The Elephant in the PD Lab

We need a better roadmap for Parkinson's Disease

The PD summit has yet to be conquered

People with Parkinson's can feel overwhelmed by the search for the most effective treatments and therapies. There are so many information bytes out there. You read all day, maybe purchase some full scientific articles only to find you don't actually understand enough or you see that the focus is so small that only scientists can analyze it.  Without a photographic memory to categorize input, without huge resources how do you find your direction through the maze?

You wonder if you are the only one missing the keys?  How do you take this mass of information and reduce it, refine it to create a map to actually get to a treatment which will not only stop progression but reverse it?

We have Centers of Excellence for research and treatment. The Morris K Udall Parkinson's Disease Research Act of 1997 was established in part "to provide for the expansion and coordination of research regarding Parkinson's disease, and to improve care and assistance for afflicted individuals and their family caregivers." But much of the research being done for PD and other conditions does not fall under that umbrella.

We have Clinical Guidelines for diagnosis and management of PD - primary and secondary care at the National Guidelines Clearinghouse.gov. The concept is both reassuring and frightening because it has an inherent structure which can slow progress of care but may not allow for slowing the progression of the disease without a readjustment period.

Searching for....

Every day we search through abstracts about Parkinson's related global research.  Sometimes it seems that the directions are so similar but we know that some replication is necessary. Other times we see dead ends - also necessary because they may be avenues for other medical conditions.

We worry that laboratory focus will be lost in the fascination for the details.  Perhaps we don't comprehend because we are not scientists but as people with hope and confidence. Perhaps it is the frustration level and the fears that keep us from understanding.  Or we don't see an organization of information, a compilation of past and present knowledge, because it just doesn't exist.

Previously we have discussed the importance of recognizing and treating the precursor symptoms, of identifying biomarkers in order to delay onset, to implement preventative therapy. We've talked about proactive patients being good "teachers" for doctors because the patient has the motivation to search for more therapeutic information about his/her condition. While some patients rely totally upon the medical professional, these days many more realize that they must integrate the common experiences of others in order to find effective supplemental treatments. And still others step completely outside the box on the promise of a cure.

The beauty of patient experience is that it can open eyes to possibilities and potential as doctors begin to treat patients and not diseases. This is one reason that we go to every medical appointment with printed material even if it is a revised medication and supplemental list which explaines why, when, how each treatment is taken.  Next we will add to a second list which explains changes in physical, cognitive and emotional condition. Many doctors do seem to hear better with their eyes...if they are going to take the time to listen at all.

Our perception of  the Parkinson's knowledge base seems at times much like the assorted parts and pieces the blind men explore when surrounding the elephant while trying to describe it. Of course we need a complete description of an elephant, not an abstract simile nor an elephant by committee. That is where Sergey Brin of the Google team found himself when his genetic testing disclosed the same LRRK2 mutation exhibited by his mother, a PwP.  Mr Brin has worked himself to a position where he has acccess to the resources to do something. He has means create the protocols to organize the data to see the patterns of the elephant. To bring, eventually, sentient life to the elephant.

Glutamate, The Caffeine Gene, and the World Parkinson's Congress

What are we learning about glutamate and Parkinson's disease?



There's good news



For years we've been asking restaurants to omit the MSG because we get funky headaches later after eating foods containing this excitotoxin. We'v been reading food labels to avoid monosodium glutamate.  We were already working on an article about glutamate and the role this protein building amino acid and neurotransmitter plays in Parkinson's disease. We learned a little about the good, the bad and the ugly in the process. 

We know that glutamate is a rapid, excitatory transmitter and that it can be associated to a vulnerability to addiction, so perhaps you could call it the smoker's nemesis.  We also know that glutamate receptors are necessary for proper central nervous system functioning, for important cognitive function including memory formation and learning.

This week everyone is talking about glutamate and GRIN2A because of the news from the World Parkinson's Congress currently being held in Glasgow, Scotland.

The coffee cups are waiting 

It has been learned that GRIN2A, is the "coffee" gene which when combined with caffeine intake appears not only to be neuroprotective for PD in a certain percentage of the population but may also affect PD clinical trial results when some study participants may have the altered GRIN2A gene.  This in turn raises the question of whether it can also influence medications used to treat Parkinson's disease symptoms.

Those people protected by the caffeine gene are carriers of a specific variation of GRIN2A according to information discussed at the World Parkinson's Congress.  At this time the focus is on a limited population.

We already know from the long Hawaii coffee study that people who had regular caffeine intake were (48%-84%) less likely to develop Parkinson's disease. It would be more than interesting to know how many members of this study also had the special GRIN2A gene version. But that was then and we didn't have the same technology or gene bank.

GRIN2A is a glutamate NMDA subunit receptor in a class of ionotropic glutamate gated ion channels, permeable to calcium. There has already been research about Bipolar disorder, ADHD and Huntington's disease as well as Parkinson's disease in connection to a hypoglutaminergic condition being involved in the pathogenesis.  And certainly the negative role of glutamate in Parkinson's development is not unknown.

