes only.
Click this image to view the video.
Another year has gone by, and in two short weeks, we celebrate National Cancer Survivor’s Day. When this day arrives, I am always taken back and remember those who never had a chance to celebrate this day.
Having practiced medicine for more than three decades, as a physician I was firmly involved with the care of little children. As a Family Doctor, Internist, and Hospitalist, I saw my fair share of childhood diseases. One could truly say, I was allowed to save many lives with help from others on the medical teams I was proud to work with, and of course the cutting edge technologies afforded those of us who are privileged to practice medicine in the United States.
It is interesting, the things in life which will push a man toward a life of education, and prepare him for the profession of medicine. One of those things was an event in my childhood in the early 1960s.
When I was a boy, I had many friends in school and outside of school alike. Growing up on a ranch in Nebraska, it was not unusual to have many friends who lived in small towns come to visit. One of my friends outside of school lived in a nearby town, but came over often. David and I were both eight years old. I remember fondly of playing “army” with David in the yard, and board-games indoors when he would come over. I liked him. He was friendly and got along with my sister and little brother too. We became fast friends, and I would always get excited when David came over or we went to his family's house. We were both Cub Scouts but in different troops. You would always hear about how much David loved Scouting.
Soon though, the visits became fewer and fewer. David seemed to look frail and discolored to me as time went by. The color thing really bothered me. I know this sounds awful, but in addition to his color, he had an odd smell around him that seemed to worsen every time I saw him. What's worse, is it seemed that I was the only person that thought he smelled funny.
I asked Mom, “What’s wrong with David?” Mom said, “He’s sick, honey. He has cancer of the blood. It’s called leukemia”. As you can imagine, this was a little difficult for an eight year old to take in, but as time went by, I learned more and more.
David’s parents were good friends of my parents, so we saw each other as families often. After he became ill, we saw less and less of them. Very rarely did I get to see my friend. David had an ever advancing condition of weight loss, bruising, sore joints, infections, was easily brought to tears, and after a while, his hair even looked funny. How does an eight year old process this inevitable plunge? As children; David, his sister, my brother, my sister and I, we were not emotionally mature enough to process this whole thing.
At home we would get the occasional phone call that he was back in the hospital. My parents were great. When we would get these calls, Mom and Dad would sit with us and try their best to explain this thing called leukemia. Understand, this was 1961, and leukemia was known as an unrelenting killer of children. There were no cures. Not even a good treatment. The medical community was desperate for a foothold.
One night we received a phone call from David’s father. David had passed away at the young age of eight. I remember, it was really the first time I heard those words, “passed away”. It was also the first funeral of someone that caused me to take pause, and realize we are mortal. I know, I was just a child. I had seen two grandfathers buried, but I was very quiet and overcome by this intense event. All of these grownups I knew as strong, would breakdown and start to cry. I never the less watched in a surreal world of sadness, my parents’ good friends bury my buddy, David…. And that image which is still so clear…. My friend, asleep in his Cub Scout uniform.
All the while I was there, I remember thinking David might come running out from behind that marble stone, but he never did.
Why had this happened? I seemed to feel a pull even then, “The Calling”, so many of us drawn to “Medicine” and trained as healers, will occasionally and quietly talk about.
Time went by, but I often thought of David and how unfair it had been for him and his family. The early 1960s saw almost all children die who had leukemia. The five year survival rates of children then, were only one in ten. All any family could do, was wait and watch while their babies died in agony. He never had a chance, I often reflected. A sweet kid, taken from his family at such a young age. He never got the chance to do anything after he became sick. Never got to be an Eagle Scout, play baseball, be cool at school, or fall in love. How scared he must have been. I come to tears just writing about this.
Time marched on and while in high school, I would hear of small advances in the fight against cancer and leukemia. Then, in the early 1970s, when I was in college studying chemistry, we began hearing about new therapies.
Although the drug, Methotrexate, had been used with some promise through the 1950s and 1960s, the survival rates continued to be low, and drug resistance was always a glaring problem. It killed leukemia cancer cells by attacking their ability to process folic acid for DNA synthesis.
But the 1970s and 1980s brought Bone Marrow Transplantation and Craniospinal Irradiation. Huge game changers which produced not just remission, but cures.
