Read about patient concerns, family dilemmas, and the clinical dynamics of a weekly movement disorder clinic. Observe ways a movement disorder neurologist manages patient symptoms with medications, surgical referrals, physical therapy, and caregiver options. Find out more in my Weekly Journal.
Endocannibinoids to Rescue Parkinson’s Brains
A recent study from the lab of Robert Malenka, MD, PhD, Pritzker Professor of Psychiatry and Behavioral Sciences at Stanford University Medical School, has found naturally occurring endocannabinoids (substances similar to the active compounds in marijuana) in the brain that when stimulated, contributed to a dramatic improvement in mice with a condition like Parkinson’s.
Endocannabinoids, naturally synthesized marijuana like substances that occur in the brain were discovered in the late 1980s and research in the early 1990s found them to be essential bio-regulation. Research suggests they have a role in inflammation and endocrine activities and also serve as messengers for other neurological and immunological conditions. Cannabinoid receptors are located all over the brain, however their roles and functions are still being researched. It is not known why they are not always activated by naturally occurring endocannabinoids
Dr. Malenka and his post-doctoral researcher, Anatol Kreitzer, PhD, focused their attention on the striatum, because it is prominent to multiple neurological disorders, including PARKINSON’S DISEASE. Dopamine is the principle neurotransmitter in the striatum, which when depleted, causes the loss of movement and rigidity experienced by people with PARKINSON’S DISEASE. While studying the striatum, they became aware that there were many cell types that appeared alike under the microscope, but only became distinguishable when mice were specially bred to have specific cells stained with fluorescent dyes. With two cell types clearly identified, they were able to probe communication and activity between the cells. They identified a unique interaction between those two cells. One cell was involved with initiating movement and the other with restraining movement, and acting together to determine appropriate movement. Endocannabinoids are the “messengers” that use dopamine to cause the cells to interact. When dopamine is absent, the endocannabinoids begin to break down, causing the initiation of movement to halt and restraint of movement to become dominant.
Introducing more dopamine into the brains to the mice resulted in only a slight improvement in movement. Using a new drug to halt the enzymatic breakdown of the endocannabinoids did nothing. But introducing a combination of dopamine replacement and the enzyme that stopped the breakdown of the endocannabinoids resulted in the mice going from completely frozen to being able to move freely in only 15 seconds.
This study is exciting on many levels, from distinguishing the subtle differences in cell types in the striatum, to finding the communication loops between previously inconspicuous cells and mostly from finding a way to restore the balance to that interrupted cell circuitry to initiate the return of movement in the Parkinson-like mice. While it is immediate good news for the mice involved, it will still be quite a matter of more research and time before the implications of this study are fully researched and the results translated to good news for human studies. It does reveal a potential new therapeutic approach to finding better treatment for the symptoms of PARKINSON’S DISEASE.
Stanford School of Medicine News Release 2-27-14
Review by Marcia McCall
Medical Marijuana and Parkinson’s Disease
When you are in pain, and stiff and suffering from PARKINSON’S DISEASE, you want something, anything, that will bring relief. And members of a certain generation probably tried marijuana, long before they had PARKINSON’S DISEASE and found the results pleasurable. Now, when those same pleasurable effects could soothe the strain of a disabling disease, political controversy impedes the Food and Drug Administration from being able to conduct the necessary research and clinical trials.
An observational study recently done in Israel showed considerable improvement in tremors, muscle rigidity, pain when subjects were tested 30 minutes after inhaling marijuana. Twenty subjects, all about 66 years of age and diagnosed with Parkinson’s Disease for over 7 years, were tested using the Unified Parkinson’s Disease Rating Scale (UPDRS) both before and 30 minutes after smoking cannabis in the clinic. Their scores on tremor, rigidity and bradykinesia all decreased significantly and the subjects claimed the benefit lasted for 2 or 3 hours after smoking. Fine motor skills were also improved and 12 of subjects reported major improvements in their sleep while 8 said that their sleep was somewhat improved. While this study had some limitations, that there were no control subjects and it was of a limited size and a short duration, it does demonstrate a therapeutic benefit for both motor and non-motor symptoms, which should lead to more in-depth studies. The potential of marijuana treatment for subjects who have limited or no response to standard medications must also be closely considered.