Researchers have been looking at the GRINB2 subunits for many years and their connection to PD in the forms of selective antagonists which can exacerbate levodopa-induced dyskinesia in animal models. In other animal studies it was discovered that loss of striatal dopamine led to an increased stimulation of NR2B aka GRIN2B which contains NMDA receptors.

Basically glutamate becomes a link in the nitric oxide chain.  Under certain conditions glutamate can break through the outer cell membrane via the NMDA (n-methyl-d-asparatate) receptors located on the neurons.  This creates a breach through which calcium can enter the cell.  We already know that calcium is implicated in the death of dopamine neurons. If this chain can be interrupted...

To read more about the 2010 World Parkinson's Congress and to see folksy photos, check out Talk Parkinson's. 

Additional reading:

Gene reference: GRIN2A 

Netherlands twin studies 

NMDA Receptors

Primate home range and GRIN2A

Webinars and Webcasts of Interest for Parkinson's Disease

For PwPs, Caregivers and Families:
You might be like to attend these online events

Drug Development Pipeline on Thursday, June 24th, 2010

2:00 pm to 4:30 pm EST

Direct from the Campus of Georgetown University, Parkinson's Action Network (PAN) is hosting "Emerging Therapies: From Microscope to Marketplace" featuring a panel of speakers from the scientific community. Each will address a different stage in the drug development pipeline process.

Howard Federoff, M.D., Ph.D.: Executive Vice President for Health Sciences and Executive Dean of the School of Medicine at Georgetown University will moderate.

The panel:

James P. Bennett, Jr., M.D., Ph.D.: Chair, Department of Neurology and Founding Director of the Virginia Commonwealth University Parkinson's Disease and Movement Disorders Multidisciplinary Research and Clinical Center

Story C. Landis, Ph.D.: Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Raymond T. Bartus, Ph.D.: Executive Vice President and Chief Scientific Officer, Ceregene, Inc.

Jackie Hunt Christensen: PAN Minnesota State Coordinator and Clinical Trial Participant

Janet Woodcock, M.D.: Director, Center for Drug Evaluation and Research, Food and Drug Administration

Registration is not required. On the day of the Webcast, simply visit the PAN home page and tune into the Webcast from your home or office computer.
For more information on the Webcast, please e-mail PAN

Registration is not required. On the day of the Webcast, simply visit the PAN home page and tune into the Webcast from your home or office computer.

~~~~~~~~~~~~~~~~~~~~~~~~

From AARP on the same day, Thursday, June 24, 2010

"The New Health Care Law: What It Means for People with Medicare"

Times are:

2:00pm -3:00pm EST

1:00-2:00 pm CST

12:00 pm-1:00 pm MST

11:00 am -12:00 pm PST

To register at AARP for this event, click here

There will be a Question and Answer period with AARP experts

~~~~~~~~~~~~~~~~~~~~

Did you miss one of the Parkinson's Disease Foundation (PDF) Educational Events?

You can see and/or hear them here.

Changing Stages of Parkinson's Disease

I'm Back

This is the first  article I have written for my blog in almost six months.  After eight years of  having Parkinson's disease and treating it fairly successfully with medication, alternative medication and nutritional supplements, exercise, massage and diet changes, I ran into trouble between Thanksgiving and Xmas last year.  I thought they were symptoms of  PD.

The urinary symptoms which had been under control were no longer controllable; perhaps because I was neglecting to take the herbals which had helped for so long. Suddenly I had to urinate really frequently and didn't always make it to the bathroom even though my bed is only 20 feet away. I became afraid to leave home for fear of being too far from a rest room. Vivid dreams occurred so often that I could not tell what was real and what was not. My overall memory of this period is vague but I felt as if I were dying.

Although I primarily stayed in bed, often I thought I was someplace else and worried about how I was going to get home. In an amazingly short period of time I went from the early stages of Parkinson's to an advanced state; it seemed to take 2 or 3 weeks. (Editor's comment: it was practically overnight)

How did I get to that state?

In early November I had an appointment with my primary care doctor to discuss some alternative treatment options.  He referred me to the neurologist to continue this discussion. The urinary issues were not discussed although we did discuss my arthritic knee and the loose tendons. One area of concern for me was the MRI he proposed.  I do not like MRIs. I do not like being in places which I cannot leave of my own free will. 

Even the open MRI which I was supposed to have done years ago, did not take place because it was too stressful for me. This doctor  suggested that we could begin with an Xray and take it from there.  He gave me the lab order but I was too shaken by the mere mention of an MRI to do even that.

We made the neurology appointment as suggested and then my wife decided that the Xrays had to be done before that appointment in three weeks.  She finally nagged me to the lab for the Xrays a few days before I was to see the neuro.  That weekend I hardly slept and the urinary issues were getting worse. I wasn't eating as much and had been limiting my coffee and tea intake because of the urinary frequency and urinary hesitancy. As a matter of fact, I was limiting all fluid intake.  No fluid - no urinary frequency - no problem. But there was a problem and the frequency urges did not stop.

By the time we were talking to the neurologist, the transition was taking place. I asked not for the intended alternative treatment but for Sinemet which I thought would help the urinary issues.  He agreed after the routine PD testing.  By the next day the nightmare was developing full force.

