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Noninvasive Options for ‘Wearing-off’ in Parkinson’s Disease: A Clinical Consensus From a Panel of Uk Parkinson’s Disease Specialists

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In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales.
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Noninvasive options for ‘wearing-off’ in
Parkinson’s disease: a clinical consensus from
a panel of UK Parkinson’s disease specialists
Robin Fackrell*,1, Camille B Carroll2, Donald G Grosset3, Biju Mohamed4, Prashanth
Reddy5, Miriam Parry5, Kallol Ray Chaudhuri6& Tom Foltynie7
1Department of Geriatric Medicine, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK
2Faculty of Medicine & Dentistry, University of Plymouth, Plymouth, UK
3Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
4Department of Medicine and Gerontology, University Hospital of Wales, Cardiff, UK
5Department of Clinical Gerontology, King’s College Hospital NHS Foundation Trust, London, UK
6Institute of Psychiatry, Psychology & Neuroscience at King’s College & Parkinson Foundation International Centre of Excellence,
King’s College Hospital NHS Foundation Trust, London, UK
7Unit of Functional Neurosurgery at UCL Institute of Neurology and the National Hospital for Neurology & Neurosurgery, London,
UK
*Author for correspondence: robin.fackrell@nhs.net
Practice points
At each consultation, ask whether your patient is experiencing motor uctuations, such as end-of-dose
wearing-off and dyskinesia. Patient diaries or wearing-off questionnaires can be helpful here.
Be aware that dopamine uctuations can manifest in a range of nonmotor symptoms; these may include pain,
problems swallowing, depression, anxiety and cognitive impairment.
Consider the relative merits of adjusting your patient’s existing regimen, for example, levodopa dose adjustments
versus incorporating an adjuvant treatment into their polypharmacy regimen.
Consider whether your patient exhibits any special features of Parkinson’s disease (e.g., fatigue, psychosis), and
how this affects the clinical decision in choice of agent.
Be aware that, at some stage, your patient may need to be evaluated for advanced Parkinson’s disease therapies.
Monitor the outcome of any major change in prescription, for example, initiating adjuvant treatment.
In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK
in patients with Parkinson’s disease (PD) and motor uctuations: opicapone, a third-generation catechol-
O-methyl transferase inhibitor, and sanamide, a monoamine oxidase B inhibitor. This clinical consensus
outlines the practical considerations relating to motor uctuations and managing wearing-off in patients
with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and sa-
namide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based
movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from
England, Scotland and Wales.
First draft submitted: 4 May 2018; Accepted for publication: 19 June 2018; Published online: 5 July 2018
Keywords: opicapone Parkinson’s disease sanamide
Parkinsons disease (PD) is the second most common neurodegenerative disorder in the world after Alzheimer’s [1].
The annual incidence of PD in the UK is 15–20 individuals per 100,000 [2], with a significantly higher incidence in
males (1.5 times greater) compared with females [3]. With an increasing aging population, the estimated prevalence
of PD in the UK is expected to rise by approximately 18% in the next 7 years; however, about 7% of people living
with PD in 2018 will be under 60 years old [4].
This progressive disorder is characterized by motor symptoms (rigidity, bradykinesia, tremor, postural insta-
bility) [5] and a range of nonmotor symptoms (NMS) such as pain, constipation, problems with swallowing,
depression, anxiety and cognitive impairment, which can occur from disease onset [6,7], and often before the onset
of motor symptoms [8]. The gold standard treatment for PD is still considered to be levodopa (L-dopa) [9].Initial
Neurodegener. Dis. Manag. (2018) 8(5), 349–360 ISSN 1758-2024 34910.2217/nmt-2018-0020 C
2018 Robin Fackrell
Special Report Fackrell, Carroll, Grosset et al.
treatment with L-dopa allows for better symptom control and patient-related quality of life (QoL) for at least
7years[10], compared with initial L-dopa sparing regimens (dopamine agonists [DAs] or monoamine oxidase B
[MAO-B] inhibitors) [10]. There remains uncertainty about the optimum first drug class treatment choice in young
onset PD, diagnosed at 45 years or younger, given the even greater long-term duration that these patients will
require [10]. However, long-term use of L-dopa has its limitations: patients develop motor complications, such as
motor fluctuations including end-of-dose wearing-off and L-dopa induced involuntary movements or dyskinesia [11]
that impact on QoL [12]. Higher doses of L-dopa, which may be required in later disease, can also result in a greater
frequency of dyskinesia as well as wearing-off symptoms [13]. Therefore, to improve motor fluctuations, ideally
without exacerbating dyskinesia, many patients with PD will eventually require add-on therapies [2].
Although recent 2017 NICE guidance provides recommendations for first- and second-line adjunctive therapies
for patients currently receiving L-dopa, the choice of drug class, treatment preference within a class, drug admin-
istration alone or in combination, when to prescribe and in what order to prescribe these treatments are personal
decisions made jointly between physician and patient [2]. Furthermore, the fact that only two new oral treatments
have been developed over the last 10 years has added to the challenge of individualizing and personalizing treatment
for people living with PD; personalized medicine in PD is therefore a key unmet need [14].
Recently, however, two adjunctive treatment options have been licensed for use in the UK: opicapone is a
third-generation catechol-O-methyl transferase (COMT) inhibitor [15] and safinamide has a main mechanism of
action as a selective and reversible MAO-B inhibitor [16]. Safinamide is known to have additional activity as a
selective sodium channel blocker and calcium modulator although the clinical utility of these properties is yet to
be established [16,17]. To determine where these new therapies are to fit within the currently available treatment
options requires expert advice and opinion from practical clinical experience.
A multidisciplinary steering group of eight UK-based experts (neurologists, geriatricians and a nurse specialist)
who are all movement disorder and PD specialists from England, Scotland and Wales convened in November 2017
to put forward a clinical consensus of practical considerations for managing motor fluctuations in patients with
PD that complement current national guidelines from NICE (England, Wales and Northern Ireland) [2] and SIGN
(Scotland) [18]. The group had direct clinical experience of using PD therapies available in the UK, including the
newer adjunctive therapies.
It is important to highlight that this article is not a review of the current literature, but practice-based opinion,
including experience of using the two more recently available therapies, opicapone and safinamide. Differences in
trial design have resulted in greater UK-wide clinical experience with opicapone within the Phase IV trial setting
compared with safinamide, and this is reflected in the steering group’s current clinical practice and experience. Also,
with formulary applications for opicapone and safinamide still in progress across the UK, the ability to prescribe
one or both agents is limited in some regions.
When considering a treatment regimen, key to the decision-making process is the agreement of a comprehensive
care plan between the patient, family members/carer(s), specialist and secondary health providers [2].
Challenges to manage wearing-off in patients with PD on L-dopa
Although L-dopa is still the most effective antiparkinsonian drug [19], the development of a treatment strategy that
provides the benefits of L-dopa with reduced motor complications, including wearing-off, remains a significant
clinical challenge for patients with PD [20].