Another small study done in the Czech Republic queried 339 subjects with PARKINSON’S DISEASE on whether or not they had used marijuana. One quarter of them responded that they had and 45 percent of them noted that their symptoms had been helped.
The above are recent examples of research on cannabinoids, but any serious researcher can find some of the earliest mentions of the use of marijuana in medicine go back thousands of years. The Chinese Emperor, Chen Nung, who is considered the father of Chinese medicine, discovered the medicinal properties of not only marijuana, but ephedra and ginseng. He lived around 2700 B.C. In 1700 B.C., the Egyptians in written medical records, referred to therapeutic marijuana use. In 1500 B.C. the Chinese pharmacopoeia, Rh-Ya, has a written entry for marijuana as a medicine.
There are many records of cannabis sativa used for medical purposes from earliest recorded history to present time–even records kept by the U.S. presidents George Washington and Thomas Jefferson about the hemp (marijuana) that they were growing in their own plantations. Early records indicate it was useful for relieving nausea, improving appetite, improving depression, and as pain reliever. Later it was found to relieve the pressure of glaucoma in the eye. Marijuana as medicine has a long history.
It was not until the late 1800s when the western world saw a development of a moralistic era of prohibitions that medical marijuana came into a decline. The prohibitionists were against not only marijuana, but alcohol, gambling, prostitution and other commonly used narcotics, such as opium and laudanum. In 1915, President Woodrow Wilson signed the “Harrison Act”, which became the model for all future drug regulation legislation and lead to the “Marijuana Act” of 1937, which effectively criminalized any use of marijuana.
Interestingly, almost 100 years later, public acceptance of marijuana for medical purposes is high and the legislative action is changing. Here in Florida, the legislators are drawing up new regulations not so much with “If’ medical marijuana is approved as for “When”. The referendum that will be on the November ballot: “Allows the medical use of marijuana for individuals with debilitating diseases as determined by a licensed Florida physician. Allows caregivers to assist patients’ medical use of marijuana….”
Review and article written by Marcia McCall
Straightening the Mis-Folded Proteins of Alpha-Synuclein
Alpha-synuclein if the protein molecule that is found in Lewy bodies and is one culprit that is thought to be responsible for the symptoms of PARKINSON’S DISEASE. Scientists have been working hard to understand how alpha-synuclein infiltrates the cells and neurons and exactly what its role is in human biology. It is known that alpha synuclein is at the root of many of the problems of neurodegenerative diseases, but how to remove or suppress this protein has proven extremely elusive and resistant to the best of scientific techniques.
Dr. James Shorter, an associate professor of Biochemistry and Biophysics from the Perelman School of Medicine at the University of Pennsylvania may have discovered a unique and interesting approach that could help solve the alpha synuclein dilemma. His research looked at yeast proteins, and he discovered a specific yeast protein Hsp104 that is able to dissolve mis-folded proteins of alpha-synuclein in the plasma of cells.
Unfortunately, it is not so simple and straightforward. Hsp104 is one of the better known proteins on our planet; however, it does not exist in humans or animals. Dr. Shorter says “We don’t understand why animals have lost the gene for Hsp104, but at the same time, we’ve been wondering: ‘Is there a therapeutic opportunity in this?’” His research has shown that although Hsp104 is effective, it is not perfectly effective and increasing the effectiveness of this protein is the new direction in his research.
His lab has been re-engineering variants of Hsp104. Finding the right variant that can suppress the mis-folded alpha synuclein while also improving the function of the cell is the challenge. While any number of variants might to the job, they might also do more than prevent the clumping of alpha-synuclein and therein would lie some serious problems. So it is no easy task to engineer this particular protein to become an accurate therapeutic product with a focused target. It is also a protein that is foreign to animal and humans, so side effects or toxicity are also important considerations.
His research up until now has been with yeast models, and has been successful. The next step was to test it in a more sophisticated, multi-cellular model, for which a primitive worm model was chosen. This work was a collaboration with Dr. Guy Caldwell from the University of Alabama. And it was successful. The next challenge is to move to even more complex animal models, such as mice.
Although this research is still in some very early stages, it is exciting that a foreign molecule can be engineered to obtain therapeutic benefit and holds the promise that perhaps eventually it will become an important agent for ameliorating the symptoms or possibly eliminating the cause of those symptoms in PARKINSON’S DISEASE and other neurodegenerative diseases.
