HISTORY OF LEVODOPA AND DOPAMINE AGONISTS IN PARKINSONS-DISEASE TREATMENT

Striatal dopamine deficiency in Parkinson's disease (PD), first descri bed in 1960, was a key event that led to the era of levodopa therapy. In 1961, levodopa was first tried in PD patients, but throughout most of the 1960s the results were inconsistent. In 1967, questions about t he effectiveness of levodopa in PD were finally set aside when Cotzias and colleagues reported dramatic improvement in PD patients with oral administration of levodopa in increasing amounts over long periods. T he major side effects of levodopa administration, i.e., dyskinesias an d motor fluctuations, also became apparent at this time. In the early 1970s, the advantages of adding a dopa decarboxylase inhibitor to trea tment were discovered-reducing side effects and gaining better symptom control-and the first levodopa combination, carbidopa/levodopa, becam e commercially available in 1975. Since then, PD researchers have atte mpted to overcome complications with such techniques as continuous lev odopa infusion and, most recently, long-acting levodopa combinations. A dopamine agonist, apomorphine, was used in 1970 as a means to overco me side effects and loss of levodopa efficacy. However, side effects a nd difficulty of administration limited its use. Dopamine agonists beg an to find a place in routine treatment of PD after the discovery of b romocriptine's benefits in PD in 1974. Since then, new approaches have been tried, such as dopamine agonist monotherapy and early therapy in combination with levodopa. The development of new dopamine agonists h as led to characterization of dopamine receptor subtypes and agonists targeted to stimulation of specific receptors.