Introduction And History

The Parkinson's-Reversing Breakthrough

Parkinson Disease Therapy

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the cardinal motor manifestations of bradykinesia/akinesia, rigidity, resting tremor, and postural instability, although nonmotor features play an important role as well, including cognitive, psychiatric, and autonomic features (1). Pathologically, there is a loss of nigrostriatal neurons in the substantia nigra pars compacta (SNpc), which is believed to represent a middle stage of the degenerative process that starts in the lower brainstem and olfactory nuclei and ascends throughout the cortex (2). Neuro-chemically, the key feature relating to current therapeutics and nigral cell death is a loss of dopamine (3).

Levodopa (L-3,4-dihydroxyphenylalanine) is the cornerstone of symptomatic therapy for PD. It is a metabolic precursor of the neurotransmitter dopamine. Dopamine was synthesized in 1910 by Barger and Ewens, but not given its name until 1952, whereas D/L Dopa racemate was first synthesized in 1911 (3-5). Guggen-hiem, in 1913, isolated levodopa from the broad bean plant Vicia faba (6), but concluded that it was devoid of biological activity (4). In 1938, Peter Holtz discovered the enzyme dopa decarboxylase that metabolized levodopa to dopamine in kidney tissue, and, a year later, Blaschko and Holtz postulated the biosynthetic pathways for catecholamines where dopamine is relegated to an intermediate in the synthesis of norepinephrine and epinephrine. The use of levodopa in PD only emerged after the important discoveries of various researchers in the late 1950s and early 1960s that ultimately led to the demonstration that dopamine depletion was characteristic of PD.

Montagu (4) discovered dopamine and levodopa in the brain in 1957. Carlsson et al. (7,8) confirmed the presence of dopamine in animal brains and found that reser-pine depleted brain dopamine along with other catecholamines. They also demonstrated that in animals rendered akinetic from reserpine, levodopa replenished dopamine and reversed parkinsonian symptoms. In addition, Bertler and Rosengren (7,8) reported that the striatum was the site of greatest dopamine concentration. Raab later made similar independent discoveries except that he did not recognize that the substance in the brain depleted by reserpine (he called it encephalin) was actually dopamine (4). Hornykiewicz (3,4,9) showed that the striatum of parkinsonian brains was depleted of dopamine, and Barbeau et al. (10) demonstrated reduced urinary excretion of dopamine in PD patients.

Hornykiewicz (3,4) treated 20 parkinsonian patients with intravenous doses of levodopa (50mg) and the results were "spectacular," leading to complete abolition or substantial relief of motor and vocal symptoms for short periods of time. Barbeau et al. demonstrated the effectiveness of low-dose oral levodopa in improving rigidity. However, studies in the early and mid 1960s showed variable results with low doses, and some investigators denounced the practical effectiveness of levodopa nearly resulting in it being abandoned for the treatment of PD. It was the seminal work of Cotzias (11,12), who persevered with the use of high-dose oral levodopa for parkinsonism, that dramatically changed the landscape of PD treatment (11,12). Yahr (13) completed the first double-blind parallel group study in 1969.

Levodopa was ultimately approved by the United States Food and Drug Administration for use in PD in 1970, 60 years after its discovery and more than 10 years after the realization that dopamine depletion was the key abnormality in PD (14). In 1973, the combined use of a peripheral aromatic amino acid decarboxylase (AAAD) inhibitor with levodopa was reported by Cotzias. Its use resulted in a decrease in peripheral metabolism of levodopa to dopamine and fewer peripheral side effects, such as hypotension, nausea, and vomiting (15,16). The resultant combination drug trade name "Sinemet®" carries the meaning "without vomiting." Controlled-release formulations were tested in the 1980s to treat fluctuations, and Sinemet CR® was approved in the United States in 1991(17-20).

Although regarded as the most potent symptomatic therapy for PD, levodopa has its drawbacks. Adverse effects such as motor fluctuations and dyskinesia are often associated with chronic administration. Neuropsychiatric disturbances are frequent and can be serious adverse effects. Questions have arisen regarding its potential toxicity to nigrostriatal neurons, as well as a possible association with melanoma. The debate of when to initiate therapy with levodopa is still ongoing. This chapter will review several of these issues, including the pharmacology of levodopa, its role in the emergence and progression of motor complications, its potential toxic or protective effects, whether tolerance develops, its role in diagnosing PD, and its effect on mortality in PD.

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