Wearing-off occurs toward the end of the treatment interval between individual doses of L-dopa, and occurs
earlier and becomes more severe with disease progression and duration of drug treatment [21]; it often consists not
only of motor symptoms (e.g., recurrent tremor, walking impairment) but also NMS (e.g., anxiety) [22].Wearing-
off generally improves with the next dose of antiparkinsonian medication [22]. Wearing-off eventually affects the
majority of patients with PD [13,20,23,24]. Observational data from the DEEP study have shown that for patients
receiving L-dopa therapy, wearing-off was experienced by: 63.0–75.6% of patients (diagnosed by neurologist and
19-item Wearing-Off Questionnaire (WOQ-19), respectively) at 1–2 years, 55.1–66.3% at 3–5 years and 76.8–
80.4% at >10 years [24]. Wearing-off of motor symptom control (e.g., recurrent tremor, slowing of walking) is
generally easier for patients and physicians to identify than NMS (e.g., anxiety, restlessness). Day-to-day variability
in symptom severity can also be dependent on how well a patient has slept, their specific activity or particular mood.
The wearing-off questionnaire can be used to help patients and clinicians identify and monitor wearing-off [25,26].
As well as wearing-off, long-term treatment with L-dopa is associated with the development of other ‘off
episodes [27]. One of the most frequent motor fluctuations is early-morning off periods [28], with the re-emergence
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Management of ‘wearing-off’ in Parkinson’s disease Special Report
of parkinsonian symptoms in the morning before the first L-dopa dose. Other motor fluctuations include dose
failures (individual L-dopa doses that do not result in the patient achieving the ‘on’ state) or delayed on-periods;
these motor fluctuations can either be predictable or unpredictable [27].
Considerations in managing wearing-off in patients with PD on L-dopa
Modiable factors
Advice from a PD specialist with expertise in managing wearing-off is essential. Before making dose adjustments
to the L-dopa regimen, or adding another class of drug, a number of modifiable factors that directly impact on
wearing-off need to be considered. These include: therapy compliance (which is influenced by depression, cognitive
function and apathy), dietary factors (such as quantity and timing of protein intake) and gastrointestinal (GI)
absorption (including Helicobacter pylori status and constipation). Other associated factors, such as insomnia and
depression, can influence overall function in patients with PD, although depression can be a nonmotor manifestation
of wearing-off [22].
GI absorption of L-dopa
Constipation
Constipation is a frequent NMS and the most common GI symptom of PD [29], affecting 60–80% of patients
with PD [30] and negatively impacting on QoL [31]. Constipation is characterized by infrequent bowel movements
and hard stools that are difficult to pass, as well as straining and pain when passing stools [32]. Constipation
may interfere with L-dopa absorption, worsening motor fluctuations [31]. Dietary intervention is recommended,
including increasing fiber intake and drinking plenty of fluids throughout the day [30]. If diet, fluid intake and
exercise do not alleviate constipation, use of osmotic laxatives may be necessary [32].
Delayed gastric emptying
Impaired mobility of the stomach results in gastroparesis that can impact on the absorption and action of L-dopa [33].
Dietary changes to help improve symptoms of delayed gastric emptying, such as multiple small meals limited in fat
and fiber content [34], together with exercise and, if necessary, pharmacotherapy, are all management options [35].
Dietary protein intake
A large protein meal can delay gastric emptying and competes with the absorption of L-dopa; therefore, the
timing of L-dopa dosing around mealtimes is an important consideration [30]. Best practice guidance on managing
patients with PD suggests a 40-min delay between L-dopa dosing and protein intake to help reduce wearing-
off symptoms [30]. Data on dietary protein intake and GI absorption of L-dopa show improvements in motor
fluctuations with dietary modifications, such as low protein diets and daily dietary protein consumed at the final
main meal of the day (protein redistribution diet). Improvements have been observed in clinical response ranging
from 30% (protein redistribution diet) to 82% (low protein diet) [36–38]. Recent recommendations advise that
clinicians should discuss the potential of a protein redistribution diet with patients who are beginning to fluctuate
in their response to dopaminergic medication [2]. Specialist advice from a dietician should also be considered [2].
Helicobacter pylori
The gut microbiome is increasingly recognized as playing an important role in the etiology of PD [39].Ahigh
prevalence of one such microbe in patients with PD, the Gram-negative H. pylori bacterium, is thought to affect
the absorption of L-dopa with the potential to cause motor fluctuations [40]. There are conflicting views as to
whether patients with PD should be tested for H. pylori status and treatment initiated to eradicate infection in
positive cases [40]. Further studies are needed to fully elucidate the relationship of L-dopa absorption in the presence
of H. pylori and its impact on clinical outcomes [40,41]. Currently, there is no direct guidance in this area, with
NICE guidance simply stating that “antiparkinsonian medicines should not be allowed to fail suddenly due to poor
absorption” [2].
Other modifiable factors that can influence overall function in patients with PD
Assessments are recommended to monitor unintentional weight loss or gain, bone health (reduced bone density
may indicate low vitamin D levels), insufficient fluid intake (which may indicate potential swallowing problems
or concerns about bladder urgency), postural hypotension (potential fluid/salt intake imbalance) and physical
difficulties that impair eating, drinking and preparing meals [30].
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Special Report Fackrell, Carroll, Grosset et al.
Increase dose
Variable /short-term control
Controlled-release preparations
Unpredictable drug absorption
Delayed ‘on’ or occasional
lack of ‘on’ response with
advancing disease
Decrease inter-dose interval
Increase dosing frequency
May work in earlier stages
Limited utility and complicated
dosing schedule beyond
4 to 5 doses/day
Higher peak concentrations
Peak-dose dyskinesias
Figure 1. Traditional strategies to treat wearing-off. Adapted from Olanow, 2001 [42].
In patients with PD, other NMS including cognitive and mood dysfunction (e.g., anxiety, apathy, depres-
sion, cognitive impairment), postural hypotension, sleep disturbance and pain can impact on overall function.
These NMS require appropriate investigation and individualized management with nonpharmacological strategies,
followed by drug treatment, where appropriate [2].
Dose-adjusting strategies for L-dopa
Several strategies involving L-dopa alone are available to treat wearing-off, including increasing the dose of L-dopa,
increasing the dosing frequency, using different formulations and adjusting dosing times (e.g., controlled-release
preparations taken at bedtime) [42]. These traditional strategies, however, usually only offer variable, short-term
control (Figure 1)[42].
Adjuvant treatment
Recent NICE guidelines recommend that patients with PD who have developed wearing-off or dyskinesia despite
optimal L-dopa therapy should be offered a choice of COMT inhibitors, DAs or MAO-B inhibitors as adjunctive
therapy to L-dopa (Figure 2)[2]. However, the decision regarding which adjunctive therapy to use or not to use,
requires considerable clinical experience from the treating clinician.
First-line adjuvant treatment choice considerations
As part of the steering group’s combined clinical experience, general factors influencing first-line adjunctive treatment
choice of drug class and preparation within class, are summarized as checklists in Table 1. For example, for an
elderly, frail patient with impaired cognition and difficulty swallowing, pill burden including complex daily regimens
and potential swallowing difficulties are important factors in the choice of adjunctive treatment. Similarly, for a
patient with recurring GI issues, tolerability and drug formulation with adequate absorption influence the choice
of adjunctive treatment. Young patients with a history of impulsive behaviors should be cautioned about the risks
of DAs.
