Recently the U.S. Food and Drug Administration (FDA) has been making headlines with multiple press releases and statements which cover several drugs commonly consumed by Parkinson’s disease patients.  It is critical that the Parkinson’s disease patient, as well as his or her family, fully understand FDA lingo.  Below is information drawn directly from the FDA’s website and from FDA press releases spanning the past decade.

A FDA Drug Recall refers to the removal of an over-the-counter or prescription drug from the market.  The recall is usually prompted by unexpected safety issues not identified during clinical trials.  Once a drug is approved, unexpected adverse effects occurring outside of a clinical trial may be reported to the FDA through a program referred to as MedWatch.  A recall may occur  “on a firm's own initiative, by FDA request, or by FDA order under statutory authority.”

The FDA specifically defines and classifies drug recalls on its website:

“Class I recall: a situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death.

Class II recall: a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.

Class III recall: a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.

Market withdrawal: occurs when a product has a minor violation that would not be subject to FDA legal action. The firm removes the product from the market or corrects the violation. For example, a product removed from the market due to tampering, without evidence of manufacturing or distribution problems, would be a market withdrawal.

Medical device safety alert: issued in situations where a medical device may present an unreasonable risk of substantial harm. In some case, these situations also are considered recalls.”

A few drugs important to patients with Parkinson’s disease have been recently recalled and are summarized below:

Cisapride (Propulsid) was a drug used to help gastrointestinal emptying issues, but was removed from the market for heart related safety issues.

Tolcapone (Tasmar) was a drug used to treat on-off fluctuations in Parkinson’s disease patients, and to extend the longevity of each sinemet dose.  It was recalled due to several cases of fatal liver toxicity.  It was however, reintroduced onto the market after the FDA mandated a black box warning.  The black box warning is named for the black border surrounding an inserted text warning.  The warning communicates a potentially serious or life threatening event that could be possibly encountered by using the drug.  Tolcapone now requires liver function tests, and is considered by most experts to be safe, as long as there is adequate drug monitoring.

Pergolide (Permax) was a drug designed to stimulate dopamine receptors (a dopamine agonist), and it was removed from the market because it was associated with damage to heart valves.

Rotigotine (Neupro patch) was a dopamine agonist patch that was reviewed by the FDA, and ultimately recalled.  The FDA will allow it back in the U.S. market after reformulation to prevent a drug crystallization problem.

Recently the FDA announced it was reviewing the drug Stalevo (a combination of carbidopa/levodopa and entacapone) for a potential increase in cardiac risk.  Stalevo was originally FDA approved in 2003, and 154,000 patients currently take the drug.  Seven heart attacks and one heart related death occurred in a recent Stalevo trial (STRIDE-PD).  The issues seemed to be exclusively isolated to the study group consuming Stalevo, and not to the study group ingesting plain carbidopa/levodopa tablets.  It is important to point out that there have been over a dozen trials of Stalevo reported without this cardiac issue.  When the available cardiac data was analyzed without the STRIDE-PD study data, the cardiovascular risk seemed to disappear. 

Interestingly, the STRIDE-PD trial also was recently placed under FDA review for potential prostate cancer risk (3.7% in the Stalevo group versus 0.9% in the carbidopa/levodopa group).  Again, like with cardiovascular risk, it was not completely clear (from the small amount of data available) that this issue was actually Stalevo related.

Patients should be aware that the data currently being reviewed by the FDA (on Stalevo) was not collected with the purpose to assess cardiovascular or prostate cancer risk.  Stalevo remains on the market pending this FDA review.

In conclusion, it is important for Parkinson’s disease patients and their family members to be vigilant in following up drug related press releases, especially those concerning drugs under review or FDA recall.  Patients should ask their doctors to discuss the risk-benefit ratio of any drug under current FDA review, and also they should inquire about potential alternative management strategies.  In cases where a drug may remain available overseas after removal from the U.S. market (e.g. rotigotine), a risk benefit ratio and a management strategy discussion should be sought.  Drug recalls, withdrawals, reviews, and safety alerts are an important reality for Parkinson’s disease patients and family members.  It is critical for patients to be ready on short notice to contact their treating physician, and to be flexible about formulating a reasonable plan.   Parkinson’s disease patients must maintain balance in their Parkinson’s drug management, and also balance in their daily lives.