Almost overnight I was having difficulty walking down the hall. I could barely stand erect. Cognitive skills were muddled by hallucinations and illusions.  I needed assistance to get into bed, instructions just to roll over. I needed help pulling up the blanket. Dressing and bathing without help was impossible. I would get up to eat but continued to drink only enough liquid to swallow a pill.  I recognized the woman who prodded me about drinking more water during the day as being very similar in appearance to the woman who responded to my nightly hollering for help. Who was she?  This nurse gave me my wife's name when I asked.  What was this place?

My wife, meanwhile, was learning what you need to do to get a doctor's secretary to relay the seriousness of a condition. Because I had signed a release allowing the office to speak to my wife about my care, she knew she was on safe ground there. Her early calls were partially successful.  The primary care office called back to refer her to the neurologist. The neurologist called back to say that Parkinson's disease can't go through such a short term transition and so we were looking for another cause possibly a UTI...and referred her back to the primary care doc.

She made the appointment for the following Monday and sat down to think and to discuss the issue with the massage therapist when she called to cancel my appointment. Sleep deprivation was only part of the problem.  So she gave me cranberry capsules insisting that I drink more water.  For half a day, I had a return to normalcy.  And she had an insight.  I was dehydrated. 

When we went to the doctor's appointment, she took my urine specimen along.  She insisted that it be tested.  When it came back negative the discussion turned to prostate issues.  We left with sample bottles of Flomax.  What we didn't know was how long it would take before the Flomax would work - that it actually would be another 5 weeks before for the compulsive insistence that she walk me to the bathroom every 20 minutes would stop.

The dehydration issue was caused by the enlarged prostate which I knew about but didn't discuss much. Years earlier I didn't want to take the meds and had found relief with herbals. But this time I had confused the prostate problem with PD which exhibits the same symptoms.  I'm an older man, older men frequently develop prostate issues.  Had I talked to my new doctor about the problems instead of accepting that they were part of the disease, I wouldn't have had to endure all of this.  The damage done by the dehydration, the stress for all of us except the cats - the dogs were very subdued during the first month - was intense.

It has been a long recovery and we learned a few lessons and revisited a few others.

 1)  Protective underwear is cheap in comparison to losing 4 productive months.

 2)  Sign that doctor's release now so that your spouse or other family member can talk to the doctors office

 3)  Don't make that call or visit the doctor without a complete written list - make copies

 4)  Symptoms of dehydration and sleep deprivation are similar to dementia and to PDD

 5)  Ask how long it will be before you can expect to feel results from a medication

 6)  If a nutritional supplement helps, don't stop taking it just because there are so many pills to take

 7)  Don't assume that the problem is caused by the Big Problem;there can also be other medical issues - tell your doctor. 

 8)  Just because a doctor prescribes it, that doesn't mean you shouldn't do your own research for contraindications. (I have a faxed-in prescription that we will never fill for just that reason - my wife did the homework)

 9)  All of you caregivers out there deserve more credit than you receive! 

10) Be persistent - it can be depressing - don't give up.    

Neupro Rotigotine Transdermal Patch Ordered Back to the Drawing Board

Parkinson's disease and Restless Leg Patients Will Have to Wait - FDA Has Ruled

The news for US Parkinson's Disease patients waiting for an early FDA clearance of the Neurpro patch formulation is not good. On April 23, 2010 UCB announced the receipt of the FDA response letter.  The FDA informed UCB Pharma that it will have to resolve all crystallization issues with the Neupro® patch.  Apparently the policy is zero tolerance despite the fact that the patch was returned to the European market about 10 months ago.

We already knew that if the patch received approval (again) from the FDA that there would be a delay while the new patches were produced.  In all likelihood, the news would not have been officially released until the patches were on their way throughout the US to pharmacies for cold storage.  This delay would have put the availability back to the end of 2010.
  

With the decision to order UCB to find a definitive solution to the crystallization issue which did not appear to negatively affect users, UCB will be back to redesign.  The FDA acknowledged that the new refrigeration conditions - the cold storage distribution would "significantly inhibit the degree of crystallization on the batches but" the order is to reformulate the product to definitively resolve the issue.

From the 4/23/10 announcement: "We have already been working on a room-temperature stable, improved formulation of Neupro® and have made significant progress in this area," the Chief Medical Officer of UCB added. "Neupro® has made a meaningful difference for many people with Parkinson's disease and Restless Legs Syndrome. We are committed to obtaining FDA approval so that people in the U.S. who live with these diseases can benefit from Neupro."

The good news for PD patients around the world with the exception of the USA are the results of the RECOVER study were presented in at the American Academy of Neurology annual meeting in Toronto, Canada in April, 2010.  The data demonstrated the rotigotine improved both early morning motor function and improved non-motor symptoms in Parkinson's patients.  Symptoms such as sleep, mood, cognition and pain were measured and found to be improved.  Nocturia, night time excessive urination remained unchanged and there were some adverse events such as site reactions, nausea and dizziness in both the rotigotine group and the placebo group.  Rotigotine was shown to be effective up to 6 years and provided improvement in movement symptoms for up to 6 years.

In another study the Neupro® Rotigotine Transdermal Patch was shown to provide sustained benefit for Restless Leg Syndrome.

