A Randomized Controlled Trial of Four Week Outpatient Treatment of Parkinson's Disease Comparing High and Low Dose Carbidopa.

A. Specific Aims:

Parkinson's disease is a common neurodegenerative disorder characterized by the progressive motor symptoms of tremor, rigidity, and bradykinesia. The prevalence is estimated at 102-109/100,000 and increases with age. It is the second most common neurodegenerative disorder after Alzheimer's disease, and the annual cost in the US is estimated to be $14.3 billion dollars per year.

In Parkinson's disease (PD) dopamine containing neurons in the substantia nigra are selectively lost, which causes motor dysfunction. Dopamine levels may be increased by giving oral levodopa, which improves motor function in PD. After oral administration, levodopa is taken into the brain and converted into dopamine by aromatic amino acid decarboxylase (AAAD) enzyme in the striatum , resulting in improved dopaminergic neurotransmission. AAAD is found in the peripheral tissues as well as in the brain, and prior to passage into the central nervous system levodopa may be decarboxylated to dopamine in the small bowel and liver. Peripheral metabolism of levodopa to dopamine significantly reduces the amount of levodopa that reaches the brain and therefore dopamine available for neurotransmission. The presence of dopamine in the periphery also produces anorexia and nausea. Carbidopa is an AAAD inhibitor that reduces the conversion of levodopa to dopamine. It is thought to not cross the blood-brain barrier and to affect only peripheral AAAD. This concept is of fundamental importance in the current treatment of PD. Carbidopa potentiates levodopa so that a much lower dose is effective. It also reduces anorexia and nausea, which often occur after giving levodopa alone. For this reason, almost all levodopa is marketed as carbidopa/levodopa tablets. This combination drug has become the standard of care for PD. As the disease progresses, increasingly high amounts of the carbidopa/levodopa combination are given to ensure adequate motor functioning, though the response to treatment becomes much less predictable with frequent fluctuations in motor ability.

Though conventional wisdom and older pharmacological studies suggest carbidopa does not penetrate the blood-brain barrier, recent animal studies contradict this. This is very important because if carbidopa entered the central nervous system in humans it could significantly inhibit levodopa conversion into dopamine, and thus reduce its therapeutic effects. A single large dose of carbidopa given to a normal rat, or a rat chemically lesioned to mimic PD, resulted in carbidopa entrance into the central nervous system, and inhibition of brain AAAD and conversion of levodopa to dopamine (1, 2). It is not known whether prolonged use of high dose carbidopa worsens motor function over time in humans. A small series of patients with PD and motor fluctuations that were switched from carbidopa/levodopa to levodopa alone were reported to have improvement in motor features(3). Carbidopa is typically given in a one to four ratio of carbidopa to levodopa in each pill, and chronic high dosing of caribopa and levodopa is common in PD. If carbidopa penetrates into the central nervous system in humans it could lead to decreased conversion of levodopa to dopamine in the central nervous system, and decrease the therapeutic response to administered levodopa.

We propose a randomized, double blind, controlled trial with crossover to explore two mechanisms by which carbidopa may accumulate in the CNS.