Laurie Barclay, MD, February 2005

Parkinson's disease is a progressive degenerative disorder of brain cells controlling muscle movement, leading to symptoms including tremor, muscle rigidity, and problems with gait, balance and coordination. The characteristic hand tremor is known as "pill rolling" because the thumb and forefinger rub back and forth. Tremors may also involve the head, lips or feet, and they tend to disappear during sleep.

Other typical symptoms include slowed movement (bradykinesia), slow and shuffling gait, stooped posture, "freezing" of gait and of other movement (akinesia), "masked" expressionless face, and softer voice volume. Disturbances of autonomic function include slowed digestion, swallowing problems, constipation, increased salivation, and decreased sweating.

If dementia develops, it may be heralded by slowed thought processes and difficulty concentrating. Nearly half of patients with Parkinson's disease develop depression, which is thought to result from the neuropathology rather than being situational in response to disability. Sleep disturbances and sexual dysfunction are not unusual.

Onset is typically after age 50, with very low prevalence under age 40 and increasing prevalence over age 70. In the United States, approximately 500,000 people have Parkinson's disease, with about 50,000 new cases reported each year.

In Parkinson's disease, decreased control over movement results from loss of brain cells in the substantia nigra. These neurons normally use the neurotransmitter dopamine to communicate with other brain cells in the corpus striatum.

Although the cause of Parkinson's disease is poorly understood, it most likely is a combination of genetic and environmental factors. Some drugs, diseases and toxins are associated with parkinsonism, lending credence to this theory. Other risk factors include male sex, reduced estrogen levels, and reduced folate levels.

Involvement of dopaminergic neurons in the substantia nigra suggests the possibility of treatment with levodopa (L-dopa), which has long been the therapeutic standard. However, this drug is limited by adverse effects, by decreased efficacy as the disease worsens, and by less predictable response over time. Combining levodopa with carbidopa (Sinemet) allows more levodopa to cross the blood-brain barrier and reduces adverse effects.

Other available drugs include dopamine agonists, which are used both as adjuncts to levodopa therapy and as initial treatment in early Parkinson's disease, especially in younger adults. These include bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex) and ropinirole (Requip). Although the adverse effects of dopamine agonists are similar to those of levodopa, they are less likely to cause involuntary movements and more likely to cause hallucinations or sleepiness.

Selegiline (Atapryl, Carbex, Eldepryl) is a monoamine oxidase B (MAO-B) inhibitor that helps prevent the breakdown of dopamine occurring naturally or formed from levodopa. COMT inhibitors, including Tolcapone (Tasmar) and entacapone, prolong the effect of levodopa by blocking an enzyme that metabolizes dopamine. Drawbacks of Tasmar include liver toxicity.

Anticholinergic drugs, such as trihexyphenidyl (Artane) and benztropine (Cogentin), are mildly effective in controlling tremors, but their use is seriously limited by adverse effects including dry mouth, nausea, urinary retention, constipation, and central nervous system symptoms.

Other pharmacological options include amantadine (Symmetrel, Symadine), an antiviral drug sometimes used in patients with involuntary movements ((dyskinesias) induced by levodopa. Coenzyme Q-10 is a nutritional supplement targeting inefficient mitochondrial metabolism in Parkinson's disease.

Nonpharmacologic treatments include deep brain stimulation (DBS) via implantable electrodes similar to a heart pacemaker. In some patients, improved control with DBS reduces the need for drug therapy. Other surgical treatments include thalamotomy to reduce tremor, and pallidotomy to counteract dyskinesias. Newer approaches include neurotrophins, or molecules that support growth and survival of neurons, and cell transplantation.

In a preclinical model of Parkinson's disease, activation of the Hedgehog signaling pathway, which regulates the normal development of the brain and spinal cord, appears to spare dopaminergic neurons from additional damage and to improve function and movement. Curis, Inc., a therapeutic drug development company, has licensed Hedgehog pathway agonist technologies to Wyeth Pharmaceuticals, in hopes that this may ultimately lead to a novel treatment for Parkinson's disease.