Where do the opicapone & sanamide t in the treatment of wearing-off?
Opicapone
Two Phase III randomized clinical trials have demonstrated efficacy of opicapone as an adjunctive therapy to L-dopa
in patients with PD and end-of-dose motor fluctuations, with both studies meeting primary end point criteria. In
the BIPARK-I trial, opicapone (50 mg) was superior to placebo and noninferior to entacapone. The primary end
point was the change from baseline to end of study treatment in absolute off-time based on patient diaries [61].In
352 Neurodegener. Dis. Manag. (2018) 8(5) future science group
Management of ‘wearing-off’ in Parkinson’s disease Special Report
Table 1. Factors inuencing the choice of adjuvant treatment for wearing-off in patients with Parkinson’s disease:
clinical considerations from the Parkinson’s disease steering group’s experience.
What are the factors inuencing adjuvant
treatment choice?
Clinical considerations Adjuvant drug class/drug considerations
Symptoms:
How symptomatic is the patient?
Which are the patient’s most troublesome
motor symptoms?
What are the patient’s most troublesome
NMS?
Is the patient very elderly and frail?
Does the patient have a history of
impulsive behaviors?
Are there any motor symptoms that are refractory to
L-dopa (e.g., tremor)? If so, consider referral for DBS (NB:
none of the L-dopa augmenting strategies will improve
symptoms that are truly L-dopa refractory)
What potential is there for exacerbation of dyskinesia?
(NB: background doses of L-dopa may need to be
reviewed early after initiating any adjuvant treatment.)
If adjustment unsuccessful, consider referral/initiating
advanced therapies (i.e., apomorphine, DBS, DuoDopa)
Does the patient have any of the following NMS:
cognitive impairment, psychosis, low mood, apathy,
fatigue, clouded thinking, excessive daytime
somnolence, postural hypotension? These can be
differentially affected by the different adjuvant drug
classes
COMT inhibitors [43–45]:
Potency: opicapone tolcapone entacapone [15]
Can exacerbate postural hypotension
Can exacerbate dyskinesia
DAs [46–48]:
Can exacerbate dyskinesia
May cause or exacerbate postural hypotension
May result in, or exacerbate, cognitive impairment,
impulsive behaviors or psychosis
Potential for use in RLS [46]
MAO-B inhibitors [16,49,50]:
Can exacerbate postural hypotension
Can exacerbate confusion
Selegiline generally avoided in presence of postural
hypotension, dementia, psychosis, cardiovascular disease
and general frailty [51]
Patient preference:
What are the patient’s priorities and
treatment objectives?
Are there inuencers for patient’s choice of
treatment?
Consider adherence to treatment/compliance and
contributory factors
Entacapone:
Potential dark discoloration/staining of secretions with
entacapone: urine, and to a lesser extent saliva and
sweat (not harmful) [51,52]
Tolerability:
What are the tolerability issues with
existing and previous PD medications?
What are the tolerability considerations
with adjunctive therapy?
Is the patient very elderly and frail?
Directly consider co-existing conditions:
GI tolerability
Neuropsychiatric problems, especially hallucinations,
impulsive behaviors
Cardiovascular effects
COMT inhibitors:
Hepatotoxicity with tolcapone requires monitoring [45]
Potential GI problems with entacapone: 10% of
patients develop diarrhea [53]; for prolonged/persistent
diarrhea, entacapone should be discontinued [44].
Approximately 1% of patients will discontinue
treatment due to diarrhea [53]; it is not possible to
predict which patients will experience diarrhea
MAO-B inhibitors:
Generally well tolerated [54]
Selegiline, specic caution: cardiovascular disease,
especially arrhythmias [50]
DAs:
May be poorly tolerated in frail, elderly patients [55]
Polypharmacy:
What other medications is the patient
taking?
Consider drug interactions with common concomitant
medications (e.g., antidepressants)
COMT inhibitors:
Avoid treatment/concomitant use with nonselective
MAO inhibitors (e.g., phenelzine,
tranylcypromine) [44,45]; concomitant use of opicapone
with MAO inhibitors used to treat PD is acceptable [43]
MAO-B inhibitors:
For rasagiline and sanamide, avoid concomitant use
with uoxetine and uvoxamine [16,49]
Forselegiline, contraindicated with antidepressants in
general [50]
DAs:
For rotigotine patch, caution when taking CNS
depressants (e.g., benzodiazepines, antipsychotics,
antidepressants) [46]
Pill burden:
Can the patient manage the frequency of
doses?
What is the total number of tablets
(including tablets for other conditions) that
this patient is taking?
Complicated daily oral regimens may be a challenge for
patients with impaired cognition
Consider timing of adjuvant dose in relation to L-dopa
dosing
Consider nonoral drug preparations
COMT inhibitors:
Opicapone is once-daily dosing taken at bedtime 1 h
before/after L-dopa [43]
Tolcapone has a shorter duration of action versus
opicapone and requires t.i.d. dosing [45]
Entacapone available in combination formulation with
L-dopa/DDCI [52]
MAO-B inhibitors:
Rasagiline, selegiline and sanamide available in
once-daily formulations [16,49,50]
DAs:
Newer (nonergot) DAs available in once-daily
preparations: oral formulations – pramipexole [56] and
ropinirole [57]; transdermal patch – rotigotine [46]
Transdermal skin patch formulations are less potent
(24-h effect) [46]
MAO-B inhibitors are also licensed for early PD.
COMT: Catechol-O-methyl transferase; DA; Dopamine agonist; DBS: Deep-brain stimulation; DDCI: Dopa decarboxylase inhibitor; L-dopa: Levodopa; MAO-B: Monoamine oxidase
B; NMS: Nonmotor symptom; PD: Parkinson’s disease; RLS: Restless leg syndrome; t.i.d.: Three times daily.
future science group www.futuremedicine.com 353
Special Report Fackrell, Carroll, Grosset et al.
Table 1. Factors inuencing the choice of adjuvant treatment for wearing-off in patients with Parkinson’s disease:
clinical considerations from the Parkinson’s disease steering group’s experience (cont.).
What are the factors inuencing adjuvant
treatment choice?
Clinical considerations Adjuvant drug class/drug considerations
Swallowing:
Does this patient have trouble swallowing?
What are the swallowing considerations
with adjunctive therapy?
Large tablet size may be an issue, especially with some
combination formulations
Consider nonoral drug preparations
COMT inhibitors:
Opicapone’s capsule form and size may offer a
potential advantage for patients with swallowing
difculties (capsule 19 ×6.9 mm) [43,58], compared with
L-dopa/carbidopa/entacapone (oval, round or
ellipse-shaped tablets up to 16.2 ×10.2 mm) [59]
MAO-B inhibitors:
Sublingual preparation available for selegiline [60]
DAs:
DA patch formulation
Easier alternative for patients who have difculties
swallowing; however, as the patch needs to be applied
to dry skin and pressed down rmly [46], difculties may
arise if skin is sweaty
MAO-B inhibitors are also licensed for early PD.
