DescriptionAn in-depth report on the causes, diagnosis, and treatment of Parkinson's Disease
Selegiline (Eldepryl, Movergan, Zelepar), also known as deprenyl, is an antioxidant drug that blocks monoamine oxidase B (MAO-B), an enzyme that degrades dopamine. (Rasagiline, another MAO-B inhibitor, is under investigation.) Until recently, selegiline was the drug most commonly used in early-onset disease and in combination with levodopa for maintenance. A major 2002 study reported, however, that although selegiline delayed the need for L-dopa by a few months, it has no effect on long-term progression.
Other Adverse Effects. Selegiline has important side effects:
Debate over Mortality Rates. Some major studies, including one in 2002, have reported a higher mortality rates in patients with advanced PD. Such findings may be due to adverse effects on the heart and blood vessels. Although other studies have not reported lower survival rates, some experts believe that, given its modest effects, selegiline may be a poorer drug choice than others, particularly in patients with risk factors for heart disease.
Dopamine agonists stimulate dopamine receptors in the substantia nigra, the part of the brain in which Parkinsons is thought to originate. Dopamine agonists are effective in delaying motor complications during the first one or two years of treatment. Studies also report that they improve impaired movements and disability compared to placebo.
Newer Dopamine Agonists. The newer dopamine agonists currently used include pramipexole (Mirapex) and ropinirole (Requip). They are proving to be safe and effective for both initial sole therapy and in combination with L-dopa. Pramipexole appears to be more effective and have fewer side effects than ropinirole. No direct comparative studies have been conducted at this time, however, to demonstrate whether the new agonists are any better or more tolerable.
Compared to three of these agents, however, studies still report that L-dopa is superior for improving motor function, and, in one study, by year three was no difference in disease progression among all of the agents. Some studies suggest that, like L-dopa, they increase the risk for dyskinesia (uncontrolled movements).
Side Effects. Side effects of pramipexole and ropinirole vary but can be severe and include the following:
Other Dopamine Agonists.
Catechol-O-Methyl Transferase (COMT) Inhibitors
Catechol-O-methyl transferase (COMT) inhibitors increase concentrations of existing dopamine in the brain. Entacapone (Comtan) is the current standard COMT inhibitor. It improves motor fluctuations related to the wearing-off effect and has shown good results in improving on time and reducing the requirements for L-dopa. If the patient does not respond to the drug within three weeks, it should be withdrawn. No one should withdraw abruptly from these drugs.
Side Effects. Side effects include the following:
Of major concern are reports of a few deaths from liver damage in patients taking tolcapone (Tasmar), another COMT inhibitor. The drug has been taken off the market in many countries and is recommended in the U.S. only for patients who cannot tolerate another other agents. Entacapone does not appear to have the same effects on the liver and does not require monitoring. A 2003 three-year study suggested that the drug is safe and effective over the long term. Still, patients should watch out for symptoms of liver damage, including jaundice (yellowish skin), fatigue, and loss of appetite.
Anticholinergics were the first drugs used for PD, but have largely been replaced by dopamine agents. They are generally used only against tremor in the early stages. They are not as effective against bradykinesia and posture problems and may increase the risk for dementia in late stages. Among the many anticholinergics are trihexyphenidyl (Artane, Trihexy), benztropine (Congentin), biperiden (Akineton), procyclidine (Kemadrin), and ethopropazine (Parisdol). Orphanadrine (Norflex) is a drug with anticholinergic properties, but is also a muscle relaxant and does not cause urinary retention.
Side effects of Anticholinergics. Anticholinergics commonly cause dryness of the mouth (which can actually be an advantage in some people who experience drooling). Other side effects are nausea, urinary retention, blurred vision, and constipation. These drugs can also increase heart rate, worsen constipation, and cause urine retention in men with enlarged prostate. Anticholinergics can sometimes cause significant mental problems, including memory loss, confusion, and even hallucinations, which can be particularly problematic for elderly people with signs of existing dementia and people taking tricyclic antidepressants. People with glaucoma should use these drugs cautiously.
Amantadine (Symadine, Symmetrel) stimulates the release of dopamine and may be used for patients with early mild symptoms. It has some benefit against muscle rigidity and slowness and may help some patients in advanced stages who are unresponsive to other drugs. It is less powerful than levodopa and may lose its effectiveness after about half a year. It may also reduce motor fluctuations brought on by levodopa, however, and these benefits appear to persist for at least a year. Large, well-conducted studies are still needed to determine its true benefits and safety.
