2.2. Treatments for Motor Symptoms in the Early Stage

2.2.1. l-Dopa
The most effective treatment of PD still remains l-dopa. The global antiparkinsonian efficacy of l-dopa is so dramatic and predictable that a positive therapeutic response is used to define the disease itself. The major issue regarding introducing l-dopa is when to start treatment, considering the well-known effects of long-term use [74]. It has been largely reported that the premature therapeutic introduction of l-dopa, especially in young patients, leads to develop long-term side effects such as dyskinesias and motor fluctuations. For this reason, some authors have recommended the l-dopa-sparing strategy, which consists of the use of other antiparkinsonian medication in young PD who are more likely to develop dyskinesias and fluctuations related to long term use of l-dopa. The reason why l-dopa long term use determines the onset of motor dysfunction might be due to the toxicity of l-dopa upon dopaminergic neurons. In an in vitro experimental setting, it has been demonstrated that l-dopa metabolites increase oxidative stress and they are toxic to cultures of mesencephalic neurons [75]. However, there is no in vivo evidence that l-dopa accelerates disease progression and, as it was shown by an ELLDOPA (Early versus Later Levodopa therapy in PD patients) study [76], that patients in l-dopa treatment actually are less impaired even after stopping medication for a few weeks compared to patients who delay l-dopa therapy. Previous studies have also documented that dopaminergic depletion is involved in visual dysfunction in PD patients, therefore l-dopa therapy may improve visual disturbances investigated by electrophysiological tests [77,78].
l-dopa formulations are generally associated with a peripheral Dopa decarboxylase inhibitors (more frequently carbidopa or benserazide) in order to inhibit peripheral metabolism of l-dopa. Slight differences in terms of tolerability are associated with the treatment with l-dopa + benserazide (Madopar) compared to l-dopa + carbidopa (Sinemet). In a triple-blind trial [79], patients were allocated at random to treatment with either l-dopa + benserazide ratio 4:1 (Madopar) or l-dopa + carbidopa ratio 10:1 (Sinemet) using dosage schedules recommended by the manufacturers which they had to adhere to for 6 months. Results showed that the effect of the two schedules on the parkinsonian symptoms were equal and they appeared equally fast but the frequency of gastrointestinal side-effects and involuntary movements seemed higher and more severe for Sinemet than for the Madopar group.
Recently, oxidative stress (OS) has been identified as one of the major factors involved in dopaminergic degeneration. Several treatments based on antioxidant therapies, such as vitamin E, creatine, coenzyme Q10, and mitoquinone, have been demonstrated effective in animal models of PD [80]. Several authors have explored the possibility to reduce OS. For example, 1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ) is a potent antioxidative agent, studied in vitro by Jin Park et al., which seems to be involved in inhibition of l-dopa-induced cytotoxicity because of its role in modulating reactive oxygen species formation in PC12 cells [81]. Moreover, Nikolova et al. [82] developed an experimental model using healthy mice and some OS indicators, such as malondialdehyde, protein carbonyl content and advanced glycation end products, were evaluated in blood plasma. In this study, healthy mice were divided into four groups: the control group, the group treated only with l-dopa, and the remaining two groups, which were respectively pre-treated with Ascorbic acid (400 mg/kg) and Rose Oil (400 mg/kg), two antioxidants. A relevant increase of OS indicators levels in l-dopa treated mice compared to controls has been shown, whereas the same parameters have been decreased in both groups pre-treated with anti-oxidant compared to the same controls [82]. These evidences suggest that antioxidants may have a relevant role in protecting dopaminergic neurons from l-dopa induced cytotoxicity [83].

2.2.2. Dopamine Agonists
DAs are commonly divided into two groups: ergot and non-ergot-derived agonists. It is noteworthy to consider that DAs are ineffective in patients without therapeutic responses to l-dopa, but they might have a role in patients with advanced PD as a treatment for motor complications related to l-dopa [84]. The use of DAs in advanced PD is discussed separately. Neurologists have debated for years whether to select l-dopa or DAs as initial therapy in relatively young PD patients. DAs should be generally avoided in patients over 70 years due to poor tolerability. Furthermore, presence of cognitive dysfunction at baseline may also influence susceptibility to side effects [82].