I had grown up with kids who had polio, but now, it was gone. Diphtheria was gone. Small pox was all but vanquished (completely eradicated by 1982). Psychiatric hospitals were giving way to more advanced neuroleptic drugs, allowing former patients to re-enter society and become productive citizens. They had just invented the CAT Scanner. They had started to use lasers in ophthalmology. And, I thought, even William DeBakey is transplanting hearts with Denton Cooley down in Texas of all places! Things were really happening in Medicine, and I wanted to be on the inside not the outside.
I had an epiphany. Already a man of science, I realized then, that I was going to be a doctor.
As time went by, more of these anti-metabolite drugs became available and we started to see a real dent in childhood mortality from leukemia. Soon after, in the late 1970s, when I was a biochemist and starting my medical career, a drug from a flower called, “The Rosy Periwinkle”, which only grows in the rain-forests of Madagascar(go figure), gave us a new drug called Vincristine. A drug that could only be brewed in mother nature’s kitchen. We were now seeing high cure rates and remissions. Lives were now being saved in this war.
My friend David had what we call one of the “acute leukemias”. There are many types of leukemia, but there are two well known leukemias that prey on children. They are Acute Lymphoblastic Leukemia, ALL, the one David had, which generally seeks out kids two to ten years of age, and Acute Myelogenous Leukemia, AML, which generally hunts down our babies under one year of age.
The acute leukemias are proliferating bone marrow tumors of cancerous precursor white cells still in the immature blast cell phase. The cells do not work like healthy white cells to combat infection. They multiply wildly, creating havoc in the body, literally consuming the patient to death, a condition we call, "cachexia". Patients have intense bone pain, anemia, infections, swollen lymph nodes, enlarged spleens and livers, and, for some, meningitis, strokes, heart attacks, and kidney failure. Without treatment, they are dead in a few weeks to a few months.
We still do not have a full grasp on their cause. Most are caused by oncogenes, which are mutated cancer inducing genetic codes for programming carcinogenisis and disrupting programmed cell death we call “apoptosis”. What causes this, is the head scratcher. Many of us feel it is radiation exposure, or certain viruses. Perhaps environmental toxins, or even cosmic radioactive bursts. And of course, man-made toxins are obvious suspects.
By the early 1990s we were seeing cure rates in both ALL and AML of fifty percent and remission rates in the eighty percent range. What a leap. In just 3 decades we saw a paradigm shift in the treatment and outcomes of our children with leukemia, moreover, a shift in therapies which utilized a team approach to protect our children from the acute depression and other collateral illness which accompany these diseases. Newer drugs like Daunorubicin have accelerated this to even better outcomes. Although this drug is very effective, it is extremely cardiotoxic and not generally used in children. However, it should be noted that we are now seeing ninety five percent remission rates and sixty percent cure rates in our children with ALL, and AML, a true shift in mortality that could only be dreamed about just thirtyfive years ago.
Drugs like Methotrexate are still at the heart of leukemia therapy, and are used in combination with other drugs, along with bone marrow transplants and radiation treatments. Unfortunately, these drugs are very expensive, which creates an obvious ethical dilemma.
But now, what treatments are on the horizon for leukemia? There is a new drug. This drug arrived on the cancer chemotherapy shelves about fifteen years ago, but shows outstanding promise even outside of cancer therapy. Used mainly for Chronic Myelogenous Leukemia, CML, a leukemia seen mostly in older adults, it is highly effective. Rendering oncogenetic codes for cancer cell induction dead in their tracks. It is a target drug aimed at a specific chromosome translocation defect which exists in more than 90% of CML patients, called the Philadelphia Chromosome. The drug, Imatinib, was built from a rational drug design based on biochemical research already in place regarding the specific allele the Philadelphia Chromosome codes from, and shuts down the production of a protein called tyrosine kinase which induces cancerous breakdown of normally functioning white cells.
Imatinib has been used as therapy for other leukemias including refractory ALL and myeloproliferative disorders (bone marrow cancers) with outstanding success. But what is also very interesting is its experimental applications which are currently being investigated.
Imatinib has been touted as a treatment for pulmonary hypertension, a rapidly fatal form of high blood pressure in the lungs. It has been shown to reduce outcropping we call smooth muscle hypertrophy and hyperplasia of the pulmonary vascular tree. In systemic sclerosis, the drug has been tested for potential use in slowing down pulmonary fibrosis. In addition, current laboratory investigations show promise in stopping the progression of atherosclerotic vascular disease. Yes, a treatment for coronary artery disease.
