Table 1.
Main results of the pharmacokinetic and pharmacodynamic analyses of L-DOPA in the selected articles (articles about CSAI, LCIG, and other continuous dopaminergic stimulation are also included)
| Article | Date | Study description | Information of interest |
| Lang and Lozano [1] | 1998 | Review | •Progressive degeneration of the nigro-striatal pathway, responsible for managing automatic motor and non-motor functions. •Dopamine scarcity manifests as physical symptoms, such as tremors, rigidity, and movement difficulties, including walking, but can also lead to cognitive and psychiatric disorders. |
| LeWitt [36] | 2004 | Review | •Pharmacokinetics and pharmacology of subcutaneously administered apomorphine. •Metabolism of apomorphine: oxidation, N-demethylation, metabolism by COMT, glucuronidation and sulfation. |
| Stocchi [46] | 2006 | Review | •Controlled-release L-DOPA preparations are not efficacious in reducing the incidence of motor fluctuations. •Adjunct therapies can be used to control symptoms and a variety of drugs can be employed to reduce OFF time, but do not address the underlying problem. |
| Khor and Hsu [37] | 2007 | Review | •Absorption of L-DOPA is via the saturable LNAA transport system for large amino acids. •A high protein diet may compete with the uptake of L-DOPA into the brain, therefore, may result in reduced L-DOPA effects. |
| Nutt [47] | 2008 | Review | •The motor fluctuations are not entirely a pharmacokinetic problem although continuous delivery certainly improves motor fluctuations by reducing ‘off time’. •Intermittent dopaminergic stimulation may also be important in the development of dyskinesia. |
| Contin and Martinelli [38] | 2010 | Review | •High pre-systemic metabolism of dopamine in the gut by the enzyme L-AADC. •Rapid intestinal absorption by a saturable facilitated transport system shared with other LNAA systems. •Facilitated transport from plasma to the brain (by the LNAA system). |
| Müller [9] | 2013 | Review | •Long-term L-DOPA use is complicated by the development of LDRC, with the short half-life of L-DOPA playing a central role in the development of these motor complications. •Pharmacokinetic investigations of three possibilities to solve the pharmacokinetic problems of L-DOPA: ∘ Sustained-release L-DOPA formulations: these did not delay onset of LDRC. The slower rise in plasma L-DOPA concentrations and reduced peak plasma concentration may prolong the duration of low, subtherapeutic concentrations of L-DOPA in patients with complex wearing-off. ∘ L-DOPA infusion systems: more stable plasma L-DOPA concentrations compared to intermittent standard-release L-DOPA formulations. •L-DOPA/carbidopa/entacapone: the longer half-life of L-DOPA with coadministration of entacapone can account for the longer durations of clinical effect of single L-DOPA/dopadecarboxylase inhibitor doses (26–56%). |
| LeWitt [26] | 2015 | Review | •Production of TOPA and TOPA-quinone à excitotoxic properties. •Production of 5-cysteinyldopa (a substrate for decarboxylation to form 5-S-cysteinyldopamine, a pharmacologically active compound that induces oxidative stress in dopaminergic neurons). •Challenges of L-DOPA transport to the brain. |
| Stoessl [43] | 2015 | Review | •This review provides in vivo validation for the hypothesis that pulsatile stimulation of dopamine receptors plays a critical role in the emergence of long-term motor complications of therapy. |
| Classen et al. [11] | 2017 | Review | •L-DOPA may lead to non-motor complications: fatigue, sleep disorders, psychiatric disorders (including mood disorders and anxiety), dysautonomia, pain, and cognitive disorders. |
| Othman et al. [39] | 2017 | Clinical Trial | •LCIG results in lower variability and fluctuations in L-DOPA and carbidopa plasma concentrations compared to LC-oral. •LCIG helps to bypass the impact of intra-subject variability in gastric emptying rate. •Even with stable plasma L-DOPA concentrations achieved with LCIG infusion, there are still many uncontrolled factors that contribute to altering the Pk/Pd response of L-DOPA, such as transport across the blood-brain barrier, enzymatic conversion of L-DOPA to dopamine, the storage capacity for dopamine in the dopaminergic nerve terminals, dopamine release at the effect site, and changes in pre- and post-synaptic dopamine receptor sensitivity. |
| Beckers et al. [35] | 2022 | Review | •Two mechanisms of peripheral L-DOPA resistance: •Excessive bacterial production of the enzyme TDC à SIBO. TDC is an enzyme which normally digests dietary tyrosine. However, TDC, produced by certain gut bacteria, can also decarboxylate L-DOPA, reducing its bioavailability. •Systemic induction of the enzyme aromatic L-AADC. |
| Added articles on LDRC | |||
| Juncos et al. [12] | 1989 | Review | •Validation of continuous dopaminergic stimulation in rats with unilateral 6-hydroxydopamine lesions. |
| Langston [2] | 2006 | Review | •Progressive degeneration of the nigro-striatal pathway, responsible for managing automatic motor and non-motor functions. •Dopamine scarcity manifests as physical symptoms such as tremors, rigidity, and movement difficulties, including walking, but can also lead to cognitive and psychiatric disorders. |
| Manson et al. [8] | 2012 | Review | •L-DOPA-induced dyskinesias affect 50% of patients within 5 years and 80% of patients after 10 years of disease progression. |