COMT: Catechol-O-methyl transferase; DA; Dopamine agonist; DBS: Deep-brain stimulation; DDCI: Dopa decarboxylase inhibitor; L-dopa: Levodopa; MAO-B: Monoamine oxidase
B; NMS: Nonmotor symptom; PD: Parkinson’s disease; RLS: Restless leg syndrome; t.i.d.: Three times daily.
the BIPARK-II trial, opicapone (50 mg) was associated with a significant reduction in mean daily off-time, with
effect maintained for at least 1 year. Primary end point was the change from baseline in absolute off-time based on
patient diaries during the double-blind phase [62]. Opicapone was well tolerated in both studies [61,62].Marketing
authorization in the EU was granted in June 2016 as an adjunctive therapy to L-dopa and decarboxylase inhibitors
in adult patients with PD and end-of-dose motor fluctuations [15].
Clinical insights & scenarios for using opicapone
Opicapone is a long-acting, once-daily, purely peripheral COMT inhibitor [15], with more sustained COMT
inhibition than tolcapone and entacapone. COMT inhibition at 1 h is 99, 82 and 68% with opicapone, tolcapone
and entacapone, respectively, and at 9 h, 91, 16 and 0%, respectively [63,64]; the corresponding average treatment
Adult diagnosed with PD
General principles
Advanced therapies:
• Deep-brain stimulation
• L-dopa/carbidopa intestinal gel
• Continuous subcutaneous
apomorphine infusion
COMT inhibitor
Dopamine agonist
MAO-B inhibitor
First-line L-dopa treatment
Adjuvant treatment
A choice of adjuvant drug class
should be made after discussing with
the patient:
• Their individual clinical
circumstances (e.g. symptoms,
comorbidities, polypharmacy risks)
• Their individual lifestyle
circumstances, preferences,
needs and goals
• The potential benefits and harms
of the different drug classes
Figure 2. Managing motor symptoms in Parkinson’s disease: patient choice in adjuvant treatment.
COMT: Catechol-O-methyl transferase; L-dopa: Levodopa; MAO-B: Monoamine oxidase B; PD: Parkinson’s disease.
354 Neurodegener. Dis. Manag. (2018) 8(5) future science group
Management of ‘wearing-off’ in Parkinson’s disease Special Report
Box 1. Clinical scenario – switching from levodopa/carbidopa/entacapone combination to opicapone
plus levodopa/decarboxylase inhibitor.
1. Patients to continue on the L-dopa/carbidopa/entacapone combination until the penultimate dose of that day
2. For the last dose of that day:
Take L-dopa without entacapone, as either L-dopa/carbidopa (Sinemet), or L-dopa/benserazide (Madopar)
Take opicapone, either 1 h before or 1 h after L-dopa/carbidopa or L-dopa/benserazide
3. For the next 5–7 days:
Keep the L-dopa dose the same at each dose intake
Continue once-daily dosing with opicapone
4. Phone the patient to check for any adverse effects, including peak L-dopa effects (e.g., postural hypotension,
psychosis, dyskinesia)
5. If peak L-dopa effects have occurred, then advise appropriate reductions in the dose of L-dopa/carbidopa or
L-dopa/benserazide preparation (possibly by increasing the dose interval in the rst instance)
L-dopa: Levodopa.
effect (off-time reduction vs placebo) is 60 min for opicapone [61], 90 min for tolcapone [65] and 40 min for
entacapone [65].
Furthermore, opicapone has a favorable tolerability profile with a lack of hepatotoxicity in clinical trials and
no severe diarrhea issues [43]. Opicapone does not produce the harmless, but often troublesome, reddish brown
discoloration/staining of secretions (urine, sweat, saliva, semen) sometimes observed with entacapone [51,52].The
capsule formulation of opicapone, together with its size (19 mm in length and 6.91 mm in width) [43,58] offers
a potential advantage for patients with swallowing difficulties, when compared with the tablet formulations of
L-dopa/carbidopa/entacapone which have sizes ranging from a round tablet of 11.3 mm diameter at the lowest
dose to an elongated ellipse-shaped tablet of 16.2 mm by 10.2 mm at the highest dose [59]. A benefit of once-daily
dosing of opicapone is that it allows titration, where necessary, of L-dopa dosing independently of opicapone [43].
It is dosed at bedtime, 1 h before or 1 h after the last L-dopa dose of the day [43].
The steering group’s combined clinical experience suggests that there are particular patients with PD where there
are important clinical drivers for switching from entacapone to opicapone. It is the group’s opinion that opicapone
may be especially suited for patients who experience intermittent dose failures (individual L-dopa doses where the
clinical effect is either none or negligible), who fail to reliably achieve good quality on time and who experience
persistent wearing-off despite entacapone. The reason for switching in these scenarios is that COMT inhibition is
both more complete and more prolonged with opicapone compared with entacapone [15]; this has been shown to
translate to additional clinical benefit [66], and is consistent with the clinical experience of the group. Diarrhea is a
common side effect (8–10%) for patients using entacapone [44,53] and the L-dopa/carbidopa/entacapone (Stalevo)
combination tablet (12%) [52]. In cases where the severity of diarrhea leads to discontinuation of treatment,
switching to opicapone is also an option. Moreover, entacapone nonresponders may be potential candidates for
opicapone.
In these switching scenarios, the last entacapone dose of the day can be directly replaced by once-daily opicapone.
Where entacapone is part of a combination tablet, for example, L-dopa/carbidopa/entacapone (Stalevo), in addition
to replacing the entacapone component with opicapone, the L-dopa/decarboxylase inhibitor component must be
substituted by either L-dopa/carbidopa (Sinemet) or L-dopa/benserazide (Madopar). Adjustment of the L-dopa
dose is not usually required with the initial switch, but may need to be adjusted at a later stage depending on response;
for instance, to avoid excessive L-dopa peaks that may cause peak dose dyskinesia, other hyperdopaminergic CNS
effects, or to optimize L-dopa levels by a reduction in L-dopa dose and/or dose frequency to give further options
as the disease progresses. The clinical team needs to make certain that patients do not inadvertently add opicapone
to entacapone (resulting in a double dosage of COMT inhibitor) or, in the case of entacapone combination drugs,
substitute this with opicapone but without L-dopa/carbidopa (Sinemet) or L-dopa/benserazide (Madopar), which
would result in no L-dopa component. For patients currently using entacapone combination preparations, clear
guidance needs to be given explaining that they are being switched from a combination tablet (entacapone/L-
dopa/carbidopa) to an individual drug regimen (see Box 1).
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Special Report Fackrell, Carroll, Grosset et al.
Box 2. Clinical scenario – considerations in the ‘tailoring’ of adjunct therapies (catechol-O-methyl
transferase inhibitors, monoamine oxidase inhibitors, dopamine agonists).