At Emory University in Atlanta, there are promising studies suggesting that Imatinib could be used as an antiviral against smallpox. Why is this important? Although this disease has been wiped off the face of the earth with the remarkable efforts of the World Health Organization, and no case has been identified in over thirty-five years, We continue to believe a weaponized form of small pox launched from a rogue nation is possible.
Studies also suggest that a modified version of imatinib can bind to the protein which increases the production and accumulation of amyloid plaques in Alzheimer’s disease, rendering it inert. Yes, a treatment for Alzheimer’s Disease.
But with all of this in our doctor bags, there is still a dark and ominous specter. Although great strides have been made, and I was privileged to meet and take care of children with leukemia, and even watch them overcome the illness and move on with their lives, one patient stands out.
I was working the Emergency Department one night in 1995. It had been relatively quiet that evening, when at approximately two in the morning a man walked in carrying his teenage son. We acted quickly and helped him get his son to a gurney in an open bay.
The staff and I immediately recognized the man’s son as Eric, a well known high school football star. The father said he found his son crawling on the floor trying to get to the kitchen to get a drink of water. Eric looked awful. There was that damn color again. Eric was delirious with fever, weak, and poor to respond. We went to work on him immediately. His dad said that he was fine just a month ago, but had developed a sore throat at about that time, and was seeing one of our local doctors who just kept giving him antibiotics.
We managed to get young Eric stabilized. Just as we were settling him in and making his father comfortable, I received a call from the laboratory. The lab tech asked me to come down to the lab. I ran to the laboratory. When I got there the tech was shaking her head as if to say, “this is really bad”. I looked at the blood count machine’s screen. “my God”, I said to the tech. “His white count is seventy thousand”. I looked in the microscope. “Blast cells”. I knew right away we were looking at an acute type of leukemia, but couldn’t recognize it with just light microscopy. We needed more tests.
When I dashed back to the Emergency Department, Eric was coming around a little. I spoke with him and reassured him. But the look on my face when I turned to his dad? He knew I didn’t have good news. We talked at length, then, I called in Eric’s regular doctor.
They talked while the team and I continued to work on Eric. I called in the helicopter, spoke with the Hematology Fellows at the university, returned to Eric and his dad, made sure they knew what we were doing, and flew them both to University Hospital. All eyes turned to the Hematology Oncology Service with hope that they could help young Eric.
One week later, while seeing patients in my office, the Hematology service at the university telephoned me to say that Eric had “passed away”. You sit by yourself and reach for introspection when these things sting you as a healer. When we lose children, most of us as doctors weep in quiet seclusion and solitude (We all have PTSD).
I wondered. How does a robust young athlete get sick with leukemia, fail in health so quickly, and die in one month? As it turned out, Eric contracted a type of AML, called Promyelocytic Leukemia, one of the most deadly forms of AML, one which preys on teen-aged children, and takes them away from us with stealth and quickness.
So you see, our job is not done. I am reminded as to why we call it a “practice”.
Our knowledge of the genome, stem cell technology, oncogenetics, and nanotechnology races onward. Our ability for rational drug design is extraordinary, and the technical savvy to produce these great magic potions has been nothing short of miraculous.
In just over four decades, we have all but squashed the disease that took my friend, David. But as you can see with Eric, we are not finished. I still think of David fifty-five years later, and how his death stirred in a young boy, "The Calling". If I was educated only to save but one human being, it was all worth it.
We already have at our fingertips two technologies that must be placed into motion. Stem cell research has already given us the ability to crush this killer, and should never be interrupted. And, the science to manipulate the oncogenes so responsible for the fuel that drives these diseases.
My hope is that with our new technologies, in the near future, we will not need any drugs for leukemia. We will simply turn off the genetic machinery of bone marrow cancer, and not allow leukemia even to exist, and therefore, never threaten our children again.
Many of you have read my article on
My Headache a Migraine
. Recently I have been approached with questions
from my college campus students regarding their children and the brittle
headaches their kids endure. Two students in particular stated that their child’s
doctor had diagnosed them as having migraines, prescribed the medicine, periactin as needed, but did not explain to them what
migraines in children are really all about.