| Smith et al. [10] | 2012 | Review | •Rapid onset of Parkinsonian symptoms is linked to rapid degeneration of dopaminergic neurons (imaging of the nigrostriatal dopaminergic system). |
| Sato et al. [27] | 2018 | Case report | •Parkinsonian patients experience drug retention in the esophagus or the epiglottic vallecula. This retention can lower the peak plasma concentration of L-DOPA. |
| Added articles on the preclinical validation of continuous delivery therapies on LDRC | |||
| Smith et al. [13] | 2005 | Preclinical trial | •Validation of continuous dopaminergic stimulation in parkinsonian primates. |
| Bibbiani et al. [14] | 2005 | Preclinical trial | •Validation of continuous dopaminergic stimulation in parkinsonian primates. |
| Added articles on clinical validation of continuous delivery therapies on LDRC | |||
| Deleu et al. [15] | 2004 | Review | •Apomorphine shows effectiveness in improving motor scores and reducing ‘off’ periods, with continuous infusion also reducing dyskinesias and offering a L-DOPA-sparing effect. •The subcutaneous route facilitates the continuous administration of apomorphine. |
| Devos et al. [20] | 2009 | Clinical Trial | •LCIG seems to be an effective last-line therapy for motor complications in PD. Technical problems are commonplace and improvements should be considered. |
| Nyholm [22] | 2012 | Review | •The large majority of studies have reported that LCIG is clinically effective at relieving the symptoms of advanced PD and improving QoL in comparison to oral therapy. |
| Olanow et al. [21] | 2014 | Clinical Trial | •12-week, randomized, double-blind, double-dummy, double-titration trial, enrolled adults with advanced PD and motor complications. •2 arms: treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. •LCIG therapy results in an average increase of 1.9 h of dyskinesia-free “on” time, compared to optimized oral treatment. |
| Trenkwalder et al. [16] | 2015 | Review | •Subcutaneous apomorphine is recognized as an effective therapy for PD patients who experience “off” periods despite optimized oral medication. |
| Drapier et al. [17] | 2016 | Observational Study | •Assessment of QoL improvement by CSAI in patients with advanced PD. •At 6 months, their HR-QoL had significantly improved (p = 0.011), as had their total UPDRS score (p < 0.001). |
| Katzenschlager et al. [18] | 2018 | Clinical Trial | •Randomized, placebo-controlled, double-blind, multicenter trial •Apomorphine infusion (mean final dose 4 · 68 mg/h (SD: 1.5)) significantly reduced off time compared with placebo (–2.47 h per day (SD: 3.70) in the apomorphine group vs –0 · 58 h per day (SD: 2.80) in the placebo group; difference –1 · 89 h per day [95% CI: –3 · 16 to –0 · 62; p = 0 · 0025). |
| Antonini et al. 19] | 2018 | Medical Opinion | •Apomorphine administration enhances motor symptoms and patients’ quality of life but does not entirely remove the need for oral treatments. |
| Bergquist et al. [54] | 2022 | Clinical trial: randomized, 3-period cross-over, open-label multicenter trial | •Continuous subcutaneous and intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady state plasma concentrations of levodopa that are equivalent in magnitude, and non-inferior in variability, to those obtained with LCIG in patients with advanced PD. |
| Added articles on deep brain stimulation as another second-line treatment of LDRC | |||
| Perestelo-Pérez et al. [50] | 2014 | Meta analysis | •Meta-analysis of RCTs describes the efficacy of DBS in improving motor signs, functionality and QoL of PD patients. •RCTs that compared DBS plus medication versus medication (alone or plus sham DBS) in PD patients were included. •More than 50% of the oral treatment is maintained under subthalamic stimulation. |
| Bratsos et al. [49] | 2018 | Review | •Systematic search including RCT comparing DBS to BMT in PD patients. •DBS was superior to BMT at improving impairment/disability, QoL and reducing medication doses •More than 50% of the oral treatment is maintained under subthalamic stimulation. |
| Added article on continuous subcutaneous foslevodopa-foscarbidopa | |||
| Soileau et al. [24] | 2022 | Clinical trial | •12-week randomized, double-blind, double-dummy, active-controlled study. •Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both ‘on time’ without troublesome dyskinesia and ‘off time’. •Average increase in dyskinesia-free “On” periods of 1.7 h. |
| Added articles on intracerebral administration of anaerobic dopamine | |||
| Laloux et al. [51] | 2017 | Preclinical trial | •A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice (MPTP treated) after 7 days. •The safety profile is highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral L-DOPA treatment. |
| Moreau et al. [52] | 2020 | Preclinical trial | •60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms of MPTP treated primates without tachyphylaxis. No dyskinesia was observed even with very high doses. |
PD, Parkinson’s disease; L-DOPA, levodopa; L-AADC, L-amino acid decarboxylase; COMT, catechol-O-methyl transferase; LCIG, levodopa-carbidopa intestinal gel; LNAA, large neutral amino acids; SIBO, small-intestinal bacterial overgrowth; TDC, tyrosine decarboxylase; TOPA, 2,4,5-trihydroxyphenylalanine; Pk, pharmacokinetics; Pd, pharmacodynamics; LDRC, L-DOPA-related complications; QoL, quality of life; CSAI, Continuous Subcutaneous Apomorphine Infusion; SD, standard deviation; DBS, deep brain stimulation; RCT, randomized controlled trial; BMT, Best Medical treatment; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.