Parkinson’s Disease- Part I

(7/17/11)- A new study shows that, in spite of the fact that the FDA requires a "black box" warning label on all anti-psychotic drugs for Parkinson disease patients who are suffering from dementia, the usage of the drugs continues to thrive. The results of the study were published in a recent edition of the Archives of Neurology.

The "black box" warning label clearly states that the risk of death increases in older dementia patients suffering from Parkinson's. The researchers examined medical-record data from the Department of Veterans Affairs in fiscal years 2002 and 2008.

Daniel Weintraub, a psychiatry and neurology professor at the Perlman School of Medicine at the University of Pennsylvania was the first author or the study.

(9/1/07)- Neuropro (Rotigotine Transdermal System, Schwarz Pharma) has been approved by the Food and Drug Administration for treatment of Parkinson's disease.It is the first transdermal system for the treatment of the disease that has been approved by the agency.

(4/4/07)- The FDA has withdrawn approval of pergolide, a drug used to treat Parkinson's disease from the market, citing a history of safety concerns. The drug is sold under the trade name of Permax by Eli Lilly & Co., as well as a generic after reports showed it could cause problems similar to those that prompted withdrawal of the diet drug combination fen-phen.

(7/5/06)- The FDA approved Novartis AG's Exelon for the treatment of dementia in patients with Parkinson's disease. Exelon is a drug currently on the market to treat mild to moderate Alzheimer's disease. To see more on this topic please see our article on Possible New Drugs for the Treatment of Alzheimer's disease.

The FDA had asked the advisory panel that studied Exelon to determine if the dementia associated with Parkinson's was a separate medical condition from Alzheimer's disease. The panel unanimously said it believed dementia associated with Parkinson's is indeed a distinct medical condition.

The approval of Exelon for the treatment of Parkinson's dementia is based on the results of a clinical study with 541 patients who showed symptoms of mild t moderate dementia two years or later after their diagnosis for Parikinson's disease.

At the end of six months, patients who received Execelon did "significantly better" on a scale that measures mental processes than patients who received a placebo.

The patients who received the Exelon had significant adverse gastrointestinal reactions. Other significant adverse reactions included vomiting, anorexia, stomach pain and loss of strength. Some patients experienced a worsening of their tremors.

(1/11/03)- A small Italian company, Newron Pharmaceuticals, SpA says its new drug, safinamide, helped to reduce by 30% the tremors that are one of the primary indicators of Parkinson's disease. Taken together with other developments it may be an indication that scientists are finally making some headway at slowing the progression of Parkinson's disease, not just treating the symptoms.

Other studies have indicated that safinamide in mice slows the progression of the disease. As we discuss later in this article, GlaxoSmithKline reported that its dopamine agonist, ReQuip had slowed the progression of Parkinson's in some clinical trials that involved human subjects. Pharmacia Corp. has obtained similar results with its drug, Mirapex.

In Newron's phase II trial, which involved 151 patients over a three month period of time, patients given safinamide and dompamine agonist showed a 30% reduction id disability, including tremors and uncontrollable movements, when compared to the placebo group. Trials for patients in the U.S. and Europe are expected to begin in about 6 months, and a large-scale Phase III trial in mid-2004. Newron was created in 1998 for the spin-off of a research group at Pharmacia & Upjohn.

A second study of transplanted fetal cells has found no benefit for patients suffering from Parkinson's disease, and in fact may cause serious side effects. C. Warren Olianow, a neuroscientist at Mount Sinai School of Medicine in New York led the study. The results thus dealt a blow to the hope that infusions of brain tissue from aborted fetuses could reverse the degenerative brain condition. An earlier study, led by Curt Freed of the University of Colorado came up with similar findings.

In both studies researchers were not able to find any measurable improvement in tests of motor and other skills. In fact both studies found severe side effects such as uncontrolled motions of the limbs. Parkinson's disease is caused in part by the death of cells that make dopamne, an important chemical in the brain. The researchers had hoped that the new cells capable of making dopamine could treat the symptoms, and prevent the disease from worsening.

Researchers at New York Presbyterian Hospital/Weill Medical College of Cornell University have received the go-ahead from a National Institute of Health review panel, and the FDA to proceed with the first clinical trials of gene therapy to treat patients with Parkinson's disease.

The researchers have revised their clinical models and safety protocol several times, and have conducted five sets of tests in rats and a safety-test in seven primates. In a paper published in the journal Science, the researchers stated that the genes, inserted into viruses and injected into rats, appeared to slow the progression of the disease. The gene therapy involves injecting the virus that will deliver the gene into nerve cells in the affected area of the brain. It is believed that these affected nerve cells became overactive due to a lack of dopamine.

The researchers are now awaiting final approval from a hospital review board before beginning the small clinical trial, which was approved by the FDA on August 2nd. The prospective patients are all younger than 65, have had the disease for over 5 years and are being selected through North Shore-Long Island Jewish Health System in New York. Dr. David Edelberg, head of neuroscience at North Shore is working with the researchers.

The two main Parkinson's gene-therapy research firms have now formed a private company called Neurologix, that has raised about $2.5 million so far for their research, including a large investment from Medtronic, Inc.