Selected References:

http://www.fda.gov
http://www.fda.gov/Safety/Recalls/default.htm

Francis Crick, one of the most famous scientists of our generation, described a double helix structure that is now known to characterize human DNA (this discovery was published in 1953 along with his colleague James Watson).  Later, in the 1970s, Crick discussed a wish-list for future discoveries, including the use of light to control human cells.  Light science and light therapy have since been considered both “crazy and far-fetched”; however, recent discoveries in the early 21st century have dramatically changed this point of view.  Thanks to some very clever scientists, a new field called optogenetics was born.

What is optogenetics?  The “opto-“ refers to placing light onto the brain to activate channels and/or enzymes that will ultimately change brain cell firing.  The technique is specific, and has the potential to add or delete firing patterns from the brain’s native cells.  Additionally, brain cell firing can be manipulated at precise millisecond intervals.  The fiber-optic light source can be mounted on the skull, or placed deep within the brain.  The genetics part of optogenetics utilizes simple virus carrier systems to deliver genes to the brain.  The most important of these genetic deliveries has been opsin.  Opsin is one of the structures potentially turned on by the light.  The most important known opsin used for this technology is Channelrhodopsin-2, and it was derived by scientists from algae-based systems. By shining light onto the inserted genetic alteration (opsin), scientists can probe the brain’s inner conversations (firing of cells).  The technique has allowed investigators to move past the classical genetic manipulation, which has much less specificity.

Last week Kravitz and colleagues (from the pioneering optogenetics group at Stanford) published an important paper in Nature.  They were able to demonstrate that optogenetics could either worsen or alternatively improve an animal model of Parkinsonism.  The investigators performed a simple experiment where they manipulated the well-established basal ganglia direct and indirect pathways, which are the best known suspects implicated in the genesis of Parkinson’s disease.  The authors reported “optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through a viral expression of channelrhodopsin-2 in mice with regulatory elements for the dopamine D1 or D2 receptor. Excitation of the indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. Activation of direct-pathway MSNs reduced freezing and increased locomotion (Kravitz, 2010).” A month prior to this Nature paper, Bass and colleagues from Wake Forest, described an optogenetic approach to controlling dopamine release (Bass, 2010).

Activating brain circuits by using both light and genetics has thus evolved from a science fiction dream into a true reality.  The technique will likely be refined over the next decade and it will have tremendous potential to unlock important clues underlying the disease processes ultimately responsible for Parkinson’s disease.  Optogenetics may also open up novel therapeutic possibilities.  We can thus conclude there is a bright future ahead for optogenetics, and there is much hope that this technology will help us shine a light on this common, and often disabling human neurodegenerative condition.

Selected References:
We refer the reader to both of these excellent references which describe optogenetics and also detail recent advances in the Parkinson’s disease research arena.

Kravitz AV, Freeze BS, Parker PR, Kay K, Thwin MT, Deisseroth K, Kreitzer AC.
Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature. 2010 Jul 29;466(7306):622-6.

Bass CE, Grinevich VP, Vance ZB, Sullivan RP, Bonin KD, Budygin EA. Optogenetic control of striatal dopamine release in rats.
J Neurochem. 2010 Jun 8.

Patients with Parkinson’s disease know the huge difference missed medication dosages can add up to. In some cases of Parkinson’s disease, missed medication dosages can lead to complications such as falling and severe mood swings. The results of a study from the United Kingdom conducted by Derry and colleagues should serve as a wake-up call to hospitals around the globe. The study’s authors carefully examined surgical admissions to the Aberdeen Royal Infirmary over an 18 month period. A shocking 71% of Parkinson’s disease patients missed medication dosages. Roughly a third of them missed over 10% of their prescribed dosages. The authors estimated that 0.7 missed dosages occurred per patient per hospital day. Interestingly, in approximately 2/3 of the cases, no reasons were reported for missing dosages. Drugs that acted against Parkinson’s disease symptoms (e.g. dopamine blockers) were “prescribed in 41%, and administered in 22% of cases.”