One thing to remember is that rotigotine is a dopamine agonist and as such there are also side effects.  It is unlikely that reformulation will alter those side effects because of the class of the medication.  For the people who have been helped by this medication, its loss was quality of life altering.

Based upon the fact that reformulation could take at least a year or two and FDA approval would probably take as long as their denial, it may be 3 years before it is seen again in US pharmacies.  After approval, there would probably be a significant period of time to begin manufacturing and distributing.

We wonder why the the FDA did not allow for a provisional approval for, say 2-3 years, while UCB worked to meet the present requirements.  Based upon the fact that the medication is on most of the world market already, it would be the humane thing to do.   

On a personal note, we'd like to apologize for the delay in posting the Neupro-FDA information.  I found it so upsetting, that although Steve gave me the information immediately, I couldn't find the words to express my disappointment.

Previous Neupro posts:

March 14, 2010

On 3/11/2010, 12/23/2009, 12/11/2009

November 26, 2009 in a Thanksgiving hope

August 16,2009

April 10, 2009 in which we included many links about the patch.

Addendum: On April 3, 2012 UCB announced that the FDA has approved the revised patch.  UCB has targeted July 2012 as for the return to the US market.

Coping with Problems of Postural Instability in Parkinson's Disease

Preventing those PD falls and What to do when you do fall

In the TRAP of Parkinson's disease, postural instability is the last of the big 4 symptoms. It is also the symptom which can lead to one of the leading causes of death for PD patients.

Postural instability can be caused by Parkinson's disease or can be related to syncope (fainting); orthostatic hypotension as a side effect of medications taken either for PD; neurogenic orthostatic hypotension as a result of a condition such as MSA; a cardiac condition, medication-induced dyskinesia, or another issue. Postural instability can also be a byproduct of depression for which PD does not lack.

Because there is little help through medication, that leaves devices, caregivers, exercise and the patient to recover from a fall or to better train the body to withstand the problems of postural instability.

Although I do not trust a lightweight walker for stability in heavy lifting, it might be of value if that is all that is around. It can be used for the patient to pull himself/herself up if someone is present to stabilize the walker. Otherwise both patient and walker could fall over. A cane with those extra legs at the bottom might do the job if there is arm strength.

There is also value to having handrails installed in hallways and even bathrooms just as they are on stairways. Avoiding backless chairs or stools is also advisable in order to avoid the risk of retropulsion - leaning back to regain balance or because of loss of balance with the resultant fall.

One important aid is exercise. Gait exercise can be crucial. We suggest asking for a referral to a therapy center so that gait training can be initiated. Gait training would include lengthening of stride, learning to open at the hips for a wider stance. The smaller the space between the legs, the less option to maintain balance. Lifting the legs almost in a march rather than shuffling and sticking to the floor may also be of value to provide a mental and physical cadence and to decrease the risk of the tripping on the shuffle.

Exercise addresses range of motion, flexibility stretching and yes, even strength training (to assist in rising if you do fall) and breathing. Yoga and Tai Chi exercises can help with balance and even graceful falling. Nautilus is important exercise equipment and there are less expensivel pieces of exercise equipment which can be purchased for home use. Don't neglect hand exercises. Being able to grip is crucial; a weak or claw-like hand won't help you.

Dance therapy might be helpful. Although its effects will not be physically apparent after the music stops, there might be a psychological-confidence effect which impacts postural instability due to PD depression. And it's FUN! Even in your living room. Get those endorphins going.

Locate a therapy center which has Forced Exercise equipment and aqua therapy. Water exercises can be beneficial to a PD patient because of the buoyancy effects of exercising - marching in the water. And Forced Exercise - not on a treadmill in this case unless there are trained spotters or with a support vest which attaches to the ceiling - but on the motorized exercise bicycles which compensate for the patient's inability to maintain the necessary rpms on his own. For some people these bikes are an affordable option for home use - for others, they are not. But the bike must be able to maintain between 80-90 rpm. There are two types of therapeutic bikes for this purpose. One is the Theracycle (there should be an ad link on this page). The other company is Reck MotoMed which makes several styles for home and therapy center usage.

Naturally there are aids such as shower seats (with backs or transfer seats), grab bars in the tub/shower area (no suction cups please), hand-held shower-heads with longer hoses and on-off buttons to prevent unnecessary standing in the shower. Soap on a rope.

No PD home should be without bath/shower aids even if they are not needed immediately. Knowing how to use them and using them regularly helps to train the body so that when the equipment is needed, there is kinetic memory to reinforce the use patterns. (Yes, I am a believer in the possibilities of kinetic memory to resist the tightening muscles and we have seen it work with my husband in entering/exiting the shower after the side effects of dehydration - another story - had some temporary but dire cognitive effects).

Little is available to address postural instability in PD. Usually discussed as a later PD symptom because it is apparent then, to many it is an invisible side effect as a very early symptom. Everyone talks about falls, the risks, prevention and the role they play, but we haven't found many solutions to address the problem by fixing the chemical imbalances which cause it because we are not sure precisely where in the brain the problem originates although the focus is on the brain stem.