Jackrel, M.E., M.E. DeSantis, B.A. Martinez, L.M. Castellano, R.M. Stewart, K.A. Caldwell, G.A. Caldwell, and J. Shorter^. (2014). Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell. 156:170–182
Review by Marcia McCall
Changes in the Brain Structure and Volume Detected with a Unique Memory Test
Researchers at Turku University Hospital in Turku, Finland used a specific test of memory and a high powered MRI to measure changes in the gray matter of subjects with PARKINSON’S DISEASE. Their results are reported in the January 16th edition of Journal of Parkinson’s Disease.
In this study, they used 28 subjects who were within 3 years of diagnosis with PARKINSON’S DISEASE but whose daily lives were not in any way affected by cognitive or memory issues and 28 healthy, non-Parkinsonian control subjects.
Previous research has been able to show loss of brain volume related to memory loss in PARKINSON’S DISEASE, but has not been able to compare brain volume and memory problems to specific structures. Part of the problem may lie in the types of tests administered and the Magnetic Resonance Imaging (MRI) data collected. This study used a more precise, advanced form of MRI, called voxel-based morphometry (VBM) that is able to measure three dimensionally the volume of selected brain regions. Together with a unique memory test, they were surprised to find slight morphological changes showing degeneration of the parietal lobe, but only on the right side.
The memory test they used was an incidental free recall test where subjects were shown a list of 30 to 60 words and images but specifically not given any instruction about remembering them. Later they were asked to recall as many of them as they could. The incidental recall test simulates more closely actual real life memory situations, where there is no intention to commit events to memory but where they are remembered freely. Attention is not focused on remembering and no cues are given to assist the memory formation in real life.
In this test, the researchers found there was significant impairment in the PARKINSON’S DISEASE group in both recall and visuospatial control tasks, but that word list learning and executive control tasks were unaffected. While the overall gray matter volume of both groups showed no significant difference, the memory tasks did show smaller volume of gray matter in the right parietal cortex of the PARKINSON’S group, but not in the control group. The researchers suggest that this particular brain region is affected because it is involved in attention to memory and visual images and not to the semantic nature of the task.
Dr. Ulla Ellfolk from the Department of Psychology and Logopedics of Abo Akademi University and the Division of Clinical Neurosciences at Turku University Hospital. Dr. Ellfolk stated “This study is one of the first to link a discrete area of the brain to a cognitive deficit in people at an early stage of PARKINSON’S DISEASE. Clinical studies have shown that free recall is more strongly affected than language, performance on simple attention tasks and visuospatial functioning in newly diagnosed PD patients.”
Brain Volumetric Correlates of Memory in Early Parkinson’s Disease; a Research Report; Ulla Ellfolk, Juho Jouts, Juha O. Rinneb, Riitta Parkkola, Pekka Jokinen, Mira Karrascha; Journal of Parkinson’s Disease 3 (2013) 593–601, IOS Press; DOI 10.3233/JPD-130276
Review by Marcia McCall
Interaction of LRRK2 and Alpha-Synuclein in PARKINSON’S Neurodegeneration
Studies have shown that in PARKINSONIAN brains, the mutated LRRK2 gene causes clumps of protein to form within neurons and an increase of kinases to develop. Ultimately, the cells die. In this particular study, researchers wanted to know if the increase of kinase was the cause of cell death or merely part of the reaction.
Early in his post doctoral work, Steve Finkbeiner, M.D., PhD, was not happy with the slow progress of examining cells and neurons one at a time. So he developed a robotic microscope that could examine multiple cells over periods of time and track their development or reaction to various other factors and agents. By using this unique robotic microscope, Dr. Gaia Skibinski and Dr. Finkbeiner of the Gladstone Institutes in San Francisco, CA, they were able to look at the long term progression within the individual cells rather than simply observing what happened to entire populations of cells.
To study this process, they developed two types of cells, one from rats genetically bred with a mutant LRRK2 gene. The second set came from induced pluripotent stem cells developed from the skin of people with the genetic LRRK2 variation of PARKINSON’S DISEASE. These human cells were a mirror image of what is actually happening in the brain cells of affected people. As they studied the development and progression of these cells, they found that it was neither the kinase activity nor the build up of LRRK2 proteins within the cells that lead to cell death, but rather the diffuse accumulation of the mutant LRRK2 gene.