My suspicion is that as eye opening as this study’s results are, this likely represents “more of the norm” in hospitals around the world. This study should help us generate and launch educational programs and initiatives aimed at educating hospital staff, physicians, patients, and families about the care of the hospitalized Parkinson’s disease patient. The NPF 2007 Summer Parkinson Report tackled this issue with an article by Chou and colleagues addressing the most frequently asked questions about Parkinson’s disease hospitalization. The article had “tear out style” checklists for hospital staff, as well as for patients and families. These types of educational materials need to readily available, and we as a Parkinson’s disease community need to advocate for the implementation of programs at every hospital claiming to be in the business of taking care of Parkinson’s disease patients.

There are both simple and complex issues that need to be addressed in managing a hospitalized Parkinson’s disease patient. One simple fix is to have the physician write the medication orders with specific times for medication administration. He or she should stress to the staff and to the staff leadership, the importance of medication timing to successful Parkinson’s disease management. Physicians and staff should be aware that abrupt withdrawal of dopaminergic medications could lead to a potentially life-threatening syndrome called neuroleptic malignant syndrome. Teams should also be aware that many anti-nausea drugs, many sedatives, and many drugs used to improve gastric mobility (e.g. phenergan, haldol, and metoclopramide) block dopamine receptors in the brain, and should not be given to the hospitalized Parkinson’s disease patient. Medication regimens can be complex to manage within the hospital setting, and a neurologist can help to smooth the transition between inpatient and outpatient care. A neurologist can help to make alternative recommendations for drugs, especially when pills cannot be taken by mouth. Therefore, the threshold for neurological consultation should be low. Finally, vigilance in identifying and treating urinary and lung infections especially early in their course, can help to decrease hospital based “confusional” states.

It won’t be easy to change the behavior of hospital-based physicians and their staff, but is possible through carefully designed and focused educational programs it is possible. The good news is that there remains a lot of potential for improvement in the care of the hospitalized Parkinson’s disease patient. I recommend to all of my Parkinson’s disease patients, and to their family members, to go ahead and step up and play the “educator role” when in the hospital. In the current absence of standardized educational programs for the care of the hospitalized Parkinson’s disease patient, families and patients actually have the best chance to effect a positive change, and to improve their own hospital-based management.

For more information:

Print this Checklist: "Information for Your Nurse and Doctor for Hospitalization"

Watch this Video: "What do Caregivers Need to Know About Hospital Stays and Complex Medication Regimens"

Selected References:

Derry CP, Shah KJ, Caie L, Counsell CE. Medication management in people with
Parkinson's disease during surgical admissions. Postgrad Med J. 2010
Jun;86(1016):334-7.

Kelvin L. Chou, M.D., Michael S. Okun, M.D., Hubert H. Fernandez, M.D., Diane Breslow, MSW, LCSW, Joseph H. Friedman, M.D. Five frequently asked questions about hospitalization for patients with Parkinson disease. The Parkinson Report, Summer, 2007

The recent removal from the United States market of the dopamine agonist patch (Rotigotine, Neupro) resulted in a shock wave that reverberated throughout the Parkinson’s disease community.  Why the big deal?Well, because patients, families, and physicians who have a stake in Parkinson’s disease, know from experience that sufferers can be dominated by multiple daily pills taken at very frequent intervals (sometimes as close as every 1-2 hours).   Also, memory problems, issues with swallowing, and problems with hand dexterity can all impact the use of common pill-form drugs.  

The quality of life for the patient with Parkinson’s disease needs to remain a critical agenda issue when considering the development of new therapies. Deep brain stimulation, duodopa pumps, and apomorphine pumps all have the potential in select patients to improve symptoms and quality of life through a mechanism referred to as continuous therapy (dopaminergic or electrical). These therapies, that require surgical insertion, can in select cases, harness the potential to decrease medication doses, and allow a reduction in the frequency of medication use throughout a day. The therapies are all invasive, requiring surgical placement, and they are currently limited to only a few well-selected patients. The patch, however, when available was a once a day alternative for patients using only medication therapy. Like surgical therapies, the patch also only worked or was appropriate for a select group of patients due to both risks and side effects.

At NPF, we have recently received many reports that patients with Parkinson’s disease were very disappointed following the news that the Rotigotine patch (Neupro) was temporarily removed from the market. The consistent story was that the patch enhanced quality of life, by reducing the need for continuous re-dosing of medications throughout the span of a day. Although there were several dopamine agonist pill formulations available, many patients felt the patch was their optimal solution. The patch issue that precipitated removal from pharmacies was an observed “crystalization” of the medication into what appeared to be “snowflakes,” on the exterior surface. After scientific review, it was discovered that storage in a refrigerated environment was a potential solution. The patch underwent review by the FDA, and a panel determined that to be re-approved, the drug would require reformulation. This reformulation process could take as long as a year or two.

