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The Science of Hope
            by Dr. Edward Drasby, D.O.

Dr. Edward Drasby, D.O. is a  neurologist who specializes in  the clinical treatment of Parkinson’s Disease in Scarborough, Maine.Parkinson’s disease (PD) was first described by Dr. James Parkinson in 1817, but had occurred in humans for thousands of years from historical descriptions.  It is the second most common neurodegenerative condition after Alzheimer’s disease (AD).  Unlike AD where an average life expectancy of 7 years after the diagnosis significantly shortens life span, individuals with PD often live many years with their slowly progressive disorder.  It is more a question of the quality of those years than a markedly shortened lifespan.  The average person with PD is 61 years old at the time of their diagnosis and the duration of their PD is 18 years.  An individual diagnosed at a much earlier age tends to live longer and someone diagnosed at a much later age generally lives a shorter time span.  It appears that there is a long pre-symptomatic phase of PD wherein brain cells are being injured, though not to the point where there are clinical symptoms.  This early stage of PD may be ongoing for 10 to 20 years prior to the first symptoms.  As human life span increases the prevalence of both PD and AD also grows as these disorders have increasing prevalence with each decade of life.   

In the 1950s and 1960s science came to understand that PD symptoms were related to a deficiency of a chemical messenger dopamine in the brain.  Since 1973 when levodopa was introduced as a dramatic treatment for Parkinson’s a great deal of pharmaceutical research has concentrated on developing additional treatments for Parkinson’s.  These medications reduce the symptoms of PD but have not been shown to slow or reverse the actual progression of PD.  

First, there was the introduction of dopamine agonists in the 1990s.  These medications act like dopamine, directly improve PD symptoms and have a longer duration of benefit than levodopa.  Also, medications that block the breakdown of dopamine by enzymes in the blood stream and brain have been introduced.  These medications fall into two categories: COMT inhibitors and MAO-B inhibitors, the two enzymes which specifically break down dopamine into inactive compounds.  Essentially, this class of medications help dopamine last longer in the body and brain of individuals with PD.  Currently, there is also a clinical trial to approve a new delivery system for levodopa (as a gel) to be pumped continuously through a very small catheter tube directly into GI tract of PD patients.  This system is currently in use in the European Union and has been shown to reduce or eliminate the fluctuations in PD symptoms inherent with oral medications.

In 2002 the FDA approved the use of Deep Brain Stimulation (DBS) surgery as a new treatment for individuals with PD who could no longer be managed with medications alone.  These patients either could not tolerate additional increases in the PD medications or had developed long term side effects such as writhing involuntary movements (dyskinesias) or cognitive and neuropsychiatric complications.  In the appropriate candidate DBS surgery can often be dramatically beneficial. 

 While treatments have significantly improved the quality of PD patients’ lives, public interest consistently focuses on the hope of either slowing the progression of PD, or an actual cure.  The long duration of both the pre-motor phase and of PD itself makes the potential for a disease delaying treatment extremely promising and hopeful.   

As we have said medications containing levodopa and dopamine agonists predominantly treat the motor symptoms of PD: Tremor, Rigidity, and Slowness of Movement.  In general, they do not improve the non-motor symptoms of PD such as poor balance, depression, anxiety, fluctuations in blood pressure and heart rate, bladder control, and cognitive slowing that can potentially result in PD dementia.  Taken together with the potential for the long term side effects including loss of responsiveness, involuntary movements, and neuropsychiatric changes both the scientific community and patients with PD hope for more than easing of their symptoms.   A treatment that slows the progression of the motor signs of PD might also delay these non-motor complications relieving caregiver burden and extending Parkinson patients’ active day to day life in their own homes. 

A number of research trials over the years have looked at the potential for various compounds to alter the progression of PD.  The DATATOP Study in the 1990’s looked at selegiline and Vitamin E as potential disease modifying therapies.   No definite benefit was identified for those preparations though. 

More recently in 2005, the ADAGIO Study explored the potential for slowing PD progression with rasagiline (Azilect) one of the selective inhibitors of the MAO-B enzyme.  The next year the PROUD Study sought to determine if pramipexole (Mirapex) could modify the course of PD.  In January of 2009 the National Institute of Health (NIH) through the auspices of the Parkinsons Study Group (PSG)  began the QE3 Study examining if a dietary supplement, CoEnzyme Q10 (CoQ10), taken at high doses would delay the progression of PD.  Both Azilect and Mirapex are already proven and available treatments for both early and advanced PD.   My practice site has had the privilege of participating in all of these trials and has enrolled more than 30 patients to this point.  We are continuing to enroll for the CoQ10 Study.  The PSG is also now considering a trial of Isradipine as a potential disease modifying therapy.

Both the ADAGIO (rasagiline) and PROUD (pramipexole) studies have been completed and analyzed. 

Pramipexole did not show any statistical benefit in slowing progression of PD symptoms.  The ADAGIO study, on the other hand, met all three of its primary clinical endpoints with statistical significance for the 1 mg dose.  The results were published in the April 2009 issue of the Movement Disorders Journal. These results have proven to be both extremely interesting and controversial in the community of PD researchers. 

By comparison, CoEnzyme-Q10 is a dietary supplement that can be purchased at any health food store or pharmacy.  Its trial is still ongoing.  It is generally extremely well tolerated, though somewhat expensive when taken at the therapeutic doses being used in the QE3 Study.  The treatment doses are 1,200 mg and 2,400 mg.

An even greater source of hope over the long term is the hope of reversing the progression or curing Parkinson’s.  Currently, the use of various lines of stem cells to provide actual functional dopamine replacement in the PD brain has begun to make significant strides.  Also the possibility of introducing genetically engineered enzymes into the brain has resulted in several research trials whose preliminary results are at least equally promising and exciting.  These enzymes are introduced by way of a benign viral vector and inserted into the dopamine rich portions of the PD brain to multiply.  They seek to eliminate the actual harmful accumulation of the protein alpha-synuclein which causes the actual cellular injury in Parkinson’s.  If this cellular injury can be halted or reversed we may very well be close to the potential cure for Parkinson’s disease we are all working toward. 

 

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