Then they made an unanticipated discovery. Another protein, alpha-synuclein, long associated with PARKINSON’S DISEASE, was also building up in some of the cells. The relationship between LRRK2 and alpha synuclein has not been clearly understood. Dr. Skibinski found that removing the alpha synuclein proteins from the cells immediately reduced the levels of LRRK2 and brought a dramatic decrease in cell death. This unexpected discovery may well lead to better understanding of the relationship and roles of these proteins in neurodegeneration. Dr. Finkbeiner said “Our discovery of this ‘synergy’ between two proteins long known to play a role in PARKINSON’S is a huge step towards developing drugs that attack the disease’s underlying mechanisms. As we continue to unravel the precise functional relationship between alpha synuclein and LRRK2, we are well on our way to halting the onslaught of PARKINSON’S on the brain.”
G. Skibinski, K. Nakamura, M. R. Cookson, S. Finkbeiner.Mutant LRRK2 Toxicity in Neurons Depends on LRRK2 Levels and Synuclein But Not Kinase Activity or Inclusion Bodies. Journal of Neuroscience, 2014; 34 (2): 418 DOI: 10.1523/JNEUROSCI.2712-13.2014
Review by Marcia McCall
Non-Motor Symptoms Associated with Sleep Disorder in PARKINSON’S DISEASE
A study done in Great Britain found that patients who reported more severe non-motor symptoms such as depression, constipation, or hallucinations also reported having serious sleep behavior problems. While it is impossible to say that the sleep disorder is causative of the other non-motor symptoms, it appears that there are some common underlying pathologies shared between them.
Rapid Eye Movement Sleep Behavior Disorder (RBD) is usually experienced by men and often is present for many years before any other symptoms of PARKINSON’S DISEASE become apparent. They have frequent terrifying nightmares, such as being chased by wild animals or being pursued by armed thugs and they violently act out their defense, often hurting themselves in the process or actually injuring their bed partners. They may yell or scream, punch or kick and actually jump out of bed during the nightmare. What causes RBD is not really well understood, but it often foreshadows the development of neurodegenerative diseases such as Lewy body dementia or PARKINSON’S DISEASE.
When the study done at the Oxford Parkinson’s Disease Center by researcher Michele Hu, M.D., Ph.D., looked at 475 patients who had been diagnosed with PARKINSON’S DISEASE in the last 3 and a half years, they found that almost half of them had probable RBD based on responses to questionnaires. These same patients also reported more problems with non-motor symptoms and had more orthostatic hypotension (low blood pressure on rising from a sitting or lying position) as well as more depression. They scored lower on Mini-Mental State Examination and while there was no significant difference in cognitive testing scores in the early stages, patients with RBD did show earlier cognitive decline as the disease progressed than non RBD patients. They also reported more problems with swallowing, chewing, turning in bed and walking and balance earlier than patients without RBD.
Patients with RBD saw themselves as having more difficulties with their motor functions and also as having a poorer quality of life. Fortunately, there is a medication that helps at least 90% of the patients affected by RBD. Clonazepam is the drug that has shown effectiveness within less than a week of beginning the medication. It needs to be taken continuously. The advice of a skilled movement disorder specialist is need to determine which medication is appropriate, as some medications can actually cause the condition to develop or worsen over time.
REM Sleep behavior disorder is associated with worse quality of life and other non-motor features in early Parkinson’s disease; Michele Hu et al; J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2013-306104
Review by Marcia McCall
Researchers in France have injected 15 volunteers who were diagnosed with advanced PARKINSON’S DISEASE with a unique gene cocktail and initial results have been exciting and promising. Using a modified and deactivated virus for a carrier, three genes necessary for the production of dopamine were injected directly into the dopamine deficient brain regions of the subjects and within 12 hours the defective brain cells began producing dopamine.
Subjects were given three different doses of ProSavin® and followed for up to four years. Motor improvements were noted in all of them, with better coordination and balance and speech improvements. The improvements did depend upon the dose, with higher doses giving better response. However there were problems with development of dyskinesias and also periods of “on-off”. The gene injection appears to encourage long term production of dopamine and improvement in motor symptoms, up to four years.
