The discovery 50 years ago of the spectacular efficacy of L-DOPA has revolutionized the treatment of Parkinson disease (PD), and indeed all modern Clinical Pharmacology. However, within a few years, PD patients on chronic L-DOPA therapy almost inevitably face disabling periods of reduced benefit, known as motor and non-motor “fluctuations” 1. In 2016, adequate management of such complications still remains one of the major unmet needs of PD therapy.
The mechanisms governing such fluctuations are complex. Two main contributing factors have been identified: the aggravation of the dopamine striatal denervation due to the progression of the neurodegenerative process, and chronic L-DOPA therapy itself1. In spite of many efforts, no efficacious “neuroprotective” treatment is available at the moment to prevent or slow down the progression of striatal denervation. Conversely, over decades, successful, though incomplete, efforts have been made to improve some of the L-DOPA-related factors governing motor fluctuations. Briefly, such initiatives have focused on improving L-DOPA pharmacokinetic profile (poor peripheral bioavailability with hectic intestinal absorption depending on gastric emptying and short elimination half-life) and the consequent “pulsatile” non-physiological stimulation induced at the level of the striatum that dysregulates dopaminergic and non-dopaminergic pharmacodynamics responses in the basal ganglia.
Based on these concepts, pharmacological attempts to reduce motor fluctuations have been targeted at delivering a more continuous dopamine stimulation to the parkinsonian brain in (1) prolonging L-DOPA elimination half-life (using controlled release L-DOPA formulations or co-treatments with amino-acids decarboxylase, MAO-B and COMT-inhibitors), (2) by-passing the obstacle of gastric emptying (using non-oral routes of administrations), (3) developing long acting dopaminergic drugs (dopamine agonists, MAO-B inhibitors), and (4) developing non-dopaminergic antiparkinsonian medications.
This article collection brings together 21 scientific articles that all deal with the challenge of improving the pharmacological management of motor fluctuations and have all been published within the last few years in the 2 journals of the International Parkinson and Movement Disorders Society: Movement Disorders and Movement Disorders Clinical Practice. In this collection, two reviews provide a global picture of the clinical spectrum of L-DOPA-induced complications2 and of the major trials that have been conducted in this field since 20133. The reader will also find in the same collection a compilation of original approaches and focused studies exploring the same topic.
A first set of articles is dedicated to new insights into apomorphine therapy. Apomorphine is an “old” dopamine agonist4. Based on empirical experience, it is the sole dopamine agonist considered to be as efficacious and potent as L-DOPA on parkinsonian motor symptoms. At the moment, apomorphine is not broadly used in clinical practice, because no orally active formulation exists. The drug must then be delivered through sub-cutaneous injections to by-pass a first hepatic effect. This can be achieved on an acute regimen, using penjets, or on a continuous regimen, using infusion pumps.
In one paper in this collection, Martinez-Martin and colleagues5 prospectively compared subcutaneous amoporphine infusion and intrajejunal L-DOPA infusion in an open-label multicenter study in 88 PD patients with refractory motor complications. This is an important issue, as there are little head-to-head comparisons between these two treatments. It is difficult for clinicians to choose and decide which strategy to favor in a given patient. The results of this study confirmed that both interventions provide robust improvement in motor symptoms and motor complications, in some non-motor symptoms and in quality-of-life scores. They also suggest that the benefit-risk ratio to be expected from the 2 modes of infusions may not be exactly similar. On one hand, L-DOPA infusion appeared to have a more pronounced effect on some non-motor symptoms (sleep/fatigue and dysautonomic signs), at the price of local abdominal device-related adverse reactions, including peritonitis for the most serious ones. On the other hand, apomorphine might have a better effect on mood and apathy scores, but at the price of local cutaneous adverse reactions (skin nodules).
Such issues related to local tolerability are in line with a case reported by Degos and colleagues6 available in this collection, and referring to a rare and unusual observation of shoulder abscess caused by the dislocation of the needle from the tubing used for continuous apomorphine therapy. In another study, Isaacson and colleagues7 provide additional open-label evidence supporting the strong and rapid efficacy of apomorphine penjet injections in aborting early morning akinesia in a large series of about 100 PD patients.