There is one rather expensive pneumatic device which can be used in the home to aid in lifting and there appear to be patent applications for more. The link to this inflatable device is provide below at a site with which we are unfamiliar.

Have a home safety evaluation conducted. These are often done by occupational therapists - they'll survey the home, watch the patient functioning in their own environment and make safety recommendations. They need to know the patient has fallen in the past and what the ensuing problems have been.

The process for assisting a patient who has fallen is step by step after you are sure there has been no injury. Do not move an injured person. Make the call for emergency medical assistance. Or use that MedAlert button.

No injuries? Whew! Let's catch our breath. Everybody breathe calmly a few times to relax.

• Encourage the patient to roll from the landing position to a prone face down position. You may be able to assist with that.
• Next the patient must raise the upper torso onto bent arms. The lower part of the arm is on the floor.
• The buttocks are next, assisted by the knees.
• With weight on the forearms, rock forward and then back as you use those abdominals to lift your butt into the air.
• The knees will walk forward and assist with the push up.
• Once the patient is on his/her knees, you can assist them if they need help. If they are unable to rise from a kneeling position, they may be able to pull up on sturdy furniture or walker. Or you may be able to brace them (their arm around your shoulders and both of you rise from a kneeling position. The caregiver must keep a straight back to avoid injury.
• If you are alone, you may be able to crawl on your knees to furniture solid enough to provide support for the pull to a standing or seated position.

At this point prevention and exercise seem to be the best methods to reduce the risks. Many caregivers are simply not strong enough to pull or lift a person lying on the floor without assistance. This is also another argument for the other forms of exercise accompanied by strength training.

additional reading:

Chronic Dizziness and Postural Instability

Repetitive training of compensatory steps:

Forced Exercise to Relieve Symptoms of Parkinson's Disease

Postural Instability in Idiopathic Parkinson's Disease

Links to inflatable device and detailed advice on its usage:

Same information if you can't view pdf format:

http://docs.google.com/viewer

It's being called WiiHab and we already know that it can help with PD depression, what about postural instability? As a diagnostic it has been found to be effective:

Nintendo Wii Balance Board Could Prevent Falls

Validity and Reliablity of the Nintendo Wii Board for Assessment of Standing Balance

To try the Wii at home: you'll need the Nintendo console, the balance board and some accessories such as the WiiFit program and controllers. The balance board must be on a firm surface to work properly. If balance is a serious problem, make sure you have support or supporters handy.

For more information check Wikipedia before you buy

Calcium Channel Blockers Crossing the Blood Brain Barrier for Parkinson's Disease

BBBs and the L-type CCBs that cross them

If you've ever looked at the common questions about Parkinson's disease and dopamine as asked in the classroom or in homework help on Yahoo!Answers, you have already seen the most common question goes something like, "Why does dopamine die in PD?"  And that's a biggie, misleading but still a $64 million dollar question.

One interesting thing about Parkinson's disease is that although dopamine is produced in several areas of the body including the brain in the substantia nigra and the ventral tegmental area, the VTA does not appear to be susceptible to over-expression of alpha synuclein. Which means there is yet another research area for the potential of grafting - or stem cell therapy.  Moreover, not that much dopamine is metabolized to norepinephrine which explains why PD may not begin officially until the number of norepinephrine neurons also diminish.

But that's not our question for today. What do we know know about saving dopamine neurons in the substantia nigra?

Mouse PD models have already demonstrated that cell "rejuvenation" protects neurons in studies at Northwestern University.  Most human cells use either potassium or sodium channels when they are young but as the body ages, the dopamine cells switch to calcium channels. By blocking the calcium channel may give the cell a chance to rest and recover which is healthier than cell death and essential for PD.  In 2007 Steve read at least two abstracts by Dr DJ Surmeier etal about this very subject.

In the first abstract it was the statement: "Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression." 

And in the second:

"The Ca(2+) channels underlying autonomous activity in dopaminergic neurons are closely related to the L-type channels found in the heart and smooth muscle. Systemic administration of isradipine, a dihydropyridine blocker of L-type channels, forces dopaminergic neurons in rodents to revert to a juvenile, Ca(2+)-independent mechanism to generate autonomous activity. More importantly, reversion confers protection against toxins that produce experimental parkinsonism, pointing to a potential neuroprotective strategy for Parkinson's disease with a drug class that has been used safely in human beings for decades."

In order to stay on target we have to mention the arguments. 

From DJ Surmeier in Neuron: "The controversy about whether dopamine contributes to cell loss in Parkinson's disease takes a new turn as Mosharov et al. in this issue of Neuron demonstrate that Ca²⁺ influx through L-type channels elevates dopamine synthesis to potentially toxic levels in vulnerable ventral mesencephalon neurons."