It cannot be considered a cure, as the disease process does continue and symptoms can only be controlled. But even a four year improvement of symptoms would provide an amazing benefit to the quality of life of people with PARKINSON’S DISEASE. This study did not address the non-motor symptoms of PARKINSON’S DISEASE, or the effects of this therapy on cognitive function, apathy or depression.
This therapy was a very preliminary test and shows that gene therapy can be delivered effectively and safely. This was not a clinical trial as none of the subjects were given placebo treatments for comparison. The researchers are excited by the results and have begun preparing a newer version of the therapy, which will provide even more dopamine production. This could last longer than four years and be better tolerated than the first therapy test. This new version is presently being evaluated in animal studies for safety before it can be approved for use in humans.
ProSavin® is a registered trademark for the gene based treatment developed by Oxford BioMedica, a pharmaceutical company from the United Kingdom. It uses a patented process called LentiVector® to deliver the gene based enzymes directly to the striatum to restore dopamine production.
Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial
Prof Stéphane Palfi MD,Jean Marc Gurruchaga MD,G Scott Ralph PhD,Helene Lepetit PhD,Sonia Lavisse PhD,Philip C Buttery PhD,Colin Watts PhD,James Miskin PhD,Michelle Kelleher PhD,Sarah Deeley MSc,Hirokazu Iwamuro MD,Jean Pascal Lefaucheur MD,Claire Thiriez MD,Gilles Fenelon MD,Cherry Lucas BA,Pierre Brugières MD,Inanna Gabriel MD,Kou Abhay MD,Xavier Drouot MD,Naoki Tani MD,Aurelie Kas MD,Prof Bijan Ghaleh MD,Philippe Le Corvoisier MD,Patrice Dolphin MSc,David P Breen MRCP,Sarah Mason BSc,Natalie Valle Guzman MSc,Prof Nicholas D Mazarakis PhD,Pippa A Radcliffe PhD,Richard Harrop PhD,Susan M Kingsman PhD,Prof Olivier Rascol MD,Stuart Naylor PhD,Prof Roger A Barker PhD,Philippe Hantraye PhD,Prof Philippe Remy MD,Prof Pierre Cesaro MD,Kyriacos A Mitrophanous PhD The Lancet - 10 January 2014
Review by Marcia McCall
Pesticides and the Genetic Link
The central valley of California is a major producer of all the fruits and vegetables consumed, not just in the United States, but all over the world. Production of huge yearly crops depends upon serious planning and management, including the use of herbicides and pesticides. So three counties in this major agricultural region (Fresno, Kern and Tulare) became a very appropriate laboratory to study the effects of pesticides for Jeff M. Bronstein, MD, PhD, professor of neurology and director of Movement Disorders at the Geffen School of Medicine, University of California at Los Angeles.
His team developed a study, The Parkinson’s Environment and Genes (PEG) Study that recruited subjects from three of the most agricultural counties in the state of California. In the laboratory they found that many pesticides inhibit aldehyde dehydrogenase (ALDH) activity and this inhibition is also associated with risk of developing PARKINSON’S DISEASE. So the team tested 26 different pesticides and found only four structural classes of ALDH inhibiting pesticides that contribute to the risk of developing PARKINSON’S DISEASE. .
All humans carry a gene for ALDH, but not all humans exposed to pesticides develop PARKINSON’S DISEASE Interestingly, some people carry polymorphisms (slightly different versions) of the ALDH gene, and if they have no exposure to pesticides they do not develop PARKINSON’S DISEASE. Also, the study suggests that only about 6 per cent of people exposed to ALDH inhibiting pesticides actually develop PARKINSON’S DISEASE.
However, if a person carries a polymorphism for the ALDH gene, the, exposure to ALDH inhibiting pesticides increases the risk of developing PARKINSON’S DISEASE proportionately to the number of pesticides to which they are exposed. If a person was exposed to one, there was risk, but if they were exposed to six, the risk would be 6 times higher, and most people exposed to pesticides in the agricultural community are exposed to many. A six fold greater risk is enormous. The study also looked at whether a person was exposed only at work or only at home or at both and found much higher correlations when the exposure was at both work and home.