Many experts have pushed the concept of continous dopamine stimulation arguing that it may postpone dyskinesia and other drug related complications. In other words, it may be preferable to have a steady state of the minimal amount of dopamine required throughout the course of a day-- in order to delay complications. This notion is controversial, however what is not controversial is that the development of any strategy that can keep a Parkinson’s disease patient in their best “on” state throughout the day should and in most cases will enhance quality of life. If that can be accomplished without continuous round the clock dosing of medications in the form of a patch or any other strategy—the Parkinson’s disease community will likely be very appreciative.

There have been scientifically challenging issues in getting levodopa and dopamine agonists to work properly in patch formulations. Additionally, patches may result in skin irritation, and be subject to the same side effect profiles as drugs taken by mouth (e.g. edema, dizziness, nausea, sleepiness, compulsive behavior, etc.). Despite these limitations, scientists continue to work in this area, and we are hopeful for new developments and new approaches to continuous stimulation. We have been bolstered by the recent availability of the Exelon patch for cognitive dysfunction, and other companies are following suit in this arena.

Ultimately, the big deal about temporarily losing the patch in the United States was bigger than losing a single medication. The patch provided hope for those suffering with Parkinson’s disease. A hope that new formulations of drugs were on the way and that these drugs would meet a growing and important need. The truth is, that despite the delays, it is fair to say, hope will eventually arrive—and that more patches and innovative therapies will be here soon.

In this month’s issue of the Lancet Neurology, the PD SURG trial results (conducted by a multicenter team of collaborative investigators from all over Britain) are including a one year follow-up of Parkinson’s disease deep brain stimulation (DBS) patients. The trial was randomized, and it compared DBS to best medical therapy. The primary outcome variable was quality of life, and interestingly, patients in the best medical therapy arm had access to apomorphine pumps. Though sites were allowed to use the subthalamic nucleus target, the globus pallidus interna target, and even lesion therapy (e.g. pallidotomy), 174/178 (98%) of patients in the surgery group were implanted with subthalamic nucleus DBS. There was a five point improvement noted in quality of life scores in the surgical compared to medical group. Although compared to other studies the quality of life improvement was less robust, this may have reflected a longer study duration, or potentially even disease progression. There were unmistakable improvements in dyskinesias, and on time in the surgical group, although diaries were not utilized. 

Though, not a perfect trial, its large size and use of a medical control group along with unique access to apomorphine made it unique among available DBS publications. The results underscored the powerful influence that DBS can have on motor fluctuations. Additionally, these SURGE investigators plan in the future a long term (9 year) follow-up, and this will surely enlighten the field as to disease progression, and other issues potentially important to DBS cohorts.

One unique and hidden aspect of this trial was the report of the “reasons why patients sought DBS surgery.” Severe off periods, dyskinesia and tremor were far and away the most common indications cited for DBS therapy. As DBS moves into a tailoring phase (the right target and approach for a particular symptom or symptom cluster) this type of information will be very useful to clinicians.

People may criticize the lower total motor change scores reported in PD SURG when comparing pre- and post-operative operative outcomes to other trials, however they must remember that as many randomized blinded DBS trial results emerge from international centers (VA PADRECC study, Cleveland Clinic/Emory Study, UF COMPARE trial), that the open label improvements previously documented will almost certainly be shown to be a study bias. The results of the PD SURG trial may offer a look at what DBS outcomes may realistically look like as the therapy migrates to centers with less expertise (remember they used a multitude of centers all over Britain).

It is fascinating to see that 98% of implants were placed in the subthalamic nucleus in this study, despite the option for surgeons to use a different target. Though the subthalamic target has many strengths, it also has relative weaknesses. Emerging data is now strongly suggestive that the motor outcomes in pallidum and subthalamic nucleus are actually similar, and that targets in the future should be tailored for individual patients and individual symptoms.

In conclusion can we say the PD SURG trial was a surge forward for the PD community? The answer is certainly yes, as the publication of more carefully controlled DBS trials will be important in guiding DBS therapy into the future.