A 64-year-old lady receiving:
L-dopa/carbidopa/entacapone 125 mg taken ve times a day (7 am, 10 am, 1 pm, 4 pm, 7 pm)
Rasagiline 1 mg once-daily
Ropinirole XL 8 mg (amantadine was not tolerated)
The patient developed signicant motor and nonmotor wearing-off, and experienced pain 30–40 min before her
next dose. Peak dose dyskinesia was also becoming socially embarrassing for her
The L-dopa/carbidopa/entacapone dose was reduced, but taken more frequently (100 mg six times a day). At this
dose the patient felt undertreated; reducing the ropinirole dose caused excessive mood disturbance. She also
reported that she had never been convinced regarding the efcacy of rasagiline and thus a decision was made to
see if sanamide would be more effective
Rasagiline was discontinued. After a washout period of 14 days (as advised in the sanamide summary of product
characteristics) [49], she was started on sanamide 50 mg
Sanamide 50 mg had a positive impact on improving wearing-off, and when the dose was increased to 100 mg,
the patient felt generally better, with a good reduction in nonmotor symptoms, and without noticeably
worsening dyskinesia
L-dopa: Levodopa.
Sanamide
Two Phase III randomized clinical trials have demonstrated efficacy of safinamide as an adjunctive therapy to
L-dopa in patients with mid- to late-stage PD with motor fluctuations. In the 24-week, double-blind, placebo-
controlled SETTLE study, safinamide (50 mg/100 mg) significantly increased on-time without troublesome
dyskinesia compared with placebo [67]. In study 016/018, a 24-week/2-year, double-blind, placebo-controlled
study, safinamide (50 mg/100 mg) also significantly increased on-time without increasing dyskinesia compared
with placebo. However, the primary end point, mean change from baseline to end point of the total score of the
dyskinesia rating scale during on-time, was not met [68]. Both safinamide doses were well tolerated [67,68].Marketing
authorization in the EU was granted in December 2014 as an add-on therapy to stable dose L-dopa, alone or in
combination with other PD therapies in mid- to late-stage fluctuating PD patients [17].
Clinical insights & scenarios for using safinamide
Safinamide is an α-aminoamide derivative that acts as a highly selective and reversible MAO-B inhibitor [17].
Safinamide has a favorable tolerability profile, but like rasagiline in this class, caution is needed with the concomitant
antidepressant medications, fluoxetine and fluvoxamine [16].
As part of the steering group’s combined clinical experience, there are particular patients with PD where clinical
drivers for using safinamide instead of rasagiline are warranted. Safinamide could be considered where patients
have been unable to tolerate rasagiline or in cases of worsening dyskinesia associated with rasagiline. Safinamide
could also be considered where patients continue to have wearing-off symptoms that have failed to respond to
rasagiline or COMT inhibitors. However, robust data are currently lacking in terms of a head-to-head clinical trial
comparison between safinamide and rasagiline. Clinical trial data have shown that safinamide reduces off-time by
about 0.62 h/day versus placebo [53], and a Cochrane review reports reduction in off-time by about 0.93 h/day for
rasagiline and selegiline [69], although comparisons of noncontemporaneous data can be misleading. Box 2 outlines
considerations in the ‘tailoring’ of these adjunct therapies.
Conclusion
This clinical consensus is not intended to provide formal guidance on managing wearing-off, but to complement
existing guidance and highlight areas of clinical practice that warrant further recognition in light of opicapone
and safinamide becoming available for patients with PD on L-dopa therapy. Individual clinical experience is
incorporated; while this experience is inevitably only anecdotal, it provides useful insights into current clinical
practice based on the experience of this steering group. It is important to note that there has been more opportunity
to gain clinical experience, including in Phase IV trials, with opicapone compared with safinamide in the UK, and
this is reflected in the greater anecdotal experiences provided by the assembled steering group.
356 Neurodegener. Dis. Manag. (2018) 8(5) future science group
Management of ‘wearing-off’ in Parkinson’s disease Special Report
Although both opicapone and safinamide are available in the UK, these agents are not universally available on
all formularies, and barriers exist in prescribing, more so in the community than the hospital setting. However,
locally conducted evaluations on the use of PD medications will help to inform local clinical practice. The sharing
of these methodologies will also be useful in facilitating the collection of data pertinent to UK clinical practice, and
to consolidate the position of new treatments in current treatment algorithms for patients with PD experiencing
wearing-off.
After more than 10 years without the development of new treatments for PD, opicapone and safinamide have
now widened the armamentarium, providing greater choice to individualize treatment for patients with PD on
L-dopa who have developed motor fluctuations.
Future perspective
The role of opicapone and safinamide alongside therapies for advanced PD in patients with wearing-off is an
area that warrants future investigation. There is a possibility that these new treatments could eventually be used
in combination with advanced PD therapies. In theory, opicapone could be used as an adjunctive therapy to
carbidopa and L-dopa gel (DuoDopa), as opicapone has the potential to increase the bioavailability of DuoDopa,
thereby reducing dosing/cassette requirements. Currently, there is no clinical evidence to support this strategy,
but it represents an example of the versatility of once-daily adjunctive therapies. Other areas that warrant future
investigation are the roles of opicapone and safinamide in early disease, the concomitant use of opicapone and
safinamide with deep-brain stimulation and the routine genotyping of patients with PD for COMT polymorphisms
to assess this as a predictor of opicapone response.
Financial & competing interests disclosure
R Fackrell has received honoraria over the last 36 months from Bial, Prole Pharma, Britannia and AbbVie for speaking engage-
ments, and received funding from Bial for the 2017 MDS congress in Vancouver. R Fackrell was part of the Guideline development
Group for the recent PD NICE guidelines. CB Carroll has received grants from NIHR, Horizon 2020, Cure Parkinson’s Trust, JP Moul-
ton Charitable Foundation; educational support from Bial; honoraria from Prole Pharma, Global Kinetic Corporation, Bial; and
advisory board fees from UCB Pharma and Bial. CB Carroll is the UK CI of the current Phase IV observational study of sanamide
– Synapses. DG Grosset has received grants from Michael’s Movers, The Neurosciences Foundation, Parkinson’s UK; honoraria
from Bial, UCB Pharma, GE Healthcare; and consultancy fees from Acorda Therapeutics, GE Healthcare. B Mohamed has received
grants from NeuroDem and Parkinson’s UK; honoraria for lectures at meetings sponsored by UCB Pharma and Prole Pharma;
and consultancy fees from AbbVie, Prole Pharma, Britannia and Bial. P Reddy has received consulting fees from AbbVie, Bial, GE
Healthcare and speaker fees from AbbVie, Britannia, UCB and Medichem. M Parry has received honoraria from UCB, Britannia,
AbbVie and Bial. KR Chaudhuri has received consultancy fees from Britannia, AbbVie, Neuronova, UCB; advisory board fees from
Britannia, AbbVie, UCB, Sunovion, Pzer, Jazz Pharma, GKC, Bial; honoraria, symposium or lecture fees from AbbVie, Britannia,
UCB, Mundipharma, Zambon; grants from Britannia Pharmaceuticals, AbbVie, UCB, GKC, Bial; academic grants from the EU, in-
cluding EU (Horizon 2020), Parkinson’s UK, NIHR, PDNMG, Kirby Laing Foundation, NPF; industry support for investigator-initiated
studies from UCB, Britannia, AbbVie, Bial. He has no stock ownership in medically related elds, and no partnerships/employment
with pharmaceutical companies, or expert testimony given. KR Chaudhuri has intellectual property rights for the KPP scale, PDSS-2.