Inhibition of ALDH is thought to occur thru a chemical, dihydroxyphenylacetaldehyde (DOPAL), which is a dopamine derivative. And therein lies a potential target to lower the risk through inhibiting the enzyme that makes DOPAL. Dr. Bronstein notes that there are already drugs on the market that can protect against pesticide poisoning, but finding the 6 percent of the population that is at risk would be difficult to accomplish.
This study is an early but important step in showing mechanism of action between genetics and the environment in PARKINSON’S DISEASE and also to the number of exposures. It helps explain why the connection between pesticides and PARKINSON’S DISEASE which has long been suspected but was so difficult to prove. This study should bring more interest and research into this area to protect the people that are exposed to pesticides and to perhaps help develop less toxic pesticides that do not inhibit ALDH. It also seriously enforces the attention to regulation and safety issues for storing and handling pesticides as well as the methods of application.
J.M. Bronstein et al; How Pesticides May Boost Parkinson’s Risk; Neurology, 2014; 82:419-126
Review by Marcia McCall
Better Thinking and Less Depression with Higher Levels of Vitamin D
Amie L. Peterson, M.D. is first author on a study that was published in The Journal of Parkinson’s Disease that reports that higher Vitamin D levels in early PARKINSON’S DISEASE improve performance on cognition and mood tests. This study may open new interventions to prevent cognitive decline if started early in the course of the disease. Dr. Peterson is on the staff of Oregon Health and Sciences University.
The study examined vitamin D levels of 286 subjects and tested their performance in a battery of tests designed to measure memory and cognitive skills as well as indications of mood, such as depression. 61 of the subjects were considered to be demented, and their testing scores also showed a correlation to lower levels of vitamin D. For the remainder of the group, higher levels of vitamin D did correlate to better performance with memory and recall tests as well as ability to name images of animals and vegetables. They were also found to be less depressed as measured on a well known depression scale.
It was not known if any of the subjects in the study were currently taking supplements of vitamin D, nor is the authors willing to comment on whether or not vitamin D was the cause of the improvement. They speculate that more advanced subjects who already were slowed by the disease and dementia were less able to get outside and had limited exposure to sunshine, the major source of vitamin D. The results do suggest that there is a strong correlation between higher levels of vitamin D and better cognition with less depression. Because cognitive impairment early in the course of PARKINSON’S DISEASE may predict the development of dementia in later stages, anything that slows the development of cognitive problems could improve the quality of life and slow the course of the disease for people in the early stages.
“Memory, Mood, and Vitamin D in Persons with Parkinson’s Disease,” by Amie L. Peterson, Charles Murchison, Cyrus Zabetian, James Leverenz, G. Stennis Watson, Thomas Montine, Natasha Carney, Gene L. Bowman, Karen Edward, and Joseph F. Quinn. Journal of Parkinson’s Disease, Volume 3/Issue 4, DOI: 10.3233/JPD-130206
Review by Marcia McCall
Apomorphine for Treatment of Advanced Symptoms of PARKINSON’S DISEASE
Apomorphine has been available for many years as a “rescue” drug to help people with symptoms of advanced PARKINSON’S DISEASE, such as becoming frozen or having debilitating “off” periods. Because of its serious side effects has not been a drug of choice for many neurologists or patients. Apomorphine needs to be injected under the skin, which is painful and causes scaring. Once injected, it causes immediate nausea and vomiting; plus it needs to be maintained in an acidic composition. All of these ‘side effects’ make it a difficult remedy for an already too difficult set of symptoms.
Many pharmaceutical companies have tried for many years to find a viable formulation and delivery method to make Apomorphine more convenient and helpful for people with PARKINSON’S DISEASE. It has been put into patches, pumps and suppositories, and none of them have been effective in getting sufficient quantities of the medication into the bloodstream without causing major irritations or side effects.
The Canadian company Cynapsus has now developed a novel packaging and delivery method that avoids the adverse reactions with this medication. They have packaged in in a thin filmstrip that dissolves under the tongue, similar to the strips of mouthwash product, Listerine. The medication is embedded in the filmstrip, called APL-130277, which maintains the acidity until it dissolves in the mouth, and it is able to penetrate into the bloodstream within two minutes. It is not quite as fast acting as the injected form, but if negotiations with the Food and Drug Administration go well, the company will be moving ahead with clinical trials this summer. Because Apomorphine is already a known and approved medication, safety trials will not be necessary, which should also help speed this product to market.