A national clinical trial with 80 Parkinson's disease patients has shown that high dosages of a naturally occurring compound, coenzyme Q10, slowed by 44 percent the progressive deterioration in function that occurs in the disease. The greatest benefit was seen in everyday activities such as feeding, dressing, bathing and walking.
The study's coordinators caution that while encouraging, the therapy needs to be tested in a larger trial with hundreds of patients before this treatment can be recommended.
Published in the Oct. 15, 2002 issue of the American Medical Association's Archives of Neurology, the study was conducted at 10 sites by the Parkinson Study Group, under the direction of principal investigator Clifford Shults, M.D., professor of neurosciences, University of California, San Diego (UCSD) School of Medicine, and chief of the Neurology Service at the VA San Diego Healthcare System. Parkinson's disease is a degenerative disorder of the brain in which patients develop tremor, slowness of movement and stiffness of muscles. It affects approximately 1 percent of Americans over the age of 65. Although certain drugs, such as levodopa, can reduce the symptoms of Parkinson's disease, no treatment has been shown to slow the progressive deterioration in function.
The selection of coenzyme Q10 as a potential treatment for Parkinson's was based on work carried out over the past decade by Shults, Richard Haas, M.D., UCSD professor of neurosciences, and Flint Beal, M.D., professor and chair of neurology, Weill Medical College of Cornell University.
Shults explained that mitochondria produce the energy-containing molecules that supply energy to chemical reactions in cells and that coenzyme Q10 plays an integral role in that process. He further explained that coenzyme Q10 is also a potent antioxidant. Over the past several years, research by Shults, Haas and Beal showed that mitochondrial function is impaired in patients with Parkinson's disease and coenzyme Q10 levels are reduced in the mitochondria of Parkinsonian patients. Beal and Shults studied coenzyme Q10 in an animal model of Parkinson's disease and found that it could protect the part of the brain affected by the disorder.
"Coenzyme Q10 plays a crucial role in normal mitochondrial function both as a component of the electron transport chain which makes cellular energy and as a molecule with antioxidant and pro-oxidant properties," Haas said. "Recently, several rare mitochondrial diseases affecting younger people resulting from coenzyme Q10 deficiency have been described. These patients may respond dramatically to coenzyme Q10 treatment. Tissue coenzyme Q10 levels fall with aging and we do not know why this occurs. The normal lower levels of Coenzyme Q10 in older individuals may be a contributing factor in the progression of some diseases of aging."
In the Parkinson Study Group national clinical trial, 80 Parkinsonian patients who had early disease and did not yet need medications typically used to treat Parkinson's disease (such as levodopa), were randomly assigned to receive coenzyme Q10 four times a day at a dosage of 300, 600 or 1200 mg/day, or a placebo, also taken four times a day. Prior to beginning the study, the patients were evaluated with a medical history, physical exam, laboratory tests, and a battery of clinical assessments of Parkinson's disease. Participants were reevaluated with tests to assess the severity of the Parkinson's disease at regular intervals and followed until the time that they needed treatment with medications used to treat the symptoms of Parkinson's disease, or for a maximum of 16 months.
By the eighth month visit, the scores among the four groups had clearly separated and established a pattern of the groups taking the lowest and intermediate dosages (300 and 600 mg/day) being similar and lower than placebo and the scores for the group receiving the highest dosage (1200 mg/day) being substantially lower than the other groups. The lower score reflected less impairment and better function. This pattern persisted to the end of the study. The benefit was seen in assessment of mental function and mood, activities of daily living and motor skills.
If the drug had merely been ameliorating symptoms - while the disease continued unchecked to kill nerve cells - the researchers would have expected the initial, first-month check-up to reveal improvement in the coenzyme Q10 groups. Since that was not the case, Shults hypothesized that the drug might have slowed the underlying progression of the disease over the 16-month period of the study. However, Shults cautioned that a study with a larger number of patients might reveal a small amelioration of symptoms early. Shults also stressed that the study was designed to look at the function of the patients and was not designed to look at whether groups treated with coenzyme Q10 did, in fact, have less damage to the nerve cells that are affected in Parkinson's disease. He and his colleagues hope to look at damage to the nerve cells in a larger study.
In appraising the results of the clinical trial, Shults noted that "while it is tremendously encouraging that our results indicate that it is likely that coenzyme Q10 slows the progression of Parkinson's disease, our study did not have sufficient numbers of patients to unequivocally prove that it does. It would be premature to recommend that patients with Parkinson's disease take high doses of coenzyme Q10."
Shults and the Parkinson Study Group are developing a proposal to carry out a larger study to confirm their results. He added that an equally important outcome of the recently completed clinical trial was that it provided an efficient design for studies, such as this one, of drugs that might slow the progression of Parkinson's disease. The design was based on previous studies carried out by the Parkinson Study Group and developed by David Oakes, Ph.D., biostatistician for the study and chair of the Department of Biostatistics at the University of Rochester, in collaboration with Shults and Drs. Ira Shoulson and Karl Kieburtz of the University of Rochester.
Shults stated that he hoped this study and its efficient design will stimulate future studies to identify treatments that are likely to slow the progression of Parkinson's disease.
Listed according to number of subjects enrolled, the investigators and trial sites for the recent study were:
- Julie Carter, R.N., M.N., A.N.P., Oregon Health & Science University
- Katie Kompoliti, M.D., Rush-Presbyterian-St. Luke's Medical Center
- Joel S. Perlmutter, M.D., Washington University in St. Louis
- Stephen Reich, M.D., Johns Hopkins University
- Matthew Stern, M.D., University of Pennsylvania
- Ray L. Watts, M.D., Emory University
- Roger Kurlan, M.D., University of Rochester
- Eric Molho, M.D., Albany Medical College
- Madaline Harrison, M.D., University of Virginia
- Mark Lew, M.D., Keck School of Medicine of the University of Southern California.