Some independent research in this paper is part funded by the National Institute for Health Research (NIHR) Biomedical Research
Centre at South London and Maudsley NHS Foundation Trust and King’s College London. T Foltynie has received honoraria for
speaking at meetings sponsored by Bial, Britannia, Prole Pharma, and has received consultancy fees from Celgene and Oxford
Biomedica. He has received grants from the Michael J Fox Foundation, European Union, John Black Charitable Foundation and
the Cure Parkinson’s Trust. The authors have no other relevant afliations or nancial involvement with any organization or entity
with a nancial interest in or nancial conict with the subject matter or materials discussed in the manuscript apart from those
disclosed.
Writing assistance has been provided by Rachel Parratt and Gillian Wain from Cello Health Communications, funded by Bial
Pharma UK Ltd, which also funded the Steering Group meeting.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license,
visit http://creativecommons.org/licenses/by-nc-nd/4.0/
future science group www.futuremedicine.com 357
Special Report Fackrell, Carroll, Grosset et al.
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... Olanzapine is a second-generation antipsychotic that produces its effect on the dopamine as well as serotonin receptors. It works primarily on the mesolimbic pathway dopamine 2 receptor as a blocker [11]. It blocks the dopamine neurotransmitter from exerting the effects on the postsynaptic receptor. ...
... It is a derivative of benzylamino which has various modes of action [2,53]. The main mode of action of safinamide is that it inhibits MAO-B selectively and reversibly [2,7,11,53,54]. Moreover, safinamide has the non-dopaminergic mechanism of action which includes the state-dependent block of voltage-gated sodium channels in the inactivated state. ...
... Furthermore, safinamide also has antiglutamatergic activity. These actions may be responsible for its pain mitigating effects [2,7,11,53,54]. Safinamide also prevents the formation of free radicals through the inhibition of MAO-B [53]. ...
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Parkinson’s Disease (PD) is a disease that involves neurodegeneration and is characterised by the motor symptoms which include muscle rigidity, tremor, and bradykinesia. Other non-motor symptoms include pain, depression, anxiety, and psychosis. This disease affects up to ten million people worldwide. The pathophysiology behind PD is due to the neurodegeneration of the nigrostriatal pathway. There are many conventional drugs used in the treatment of PD. However, there are limitations associated with conventional drugs. For instance, levodopa is associated with the on-off phenomenon, and it may induce wearing off as time progresses. Therefore, this review aimed to analyze the newly approved drugs by the United States-Food and Drug Administration (US-FDA) from 2016–2019 as the adjuvant therapy for the treatment of PD symptoms in terms of efficacy and safety. The new drugs include safinamide, istradefylline and pimavanserin. From this review, safinamide is considered to be more efficacious and safer as the adjunct therapy to levodopa as compared to istradefylline in controlling the motor symptoms. In Study 016, both safinamide 50 mg (p = 0.0138) and 100 mg (p = 0.0006) have improved the Unified Parkinson’s Disease Rating Scale (UPDRS) part III score as compared to placebo. Improvement in Clinical Global Impression—Change (CGI-C), Clinical Global Impression—Severity of Illness (CGI-S) and off time were also seen in both groups of patients following the morning levodopa dose. Pimavanserin also showed favorable effects in ameliorating the symptoms of Parkinson’s Disease Psychosis (PDP). A combination of conventional therapy and non-pharmacological treatment is warranted to enhance the well-being of PD patients.
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Background Oral levodopa remains the mainstay of treatment for Parkinson’s disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson’s Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. Patients and Methods PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10–15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. Results Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2–3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). Conclusion This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.
... Current studies have shown that wearable devices can provide information on how medication treatment affects patient outcomes [70,76,82]. Newer studies included in the scoping review have shown development in addressing whether patients were receiving appropriate medication doses or identifying if the patient's PD was controlled by using PKGs to identify novel biomarkers and correlations that may influence the patient's condition [88,101]; for example, wearing-off [102] in levodopa therapy was identified by PKGs as a key clinical concern, allowing clinicians to modify medication or therapy to address wearing-off and facilitate discussion of new clinical findings with patients. PKGs were shown to be an appropriate support tool for minimizing incidents of undetected symptoms in newly diagnosed patients with PD, undertreated patients, and clinical bias, as well as for analyzing how symptoms progressed throughout the day [77,89]. ...
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Background: The prevalence of Parkinson disease (PD) is becoming an increasing concern owing to the aging population in the United Kingdom. Wearable devices have the potential to improve the clinical care of patients with PD while reducing health care costs. Consequently, exploring the features of these wearable devices is important to identify the limitations and further areas of investigation of how wearable devices are currently used in clinical care in the United Kingdom. Objective: In this scoping review, we aimed to explore the features of wearable devices used for PD in hospitals in the United Kingdom. Methods: A scoping review of the current research was undertaken and reported according to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The literature search was undertaken on June 6, 2022, and publications were obtained from MEDLINE or PubMed, Embase, and the Cochrane Library. Eligible publications were initially screened by their titles and abstracts. Publications that passed the initial screening underwent a full review. The study characteristics were extracted from the final publications, and the evidence was synthesized using a narrative approach. Any queries were reviewed by the first and second authors. Results: Of the 4543 publications identified, 39 (0.86%) publications underwent a full review, and 20 (0.44%) publications were included in the scoping review. Most studies (11/20, 55%) were conducted at the Newcastle upon Tyne Hospitals NHS Foundation Trust, with sample sizes ranging from 10 to 418. Most study participants were male individuals with a mean age ranging from 57.7 to 78.0 years. The AX3 was the most popular device brand used, and it was commercially manufactured by Axivity. Common wearable device types included body-worn sensors, inertial measurement units, and smartwatches that used accelerometers and gyroscopes to measure the clinical features of PD. Most wearable device primary measures involved the measured gait, bradykinesia, and dyskinesia. The most common wearable device placements were the lumbar region, head, and wrist. Furthermore, 65% (13/20) of the studies used artificial intelligence or machine learning to support PD data analysis. Conclusions: This study demonstrated that wearable devices could help provide a more detailed analysis of PD symptoms during the assessment phase and personalize treatment. Using machine learning, wearable devices could differentiate PD from other neurodegenerative diseases. The identified evidence gaps include the lack of analysis of wearable device cybersecurity and data management. The lack of cost-effectiveness analysis and large-scale participation in studies resulted in uncertainty regarding the feasibility of the widespread use of wearable devices. The uncertainty around the identified research gaps was further exacerbated by the lack of medical regulation of wearable devices for PD, particularly in the United Kingdom where regulations were changing due to the political landscape.
... Also, tolcapone has adverse side effects compared to entacapone. Opicapone is a 3 rd generation inhibitor with a longer half-life and better efficacy compared to tolcapone, but there is a risk of L-DOPA toxicity as the concentration of L-DOPA in the systemic circulation will peak upon administration (Fackrell et al., 2018). This calls for a need for novel inhibitors for COMT with better therapeutic efficacy and safer as well. ...
