there is currently no evidence of neurological improvement clinically, usingtrial designs with sufﬁcient duration and washout periods to assessneurological status beyond therapeutic response.This chapter will review the history of DA usage in the treatment of PD and provide a summary of data concerning efﬁcacy, treatmentapproaches, and comparison between commonly prescribed DA. Inaddition, data suggesting long-term favorability when compared tolevodopa will be reviewed. Lastly, similarly designed clinical trials will bediscussed with direct comparative trials in an effort to better deﬁne therelative efﬁcacy of these agents.
DOPAMINE AGONISTS AND DOPAMINE RECEPTORS
The DA most often used in treating symptoms of PD include apomorphine,bromocriptine, cabergoline, lisuride, pergolide, pramipexole, and ropinirole.All of these agents activate D
receptors, while pergolide has been shown tobe a mild D
agonist, and pramipexole may have higher afﬁnity for D
(Table 1).Five subtypes of DA receptors have been identiﬁed and may be
classiﬁed into striatal (D
) receptors or cortical (D
, and D
)receptors. The D
receptors are present in the limbic system and otherdopaminergic pathways. Although the different roles of D
receptors in regulation of striatal function are more fully outlined elsewherein this volume, the D
) family is associated with activation of adenylate cyclase, and dopamine and DA activate the D
) (6). Postmortem examination of brains of subjects with PD revealupregulation of striatal D
and downregulation of the D
receptors. It ispostulated that these changes lead to alteration of the indirect D
-mediatedpathway and disinhibition of the subthalamic nucleus. Intracorticalinhibition studies comparing apomorphine, a rapid-acting DA, to deepbrain stimulation found comparable changes in Uniﬁed Parkinson’s DiseaseRating Scale (UPDRS) and intracortical inhibition with bilateral sub-thalamic nuclei or globus pallidus stimulation or with apomorphineinfusion, suggesting a connection between the nigral dopaminergic pathwayand the thalamo-cortical motor pathway (7).
Because of the powerful emetic action of apomorphine, clinical usage of thiscompound in treating PD has been avoided (8). More recently, this short-acting DA has been developed as injectable and sublingual forms to be usedin ‘‘rescuing’’ PD patients from unpredictable off-periods. This therapy may
Copyright 2003 by Marcel Dekker, Inc. All Rights Reserved.