Shults and his colleagues strongly caution patients against choosing to take coenzyme Q10 until a larger, definitive trial can be conducted. Because coenzyme Q10 is classified as a dietary supplement, it is not regulated by the U.S. Food and Drug Administration. The versions of the coenzyme Q10 sold in stores may differ and may not contain potentially beneficial amounts of the compound, Shults said. He added that if many people begin taking coenzyme Q10 after these early results, it may make it impossible for investigators to find enough patients to carry out definitive studies of the compound's effectiveness and the proper dosages, since patients must not be taking any treatments in order to be considered for enrollment in a definitive trial.
The UCSD-led clinical trial was sponsored by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The coenzyme Q10 and placebo used in the study were formulated into wafers and packaged without charge by Vitaline Formula, Wilsonville, OR. Shults and Jed Meese are co-inventors of the coenzyme Q10 compound in a pending patent application. The application is jointly owned by Enzymatic Therapy, Inc. (owner of Vitaline Corp.), The Regents of the University of California, and the Department of Veterans Affairs.
The results of the study will be discussed by Shults on Oct. 15, 2002 at the annual meeting of the American Neurological Association in New York City.
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Investigators, Parkinson Study Group
Julie Carter, R.N., M.N., ANP
Oregon Health & Science University
Contact: Jim Newman
Katie Kompoliti, M.D.
Rush-Presbyterian-St. Luke's Medical Center
Contact: Chris Martin
Joel S. Perlmutter, M.D.
Washington University in St. Louis
Contact: Gila Reckess
Stephen Reich, M.D.
Clinical Trial held at Johns Hopkins University
Dr. Reich now at University of Maryland School of Medicine
Contact: Ellen Beth Levitt
Matthew Stern, M.D.
University of Pennsylvania
Contact: Felicia R. Phillips
Ray L. Watts, M.D.
Contact: Janet M. Christenbury
Roger Kurlan, M.D.
University of Rochester
Contact: Tom Rickey
Eric Molho, M.D.
Albany Medical College
Contact: Gregory McGarry
Madaline Harrison, M.D.
University of Virginia
Contact: Marguerite Beck
Mark Lew, M.D.
Keck School of Medicine
University of Southern California
Contact: Jon Weiner
Mitochondria are long, oval-shaped specialized components within cells that are responsible for converting nutrients into energy. These tiny organelles consume more than 80 percent of the oxygen humans breathe and use it to make over 90 percent of the energy that cells need to function. Mitochondria contain their own DNA, separate from a cell's nuclear DNA.
Located in the cell's cytoplasm outside the nucleus, mitochondria consist of two sets of membranes, a smooth outer coat and an inner membrane arranged in tube-like folds called cristae. The inner membrane contains the components of the electron transport chain, a series of compounds that transfer electrons to oxygen in the process of energy production.
An important compound involved in the electron transport chain is ubiquinone, a small molecule also known as coenzyme Q10, that acts as an electron carrier.
First identified in 1957, coenzyme Q10 (ubiquinone) is a compound naturally made in the body. A coenzyme is a small molecule that, by itself, does not catalyze a reaction. Rather, a coenzyme enhances an enzyme, which is a protein that speeds up a chemical reaction. The "10" in coenzyme Q10, refers to a portion of the coenzyme's chemical structure.
In addition to its role in the metabolic process, coenzyme Q10 is known to act as an antioxidant that helps neutralize cell-damaging molecules known as free radicals.
Mitochondrial Function and Coenzyme Q10 in Parkinson's Disease
Patients with Parkinson's disease have lost dopamine-producing nerve cells in the substantia nigra, a part of the mid-brain's grey matter.
Previous research has shown that interference with a certain step in mitochondrial energy production, called complex I, causes an increase in the number of oxygen free radicals, which are known to be toxic to cells, such as those in the substantia nigra.
To determine if there might be a connection between mitochondrial function and Parkinson's disease, Clifford Shults, M.D. and Richard Haas, M.D., in the UCSD Department of Neurosciences, began a series of experiments. Reasoning that the reduction in complex I activity might be part of the process that resulted in death of the dopamine-producing nerve cells, they compared the mitochondrial function in platelets of early-stage Parkinsonian patients not yet on medication, to control groups. They found that the activity of complex I was significantly lower in the Parkinsonian patients.
To evaluate the potential effect of medications such as levodopa, the researchers evaluated platelet mitochondrial function in 11 patients who had received carbidopa/levodopa or selegiline. Neither of the treatments affected the mitochondrial function.
Knowing that an important molecule involved in the electron transport process in mitochondria is coenzyme Q10, Shults and Haas worked with Flint Beal, M.D., formerly at Massachusetts General Hospital (and currently at Weill Medical College, Cornell University), to measure the levels of coenzyme Q10 in the platelet mitochondria and found that coenzyme Q10 levels were significantly lower in Parkinsonian patients, as compared to the control group. In follow-up investigations first with mice and then a pilot study with 15 human patients, the researchers provided coenzyme Q10 supplements. In the animals, they found that the dopaminergic nerve fibers were significantly preserved. In the human patients, the coenzyme Q10 was well tolerated and evaluations of patients' plasma levels showed a trend toward an increase in complex I activity.
These findings led to the recent study by the Parkinson Study Group, a consortium of more than 50 Parkinson's disease centers in the United States and Canada.