Drug therapy for Parkinson’s disease: An update

Table 1 Currently available dopaminergic receptor agonists

Drug	D-receptor specificity	Dose range	Side effects
Ergot derivatives
Bromocryptine	D2 receptor agonist with partial dopamine D1 antagonist activity	7.5-15 mg/d orally	Risk of developing valvular regurgitation (cumulative and dose-dependent)
Lisuride	D2 receptor agonist (also has a weak dopamine D1 antagonistic, serotonin 5-HT1A agonistic, and 5-HT2B receptor antagonist properties)	0.2-3 mg/d orally	Dry mouth, nausea, weakness, postural hypotension, and headache
Cabergoline	D1 and D2 receptor agonist	0.5-4 mg/d orally	Risk of developing moderate to severe valvular regurgitation
Non-ergot derivatives
Piribedil	D2/D3 receptor agonist with alpha(2) antagonist properties	150-300 mg/d orally
Rotigotine transdermal patch	D1, D2, and D3 receptor agonist	2-16 mg patch/d	Patch site reactions, nausea, vomiting, dry mouth, somnolence , peripheral edema, and dyskinesia
Ropinirole (immediate and extended release)	D2/D3 receptor agonist	4-24 mg/d orally	Nausea, dyspepsia, dizziness, back pain, headache, uncontrollable sleep attacks, orthostatic hypotension, leg oedema
Pramipexole (immediate and extended release)	D2/D3 receptor agonist	0.25 - 4.5/d orally (Extended release pramipexole is approved as monotherapy in early PD, as well as an adjunct therapy to levodopa in advanced PD	Somnolence, cognitive adverse events, fatigue, nausea, constipation, and peripheral oedema
Apomorphine	D1 and D2 receptor agonist (also stimulates serotonin and α-adrenergic receptors)	4 mg subcutaneously 20 mg continuously daily via a pump system	Local inflammation and granuloma at the subcutaneously infusion site Intravascular thrombotic complications secondary to apomorphine crystal accumulation after iv administration

iv: Intravenous.

Table 2 Results of randomized, double-blind, placebo-controlled trials involving new antiparkinsonian drugs

Drug	Study objective	Outcomes	Adverse events	Ref.
Istradefylline	Evaluated the efficacy and safety of istradefylline, 20 and 40 mg once daily as adjunctive to L-dopa in patients with motor complications (12 wk)	↓ daily change in "off" time vs placebo	↑ dyskinesia	[203]
Istradefylline	Evaluated the efficacy and safety of istradefylline, 10, 20 and 40 mg once daily as adjunctive to L-dopa in patients with motor complications (12 wk)	No effect on "off" time duration Improved motor scores at 40 mg	-	[199]
Istradefylline	Evaluated the efficacy of istradefylline at an oral dose of 20 and 40 mg once daily for 12 wk in PD patients with motor complications on levodopa therapy	↓ "off" time vs placebo	↑ dyskinesia	[204]
Istradefylline	Evaluated the safety and efficacy of istradefylline 40 mg, as monotherapy in patients with PD	No significant effect in improving motor symptoms	-	[198]
Istradefylline	To evaluate efficacy, safety, and tolerability of istradefylline 20 mg once daily vs placebo as an adjunct to levodopa in PD subjects with motor fluctuations	↓ "off" time	Dyskinesia, lightheadedness, tremor, constipation, and weight decrease	[201]
Istradefylline	To evaluate safety and efficacy of istradefylline 20 or 60 mg/d in L-dopa-treated PD subjects with motor complications	↓ "off" time without an increase in “on” time	Dyskinesia, nausea, dizziness, and hallucinations	[200]
Istradefylline	To evaluate safety and efficacy of istradefylline 40 mg/d in L-dopa-treated PD subjects with prominent wearing-off motor fluctuations	↓ "off" time without increased troublesome dyskinesia	-	[202]
Istradefylline	To evaluate safety and efficacy of istradefylline 20 or 40 mg/d in patients with L-dopa-motor fluctuations and peak-dose dyskinesias	↓ "off" time	Severity of dyskinesia was unchanged, but "on" time with dyskinesia increased	[205]
Preladenant	To evaluate efficacy of using preladenant 5 mg twice a day as a levodopa adjunct in subjects with fluctuating PD	↓ "off" time ↑ "on" time throughout the 36-wk treatment relative to the baseline	Dyskinesia and constipation	[209]
Preladenant	To evaluate safety of single and multiple rising preladenant doses compared with placebo	Preladenant was generally well tolerated up to the maximum dose tested (200 mg/d)	Transient mild increases in blood pressure within a few hours after preladenant administration	[207]
Preladenant	To evaluate efficacy and safety of 1, 2, 5, or 10 mg oral preladenant twice daily in patients with PD and motor fluctuations on L-dopa	5 and 10 mg preladenant ↓ "off" time	Worsening of PD, dyskinesia, nausea, constipation, and insomnia	[208]
Safinamide	To evaluate efficacy and safety of safinamide 50 or 100 mg/d, as add-on to L-dopa in the treatment of PD patients with motor fluctuations	↑ total on time with no or nontroublesome dyskinesia, ↓ decreased off time, without worsening dyskinesia	-	[216]
Safinamide	To evaluate efficacy of safinamide 100 or 200 mg/d as add-on treatment to single dopaminergic receptor agonist single in early PD	Safinamide 100 mg/d may be effective as add-on treatment	-	[215]
Safinamide	To evaluate efficacy and safety of once-daily 100 or 200 mg safinamide in patients with early PD receiving a stable dose of a single dopaminergic receptor agonist	Safinamide 100 mg/d improved motor symptoms (UPDRS part III total score)	-	[214]
Zonisamide	To evaluate the efficacy, safety and tolerability of daily doses of 25, 50, and 100 mg of zonisamide as an adjunctive treatment in PD	Zonisamide 25 and 50 mg/d improved motor symptoms (UPDRS part III total score) Zonisamide 50 and 100 mg ↓ "off" time without ↑ dyskinesia	-	[221]
Isradipine	To establish a tolerable and efficacious dosage of isradipine controlled-release in subjects with early PD not requiring dopaminergic therapy	The tolerability of 5, 10, or 20 mg of isradipine was dose dependent No difference in change in UPDRS among dosages	Peripheral oedema and dizziness	[295]
Isradipine	To evaluate safety and tolerability of isradipine controlled release in patients with early PD	Tolerability of isradipine CR 5, 10, 15, or 20 mg was dose dependent Isradipine had no significant effect on blood pressure or PD motor disability	Leg oedema and dizziness	[294]

L-dopa: Levodopa; PD: Parkinson’s disease; UPDRS: Unified Parkinson’s disease rating scale; CR: Controlled release.