Side Effects. Side effects are similar to those of anticholinergic drugs and also may include swollen ankles and mottled skin. It can also cause visual hallucinations. Overdose can cause serious and even life-threatening toxicity. Patients with Parkinsons should not withdraw from this drug abruptly. In rare instances, it can cause acute delirium or a life-threatening condition called neuroleptic malignant syndrome. Pregnant or nursing women should not use this drug.
Coenzyme Q10 (Ubiquinone). Coenzyme Q10 (also called ubiquinone) is an antioxidant that is being studied for Parkinson's disease. This enzyme is important for cellular energy, which may be impaired in PD. In one study, patients who took coenzyme Q10 experienced slower decline in daily activities and mental and motor skills compared to patients on placebo. This is available as a supplement in health food stores, but such products are not necessarily those used in clinical studies. Patients should check with their physician about taking it.
Budipine and Other Glutamate Blockers. A number of experimental drugs are being investigated for Parkinsons disease because they block the actions of glutamate, an amino acid that is a particularly potent nerve cell killer. Some of these drugs block a receptor group to glutamate called N-methyl-D-aspartate (NMDA). Investigative NMDA antagonists include remacemide, memantine, riluzole, and budipine. Budipine is of particular interest. It not only blocks NMDA, but it increases levels of two enzymes involved in the production of dopamine. Studies suggest that it reduces tremor in PD and it proving to be beneficial in combination with levodopa.
Testosterone Replacement. One very small and short term study investigated the effects of testosterone replacement on depression and other nonmotor symptoms in PD patients with testosterone deficiencies. (Such deficiencies affect about 20% and 25% of men over 60.) After a month of using a topical testosterone gel, such patients reported improvements in depression, fatigue, and sexual interest. More research is needed to determine if this treatment is actually beneficial and safe in this population. Testosterone replacement is generally not appropriate for men with normal hormonal levels, since it may increase the risk for prostate cancer, benign prostatic hyperplasia, and heart disease.
Cannabinoids. Drugs derived from cannabinoids, the active ingredients in marijuana, may have nerve protecting properties. Adverse effects include anxiety and sedation. Investigators are studying cannabinoid derivatives, including cannabidiol and dronabinol, which do not have psychologic side effects.
Genetic Therapy. Another area of research is therapy that administers genes that code proteins responsible for producing dopamine to protect or even heal nerve cells damaged by Parkinsons disease. The GAD gene, which produces g-aminobutyric acid (GABA), is of particular interest. GABA quiets brain activity and may actually free up movement in PD patients.
Treatments for Disorders Associated with Parkinsons
Conditions associated with motor impairment and other symptoms of Parkinsons disease may require a variety of treatments. The following is a brief sample of some of them.
Depression. Although depression is very common in PD, there have been surprisingly few controlled studies that will help physicians determine the right antidepressant for these patients. Antidepressants used for PD include tricyclics, particularly nortriptyline (Pamelor, Aventyl), and selective serotonin-reuptake inhibitors (SSRIs), which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). A number of studies suggest, however, that SSRIs may worsen Parkinson symptoms. Patients taking SSRIs should be monitored.
Psychotic Side Effects. Some studies indicate that the drug clozapine (Clozaril) and quetiapine (Seroquel), normally used in schizophrenia, may be the optimal agents at this time to help offset the psychiatric side effects. In one study quetiapine also improved memory and concentration. These drugs have some serious side effects and need to be used with caution. (Some studies have suggested that similar drugs, such as risperidone or olanzapine, do not have the same benefits.)
Dementia. Drugs used to treat Alzheimer's disease (donepezil, tacrine, galantamine) are also being investigated from this problem.
Daytime Sleepiness. Modafinil (Provigil), an agent used to treat narcolepsy, is proving to be very helpful for PD patients with sleepiness related to their disease.
Drooling. In search of a simple solution for the problem of drooling, scientists have reported that injections of very small amounts of botulinum toxin A effectively reduce saliva production and drooling. In such small amounts the toxin is safe.
Constipation. Cisapride is being investigated for relieving constipation.
Voice Loss. A relatively simple procedure using collagen injections in the neck appears to be a safe and effective method of improving the voice and speech disorders caused by PD. The procedure augments the collagen in the vocal fold and works best in patients who can still initiate speech. A 2001 study reported improvements that lasted from two to seven months in 61% of patients.
Impotence. Sildenafil (Viagra) is proving to be very helpful for men who suffer from impotence from Parkinsons disease. However, the agent may worsen orthostatic hypotension, which may be a side effect of some of the PD medications.