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Parkinson's disease (PD), the second most prevalent neurodegenerative disease affecting individuals at 50-60 years of age, still does not have any cure. Even the golden therapy for PD like L-DOPA has its switch-on and off effects manifesting over-continuous use. Therefore, the need for a potential drug is the demand of the time, that would help in reducing the progression of neurodegeneration. The enzyme catechol-o-methyltransferase (COMT) involved in the metabolism of L-DOPA and DOPA is one of the targets of PD pathogenesis. Although there are three clinically prescribed COMT inhibitors available, only one traverses the blood-brain barrier (BBB) but also exhibits high hepatotoxicity. This makes it imperative to search for alternative natural molecules with comparative therapeutic effects, lipophilicity, with low toxicity. The Rhododendron family is known to have neuroprotective potential but very little is known about the species Rhododendron arboreum and its therapeutic effect on PD. In this study, we reported in silico docking analysis according to the Lamarckian algorithm principle, inhibition constant, binding energy, and ADMET studies on 12 selected phytochemicals, followed by molecular docking with respect to COMT to determine their potential inhibitory effects compared to commercial drugs. However, further in vitro, and in vivo studies are required for the clinical development of novel therapeutic drugs.
... Levodopa, also known as L-DOPA, is an effective and generally well-tolerated dopamine replacement agent that is widely used to treat Parkinson's disease (PD) [1][2][3]. Reichmann However, long-term use of levodopa can cause wearingoff symptoms, other motor and non-motor fluctuations and dyskinesias, which can affect mobility, activities of daily living, and communication [4,5]. Wearing-off symptoms are experienced by 40-50% of patients treated for 5 years and affect approximately two-thirds of patients after 10 or more years of levodopa therapy [6]. ...
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Introduction: The OPTIPARK study confirmed the effectiveness and safety of opicapone as adjunct therapy to levodopa in patients with Parkinson's disease (PD) and motor fluctuations under real-world conditions. The aim of this sub-analysis was to evaluate opicapone in the German patient cohort of OPTIPARK in order to provide country-specific data. Methods: OPTIPARK was an open-label, single-arm study conducted in routine clinical practice across Germany and the UK. Patients with PD and motor fluctuations received once-daily opicapone 50 mg for 3 months in addition to levodopa. The primary endpoint was Clinicians' Global Impression of Change (CGI-C). Secondary assessments included Patients' Global Impressions of Change (PGI-C), Unified Parkinson's Disease Rating Scale (UPDRS) I-IV, Parkinson's Disease Questionnaire (PDQ-8), and Non-Motor Symptoms Scale (NMSS). This sub-analysis reports outcomes from the German patients only. Results: Overall, 363 (97.6%) of the 372 patients included in the German cohort received ≥1 dose of opicapone and 291 (80.2%) completed the study. Improvements on CGI-C and PGI-C were reported by 70.8% and 76.3% of patients, respectively. UPDRS scores improved for activities of daily living during OFF time by -3.3 ± 4.5 points and motor scores during ON time by -5.3 ± 7.9 points. PDQ-8 and NMSS scores also demonstrated improvements. Treatment emergent adverse events considered at least possibly related to opicapone occurred in 37.7% of patients, with most being of mild or moderate intensity. Conclusion: Opicapone added to levodopa in patients with PD and motor fluctuations was effective and generally well tolerated in routine clinical practice across Germany.
... Opicapone is a reversible, peripherally selective, high binding affinity, and long-acting third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, devoid of cytotoxic effects, 1,2 and has been shown to reduce the peripheral metabolism of levodopa (the mainstay antiparkinsonian drug) to 3-O-methyl-levodopa, 3 and hereby improves motor response in Parkinson's disease (PD) patients. [4][5][6][7][8][9][10][11][12] Opicapone has recently been granted marketing authorization under the trade name Ongentys ® by EMA, MHLW, and FDA, to be used in the adjunctive levodopa therapy of PD patients. ...
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Opicapone (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide) is a selective catechol-O-methyltransferase inhibitor that has been granted marketing authorization in Europe, Japan, and United States. The present work describes the metabolism and disposition of opicapone in the rat obtained in support to its development and regulatory filling. Plasma levels and elimination of total radioactivity were determined after oral and intravenous administration of [14C]-opicapone. The maximum plasma concentrations of opicapone-related radioactivity were reached at early time points followed by a gradual return to baseline with a biphasic elimination. Fecal excretion was the primary route of elimination of total radioactivity. Quantitative distribution of drug-related radioactivity demonstrated that opicapone and related metabolites did not distribute to the central nervous system. Opicapone was extensively metabolized in rats resulting in more than 20 phase I and phase II metabolites. Although O-glucuronidation, -sulfation, and -methylation of the nitrocatechol moiety were the principal metabolic pathways, small amount of the N-acetyl derivative was detected, as a result of reduction of the nitro group and subsequent conjugation. Other metabolic transformations included N-oxide reduction to the pyridine derivative and reductive cleavage of 1,2,4-oxadiazole ring followed by further conjugative reactions. Reaction phenotyping studies suggested that SULT 1A1*1 and *2 and UGT1A7, UGT1A8, UGT1A9, and UGT1A10 may be involved in opicapone sulfation and glucuronidation, respectively. However, the reductive metabolic pathways mediated by gut microflora cannot be excluded. Opicapone, in the rat, was found to be rapidly absorbed, widely distributed to peripheric tissues, metabolized mainly via conjugative pathways at the nitro catechol ring, and primarily excreted via feces.
... Research has shown that opicapone, a new type of thirdgeneration and long-acting COMT inhibitor, can significantly reduce COMT activity and increase systemic exposure to levodopa (12,13). Therefore, there is a need for a COMT inhibitor that is more effective and easier to use in routine clinical practice. ...
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Parkinson's disease (PD) is a common, chronic, progressive, debilitating neurodegenerative disease. The current levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced PD. Therefore, a theoretical reference for treatment is urgently needed. In this study, an appropriate search strategy was used to screen eligible studies on different drugs to treat patients with PD from the Embase, PubMed, and Cochrane Library. The publication dates were from January 1990 to June 2021. We integrated eligible randomized controlled trials, and statistical analysis was performed on three kinds of effectiveness outcomes and two types of safety outcomes. We assessed the average difference or odds ratio between each drug and placebo and summarized them as the average and 95% confidence interval (CI), respectively. In terms of efficacy, entacapone (mean difference [MD], 0.64 h; 95% CI, 0.29–1.0), opicapone (MD, 0.92 h; 95% CI, 0.35–1.5), and tolcapone (MD, 3.2 h; 95% CI, 2.1–4.2) increased patients' total ON-time compared to placebo. Tolcapone (MD, −100 mg; 95% CI −160 to −45) reduced the total daily dose of levodopa therapy. None of these three drugs was found to have statistical significance in mean change from baseline in UPDRS part III scores when compared with others. In terms of safety, tolcapone (MD, 3.8; 95% CI, 2.1–6.8), opicapone (MD, 3.7; 95% CI, 2–7.2), and entacapone (MD, 2.2; 95% CI, 1.5–3.3) increased the number of cases of dyskinesia compared to placebo. Entacapone (MD, 1.7; 95% CI, 1.3–2.2) and tolcapone (MD, 4.3; 95% CI, 1.3–15) were more likely to cause adverse events than placebo. In conclusion, opicapone showed higher efficiency and fewer safety problems in five indicators we selected when compared with the other two drugs.