Two other articles dedicated to apomorphine in this collection provide highly novel information that enlarges our vison of the potential place of the drug in the future management of PD. The first one, by Yarnall and colleagues8, report that antemortem exposure to apomorphine may have a positive modifying effect on amyloid deposition in non-demented PD cases. This was based on an exploratory clinic-pathological analysis conducted in 71 donors to the Queen Square Brain Bank. This is consistent with experiments in animal models demonstrating improvement in memory and reduced amyloid-beta burden in transgenic murine Alzheimer models given subcutaneous apomorphine. If such findings can be confirmed in subsequent works, this concept will open entirely new perspectives regarding the place of apomorphine in the management of PD and other neurodegenerative disorders. Apomorhine’s practical use could also be dramatically modified if the drug could be administered orally. Currently, the need of subcutaneous injections represents a major limitation. An orally active formulation would significantly broaden the spectrum of patients who could benefit from apomorphine. The paper by Lincoln and colleagues9 presented in this collection suggests that this might be feasible in the future, as shown by their encouraging experimental results in MPTP-treated marmosets using a novel orally active apomorphine-related compound, R-(-)-11-O-valeryl-N-n-propylnoraporphine.
A second approach to manage motor fluctuations without using dopamine agonists is to develop better formulations and modes of delivery of L-DOPA itself, as nicely summarized in this collection in a review by Poewe and Antonini10. In line with this approach, the paper by Fernandez and colleagues11 is of interest as it describes the effects of L-DOPA-carbidopa intestinal gel in one of the largest (354 enrolled patients) and longest (12 month) cohorts of patients with advanced PD. Although conducted in an uncontrolled open-label manner, this study reported interesting efficacy (reduction in time spent OFF, reduction in time spent ON with troublesome dyskinesia) and safety data (especially adverse events associated with the device/procedure). These results are consistent with those reported by Martinez-Martin5 and already mentioned previously in this editorial.
The advantage of by-passing the obstacle to L-DOPA absorption due to gastric emptying using L-DOPA duodenal infusion is nicely illustrated in this collection by the case of a PD patient with severe gastroparesis reported by Venkitachalam and colleagues12. L-DOPA duodenal infusions are efficacious on severely impaired PD patients, facing fluctuations that are resistant to more simple alternatives and justify using device-based approaches. Nevertheless, the main disadvantages of duodenal infusion are its cost and the fact that it requires invasive procedures that limit its practicality. Developing novel orally active extended-release formulations of L-DOPA that maximize L-DOPA absorption is therefore an urgent priority. This would allow delivering L-DOPA to the brain in a more appropriate manner without resorting to complex, expensive and aggressive devices.
At the moment, there are several promising development initiatives in this field, and it is therefore interesting to emphasize the reports of 2 pilot Phase II trials that have also been incorporated into this collection. The first one was published by LeWitt and colleagues13, using XP21279, a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastro-intestinal tract and then is rapidly converted to L-DOPA by carboxylesterases. The second was published by Verhagen Metman and colleagues14, using DM-19925, an extended-release of carbidopa-L-DOPA formulated with a gastro-retentive technology allowing a gradual delivery of L-DOPA over an extended period compensating for the drug short half-life. It is too early at this stage, based only on these 2 pilot studies, to anticipate if and how these novel L-DOPA formulations could change our management of motor complications in the future. They could be useful in the late stages of PD according to a “curative” approach once ON-OFF problems are already established, or at an earlier stage of the disease, according to a “preventive” approach before fluctuations occurrence in an attempt to reduce their subsequent incidence.
