This is a revised application to the national Institutes of Health to support Phase 2 clinical trials of intravenous dopamine agonist therapy for patients with advanced Parkinson's disease (PD). Idiopathic Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among adults and afflicts about 500,000 Americans. PD symptoms of tremor, muscular rigidity and slowness of voluntary movement arise when about 75 percent of midbrain dopamine (DA) neurons in the substantia nigra die. The resulting brain DA deficiency state can be treated successfully for several years with oral L-DOPA, the naturally occurring amino acid derivative of tyrosine and precursor of DA, and/or direct DA agonists (pergolide, bromocriptine). After several years of oral treatment, the initial smooth control of PD symptoms gives way to fluctuations in response to medication doses and distressing side effects such as dyskinesias and on-off phenomena. These fluctuations in response and drug side effects are not adequately controlled by oral therapy with available agents and result in permanent disability and poor quality of life for about 10-20 percent of the PD population. Such fluctuations can be variably controlled by continuous parenteral L-DOPA/agonist administration, and central nervous pharmacodynamic responses can be altered in favor of improved control of PD symptoms.
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