Parkinson's Disease
Parkinson’s disease is a neurodegenerative disorder that primarily affects the motor neurons. In Parkinson’s, degeneration of the dopaminergic neurons in the substantia nigra of the brainstem leads to dopamine deficiency, which constitutes a major factor in the pathogenesis of Parkinson’s disease. Patients on average have lost about 80% of their dopaminergic neurons by the time their Parkinson’s disease symptoms appear.
The motor symptoms of Parkinson’s disease usually begin in one side of the body and becomes bi-lateral (affecting both sides of the body) as the disease progresses. Specifically, the following are the cardinal signs of Parkinson’s disease:
Bradykinesia is slowness in voluntary movement. It is a result of delayed signal transmission from the brain to skeletal muscles due to deficiency of the dopaminergic neurons.
Resting tremor occurs when a patient is standing or sitting still. It is often the first sign a patient or his/her family/friends notice.
Over the past few years, non-motor symptoms associated with Parkinson’s disease have gained wider recognition. These may include sleep disturbance, depression and apathy, and in some cases, a diminished sense of smell.
How Common Is Parkinson's Disease?
Age is a recognized risk factor for sporadic Parkinson’s disease. The median age of onset is 62 years old. In addition, men have a slightly higher chance of developing the disease.
The prevalence of Parkinson’s disease varies from study to study. However, it is generally accepted that the prevalence rate in the US is about 0.3%, leading to about 1 million people in the US. Examples of well-known figures who have been affected by Parkinson’s disease include the late Pope John Paul II, actor Michael J. Fox and legendary boxer Muhammad Ali.
How is Parkinson's Disease Treated Pharmacologically?
The pharmacological treatments currently available for Parkinson’s disease mostly act to enhance dopaminergic transmission. Specifically, the following outlines the major classes of treatment for Parkinson’s disease.
Levodopa therapy has been the cornerstone for managing the symptoms of Parkinson’s disease since its introduction decades ago. Levodopa is a precursor of dopamine, the neurotransmitter deficient in Parkinson’s disease which cannot cross the blood brain barrier. Levodopa, on the other hand, is able to cross the blood brain barrier. It is converted to dopamine inside the body by aromatic amino acid decarboxylase. To help reduce gastrointestinal side effects, carbidopa, a decarboxylase inhibitor, is formulated together with levodopa to prevent the perenfreal breakdown of levodopa. The treatment algorithm endorsed by the American Academy of Neurology (AAN) calls for carbidopa-levodopa to be initiated upon diagnosis of Parkinson’s disease in patients older than 65. As disease progresses, the majority of PD patients will require levodopa containing therapy.
Dopamine agonists primarily act through their binding to post-synaptic dopamine receptors and are more commonly prescribed in early Parkinson’s disease.
Monoamine oxidase B inhibitors function to prevent the breakdown of dopamine, leading to enhanced dopaminergic transmission. These agents are typically used in early Parkinson’s disease patients and are also used as an adjunct to levodopa therapy in advanced Parkinson’s disease patients.
Catechol-O-methyl transferase (COMT) inhibitors serve to prevent the breakdown of levodopa, effectively increasing the exposure to levodopa and are always used together with levodopa.
What Are the Unmet Needs?
Carbidopa-levodopa has been the most effective symptomatic management for Parkinson’s disease. However, it is not without limitations. Current levodopa formulations have a short duration of action, inconsistent pharmacokinetic effects and early extended release formulations have failed to turn patients to the “On” state consistently. Further, the pulsatile delivery of levodopa through the currently available formulations is thought to contribute to the development of motor complications. It is postulated that more continuous-dopaminergic stimulations such as those delivered by levodopa infusion or longer acting dopamine agonists may help delay the onset of motor complications. Thus, there are significant needs for a fast-acting, consistent and more continuous delivery of levodopa in an oral formulation to meet the needs of PD patients.
Given the progressive nature of the disease, disease modifying agents represent another area of unmet needs for Parkinson’s disease.