CenterWatch has identified a pipeline of 23 drugs in various stages of development for Parkinson's disease. These include genetic therapies, neuroprotective agents, and neurotransmitter analogues or modulators.

For early diagnosis of Parkinson's disease, Boston Life Sciences is in Phase III testing of Altropane, a small, 123I-based radioactive molecule that specifically binds to dopamine transporters (DATs) in the brain. If single photon emission computed tomography (SPECT) scannning reveals low levels of DATs using this agent, the patient may have Parkinson's disease, whereas excessively high levels may indicate attention deficit hyperactivity disorder.

Istradefylline (KW-6002) is an adenosine A2a receptor antagonist, in Phase III testing by Kyowa Hakko. In a 12- week, double-blind, randomized, placebo-controlled, study, patients with levodopa-treated Parkinson's disease (PD) with both motor fluctuations and peak-dose dyskinesias were randomized to treatment with placebo (n = 29), istradefylline up to 20 mg/day (n = 26), or istradefylline up to 40 mg/day (n = 28).

Home diaries revealed that subjects assigned to istradefylline experienced a mean reduction in the proportion of awake time spent in the "off" state of 7.1 ± 2.0%, compared with an increase of 2.2 ± 2.7% in the placebo group (p = .008). This corresponded to a decrease in "off" time of 1.2 ± 0.3 hours in the istradefylline group and an increase of 0.5 ± 0.5 hour in the placebo group (p = .004). However, "on" time with dyskinesia was significantly increased in the istradefylline group compared with the placebo group, and there were no differences between groups in change in Unified Parkinson's Disease Rating Scale scores or Clinical Global Impression of Change. Istradefylline was generally well tolerated, although nausea was the most common adverse event.

Newron Pharmaceuticals is in Phase III development of safinamide (NW-1015), a unique molecule with multiple mechanisms of action and a very high therapeutic index. It inhibits dopamine uptake and is a potent, selective and reversible inhibitor of monoamine oxidase (MAO) B, without an MAO-A effect. It is also a potent blocker of the sodium (Na+) channel and modulator of the calcium (Ca2+) channel. Through these multiple activities, safinamide can selectively affect those neurons with abnormal firing patterns without affecting normal activity.

In a multinational, Phase II, controlled trial, safinamide improved motor disability in early Parkinson's disease by about 30% compared with placebo, and it was equally well tolerated. The greatest benefit was in those patients receiving stable treatment with a single dopamine agonist. Advantages of safinamide include excellent bioavailability, linear kinetics, and suitability for once-daily administration.

Rotigotine CDS (Neupro; SPM-962), a novel dopamine receptor-agonist and neuroprotective agent formulated as a skin patch for continuous transdermal delivery, is in Phase III testing by Schwarz Pharma. Fifteen multinational clinical trials enrolling more than 1,500 patients with Parkinson's disease have demonstrated the efficacy and safety of the patch, which is applied to the skin once a day.

In the U.S. Phase III trial with Neupro as adjunctive therapy, patients with advanced Parkinson's disease tolerated the patch well and had a statistically significant and clinically relevant reduction in 'off' time, with no increase in dyskinesias. As a nasal spray, rotigotine has entered Phase I development for treatment of acute symptoms in patients with Parkinson's disease.

Solvay Pharmaceuticals is in Phase III testing of DU127090, a controlled-release formulation of Luvox. This selective serotonin reuptake inhibitor is a partial dopamine D2 receptor agonist. Because a partial agonist suppresses activity when a neurotransmitter system is hyperactive but increases activity when the system is hypoactive, DU 127090 is theoretically poised to address dyskinesias and tremor, as well as bradykinesia and akinesia.