This is a little disturbing to me, as I feel the more educated my patients are, the better they are able to manage their headaches and lead normal healthy lives. This falls on the treating doctor, and unfortunately, it seems this new era of doctors is in such a hurry, it has forgotten how to teach. Osler would role in his grave!
This part of treatment is obviously more important than the "periactin". And both should be part of an overall plan. "Written down and easy to follow", by both the parents and the little one.
So, I thought this would be a good
time to again discuss this very debilitating disorder. No one ever wants to see a child suffer through these. I recommend reviewing the
above article in addition to this one.
When you think about someone having
a headache, you probably think of an adult. But many kids have headaches too,
and for many of the very same reasons that adults have them.
Children and teens can experience
muscle tension or migraine headaches. Among school age children ages 5 to 17 in the
United States, 20% are prone to headaches. Approximately 15% of these kids
experience muscle tension headaches and 5% are dealing with migraines.
Chronic or frequent headaches can be
tough to handle, and are even harder to understand when you are young, especially
if you do not know anyone else who has them.
By the time they reach high school,
most young people have experienced some type of headache. Fortunately, less
than 5% of headaches are the result of serious disease, such as a tumor,
abscess, infectious disease, or head trauma.
Most headaches are muscle tension type, the
result of good and bad stress, sleep issues, or in a few instances,
environmental or food triggers. About 5% of recurrent headaches will be diagnosed
Episodic headaches are those that
occur a few times a month at most. Chronic headaches occur with much more
frequency, even several times in a week. If a child who has only had an
occasional headache (once or twice a month) starts experiencing them more
frequently (two, or three times a week), then these should be considered
chronic and medical attention should be sought as soon as possible.
One of the most frustrating aspects
of chronic headaches is the stress factor. Avoiding a known trigger is usually
easier than avoiding stress. Young people want to do well on tests and in
school, and they want to attend important events, but anticipating a math quiz
or musical recital, or eagerly looking forward to a party or being in the
school play, can result in anxiety or excitement. And, for some kids, this
leads to a headache.
Up to 4% of children have their
first headache before they reach elementary school, and they may not yet know
how to describe the pain. If a young child has been crying or not eating, or
has been restless or irritable, consult with your doctor about finding the
source of discomfort or pain. Remember, the child has no idea what is happening and this can be very frightening.
The more knowledge (and easy to understand guide lines) school health officials, as well as parents have about children and chronic migraines, such as common
triggers, symptoms, prevention, and treatments, the easier it will be to
identify the child who is suffering through these headaches.
The best evidence based approach to treatment, interestingly, is the more holistic approach to little patients. It entails two things: 'chronic therapy', which addresses decreasing the frequency and intensity of the headaches, and 'acute therapy', which gives the patient and parents weapons to stave off an evolving attack.
As I have discussed in other
articles, in adults, a migraine's throbbing head pain usually occurs on one side
of the head, but in children it can affect both sides. The migraine is often
accompanied by nausea, vomiting, dizziness, blurred vision, sensitivity to
light and sound, and changes in temperament and personality. A headache's duration
varies from individual to individual. But, generally, unlike adult migraine,
which can continue up to four days, a child's migraine might be as short as one
hour or may last for a day or so. Children also improve more rapidly to sleep.
So, the best treatment for children is a nap in a quiet, and dark room.
About 15% of kids experience a migraine
headache with an Aura. A typical aura is seeing colored or flashing lights,
blind spots, or wavy lines or feeling a tingling in the face or an arm or leg.
An aura alerts a migraine sufferer to the onset of a headache, warning the
child several minutes before the pain starts. A small percentage of migraine
sufferers also encounter temporary motor weakness, as they may lose their sense
of coordination, stumble, or have trouble expressing themselves.
Young children with migraine may not
have head pain at all but rather experience recurrent stomach problems or
dizziness. These types of migraine are called migraine variants (Migraine
Variants will be addressed in a future article). Children who have migraine
also are more prone to motion sickness.
For most kids, migraine is inherited from a parent. Migraine
occurs because of alterations in a person’s genetic makeup. An
individual migraine attack is often triggered by a particular environmental or
emotional event. In some cases, triggers can be identified. Among the most
commonly recognized ones are stress (good or bad), a change in routine, a change in sleep
pattern, bright lights or loud noises, or certain foods and beverages. Let’s
look at these for moment.