Two drugs seem to show promise in slowing the progression of Parkinson's disease. Please remember that the slowing of the progression of the disease differs from the treatment of the symptoms of the disease, which is what the present medication deals with in cases of Parkinson's disease.

GlaxoSmithKline PLC said patients who took it Parkinson's drug, Requip ( ropinirole), showed evidence of "slowing of the disease" when compared with a group of patients who were given levodopa, the current standard treatment. Pharmacia Corp. of Peapack N.J. claimed that it had obtained similar results for its drug, Mirapex (pramipexole).

Present estimates are that there are 1/2 million people in the U.S. with Parkinson's disease and over 10 million worldwide who suffer from the disease. In the Glaxo study 186 early-stage Parkinson's patients were tested over a two- year period of time. Researchers believe Parkinson's is caused when the nerve cells that produce the brain chemical dopamine degenerate. "The Requip group lost one-third less dopamine in the brain that those on levodopa," said Mr David Brooks, a professor of neurology at the Hammersmith Hospital in London where the trial was carried out.

In the Pharmacia study, similar comparisons were made during four years of testing on a group of 82 patients. Patients who were given Mirapex showed a 40% slower rate of loss of dopamine compared with the levodopa group. Mirapex, has been on the market for about 5 years, and was co-developed with Boehringer-Ingelheim GmbH of Germany.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive development of resting tremor, slowness of movement (bradykinesis), muscular rigidity and impairment of postural reflexes. Neurodegeneration in PD is associated with a cascade of events that may also involve mitochondrial abnormalities, excitatory amino acids, a rise in intracytoplasmic free calcium, cytokines and trophic factors.

In general, PD is a disorder that manifests clinically with a variety of movement impairments. James Parkinson first defined it in 1817. He described PD as the "saddest of all diseases". About one million Americans suffer from Parkinson’s disease. Each year about 50,000 individuals are diagnosed with this neurodegenerative disease.

Parkinson's disease affects about one percent of the population over the age of 60 years in the United States. It is more common among men than among women and also seems to be more widespread in northern countries. The incidence of the disease increases with age although aging itself is not believed to be a causative factor. Early symptoms may go undiagnosed in as many as 5 to 10% of individuals over 60 years of age.

Arvid Carlsson was awarded the Nobel Prize in Physiology or Medicine, based on his discovery in the 1950’s that dopamine is a neurotransmitter in its own right. In the 1960’s, levodopa (the immediate precursor of dopamine) was used in the treatment of PD. This treatment replenished brain dopamine levels in the basal ganglia (putamen and caudate).

Levodopa treatment is associated with development of motor complications such as the "wearing off" of beneficial therapeutic effect and dyskinesia. About 75% of patients develop these complications after 6 years of levodopa therapy. L-dopa is the mainstay medication used to treat PD. It is a palliative treatment, with research still going on to develop an understanding of the etiology (the pathogenic biochemical pathways that lead to clinical symptoms) of the disease. (See: Hardy J. Genetic dissection of neurodegenerative disease. Clinical Neuroscience Research Journal 2001; 1:134-141.This is an excellent clinical neuroscience review of the major neurodegenerative diseases. )

Currently the primary treatment for Parkinson's disease is the compund L-dopa, which is converted to dopamine in the brain. Higher doses are required with the passage of time to effectively manage the treatment.

A new treatment has been proposed by Avigen, Inc. of San Francisco, which uses adeno-associated virus (AAV) vector to deliver a gene that makes a chemical that is deficient in patients with Parkinson's disease. Pre-clinical studies were performed in collaboration with Krys Bankiewicz, MD, PhD, Associate Professor in the Department of Neurosurgery at the University of California, San Francisco, who is a leading researcher in the field of Parkinson's disease.

Newer treatment steps are being explored. One treatment, a surgical procedure, involves transplanting fetal nerve tissue into the brains of PD patients to replace dopamine neurons that have been lost. The goal is to replace lost dopaminergic neurons or disrupt aberrant basal ganglia circuitry. This method is usually used in late-stages of the disease. The literature indicates that this method is not always successful.

A newer method being explored involves a strategy to halt the continuing loss of dopamine neurons through a potent stimulator of dopamine neuron growth. This involves a substance known as glial cell line-derived neurotrophic factor (GDNF). A recent research article in Science (2000; 290: 767-773) presents encouraging results with GDNF gene therapy in two primate models of PD.

The researchers conclude "[T]hese data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients." (See: Kordower JH., Emborg ME., Bloch J., Ma SY., Chu y., Leventhal L., McBride J. Neurodegeneration Prevented by Lentiviral Vector Delivery of GDNF in Primate Models of Parkinson’s Disease. Science 2000; 290: 767-773)

While all these treatment methods are potentially helpful, the ideal treatment would be development of a neuroprotective therapy that prevents neuronal loss. As geneticists explore the nature of this disease, they realize it is a multifactorial disease, with the rare early onset form of the disease being an inherited autosomal dominant disease.