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Aims The absorption, metabolism and excretion of opicapone (2,5‐dichloro‐3‐(5‐[3,4‐dihydroxy‐5‐nitrophenyl]‐1,2,4‐oxadiazol‐3‐yl)‐4,6‐dimethylpyridine 1‐oxide), a selective catechol‐O‐methyltransferase inhibitor, were investigated. Methods Plasma, urine and faeces were collected from healthy male subjects following a single oral dose of 100 mg [¹⁴C]‐opicapone. The mass balance of [¹⁴C]‐opicapone and metabolic profile were evaluated. Results The recovery of total administered radioactivity averaged >90% after 144 hours. Faeces were the major route of elimination, representing 70% of the administered dose; 5% and 20% were excreted in urine and expired air, respectively. The Cmax of total radioactivity matched that of unchanged opicapone, whereas the total radioactivity remained quantifiable for a longer period, attributed to the contribution of opicapone metabolites, involving primarily 3‐O‐sulfate conjugation (58.6% of total circulating radioactivity) at the nitrocatechol ring. Other circulating metabolites, accounting for <10% of the radioactivity exposure, were formed by glucuronidation, methylation, N‐oxide reduction and gluthatione conjugation. Additionally, various other metabolites resulting from combinations with the opicapone N‐oxide reduced form at the 2,5‐dichloro‐4,6‐dimethylpyridine 1‐oxide moiety, including nitro reduction and N‐acetylation, reductive opening and cleavage of the 1,2,4‐oxadiazole ring and the subsequent hydrolysis products were identified, but only in faeces, suggesting the involvement of gut bacteria. Conclusion [¹⁴C]‐opicapone was fully excreted through multiple metabolic pathways. The main route of excretion was in faeces, where opicapone may be further metabolized via reductive metabolism involving the 1,2,4‐oxadiazole ring‐opening and subsequent hydrolysis.
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Gastroparesis (Gp) is a chronic disease that presents with clinical symptoms of early satiety, bloating, nausea, vomiting, and abdominal pain. Along with these symptoms, an objective finding of delayed gastric emptying, along with a documented absence of gastric outlet obstruction, are required for diagnosis. This article focuses on updates in the pathogenesis and management of Gp. Recent studies on full thickness biopsies of Gp patients have shed light on the complex interactions of the central, autonomic, and enteric nervous systems, which all play key roles in maintaining normal gut motility. The management of Gp has evolved beyond prokinetics and antiemetics with the use of gastric electrical stimulators (GES). In addition, this review aims to introduce the concept of gastroparesis-like syndrome (GLS). GLS helps groups of patients who have the cardinal symptoms of Gp but have a normal or rapid emptying test. Recent tests have shown that patients with Gp and GLS have similar pathophysiology, benefit greatly from GES placement, and likely should be treated in a similar manner.
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Importance: Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge. Objective: To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations. Design, setting, and participants: From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with "off" time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient's regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group. Interventions: Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg. Main outcomes and measures: The prespecified primary outcome was each treatment group's mean change from baseline to week 24 (or last "on" treatment value) in daily "on" time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data. Results: At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]). Conclusions and relevance: The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off. Trial registration: clinicaltrials.gov Identifier NCT00627640.
Article
Objective: To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching from entacapone over 1 year of treatment in patients with fluctuating Parkinson disease. Methods: After completion of a placebo- and entacapone-controlled double-blind study of opicapone (5, 25, or 50 mg), 495 patients continued to a 1-year extension phase in which patients were treated with opicapone. Patients began with once-daily opicapone 25 mg for 1 week, followed by individually tailored levodopa and/or opicapone dose adjustments. The primary efficacy variable was the change from baseline in absolute "off" time based on patient diaries. Other outcomes included proportion of responders, scale-based assessments, and standard safety assessments. Results: One year of treatment with opicapone reduced "off" time by a half-hour (33.8 minutes) vs the open-label baseline and >2 hours (126.9 minutes) vs the double-blind baseline. Whereas patients who were originally treated with opicapone 50 mg in the double-blind phase maintained their efficacy, switching treatments led to further decreases in "off" time (-64.9, -39.3, -27.5, and -23.0 minutes for switching from placebo, entacapone, and opicapone 5 and 25 mg, respectively). Dyskinesia was the most frequently reported adverse event (14.5%) and was managed by adjustment of dopaminergic therapy. No new safety concerns were observed with long-term opicapone administration. Conclusion: Long-term use of opicapone provided sustained efficacy over 1 year. Switching from entacapone to opicapone led to enhanced efficacy under the conditions of the study. Classification of evidence: This study provides Class III evidence that for patients with Parkinson disease and end-of-dose motor fluctuations, long-term use (52 weeks) of opicapone is well tolerated and reduces "off" time.
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IMPORTANCE: Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge. OBJECTIVE: To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with “off” time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient’s regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group. INTERVENTIONS: Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was each treatment group’s mean change from baseline to week 24 (or last “on” treatment value) in daily “on” time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data. RESULTS: At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]). CONCLUSIONS AND RELEVANCE: The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off.
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Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.
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Objectives: Previous studies have shown that Helicobacter pylori infection might make clinical status worse in patients with Parkinson's disease and Helicobacter pylori eradication might improve clinical status by modifying the pharmacokinetics of L-dopa. Here, we investigate whether Helicobacter pylori eradication could benefit idiopathic parkinsonism and Helicobacter pylori infection will effect which aspect of motor symptom significantly. Patients and methods: A cohort study involving idiopathic Parkinson's disease patients, screened for Helicobacter status by (13)C urea breath test. Clinical status was evaluated by using the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn-Yahr stage. If patients had motor complications, they were quantified at the "on" time. The Helicobacter pylori positive patients could choose to receive Helicobacter pylori eradication or not by themselves. Group 1 was Helicobacter pylori negative patients. Group 2 was Helicobacter pylori positive patients who didn't receive eradication treatment. Group 3 was Helicobacter pylori positive patients who received successful eradication treatment. Repeat clinical assessments and (13)C urea breath test was performed at 1year later. Numerical data were expressed as mean±standard deviation (SD) RESULTS: Ninety-four consecutive patients with Parkinson's disease were recruited and underwent the initial (13)C urea breath test, but only forty-eight patients successfully completed the total study. In Group 3, the UPDRS-III scores (=Motor Examination Section Scores) were significantly lower 1year later compared to baseline (18.3±8.38 vs. 25.9±8.37, P=0.007). The differences were main in UPDRS-23 (=Finger Taps) (1.7±1.16 vs. 2.4±1.51, P=0.045), UPDRS-25 (Rapid Alternation Movements of Hands) (1.6±1.35 vs. 2.4±1.71, P=0.031) and UPDRS-26 (=Leg Agility) (1.3±1.25 vs.2.1±0.99, P=0.011). There was difference among three groups in the UPDRS-26 (P=0.040) of clinical status change of one year. Conclusion: The eradication of Helicobacter might improve the clinical status of idiopathic parkinsonism, especially on bradykinesia.
Article
Importance: Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. Objective: To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. Design: This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014. Main outcomes and measures: The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time. Results: A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, -101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 [95% CI, -96.2 to -12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 [95% CI, -80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase. Conclusions and relevance: Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated. Trial registration: clinicaltrials.gov Identifier: NCT01227655.
Article
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson’s disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.