A third dopaminergic approach to manage motor fluctuations nicely illustrated in this collection is to block enzymes that are catabolizing L-DOPA or dopamine, like mono-amine-oxidase-B (MAO-B) inhibitors, for example. There are already 2 MAO-B inhibitors available on the market to treat PD, namely selegiline and rasagiline. A third one has been developed recently: safinamide. Safinamide is a novel alpha-aminoamide that has both dopaminergic and non-dopaminergic mechanisms of action, including inhibition of MAO-B, sodium channel blockade and modulation of stimulated release glutamate. An original property of safinamide is that it has been shown to reduce L-DOPA-induced dyskinesia in animal models, while other dopaminergic drugs usually worsen such involuntary movements. This collection presents 2 articles by Borgohain and colleagues15,16, summarizing the results of a large randomized phase III study showing that safinamide increased “good” ON time (without dyskinesia or with non-troublesome dyskinesia) and decreased OFF time in PD patients with advanced PD and motor fluctuations. Such a benefit was present in placebo-controlled double-blind conditions at 6 months, but also after 2 years of exposure. This is the first time that such long double-bind placebo-controlled data are available in PD. No such data exist with other antiparkinsonian medications, making this study an original one. Further comparative studies are however necessary before accepting definitely the potentially interesting low propensity of safinamide to induce or worsen dyskinesia on the long-term. The reasons why safinamide might have this original profile that would make it different from other dopaminergic medications is not fully understood. This could be related to its non-dopaminergic effects.
A final pharmacological approach to better manage motor fluctuations that is illustrated in this collection relates to the non-dopaminergic mechanisms involved in the pathophysiology of motor fluctuations. Many abnormalities of non-dopaminergic systems are present in the brain and basal ganglia of patients with PD and in animal models of PD17. These may result from lesions due to the neurodegenerative process of the disorder, but also as a consequent functional change secondary to dopamine denervation and L-DOPA exposure. In animal models of PD, drugs involved in various non-dopaminergic mechanisms improve motor behaviors. It has been challenging, however, not to say difficult, to translate into humans and clinical practice such recent pre-clinical findings, although drugs like trihexyphenidyl, acting on cholinergic receptors, and amantadine, acting on glutamatergic receptors, have been used for long as antiparkinsonian medications. The present collection offers two examples of this approach with 2 types of non-dopaminergic medications. The first one refers to zonisamide, a drug that is launched in Japan as an antiepileptic. Zonisomide has multiple pharmacodynamic effects, including inhibition of sodium and calcium channels and MAO-B activity. This is quite reminiscent of safinamide (see above). In a large randomized placebo-controlled trial presented in this collection, Murata and colleagues18 reported that zonisamide reduced time spent OFF in PD patients with motor fluctuations. Interestingly, these authors noticed that dyskinesia were not more frequent on zonisamide than on placebo, in line with Borgohain’s observations with safinamide15,16.
The second example of a non-dopaminergic hypothesis tested to treat motor fluctuations refers in this collection to the antagonism of adenosine A2A receptors. Several A2A antagonists, including istradefylline and preladenent, have been tested in the recent years in this indication, as reviewed in the present collection by Pourcher and Huot19. The overall global results of the development programs with these drugs have not been as consistent as expected. For that reason, istradefylline is only marketed in this indication in Japan but not yet in western countries. The development of preladenent has been abandoned. In the present collection, the reader will have access to the results of recent trials conducted with each drug20,21.
In summary, it is appropriate, on regular intervals, to provide a global overview on important issues related to the management of patients with PD, as concepts, technics and findings are evolving over time. This collection dedicated to the pharmacological management of motor fluctuations, is a nice example of such an initiative, in order to facilitate and update our understanding and knowledge in the field, in putting together the scientific articles that have been published recently in the two official journals of the International Parkinson and Movement Disorders Society.
1- Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease (2009).Neurology. 2009 May 26;72(21 Suppl 4):S1-136
2- C.Aquino, S H. Fox. “Clinical Spectrum of Levodopa-Induced Complications”. Mov Disord 2015 Jan;30(1):80-9.
4- Unti E, Ceravolo R, Bonuccelli U. Apomorphine hydrochloride for the treatment of Parkinson’s disease. Expert Rev Neurother. 2015;15(7):723-32.