In the study entitled "Interplay between Cytosolic Dopamin(e), Calcium, and alpha-synuclein causes selective death of Substantia Nigra Neurons"
"They attribute this specific elevation of cytosolic dopamine in SN neurons to the presence of a pace-making L-type calcium channel as a source of calcium entry, present in SN, but not VTA, neurons. Blockade of this channel, as well as treatment with intracellular calcium chelators protects SN neurons from cytosolic dopamine build-up....the pace-making L-type Ca channel may prove to be a useful therapeutic target in PD"

Faculty of 1000 Biology: evaluations for Mosharov EV et al Neurorn 2009 62 :218-229

 

We've written before about the studies which found that neurons die because calcium channels lead to an increase of dopamine inside the cell; excess dopamine then reacts with alpha-synuclein to form inactive complexes; and then the complexes gum up the cell's ability to dispose of toxic waste accumulating in the cell over time. The waste eventually kills the cell. Put another way, Dopamine in presynaptic terminals prior leaving the vesicle, signal the post synaptic terminal.  "A better treatment may be to push more dopamine into the compartments where it has no toxic effect on the cell" according to Eugene Mosharov, Ph.D., associate research scientist, and David Sulzer, Ph.D., professor of neurology; psychiatry at Columbia University Medical Center.

The question is why? And that is the answer being sought in the Calcium Channel inhibitor research - does the Ca inhibitor restore a more youthful saline condition to the cell in order to prevent cytosolic death?  And if so what is required of that inhibitor?  It has been proposed that the inflow of calcium is the last pathway "for irreversible neuronal injury" because the oxidative stress of free radicals "prevents neurons from maintaining ionic homeostasis."  One result is that neuronal depolarization triggers an action potential which opens the Ca channels. So what we need is a way to prevent the floodgates from opening to cause that neuron damage.

The first thing that this CCB must be able to do is get to the brain in order to work. Crossing the blood brain barrier (BBB) depends upon lipid solubility of small molecular size. To be lipid soluble means that it must be rendered more polar by metabolism prior to excretion in urine. Where can we find those small lipid soluble molecules? 

 

Within the dihydropyridine class of CCBs is a subtype of L-type (L representing long-lasting length of activation - slow CA channels in the cell membranes) voltage-gated calcium channel blockers. These L-type Ca blockers exert an anti-inflammatory effect and we know that some scientists have referred to PD as an inflammatory disease. As it happens, neurons which die in Parkinson's also contain a type of L-type calcium channel. CCBs affect SN neurons in a manner similar to the way they affect the heart. 

  

Now it happens that the channels are not identical.  In the substantia nigra we find a CaV1.3 channel.  The current drugs in the L-type class happen to prefer CaV1.2 channels so we aren't there yet.  As a matter of fact, there is an open door for more R&D in this area.  But if you have PD, you often try what is available. 

 

Research at Northwestern University, at Emory University, at Columbia University may find the precise answer.  Meanwhile at Northwestern Dr Surmeier has explained, "...partial blockade of Cav1.3 channels is sufficient to provide protection against a toxin challenge... We also know from epidemiological studies (Becker et al., 2008 and a study by Ritz et al. in press) that dihydropyridine use for hypertension is associated with a significantly reduced risk of Parkinson’s disease...If it turns out that more complete antagonism of Cav1.3 channels is necessary to achieve protection in humans, then more selective drugs would have to be developed that spare the cardiovascular system."

Of the dihydropyridine class (note that they all end in "dipine"), the L-type inhibitors which cross the blood brain barrier are: Amlodopine, Azenlnipidine, Clevidipine, Felodipine, Isradipine, Nicardipine, Nefedipine and Nimodipine.

additional reading:

Neurons and action potential - scroll down the page

Neurotransmitters and their molecules  

Brain diagrams: the basal ganglia and the cerebellum  sorry to say this link no longer works
A unique interactive brain diagram thanks to Open Colleges

Previous posts and comments:

The PD Triangle for cell death

What I Did when DynaCirc Wasn't Available Nifidiac vs DynaCirc: my experience

DynaCirc or Isradipine - generic vs brand

Switching back to DynaCirc Cr      

The Future of Isradipine and PD

April is Parkinson's Awareness Month
Visit PDF for suggestions of group activities

And if you live in Northeast Ohio

There is a Benefit Recital

for Parkinson's Disease

to be given by Clair Allen, violinist

whose Father passed away earlier this year

following a long battle with PD.

Claire is dedicating her Senior Recital to his honor.

Donations will go to the Michael J Fox Foundation

to support Parkinson's research.

Works by Schumann, Bach, Dvorak and Bartok

Sunday, April 11th, 2010 at 2:00pm

Baldwin-Wallace College 
Gamble Auditorium, Kulas Musical Arts Building

To make a donation follow the links at TeamFox.org

Parkinson's Disease: Calcium Channel Blockers with Treatment Potential

CCBs that cross the Blood Brain Barrier for PD

Most of us read of the California-Denmark study based upon many years of data

from which it was observed that some calcium channel blockers have been found

to decrease the PD risk factor by about 27%.

 

But what about those who already have Parkinson's?

Today we'll skip the toxic dopamine argument between Mosharov and Surmeier etal

and just take an actual look at the CCBs in the Dihydropyridine class.

Specifically we show the L-type CA(2+) CCBs that can cross the blood brain barrier.  

Next we'll post the discussions, the disagreement and study links. 

DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS	Also known as	Notes
Amlodipine	Norvasc Perivasc, Istin, Agen, Aken Amidipin, Dailyvasc, Lopin, Amcard, Ambolet	Crosses BBB  3rd generation Lipophilic Dihydropyridine May accumulate in brain
Aranidipine	Sapresta	-
Azelnipidine	Calblock	Crosses BBB scavenges hydroxyl radicals but not superxide radicals Reduced levels of intercellular ROS
Barnidipine	HypoCa	-
Benidipine	Coniel	may act in a similar manner to nimodopine
Cilnidipine	Atelec, Cinalong, Siscard, Cilacar	Crosses BBB dual blocker of L & N-type calcium channels does not target protein kinase C
Clevidipine	Cleviprex	Crosses BBB ultra short acting intravenous CA2+ CB
Efonidipine	Landel	Another T-type selective CCB some L-type inhibition
Felodipine	Plendil Renedil (in Canada)	Crosses BBB 2nd generation
Isradipine	DynaCirc, Prescal	Crosses BBB 8 hour half-life 2nd generation
Lacidipine	Motens, Lacipil	Exhibits high partition coefficients into phosphatidycholine
Lercanidipine	Zandip	Does not readily cross BBB 3rd generation has a molecular design which imparts greater solubility within the arterial cellular membrane bilayer, membrane-controlled kinetics and a high cholesterol tolerance factor.
Mandipine	Artedil, Calslot, Manyper, Iperten, Mandipot Manivasc, Vascoman	3rd generation less potential for pedal edema than other CCBs
Nicardipine	Cardene,  Carden SR	Crosses BBB Similar to Nifedipine 2nd generation
Nifedipine	Adalat, Procardia Apo-Nifed (Canada) Novo-nifedin (Canda) Nu-nifed (Canada	Crosses BBB Lipophilic Dihydropyridine
Nilvadipine	Nivadil	Blocks L-type channels
Nimodipine	Nimotop, NIMO Nimodipina	Crosses BBB similar to Nifedipine Lipophilic Dihydropyridine
Nisoldipine	Baymycard, Sular, Syscor	-
Nitrendipine	Cardif, Baylotensin, Baypress, Deiten, Nidrel, Nitrepin	-
Pranidipine	Acalas	Carries grapefruit juice warning as do other CCBs
DIHYDROPYRIDINE CCBs	Known as	Notes

Differential Diagnoses and Parkinson's Disease

What do the stereotypes mean for you and PD?

We already know that the precursor symptoms of Parkinson's disease can show their presence years before the disease is full blown and diagnosable.  We always want to be reassuring or to be reassured when we notice them. So we tell each other and ourselves:

"Oh, it's nothing"

"You're just stressed"

"Well who wouldn't have sleeping problems, you're depressed"

"Losing your sense of smell is convenient, now you can avoid changing the cat box"

"Perhaps that neck and shoulder pain is from the way you sit at the computer"

"Get another pair of shoes, you're dragging your leg when you walk"

"Get a new pen, your handwriting has changed"

"That tingling is the beginning of carpal tunnel, get a wrist rest"

"Try these pills to help you sleep or for your depression"

"Who wouldn't be depressed, you're not sleeping enough"

And so a few years pass and the next symptoms appear and you make that dreaded appointment.  Afraid to know but afraid to delay treatment.

When that tremor appears, people know it is time. The good news for many is that that an action or a postural tremor is not PD. Sometimes it is a sign of Essential Tremor, which isn't curable but in many cases more manageable.  And you can drink to that.  But that postural tremor which occurs not when the limb is at rest but rather when performing an action can also be a sign of renal or liver failure, of hyperthyroidism, of Dystonia; it can be caused by medications, hypoglycemia or Fragile X Syndrome(FXTAS). The list is long and the diagnosis needs a professional so that the proper treatment can be initiated.

Then there are the people diagnosed with Parkinson's Disease who actually have Parkinson's Plus: the Multiple System Atrophy group (MSA), Progressive Supra-nuclear Palsy (PSP), Dementia with Lewy Bodies (DLB) and Corticobasal Ganglionic Degeneration (CBGD).  There is even Parkinson's with ALS The correct diagnosis is necessary to avoid delaying the correct treatment to improve quality of life.

Let's face it, for many people it may seem to be less frightening if they can arm themselves with information before their doctor's appointment. Reading about conditions can actually help you prepare a more thorough list of symptoms. Other people only want to know more after the diagnosis. Before getting any on-line prompts and suggestions, it's a good idea to make that list of all  your symptoms and when they occur. That way you won't be as easily swayed by suggestion.
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Although there is not always good news, there are helpful online sites for many conditions.  The Parkinson's sites are listed in the right hand column here as Helpful Links.  For Parkinson's Plus one of the most informative sites is actually eMedicine from WebMD.  The National Institute of Neurological Disorders and Stroke (NINDS) provides a brief but helpful overview of tremor. So does Medline Plus.  You can read about Essential Tremor at several sites.  In our opinion the best site for Essential Tremor information is WeMove.org.  Another site with a helpful chart of pathology of the nervous system is Wikipedia.

The point is that if you are prepared for your doctor's appointment by having a symptom journal, you can be not only proactive in providing some of the information needed to make the most accurate diagnosis but you can also become a significant part of your medical team.  And yes, you are going to need you.