2.2.3. Non-Ergot Dopamine Agonists
Three Non-Ergot DAs, such as Pramipexole, Ropinirole, and transdermal Rotigotine, are commonly used in PD and they have been shown to be effective as monotherapy in patients in an early stage of the disease [85,86]. Few studies have compared efficacy between various DAs and no significant difference has been found [87]. Pramipexole immediate release is usually started at 0.125 mg three times daily. Its dose should be increased gradually by 0.125 mg per dose every 5–7 days. Pramipexole extended release is usually started at 0.375 mg daily at bedtime, eventually increased by 0.375 mg every 5–7 days. Commonly, the mean daily dose used is 1.5–4.5 mg. Dose adjustments are required for renal insufficiency, but the extended-release formulation is not recommended in patients with a creatinine clearance <30 mL/minute [88]. Ropinirole immediate release is usually started at 0.25 mg three times daily and it should be increased gradually by 0.25 mg per dose each week for 4 weeks to a total daily dose of 3 mg. After 4 weeks, its dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. The extended release formulation is usually started at 2 mg daily at bedtime and increased by 2 mg every 5–7 days, up to a maximum of 24 mg. Benefits most commonly occur in a dose range of 12–16 mg daily. Transdermal Rotigotine is a once-daily patch which is usually started at 2 mg/daily and titrated weekly by increasing the patch size in 2 mg/daily increments to a dose of 6 mg/daily. Transdermal formulations are generally preferred in order to avoid issues such as renal impairment or inability to swallow whole pills.
Adverse effects caused by DAs are similar to those of l-dopa, including nausea, vomiting, sleepiness, orthostatic hypotension, confusion, and hallucinations. Peripheral edema is common during chronic use of DAs but does not occur in patients using l-dopa as monotherapy [87]. Most side effects can be avoided by initiating treatment with small doses and titrating to therapeutic levels slowly over several weeks. Moreover, patients’ intolerance of one DA may tolerate another one. In up to 50% of patients with long-term use, DAs are associated with ICD, such as pathologic gambling, compulsive sexual behavior, or compulsive buying [89]. Dopamine receptor agonists decrease prolactin concentration [90]. Thus, a potential decreased milk production is observed in postpartum women taking these agents, which are contraindicated in women who are breastfeeding. A recent warning on Pramipexole has been issued regarding its risk of excessive somnolence, which can occur abruptly, at a dose above 1.5 mg/day [91]. Therefore, PD patients who drive may consider this adverse effect. Moreover, a DA withdrawal syndrome is described in some PD patients which abruptly stop taking a DA. A subset of patients experience physical and psychiatric disturbances, such as agitation, anxiety, diaphoresis, and drug craving, that only respond to DAs repletion. Indeed, these symptoms are refractory to other antiparkinsonian medications, including l-dopa. This phenomenon, named Dopamine Agonist Withdrawal Syndrome (DAWS), was firstly described in 2010 by Rabinak and Nirenberg [92]. In retrospective studies, frequency of DAWS is reported to range from 8% to 19% of PD patients [93].

2.2.4. Ergot-Derived Dopamine Agonists
Ergot-derived DAs, as bromocriptine, cabergoline, pergolide, and lisuride, are considered a first-generation class of DAs, rarely used because of recurrent side effects. Therefore, these drugs have been largely replaced by Non-Ergot DAs. Pergolide and cabergoline have been associated with cardiac, pulmonary and peritoneal fibrosis and also valvular heart due to chronic use [94]. Those side effects are uncommon with bromocriptine, which can be used in combination with l-dopa in both early and late PD.

2.2.5. Monoamine Oxidase Inhibitors
MAO-BIs represent the first step in PD treatment in order to prevent disease progression by their neuroprotective properties. In the DATATOP trial (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) [95] Selegiline has shown successful results in order to delay disease progression, which was calculated by the time until the patients needed potent symptomatic dopaminergic therapy. Another MAO-BI, Rasagiline, has been shown to have modest symptomatic benefits although its neuroprotective properties are still debated. In the ADAGIO trial (Attenuation of Disease Progression with Azilect Given Once-Daily) [96], it has been demonstrated that 1 mg dose of Rasagiline seems to slow disease progression. However, in a recent metanalysis, effective neuroprotective role of MAO-BI therapies was controversial and their role in a prodromal or pauci-symptomatic stage of PD is still debated.

2.2.6. Anticholinergics
Anticholinergics could represent another choice in therapeutic settings, although they represent less effective anti-parkinsonian agents than DAs. However, they seem to be effective in controlling tremors and in reducing rigidity [60]. Triphexyphenidil is one of the most commonly used. The stating dose should be 2 mg three times per day, which can be gradually increased up to 15 mg or more per day. Regarding the safety profile, because of their well-known neuropsychiatric side effects due to central receptor antagonism (such as confusion, decrease short term memory, hallucinations, and psychosis) their use is generally limited to young and cognitively intact patients.

2.2.7. Amantadine
Although Amantadine has been available for nearly four decades (it was originally marked as an antiviral agent), little is known about its mechanism of action. It has been thought that Amantadine has both anticholinergic and anti-glutamatergic properties and for this reason is the only antiparkinsonian drug that could improve the characteristic l-dopa induced dyskinesias often present in the latter stage of PD [97]. However, Amantadine can be useful in the first stages of PD even though its effects are more appreciable in the first months of treatment. Moreover, Amantadine use could be associated with several side effects such as visual hallucinations, ankle edema, and livedo reticularis, which can influence therapeutic compliance. The usual dose is 100 mg two times per day but dose adjustment up to 200 mg two times per day might be allowed.