Approximately 5-15% of PD patients have familial Parkinsonism and a genetic history consistent with autosomal dominant pattern of inheritance. There is some evidence that the mutation in the human alpha-synuclein gene is associated with development of PD and that this single gene deficit may well be sufficient to account for the PD phenotype. How this gene leads to PD is unknown. Alpha -synuclein is a presynaptic protein that is thought to be involved in neuronal plasticity. There are probably also genetic components to the common late-onset forms of PD, but until we have a fuller understanding of the causes of this disease, L-dopa will remain the first line therapy.

Medical treatment should be started when functional disability appears, which is a different threshold for each patient. For patients below 65 years old, or above 65 years old but with preserved mental function and with no severe comorbidity, initial monotherapy with a dopamine agonist is advisable. This approach appears to delay the appearance and reduce the amount of late motor complications with subsequent levodopa treatment.

Levodopa in combination with carbidopa is the most effective medication for treatment of motor symptoms of PD. At least 50% of patients experience a significant reduction in tremor with levodopa. Usual starting dose is one tablet (carbidopa 25 mg plus levodopa 150 mg) administered 2 to 3 times daily which can be titrated upward by one tablet per day every one to two weeks to a maximum of 1000 to 1200 mg/day in three or four divided doses. Exacerbation of postural and action tremor can occur with levodopa.

Entacapone (Comtan-Novartis), a catechol-O-methyl-transferase (COMT) inhibitor, has been approved by FDA for adjunctive use with levodopa/carbidopa (Sinemet and others) in patients with PD who have end-of-dose "wearing off" symptoms. The dosage of Comtan is one 200 mg tablet with each levodopa/carbidopa dose, up to a maximum of 8 doses per day.

It is the second COMT inhibitor to be marketed in the USA. Tolcapane (Tasmar) has already caused serious hepatotoxicity and was withdrawn from the market in Canada, but is still available in US.

Adverse effects of entacapone: increases levodopa-related (dopaminergic) effects, including dyskinesias, anorexia, insomnia, orthostatic hypotension, syncope, nausea, vomiting and hallucinations. Diarrhea, and orange discolorations of urine. No hepatotoxicity has been reported.

Common symptoms of PD include: tremor, slowness of movement, dizziness, loss of balance, confusion, memory loss, difficulty in swallowing, dribbling, nausea, vomiting, difficulty with speech, urine problems, worry/anxiety, diarrhea, constipation, difficulty undressing, pain, dyskinesia, weakness, stiffness, on/off attacks, cramp, freezing, end of dose effects, sleeplessness, depression. The above symptoms do not develop all at once, nor do they manifest themselves in all cases of the disease. They are dependent on the progressive stage of the disease.

Common adverse effects of all L-dopa medications include: nausea, dyskinesia, hallucinations, confusion, postural hypotension, sedation, constipation, sleep disturbances and hypersexuality. (See: Wolen, Cheryl H. Comparative Tolerability of Newer Generation Antiparkinsonian Agents. Drug and Aging 2000; 16(1):55-65) . Patients aged < 60 years are especially prone to motor complications.  

The most frequent challenge in diagnosing Parkinson Disease is the conditions of essential tremor and multiple systems atrophy. Parkinson disease has three stages of development:

  1. Early—from onset of symptoms to the appearance of motor fluctuations.
  2. Middle—from motor fluctuations to the appearance of moderate-to-severe disability.
  3. Advanced—when moderate to severe disability is present

Memory impairment and cognitive dysfunction are rarely encountered in early stage Parkinson's disease. Depression is, however, a common feature and about 30 per cent of Parkinson's disease victims eventually develop Alzheimer's disease or other forms of dementia.

The following are considered pre-symptomatic markers of Parkinson’s disease:

  1. changes in odor detection
  2. handwriting
  3. movement time of self-initiated motor acts
  4. speech
  5. personality traits
  6. presence of antibodies against dopamine neurons
  7. pattern of positron emission tomography (PET) results
  8. age
  9. appearance of mitochondrial DNA mutation profile.

Some of the references used for this article:

Beal, M. Flint, et al. Parkinson's Disease and other Extrapyramidal Disorders. Harrison's Principles of Internal Medicine, 13th edition, McGraw- Hill, 1994, pp. 2275-80

Kordower JH., Emborg ME., Bloch J., Ma SY., Chu y., Leventhal L., McBride J. Neurodegeneration Prevented by Lentiviral Vector Delivery of GDNF in Primate Models of Parkinson’s Disease. Science 2000; 290: 767-773)

Hardy J. Genetic dissection of neurodegenerative disease. Clinical Neuroscience Research Journal 2001; 1:134-141

Nadeau, Stephen E. Parkinson's disease. Journal of the American Geriatrics Society, 1997; 45( 2): 233-240

Wolen, Cheryl H. Comparative Tolerability of Newer Generation Antiparkinsonian Agents. Drug and Aging 2000; 16(1): 55-65

Youdim, Moussa B.H. and Riederer, Peter. Understanding Parkinson's disease. Scientific American, January 1997, pp. 52-59

Please see our article on Parkinson Disease-Diagnostic Studies- Part II


Allan and Harold Rubin, MS, ABD, CRC, Guest Lecturer
updated July 17, 2011

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