5-Martinez-Martin P, Reddy P, Katzenschlager R, Antonini A, Todorova A, Odin P, Henriksen T, Martin A, Calandrella D, Rizos A, Bryndum N, Glad A, Dafsari HS, Timmermann L, Ebersbach G, Kramberger MG, Samuel M, Wenzel K, Tomantschger V, Storch A, Reichmann H, Pirtosek Z, Trost M, Svenningsson P, Palhagen S, Volkmann J, Chaudhuri KR. “EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson’s disease”. Mov Disord. 2015 Apr;30(4):510-6.
6- Degos B, Aix S, Roze E, Vidailhet M. “Apomorphine Therapy: The Hazard of Left Over Needles”. Mov Disord Clin Practice. 2014: 199-200.
7- Isaacson S, Lew M, Ondo W, Hubble J, Clinch T, Pagan F. Apomorphione subcutaneous injection for the management of morning akinesia in Parkinson disease. Movement Disorder Clinical Practice 2016 (in press)
8- Yarnall AJ, Lashley T, Ling H, Lees AJ, Coleman SY, O’Sullivan SS, Compta Y, Revesz T, and Burn DJ. “ Apomorphine: A Potential Modifier of Amyloid Deposition in Parkinson Disease?” Movement Disorders, 2015 ???
9- Lincoln L, Fisher R, Jackson MJ, Jenner P, Neumeyer J, Sromek AW, Lees AJ, Rose S, Oral R-(-)-11-O-valeryl-N-n-propylnoraporphine reverses motor deficits in MPTP treated marmosets. Mov Disorders 2016 (in press)
10- Poewe W, Antonini A. “Novel Formulations and Modes of Delivery of Levodopa”. Mov Disord. 2015 Jan;30(1):114-20
11- Fernandez HH, Standaert DG, Hauser RA, Lang AE, Fung VSC, Klostermann F, Lew MF, Odin P, Steiger M, Yakupov EZ, Chouinard S, Suchowersky O, Dubow J, Hall CM, Chatamra K, Robieson WZ, Benesh JA, Espay AJ. “Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson’s Disease: Final 12-Month, Open-Label Results”. Mov Disord. 2015 Apr;30(4):500-9.
12- Venkitachalam A, Lazarescu A, Suchowersky O. “Enteral Levodopa Therapy in Advanced Parkinson’s Disease with Gastroparesis”. Mov Disord Clin Practice 2015; 321-322.
13- LeWitt PA, Huff FJ, Hauser RA, Chen D, Lissin D, Zomorodi K, Cundy KC. “Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson’s disease”. Mov Disord. 2014 Jan;29(1):75-82.
15- Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt MH, Chirilineau D, Stocchi F, Lucini V, Giuliani R, Forrest E, Rice P, Anand R; Study 018 Investigators. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord. 2014 Feb;29(2):229-37.
16- Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt MH, Chirilineau D, Stocchi F, Lucini V, Giuliani R, Forrest E, Rice P, Anand R; Study 018 Investigators. “Two-Year, Randomized, Controlled Study of Safinamide as Add-on to Levodopa in Mid to Late Parkinson’s Disease”. Mov Disord. 2014 Sep;29(10):1273-80.
17- Fox SH. Non-dopaminergic treatments for motor control in Parkinson’s disease. Drugs. 2013 Sep;73(13):1405-15
18- Murata M, Hasegawa K, Kanazawa I, Fukasaka J, Kochi K, Shimazu R; Japan Zonisamide on PD Study Group. “Zonisamide improves wearing-off in Parkinson’s disease: A randomized, double-blind study”. Mov Disord. 2015 Sep;30(10):1343-50.
19- Pourcher E, Huot P. “Adenosine 2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson’s Disease”. Mov Disord Clin Practice 2015: 331-340
21- Factor SA1, Wolski K, Togasaki DM, Huyck S, Cantillon M, Ho TW, Hauser RA, Pourcher E. “Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson’s disease”. Mov Disord. 2013 Jun;28(6):817-20.