One of the things I first have
patients, especially children do regarding brittle migraines, is keep a diary
of foods, sleep patterns, and other possible triggers. The best way to do this
is to get the whole
family involved, and
use a big wall calender with plenty of space for everyone to write down what
they observe, as one person may notice something another didn't.
There are many triggers in childhood
migraines that should be weeded out. Foods are huge, but other things as
mentioned above, like stress level, even positive stressors like more money,
new teacher, family gatherings, etc. can be big. Sleep can be a major player. I can't stress enough, the value of regular sleep
patterns and at least 9 hours of sleep every day for kids.
Food is probably the biggest player, so you have to read labels closely. Here
are the biggest triggers I've seen in practice:
(1), Caffeine in any form, even in medicines. Keep in mind that caffeine is
also used to treat headaches, but can be a two edged sword, and, induce “rebound
phenomena”. (2), Mint, it's in everything, start tossing it out. (3), Red food
dyes. (4), Yellow food dyes. (5), Hard aged cheeses, like Parmesan, and
cheddars, remember also, that cheeses are not naturally yellow ( they have
yellow dye in them). (6), Pizza. (7), Lunch meats. (8), Hot dogs and sausages. (9),
Bacon, use "fresh-side", or "sugar cured".
The above meats have nitrates in them which
(10), chocolate in any form. (11), yogurt. (12), Chinese food (oriental).
(13), The additive, Mono-Sodium Glutamate (MSG) is a monster and must be avoided, it is in
everything from snack foods, frozen foods, bullion, and ramen, to canned soups. (14), All citrus products. And watch out for sugar binges. Remember to write down every little detail that appears significant on that calendar,
and let your doctor know how it's going.
After a formal diagnosis, a doctor's
goal is to help reduce or eliminate the symptoms of a migraine and prevent
to treatment, sometimes children, especially young
children, do not need any medication to treat a headache. Often there are
non-medicinal treatments that can provide primary, or added benefit.
During a migraine attack, a child
should be allowed to rest, and even sleep, in a quiet, dark and cool room.
Raising the child’s head up on a pillow and providing a cool compress for the
eyes or forehead can help them feel more comfortable. When at school, a child should
be allowed to go to the nurse’s office and rest. Sometimes a quick nap is all
it takes and they can return to the rest of the school day.
Trigger avoidance and a regular
schedule are huge preventive measures that can be taken to avoid the frequency of
attacks. Relaxation and stress management
techniques can be helpful during an attack and to help alleviate stress before
it becomes a full blown an attack. Daily physical activity is also very
important in headache management and stress reduction. Two methods that have
been well documented to help children with migraine include meditation and
biofeedback. There is also much research that suggests hyper-hydration with plain water may
prevent frequency in migraine attack.
Once a migraine has begun, several
types of medication can alleviate the symptoms. Analgesics, such as acetaminophen or
ibuprofen, are first-line pain relievers for treatment of headaches in children
and adolescents. The Triptans can be helpful in those children who don’t find
simple analgesics helpful. There are several different triptans available and
two (almotriptan [Axert®] and rizatriptan [Maxalt®]) are FDA-approved for
children. In addition, your doctor may also prescribe anti-emetics to stop the
nausea and vomiting or a sedative to help a child rest.
Aspirin is not generally recommended
for kids, as there is now, well documented evidence linking aspirin to the development of
Reye's Syndrome, a rare disorder that children and teenagers can get while they
are recovering from childhood infections, such as chicken pox, flu, and other
viral infections. Reye's symptoms include nausea, severe vomiting, fever,
lethargy, stupor, restlessness, and even delirium.
Children and adolescents who
experience migraine attacks more than twice a week and which interfere with
school or social activities, may be prescribed a daily medicine to try to
prevent headaches. There are no medications that have been specifically
designed for migraine so they all come from other categories including
anti-seizure, blood pressure and anti-depressant drug classes. Common
preventive medicines include beta blockers, tricyclic antidepressants,
topiramate, and valproate. Please note: none of these medications are approved
for migraine treatment in children. However, research in this area continues
with excellent progress and doctors will utilize these medications as "off label" prescriptions.
Frequent headaches, especially those
that occur more than once a week, deserve treatment, with both medication and
non-medicinal options. Headaches are not good for the brain and
headaches often lead to more headaches. With the right treatment regimen your
child can get his or her headaches under control and prevent further
Further questions can be directed
below, and look for continued articles on headaches in future posts on The Searchlight Messenger.