We know of patients who have been told to go home to die. While having your financial affairs in the best order possible and by spending quality time with family and friends is excellent advice for everyone, we just heard a patient's take on that give-up advice from a very courageous woman. When told that there was nothing she could do for her MSA, she asked the doctor if he would give his wife, daughter, mother or sister that same advice. He saw her point and treatment became interactive. We think she's doing very well in finding a course of alternative treatment. She said she had no choice, she wanted to live and there was no hope by following the doctor's advice.    

Even if those early warning signs don't send you to the doctor, at least make a mental or written note.  If the symptom persists, pay attention, your body is telling you something that could be important.

Finding a Safe Online Pharmacy for Parkinson's Disease Medicine - part I

What if you can't find the PD medications you need for your treatment at a local pharmacy?

For those of us who were born in a time when information on almost everything was not readily available in our homes, it is amazing to be alive when vast stores of knowledge are finger taps away even when we are in our cars or hiking in the park.  When our children were growing, we kept a dictionary in almost every room.  A phone interruption at dinner time was not acceptable but stopping to look up the meaning of a word was encouraged.

When I was a child, there was an encyclopedia set to put one on the right track or just to read, page by page for the fun of learning about anything.  What do you want to know about Anacondas?

Now there is a huge overload of information.  We love that. But not all of it is factual.  Some is poorly edited or not accurate; some is sound- byte brief and some is just designed to separate us from our money. 

Because UCB has not been able to provide positive news about the Neupro patch availablability in the USA as they wait on the FDA, I thought I would continue the search of online pharmacies to see what I could find out there.  I found several online pharmacies which list the patch. I noticed was that the patch is very expensive. Because we had no knowledge of the prior US cost of the patch I decided to compare other medications for which I knew the price. They were expensive...not that expensive but at least 25% higher in price.  Of course there is also the question of the cold storage delivery.  And that is a BIG question.

We began to receive questions about the availability of other medications.   These questions were from markets with which we were not familiar. I just did a check on an L-type CCB, DynaCirc CR, availability and communicated with GlaxoSmithKline (GSK) as part of that search.  Turns out that despite the fact that they make the product and have offices in Australia, you can't find DynaCirc in there. You can, however, buy it from an online pharmacy in New Zealand, not to mention Israel, Canada and a few other places where I could not verify the online pharmacy.

I also found an online site which will check for some comparative prices and provide information about the pharmacies.  Therefore I did a domain search online because it is important to know the company trail - how long have they been operating their site - are they here today but gone when you are entitled to a refund or didn't receive the product they didn't really mail to you after charging your card. 

Since this company has been in business since 2002 with a 2008 update, we're passing that backlink along to you with a warning.  Although there are several ways to check for information things at the Pharmacy Checker website be advised, they do not list every bona fide online pharmacy, only their clients, and it is possible that they have some questionable clients on-board or at least did at one time.

This problem means that before you use any online company check the domain and also look for scam warnings. Due Diligence on your part.

Not all scam warnings are valid.  Some are just from customers who didn't read the shipping charges or the estimated wait time for arrival. Other complaints are very serious.  These complaints includethe company shipping the wrong item and labeling it incorrectly; taking  money for the brand and getting a generic which while similar might not be the same. And even worse, counterfeit pills.  Other scams include charging your card while not actually shipping the itemor submitting charges without authorization.

Companies can charge for shipping on a regular basis when you did not authorize such a program. Another danger is that you might receive out of date medication.

If your credit card is charged for any fradulent reason, report it to your card company immediately as this will enable to limit your obligation and in some cases your card company can bill back to recover your funds. If you reach this point, you can help others by reporting the scam and company to lots of online scam reporting sites and to any governing authority.

You need a prescription for prescription medication 
No prescription required is a red flag!

Another cautionary when ordering from a Canadian pharmacy is to look for the seals of accreditation. Some are real and some are fake. Note the seal and check with the issuer.  You can use either of the following links at the Canadian International Pharmacy Association (CIPA) to verify accreditation of the pharmacy you are considering. If you want to verify membership: contact CIPA.  They have a similar link under consumer safety. They will also list known sites which display a fake CIPA seal. There are other seals as well. Individual provinces will also require accreditation. As a matter of fact there is also a seal for the

Pharmacy Checker website.

Things to watch for: 

• Phone and fax numbers. Give them a call on their 800 number ostensibly to verify their mailing address or shipping & handling fees, whatever. But try calling at an off business hour.  Did you get a voice mail?  Anything?  Nothing tells you to move on. Don't leave a phone number or an email address.
• Does the site list an address - although this could be a mailbox company which would provide both street number and suite number they should be a legitimate pharmacy with a regular address.  I'm not so sure about companies which have drop shipping.
• Is their domain check questionable datewise?
• The AARP reported Double Drug Sting - just noticed this one - interesting 
• Do you have online access to the company pharmacist? 
• Do they ask for the prescription - if they don't - let your fingers walk away
• Is the price too low to be believed - don't believe and don't buy!
• Have you done your due diligence?  Are you dealing with a legitimate company? 

We wish that Parkinson's medications were available to all patients everwhere at affordable prices for everyone.  But the sad fact is then this isn't the case.  So we click our fingers on the keyboard and our options are displayed on the screen before us.