CEP-1347, a selective inhibitor of the stress-activated protein kinase pathway, is in Phase II/III testing by Cephalon. The kinases inhibited by CEP-1347 have been shown to play a key role in apoptosis, or programmed cell death, in neurons. A randomized, double-blind, placebo- controlled, Phase II/III clinical trial in 800 patients with early-stage Parkinson's disease should help determine if CEP-1347 can slow progression.

Amgen has completed Phase II testing of Liatermine, a glial-derived neurotrophic factor (GDNF). After six months of continuous infusion into the putamen region of the brain in patients with advanced Parkinson's disease, GDNF was safe and well-tolerated and had a documented biological effect, but it did not meet the primary endpoint of clinical improvement on the Unified Parkinson's Disease Rating Scale. However, ll of 34 patients enrolled in the double-blind trial are now receiving GDNF in an open-label extension study.

ACP-103, an orally administered selective inverse agonist at the 5-HT2A receptor, is in Phase II development by Acadia Pharmaceuticals for treatment-induced psychosis and other drug-related dysfunction. In a Phase Ib/IIa clinical trial, ACP-103 was safe and well tolerated with no adverse events reported, no worsening in pre-existing motor deficits, and fewer treatment-induced dyskinesias in a subgroup of patients.

NeuroSearch is in Phase II development of the monoamine reuptake inhibitor NS-2330. Preclinical experiments suggest that NS2330 reverses akinesia in monkeys treated with L-dopa, that it has a relatively long duration of action, and that the quality of movement in Parkinson test animals treated with NS2330 is at least as good as that seen with L-dopa and other anti-Parkinson drugs. To determine the optimal dosages and clinical effect of NS2330, three clinical Phase II studies are enrolling a total of approximately 930 patients.

Fipamezole (JP-1730), an alpha-2 adrenoceptor antagonist, is in Phase II development by Juvantia Pharma. Unlike other drugs targeting the loss of dopaminergic neurons, this drug is designed to counteract the loss of noradrenergic neurons in the locus ceruleus and generalized depletion of noradrenaline in the brain, which may contribute significantly to the non-motor syndromes in Parkinson's disease, and which may also make dopaminergic terminals more susceptible to drug-induced damage. In clinical trials, fipamezole appears to be able to suppress dyskinesia, and in an animal model with MPTP-treated primates, it appears to extend the duration of action of L-dopa. Three clinical Phase I studies showed that fipamezole was safe and well tolerated.

A unique therapeutic approach to Parkinson's disease is spheramine, in Phase II testing by Titan Pharmaceuticals. This treatment involves dopamine-producing retinal pigment epithelial (RPE) cells grown in tissue culture, uniformly and in large quantities, from normal, fully-differentiated human cells. Providing a bead matrix on which the cells attach allows them to survive when transplanted and eliminates the need for immunosuppression. After positive results in primate studies, six patients with moderately severe to severe Parkinson's disease had an improvement in motor function of 48% over baseline three to four years post treatment with spheramine. A 68-patient, randomized, blinded, controlled Phase IIb clinical study is underway.

Guilford Pharmaceuticals is in Phase II testing of GPI-1485, a neuroimmunophilin ligand that stimulates growth and regeneration of damaged neurons. In animal models, neuroimmunophilin ligands preferentially target only damaged nerve cells, whereas earlier compounds stimulated regrowth of both normal and damaged nerves. Other benefits include oral route of administration and penetration of the blood-brain barrier without direct injection into the brain. A Phase II, two year, randomized, double-blind, placebo-controlled, multicenter trial of GPI 1485 in 200 patients with mild to moderate Parkinson's disease should be completed soon.

From the early days of pharmacotherapy in Parkinson's disease, understanding of the relevant neurotransmitter deficits and of selective neuronal loss has always allowed rational development of pharmaceutical agents. Recent advances in drug delivery technology and in clarifying the role of neurotrophic agents should hopefully allow further breakthroughs, not only in treating the paucity of movement characterizing this disease, but also in preventing or reversing the dyskinesias associated with drug therapy.